@article {10750, title = {Administering analgesia sublingually is a suitable option for children with acute abdominal pain in the emergency department.}, journal = {Acta Paediatr}, volume = {108}, year = {2019}, month = {2019 Jan}, pages = {143-148}, abstract = {

AIM: Acute abdominal pain is a frequent complaint in children attending emergency departments. The aim of this study was to investigate the pain score reductions when children with acute abdominal pain received medication sublingually.

METHODS: We carried out a multicentre randomised controlled trial in three children{\textquoteright}s hospitals in Italy between March 2015 and June 2017. Children from four to 18~years of age with acute abdominal pain were recruited if their self-reported pain was at least six on a scale from 0-10. The children were randomised to receive ketorolac 0.5~mg/kg (n~=~70) or tramadol 2~mg/kg (n~=~70) sublingually or a melt in the mouth powder of 20~mg/kg paracetamol (n~=~70). The main study outcome was the pain scores for the three drugs after two hours.

RESULTS: The 210 children (58.6\% girls) had a median age of 12~years with an interquartile range of 9-14.3. The median pain scores at two hours were not significantly different between ketorolac 2.0 (interquartile ranges, IQR 0.0-4.3) and tramadol 3.0 (IQR 1.0-5.0) vs paracetamol 3.0 (IQR 0.8-5.0). The median pain reductions were all 5.0 points.

CONCLUSION: Delivering analgesia sublingually was a suitable option for pain relief in children with acute abdominal pain in the emergency department.

}, issn = {1651-2227}, doi = {10.1111/apa.14514}, author = {Cozzi, Giorgio and Zanchi, Chiara and Chiaretti, Antonio and Tipo, Vincenzo and Cernich, Marta and D{\textquoteright}Anna, Carolina and Fantacci, Claudia and Conversano, Ester and Zanon, Davide and Ronfani, Luca and Barbi, Egidio} } @article {10757, title = {Antibodies reacting to mimotopes of Simian virus 40 large T antigen, the viral oncoprotein, in sera from children.}, journal = {J Cell Physiol}, volume = {234}, year = {2019}, month = {2019 Apr}, pages = {3170-3179}, abstract = {

Recent data indicate that the Simian virus 40 (SV40) infection appears to be transmitted in humans independently from early SV40-contaminated antipolio vaccines. Serum antibodies against SV40 large T antigen (Tag) were analyzed in children/adolescents and young adults. To investigate antibodies reacting to SV40 Tag antigens, serum samples ( n = 812) from children and young adults were analyzed by indirect ELISAs using specific SV40 Tag mimotopes. Mimotopes were synthetic peptides corresponding to SV40 Tag epitopes. In sera ( n = 412) from healthy children up to 17 years old, IgG antibodies against SV40 Tag mimotopes reached an overall prevalence of 15\%. IgM antibodies against SV40 Tag were detected in sera of children 6-8 months old confirming and extending the knowledge that SV40 seroconversion occurs early in life. In children/adolescents affected by different diseases ( n = 180) SV40 Tag had a prevalence of 18\%, being the difference no significant compared to healthy subjects ( n = 220; 16\%) of the same age. Our immunological data indicate that SV40 circulates in children and young adults, both in healthy conditions and affected by distinct diseases. The IgM detection in sera from healthy children suggests that the SV40 infection/seroconversion occurs early in life (>6 months). Our immunological data support the hypothesis that SV40, or a closely related still unknown polyomavirus, infects humans. The SV40 seroprevalence is lower than common polyomaviruses, such as BKPyV and JCPyV, and other new human polyomaviruses. In addition, our immunological surveillance indicates a lack of association between different diseases, considered herein, and SV40.

}, issn = {1097-4652}, doi = {10.1002/jcp.27490}, author = {Mazzoni, Elisa and Frontini, Francesca and Rotondo, John Charles and Zanotta, Nunzia and Fioravanti, Arianna and Minelli, Francesca and Torreggiani, Elena and Campisciano, Giuseppina and Marcuzzi, Annalisa and Guerra, Giovanni and Tommasini, Alberto and Touz{\'e}, Antoine and Martini, Fernanda and Tognon, Mauro and Comar, Manola} } @article {10761, title = {Causes of Treatment Failure in Children With Inflammatory Bowel Disease Treated With Infliximab: A Pharmacokinetic Study.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {68}, year = {2019}, month = {2019 Jan}, pages = {37-44}, abstract = {

OBJECTIVES: Anti-tumor necrosis factor antibodies have led to a revolution in the treatment of inflammatory bowel diseases (IBD); however, a sizable proportion of patients does not respond to therapy. There is increasing evidence suggesting that treatment failure may be classified as mechanistic (pharmacodynamic), pharmacokinetic, or immune-mediated. Data regarding the contribution of these factors in children with IBD treated with infliximab (IFX) are still incomplete. The aim was to assess the causes of treatment failure in a prospective cohort of pediatric patients treated with IFX.

METHODS: This observational study considered 49 pediatric (median age 14.4) IBD patients (34 Crohn disease, 15 ulcerative colitis) treated with IFX. Serum samples were collected at 6, 14, 22 and 54 weeks, before IFX infusions. IFX and anti-infliximab antibodies (AIA) were measured using enzyme linked immunosorbent assays. Disease activity was determined by Pediatric Crohn{\textquoteright}s Disease Activity Index or Pediatric Ulcerative Colitis Activity Index.

RESULTS: Clinical remission, defined as a clinical score <10, was obtained by 76.3\% of patients at week 14 and by 73.9\% at week 54. Median trough IFX concentration was higher at all time points in patients achieving sustained clinical remission. IFX levels during maintenance correlated also with C-reactive protein, albumin, and fecal calprotectin. After multivariate analysis, IFX concentration at week 14 >3.11 μg/mL emerged as the strongest predictor of sustained clinical remission. AIA concentrations were correlated inversely with IFX concentrations and directly with adverse reactions.

CONCLUSIONS: Most cases of therapeutic failure were associated with low serum drug levels. IFX trough levels at the end of induction are associated with sustained long-term response.

}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000002112}, author = {Naviglio, Samuele and Lacorte, Doriana and Lucaf{\`o}, Marianna and Cif{\`u}, Adriana and Favretto, Diego and Cuzzoni, Eva and Silvestri, Tania and Pozzi Mucelli, Martina and Radillo, Oriano and Decorti, Giuliana and Fabris, Martina and Bramuzzo, Matteo and Taddio, Andrea and Stocco, Gabriele and Alvisi, Patrizia and Ventura, Alessandro and Martelossi, Stefano} } @article {10797, title = {Idiopathic neutropenia of infancy: Data from the Italian Neutropenia Registry.}, journal = {Am J Hematol}, volume = {94}, year = {2019}, month = {2019 Feb}, pages = {216-222}, abstract = {

Autoimmune neutropenia of infancy (AIN) is characterized by low risk of severe infection, tendency to spontaneously resolve and typically onset at <=4-5 years of age; it is due to auto-antibodies whose detection is often difficult. In case of negativity of 4 antineutrophils autoantibody tests, after having excluded ethnic, postinfection, drug induced, or congenital neutropenia, according to the Italian guidelines the patients will be defined as affected by "idiopathic neutropenia" (IN). We describe the characteristics of 85 IN patients enrolled in the Italian neutropenia registry: they were compared with 336 children affected by AIN. The 2 groups were clinically very similar and the main differences were detection age (later in IN), length of disease (longer in IN) and, among recovered patients, age of spontaneous recovery: the median age at resolution was 2.13 years in AINs and 3.03 years in INs (P = .00002). At bivariate analysis among AIN patients earlier detection age (P = .00013), male sex (P = .000748), absence of leucopenia (P = .0045), and absence of monocytosis (P = .0419) were significantly associated with earlier recovery; in the IN group only detection age (P = .013) and absence of monocytosis (P = .0333) were significant. At multivariate analysis detection age and absence of monocytosis were independently significant (P = 6.7e-05 and 4.4e-03, respectively) in the AIN group, whereas in the IN group only detection age stayed significant (P = .013).

}, issn = {1096-8652}, doi = {10.1002/ajh.25353}, author = {Farruggia, Piero and Fioredda, Francesca and Puccio, Giuseppe and Onofrillo, Daniela and Russo, Giovanna and Barone, Angelica and Bonanomi, Sonia and Boscarol, Gianluca and Finocchi, Andrea and Ghilardi, Roberta and Giordano, Paola and Ladogana, Saverio and Lassandro, Giuseppe and Luti, Laura and Lanza, Tiziana and Mandaglio, Rosalba and Marra, Nicoletta and Martire, Baldassare and Mastrodicasa, Elena and Motta, Milena and Notarangelo, Lucia Dora and Pillon, Marta and Porretti, Laura and Serafinelli, Jessica and Trizzino, Angela and Tucci, Fabio and Veltroni, Marinella and Verzegnassi, Federico and Ramenghi, Ugo and Dufour, Carlo} } @article {10745, title = {Loss-of-function mutations in cause a new form of inherited thrombocytopenia.}, journal = {Blood}, volume = {133}, year = {2019}, month = {2019 Mar 21}, pages = {1346-1357}, abstract = {

Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet count that may result in bleeding tendency. Despite progress being made in defining the genetic causes of ITs, nearly 50\% of patients with familial thrombocytopenia are affected with forms of unknown origin. Here, through exome sequencing of 2 siblings with autosomal-recessive thrombocytopenia, we identified biallelic loss-of-function variants in This gene encodes for a receptor-like PTP, PTPRJ (or CD148), which is expressed abundantly in platelets and megakaryocytes. Consistent with the predicted effects of the variants, both probands have an almost complete loss of PTPRJ at the messenger RNA and protein levels. To investigate the pathogenic role of PTPRJ deficiency in hematopoiesis in vivo, we carried out CRISPR/Cas9-mediated ablation of (the ortholog of human ) in zebrafish, which induced a significantly decreased number of CD41 thrombocytes in vivo. Moreover, megakaryocytes of our patients showed impaired maturation and profound defects in SDF1-driven migration and formation of proplatelets in vitro. Silencing of in a human megakaryocytic cell line reproduced the functional defects observed in patients{\textquoteright} megakaryocytes. The disorder caused by mutations presented as a nonsyndromic thrombocytopenia characterized by spontaneous bleeding, small-sized platelets, and impaired platelet responses to the GPVI agonists collagen and convulxin. These platelet functional defects could be attributed to reduced activation of Src family kinases. Taken together, our data identify a new form of IT and highlight a hitherto unknown fundamental role for PTPRJ in platelet biogenesis.

}, issn = {1528-0020}, doi = {10.1182/blood-2018-07-859496}, author = {Marconi, Caterina and Di Buduo, Christian A and LeVine, Kellie and Barozzi, Serena and Faleschini, Michela and Bozzi, Valeria and Palombo, Flavia and McKinstry, Spencer and Lassandro, Giuseppe and Giordano, Paola and Noris, Patrizia and Balduini, Carlo L and Savoia, Anna and Balduini, Alessandra and Pippucci, Tommaso and Seri, Marco and Katsanis, Nicholas and Pecci, Alessandro} } @article {10822, title = {Next-generation sequencing identified SPATC1L as a possible candidate gene for both early-onset and age-related hearing loss.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 01}, pages = {70-79}, abstract = {

Hereditary hearing loss (HHL) and age-related hearing loss (ARHL) are two major sensory diseases affecting millions of people worldwide. Despite many efforts, additional HHL-genes and ARHL genetic risk factors still need to be identified. To fill this gap a large genomic screening based on next-generation sequencing technologies was performed. Whole exome sequencing in a 3-generation Italian HHL family and targeted re-sequencing in 464 ARHL patients were performed. We detected three variants in SPATC1L: a nonsense allele in an HHL family and a frameshift insertion and a missense variation in two unrelated ARHL patients. In silico molecular modelling of all variants suggested a significant impact on the structural stability of the protein itself, likely leading to deleterious effects and resulting in truncated isoforms. After demonstrating Spatc1l expression in mice inner ear, in vitro functional experiments were performed confirming the results of the molecular modelling studies. Finally, a candidate-gene population-based statistical study in cohorts from Caucasus and Central Asia revealed a statistically significant association of SPATC1L with normal hearing function at low and medium hearing frequencies. Overall, the amount of different genetic data presented here (variants with early-onset and late-onset hearing loss in addition to genetic association with normal hearing function), together with relevant functional evidence, likely suggest a role of SPATC1L in hearing function and loss.

}, issn = {1476-5438}, doi = {10.1038/s41431-018-0229-9}, author = {Morgan, Anna and Vuckovic, Dragana and Krishnamoorthy, Navaneethakrishnan and Rubinato, Elisa and Ambrosetti, Umberto and Castorina, Pierangela and Franz{\`e}, Annamaria and Vozzi, Diego and La Bianca, Martina and Cappellani, Stefania and Di Stazio, Mariateresa and Gasparini, Paolo and Girotto, Giorgia} } @article {10866, title = {Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy.}, journal = {Eur J Neurol}, volume = {26}, year = {2019}, month = {2019 Jan}, pages = {80-86}, abstract = {

BACKGROUND AND PURPOSE: Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM$\#$607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant.

METHODS: We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing.

RESULTS: We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (~80\% of patients), urinary urgency (~30\%) and pyramidal signs (~70\%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes.

CONCLUSIONS: The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3\% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.

}, issn = {1468-1331}, doi = {10.1111/ene.13768}, author = {Mancini, C and Giorgio, E and Rubegni, A and Pradotto, L and Bagnoli, S and Rubino, E and Prontera, P and Cavalieri, S and Di Gregorio, E and Ferrero, M and Pozzi, E and Riberi, E and Ferrero, P and Nigro, P and Mauro, A and Zibetti, M and Tessa, A and Barghigiani, M and Antenora, A and Sirchia, F and Piacentini, S and Silvestri, G and De Michele, G and Filla, A and Orsi, L and Santorelli, F M and Brusco, A} } @article {10748, title = {ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia.}, journal = {Br J Haematol}, volume = {183}, year = {2018}, month = {2018 Oct}, pages = {276-288}, abstract = {

The inherited thrombocytopenias (IT) are a heterogeneous group of diseases resulting from mutations in more than 30 different genes. Among them, ACTN1-related thrombocytopenia (ACTN1-RT; Online Mendelian Inheritance in Man: 615193) is one of the most recently identified forms. It has been described as a mild autosomal dominant macrothrombocytopenia caused by mutations in ACTN1, a gene encoding for one of the two non-muscle isoforms of α-actinin. We recently identified seven new unrelated families with ACTN1-RT caused by different mutations. Two of them are novel missense variants (p.Trp128Cys and p.Pro233Leu), whose pathogenic role has been confirmed by in~vitro studies. Together with the 10 families we have previously described, our cohort of ACTN1-RT now consists of 49 individuals carrying ACTN1 mutations. This is the largest case series ever collected and enabled a critical evaluation of the clinical aspects of the disease. We concluded that ACTN1-RT is the fourth most frequent form of IT worldwide and it is characterized by platelet macrocytosis in all affected subjects and mild thrombocytopenia in less than 80\% of cases. The risk of bleeding, either spontaneous or upon haemostatic challenge, is negligible and there are no other associated defects, either congenital or acquired. Therefore, ACTN1-RT is a benign form of IT, whose diagnosis provides affected individuals and their families with a good prognosis.

}, issn = {1365-2141}, doi = {10.1111/bjh.15531}, author = {Faleschini, Michela and Melazzini, Federica and Marconi, Caterina and Giangregorio, Tania and Pippucci, Tommaso and Cigalini, Elena and Pecci, Alessandro and Bottega, Roberta and Ramenghi, Ugo and Siitonen, Timo and Seri, Marco and Pastore, Annalisa and Savoia, Anna and Noris, Patrizia} } @article {10753, title = {Afebrile seizures in infants: Never forget magnesium!}, journal = {J Paediatr Child Health}, volume = {54}, year = {2018}, month = {2018 Apr}, pages = {446-448}, issn = {1440-1754}, doi = {10.1111/jpc.13854}, author = {Minute, Marta and Ventura, Giovanna and Giorgi, Rita and Faletra, Flavio and Costa, Paola and Cozzi, Giorgio} } @article {10758, title = {Are aortic coarctation and rheumatoid arthritis different models of aortic stiffness? Data from an echocardiographic study.}, journal = {Cardiovasc Ultrasound}, volume = {16}, year = {2018}, month = {2018 Jun 26}, pages = {9}, abstract = {

BACKGROUND: Patients who underwent a successful repair of the aortic coarctation (CoA) show high risk for cardiovascular (CV) events. Mechanical and structural abnormalities in the ascending aorta (Ao) might have a role in the prognosis of CoA patients. We analyzed the elastic properties of Ao measured as aortic stiffness index (AoSI) in CoA patients in the long-term period and we compared AoSI with a cohort of 38 patients with rheumatoid arthritis (RA) and 38 non-RA matched controls.

METHODS: Data from 19 CoA patients were analyzed 28 {\textpm} 13~years after surgery. Abnormally high AoSI was diagnosed if AoSI > 6.07\% (95th percentile of the AoSI detected in our reference healthy population). AoSI was assessed at the level of the aortic root by two-dimensional guided M-mode evaluation.

RESULTS: CoA patients showed more than two-fold higher AoSI compared to RA and controls (9.8 {\textpm} 12.6 vs 4.8 {\textpm} 2.5\% and 3.1 {\textpm} 2.0\%, respectively; all p < 0.05 and in 5 of 19 patients with CoA (26\%) AoSI was exceptionally high. The 5 patients with abnormally high AoSI were older with higher BP, LV mass and prevalence of LV diastolic dysfunction. Multiple linear regression analysis revealed that AoSI was independently related to the presence of LV hypertrophy and higher LV relative wall thickness.

CONCLUSIONS: CoA patients have higher AoSI levels than RA patients and non-RA matched controls. AoSI levels are abnormally high in a small sub-group of CoA patients who show a very high-risk clinical profile for adverse CV events.

}, keywords = {Aorta, Aortic Coarctation, Arthritis, Rheumatoid, Humans, Prognosis, Vascular Stiffness}, issn = {1476-7120}, doi = {10.1186/s12947-018-0126-y}, author = {Faganello, Giorgio and Cioffi, Giovanni and Rossini, Maurizio and Ognibeni, Federica and Giollo, Alessandro and Fisicaro, Maurizio and Russo, Giulia and Di Nora, Concetta and Doimo, Sara and Tarantini, Luigi and Mazzone, Carmine and Cherubini, Antonella and D{\textquoteright}Agata Mottolesi, Biancamaria and Pandullo, Claudio and Di Lenarda, Andrea and Sinagra, Gianfranco and Viapiana, Ombretta} } @article {10505, title = {Cervical-length measurement in mid-gestation to predict spontaneous preterm birth in asymptomatic triplet pregnancy.}, journal = {Ultrasound Obstet Gynecol}, volume = {51}, year = {2018}, month = {2018 May}, pages = {614-620}, abstract = {

OBJECTIVE: To assess the predictive value of sonographic cervical-length (CL) measurement in mid-gestation for spontaneous preterm birth (PTB) in asymptomatic triplet pregnancy.

METHODS: This was a retrospective study of asymptomatic triplet pregnancies followed at five Italian tertiary referral centers, between 2002 and 2015. CL was measured transvaginally between 18 and 24 weeks{\textquoteright} gestation. Pregnancies with medically indicated PTB were excluded. Demographic and pregnancy characteristics of pregnancies complicated by PTB were analyzed and the distributions of CL measurements in these patients were calculated. Logistic regression analysis was performed to assess the association between CL and PTB, adjusted for confounders. Performance of CL measurement in prediction of PTB < 28, < 30 and < 32 weeks of gestation was assessed.

RESULTS: A total of 120 triplet pregnancies were included in the final analysis. Median CL was 35 (interquartile range (IQR), 29-40) mm measured at a median gestational age of 20 + 2 (IQR, 20 + 0 to 23 + 4) weeks. Overall, 23 (19.2\%), 17 (14.2\%) and eight (6.7\%) patients had a CL < 25, < 20 and < 15 mm, respectively. Spontaneous PTB < 32 weeks occurred in 41 (34.2\%) cases, < 30 weeks in 23 (19.2\%) and < 28 weeks in 12 (10\%) cases. CL < 15 mm was significantly more frequent in the group of patients who delivered < 28 (P = 0.03) and < 30 (P = 0.01) weeks{\textquoteright} gestation, compared with those who delivered after 28 and after 30 weeks, respectively, while CL < 20 mm was more common in triplet pregnancies with delivery < 32 weeks compared with those delivered >= 32 weeks (P = 0.03). Logistic regression analysis was possible only for PTB < 32 weeks due to the small number of cases that delivered < 30 and < 28 weeks. After adjustment for confounders, CL was not significantly associated with PTB < 32 weeks (adjusted odds ratio, 0.97; 95\% CI, 0.94-1.01). CL measurement had an area under the receiver-operating characteristics curve of 0.41 (95\% CI, 0.20-0.62), 0.41 (95\% CI, 0.26-0.56) and 0.42 (95\% CI, 0.31-0.54) for the prediction of spontaneous PTB < 28, < 30 and < 32 weeks, respectively.

CONCLUSION: CL assessed in mid-gestation is a poor predictor of PTB < 28, < 30 and < 32 weeks{\textquoteright} gestation in asymptomatic triplet pregnancy. Copyright {\textcopyright} 2017 ISUOG. Published by John Wiley \& Sons Ltd.

}, keywords = {Adult, Cervical Length Measurement, Female, Gestational Age, Humans, Infant, Newborn, Logistic Models, Predictive Value of Tests, Pregnancy, Pregnancy, Triplet, Premature Birth, Retrospective Studies}, issn = {1469-0705}, doi = {10.1002/uog.17464}, author = {Fichera, A and Pagani, G and Stagnati, V and Cascella, S and Faiola, S and Gaini, C and Lanna, M and Pasquini, L and Raffaelli, R and Stampalija, T and Tommasini, A and Prefumo, F} } @article {10765, title = {Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders.}, journal = {Epigenetics}, volume = {13}, year = {2018}, month = {2018}, pages = {897-909}, abstract = {

The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50\% of BWS and 29\% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Beckwith-Wiedemann Syndrome, Child, Child, Preschool, Chromosomes, Human, Pair 15, DNA Methylation, Female, Genomic Imprinting, Humans, Infant, Kruppel-Like Transcription Factors, Male, Mutation, Missense, Silver-Russell Syndrome, Young Adult}, issn = {1559-2308}, doi = {10.1080/15592294.2018.1514230}, author = {Fontana, L and Bedeschi, M F and Maitz, S and Cereda, A and Far{\'e}, C and Motta, S and Seresini, A and D{\textquoteright}Ursi, P and Orro, A and Pecile, V and Calvello, M and Selicorni, A and Lalatta, F and Milani, D and Sirchia, S M and Miozzo, M and Tabano, S} } @article {10849, title = {The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases.}, journal = {Int J Mol Sci}, volume = {19}, year = {2018}, month = {2018 Dec 14}, abstract = {

Lipids and inflammation regulate each other. Early studies on this topic focused on the systemic effects that the acute inflammatory response-and interleukins-had on lipid metabolism. Today, in the era of the obesity epidemic, whose primary complications are cardio-metabolic diseases, attention has moved to the effects that the nutritional environment and lipid derangements have on peripheral tissues, where lipotoxicity leads to organ damage through an imbalance of chronic inflammatory responses. After an overview of the effects that acute inflammation has on the systemic lipid metabolism, this review will describe the lipid-induced immune responses that take place in peripheral tissues and lead to chronic cardio-metabolic diseases. Moreover, the anti-inflammatory effects of lipid lowering drugs, as well as the possibility of using anti-inflammatory agents against cardio-metabolic diseases, will be discussed.

}, keywords = {Anti-Inflammatory Agents, Cardiovascular Diseases, Humans, Hypolipidemic Agents, Immune System, Inflammation, Interleukins, Lipid Metabolism, Lipids, Metabolic Diseases}, issn = {1422-0067}, doi = {10.3390/ijms19124058}, author = {Bernardi, Stella and Marcuzzi, Annalisa and Piscianz, Elisa and Tommasini, Alberto and Fabris, Bruno} } @article {10767, title = {Cooking influence in tolerance acquisition in egg-induced acute food protein enterocolitis syndrome.}, journal = {Allergol Immunopathol (Madr)}, year = {2018}, month = {2018 Oct 10}, abstract = {

BACKGROUND: Few studies on the age of resolution of Food Protein Induced Enterocolitis Syndrome (FPIES) induced by solid foods are available. In particular, for FPIES induced by egg, the mean age of tolerance acquisition reported in the literature ranges from 42 to 63 months.

OBJECTIVE: We have assessed whether the age of tolerance acquisition in acute egg FPIES varies depending on whether the egg is cooked or raw.

METHODS: We conducted a retrospective and multicentric study of children with diagnosis of acute egg FPIES seen in 10 Italian allergy units between July 2003 and October 2017. The collected data regarded sex, presence of other allergic diseases, age of onset of symptoms, kind and severity of symptoms, cooking technique of the ingested egg, outcome of the allergy test, age of tolerance acquisition.

RESULTS: Sixty-one children with acute egg FPIES were enrolled, 34 (56\%) males and 27 (44\%) females. Tolerance to cooked egg has been demonstrated by 47/61 (77\%) children at a mean age of 30.2 months. For 32 of them, tolerance to raw egg has been demonstrated at a mean age of 43.9 months. No episodes of severe adverse reaction after baked egg ingestion have been recorded.

CONCLUSIONS: It is possible to perform an OFC with baked egg, to verify the possible acquisition of tolerance, at about 30 months of life in children with acute egg FPIES.

}, issn = {1578-1267}, doi = {10.1016/j.aller.2018.07.006}, author = {Miceli Sopo, S and Romano, A and Bersani, G and Fantacci, C and Badina, L and Longo, G and Monti, G and Viola, S and Tripodi, S and Barilaro, G and Iacono, I D and Caffarelli, C and Mastrorilli, C and Barni, S and Mori, F and Liotti, L and Cuomo, B and Franceschini, F and Viggiano, D and Monaco, S} } @article {10768, title = {Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway.}, journal = {Redox Biol}, volume = {19}, year = {2018}, month = {2018 10}, pages = {301-317}, abstract = {

Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2 mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2 mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2 mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4 {\texttimes} 10) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis.

}, keywords = {Animals, Apoptosis, Connexin 26, Female, Gene Deletion, Male, Mice, Mice, Inbred C57BL, NF-E2-Related Factor 2, Oxidation-Reduction, Presbycusis, Signal Transduction}, issn = {2213-2317}, doi = {10.1016/j.redox.2018.08.002}, author = {Fetoni, Anna Rita and Zorzi, Veronica and Paciello, Fabiola and Ziraldo, Gaia and Peres, Chiara and Raspa, Marcello and Scavizzi, Ferdinando and Salvatore, Anna Maria and Crispino, Giulia and Tognola, Gabriella and Gentile, Giulia and Spampinato, Antonio Gianmaria and Cuccaro, Denis and Guarnaccia, Maria and Morello, Giovanna and Van Camp, Guy and Fransen, Erik and Brumat, Marco and Girotto, Giorgia and Paludetti, Gaetano and Gasparini, Paolo and Cavallaro, Sebastiano and Mammano, Fabio} } @article {10769, title = {De novo unbalanced translocations have a complex history/aetiology.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Oct}, pages = {817-829}, abstract = {

We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin. Moreover, the duplicated region was of maternal origin in more than half of the cases, with 25\% of them showing two maternal and one paternal haplotype. In all these cases, maternal age was increased. These findings indicate that the primary driver for the occurrence of the de novo unbalanced translocations is a maternal meiotic non-disjunction, followed by partial trisomy rescue of the supernumerary chromosome present in the trisomic zygote. In contrast, asymmetric breakage of a dicentric chromosome, originated either at the meiosis or postzygotically, in which the two resulting chromosomes, one being deleted and the other one inv-dup del, are repaired by telomere capture, appears at the basis of all inv-dup del translocations. Notably, this mechanism also fits with the origin of some simple translocations in which the duplicated region was of paternal origin. In all cases, the signature at the translocation junctions was that of non-homologous end joining (NHEJ) rather than non-allelic homologous recombination (NAHR). Our data imply that there is no risk of recurrence in the following pregnancies for any of the de novo unbalanced translocations we discuss here.

}, keywords = {DNA End-Joining Repair, Female, Humans, Male, Meiosis, Recombinational DNA Repair, Translocation, Genetic}, issn = {1432-1203}, doi = {10.1007/s00439-018-1941-9}, author = {Bonaglia, Maria Clara and Kurtas, Nehir Edibe and Errichiello, Edoardo and Bertuzzo, Sara and Beri, Silvana and Mehrjouy, Mana M and Provenzano, Aldesia and Vergani, Debora and Pecile, Vanna and Novara, Francesca and Reho, Paolo and Di Giacomo, Marilena Carmela and Discepoli, Giancarlo and Giorda, Roberto and Aldred, Micheala A and Santos-Rebou{\c c}as, C{\'\i}ntia Barros and Goncalves, Andressa Pereira and Abuelo, Diane N and Giglio, Sabrina and Ricca, Ivana and Franchi, Fabrizia and Patsalis, Philippos and Sismani, Carolina and Mor{\'\i}, Mar{\'\i}a Angeles and Nevado, Juli{\'a}n and Tommerup, Niels and Zuffardi, Orsetta} } @article {10773, title = {Endocrine and psychological aspects of sexual dysfunction in Klinefelter patients.}, journal = {Andrology}, volume = {6}, year = {2018}, month = {2018 05}, pages = {414-419}, abstract = {

Klinefelter syndrome is a frequent cause of hypogonadism, but despite hundreds of publications on different aspects of Klinefelter syndrome, only a few studies dealt with sexual dysfunction. In particular, testosterone is critical for various aspects of sexual response, but its role on sexuality in Klinefelter syndrome patients is debatable and no studies have evaluated the efficacy of testosterone treatment on sexual dysfunction in these subjects. Furthermore, the impact of psychological and relational aspects on sexual function of Klinefelter syndrome subjects is poorly defined. In this study, we aimed to determine the presence and type of sexual dysfunctions in Klinefelter syndrome subjects; to correlate them with testosterone levels and psychosexological and relational domains; and to evaluate the effects of testosterone therapy. We studied 62 non-mosaic na{\"\i}ve Klinefelter syndrome patients and 60 age-matched controls by means of medical history, psychosexological history, 15-item International Index of Erectile Function questionnaire, endocrine assessment, and dynamic penile color Doppler ultrasound. Twenty-five hypogonadal Klinefelter syndrome patients were studied after 6~months of testosterone replacement therapy. Klinefelter syndrome subjects have reduced 15-item International Index of Erectile Function scores regarding sexual desire, intercourse satisfaction, and overall satisfaction with respect to controls, and these aspects were significantly associated with testosterone levels. Klinefelter syndrome subjects had also higher prevalence of erectile dysfunction, but no relation with testosterone levels was evident. A high prevalence of a range of psychological disturbances was present in Klinefelter syndrome subjects with erectile dysfunction with respect to those without erectile dysfunction. No statistical difference in the prevalence of premature and delayed ejaculation was observed between Klinefelter syndrome and control subjects. Testosterone replacement therapy improved sexual desire, intercourse satisfaction, and overall satisfaction scores, but had no effect on erectile function. Penile color Doppler ultrasound was normal in all subjects. This study shows that sexual dysfunction in Klinefelter syndrome is multifactorial and related only in part to hypogonadism and largely to psychological disturbances. Evaluation and therapy of sexual dysfunction should include a combined andrological and psychosexological approach.

}, issn = {2047-2927}, doi = {10.1111/andr.12474}, author = {Ferlin, A and Selice, R and Angelini, S and Di Grazia, M and Caretta, N and Cavalieri, F and Di Mambro, A and Foresta, C} } @article {10775, title = {Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.}, journal = {Genome Biol}, volume = {19}, year = {2018}, month = {2018 07 17}, pages = {87}, abstract = {

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.

RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874~individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.

CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

}, keywords = {ADAMTS Proteins, African Continental Ancestry Group, Animals, Connexin 43, Electrocardiography, European Continental Ancestry Group, Exome, Female, Gene Expression, Gene Expression Profiling, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Mice, Middle Aged, Myocardium, Open Reading Frames, Polymorphism, Single Nucleotide, Whole Exome Sequencing}, issn = {1474-760X}, doi = {10.1186/s13059-018-1457-6}, author = {Prins, Bram P and Mead, Timothy J and Brody, Jennifer A and Sveinbjornsson, Gardar and Ntalla, Ioanna and Bihlmeyer, Nathan A and van den Berg, Marten and Bork-Jensen, Jette and Cappellani, Stefania and Van Duijvenboden, Stefan and Klena, Nikolai T and Gabriel, George C and Liu, Xiaoqin and Gulec, Cagri and Grarup, Niels and Haessler, Jeffrey and Hall, Leanne M and Iorio, Annamaria and Isaacs, Aaron and Li-Gao, Ruifang and Lin, Honghuang and Liu, Ching-Ti and Lyytik{\"a}inen, Leo-Pekka and Marten, Jonathan and Mei, Hao and M{\"u}ller-Nurasyid, Martina and Orini, Michele and Padmanabhan, Sandosh and Radmanesh, Farid and Ramirez, Julia and Robino, Antonietta and Schwartz, Molly and van Setten, Jessica and Smith, Albert V and Verweij, Niek and Warren, Helen R and Weiss, Stefan and Alonso, Alvaro and Arnar, David O and Bots, Michiel L and de Boer, Rudolf A and Dominiczak, Anna F and Eijgelsheim, Mark and Ellinor, Patrick T and Guo, Xiuqing and Felix, Stephan B and Harris, Tamara B and Hayward, Caroline and Heckbert, Susan R and Huang, Paul L and Jukema, J W and K{\"a}h{\"o}nen, Mika and Kors, Jan A and Lambiase, Pier D and Launer, Lenore J and Li, Man and Linneberg, Allan and Nelson, Christopher P and Pedersen, Oluf and Perez, Marco and Peters, Annette and Polasek, Ozren and Psaty, Bruce M and Raitakari, Olli T and Rice, Kenneth M and Rotter, Jerome I and Sinner, Moritz F and Soliman, Elsayed Z and Spector, Tim D and Strauch, Konstantin and Thorsteinsdottir, Unnur and Tinker, Andrew and Trompet, Stella and Uitterlinden, Andr{\'e} and Vaartjes, Ilonca and van der Meer, Peter and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wilson, James G and Xie, Zhijun and Asselbergs, Folkert W and D{\"o}rr, Marcus and van Duijn, Cornelia M and Gasparini, Paolo and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Hansen, Torben and K{\"a}{\"a}b, Stefan and Kanters, J{\o}rgen K and Kooperberg, Charles and Lehtim{\"a}ki, Terho and Lin, Henry J and Lubitz, Steven A and Mook-Kanamori, Dennis O and Conti, Francesco J and Newton-Cheh, Christopher H and Rosand, Jonathan and Rudan, Igor and Samani, Nilesh J and Sinagra, Gianfranco and Smith, Blair H and Holm, Hilma and Stricker, Bruno H and Ulivi, Sheila and Sotoodehnia, Nona and Apte, Suneel S and van der Harst, Pim and Stefansson, Kari and Munroe, Patricia B and Arking, Dan E and Lo, Cecilia W and Jamshidi, Yalda} } @article {10778, title = {Fecal Calprotectin to Detect Inflammatory Bowel Disease in Juvenile Idiopathic Arthritis.}, journal = {J Rheumatol}, volume = {45}, year = {2018}, month = {2018 Oct}, pages = {1418-1421}, abstract = {

OBJECTIVE: This study aimed to test fecal calprotectin (FC) as a screening tool to identify inflammatory bowel disease (IBD) among patients with juvenile idiopathic arthritis (JIA).

METHODS: FC level < 100 g/kg was considered normal. Patients with 2 consecutive FC dosage >= 100 g/kg underwent endoscopic evaluation.

RESULTS: There were 113 patients with JIA enrolled. FC was raised in 7 patients out of 113. All patients had IBD. In 3/7 patients, high FC levels were the only sign consistent with IBD.

CONCLUSION: FC is a useful, economical, and noninvasive diagnostic tool to identify JIA patients with underlying IBD.

}, issn = {0315-162X}, doi = {10.3899/jrheum.171200}, author = {Ferrara, Giovanna and Pastore, Serena and Sancin, Lara and Torelli, Lucio and Radillo, Oriano and Bramuzzo, Matteo and Bibalo, Chiara and Tommasini, Alberto and Ventura, Alessandro and Taddio, Andrea} } @article {10579, title = {Flares After Withdrawal of Biologic Therapies in Juvenile Idiopathic Arthritis: Clinical and Laboratory Correlates of Remission Duration.}, journal = {Arthritis Care Res (Hoboken)}, volume = {70}, year = {2018}, month = {2018 Jul}, pages = {1046-1051}, abstract = {

OBJECTIVE: To assess the time in remission after discontinuing biologic therapy in patients with juvenile idiopathic arthritis (JIA).

METHODS: We enrolled 135 patients followed in 3 tertiary-care centers. The primary outcome was to assess, once remission was achieved, the time in remission up to the first flare after discontinuing treatment. Mann-Whitney U test, Wilcoxon{\textquoteright}s signed rank test for paired samples, chi-square tests, and Fisher{\textquoteright}s exact test were used to compare data. Pearson{\textquoteright}s and Spearman{\textquoteright}s correlation tests were used to determine correlation coefficients for different variables. To identify predictors of outcome, Cox regression model and Kaplan-Meier curves were constructed, each one at the mean of entered covariates.

RESULTS: The majority of enrolled patients flared after stopping treatment with biologics (102 of 135, 75.6\%) after a median followup time in remission off therapy of 6 months (range 3-109 months). A higher probability of maintaining remission after discontinuing treatment was present in systemic-onset disease compared to the rest of the JIA patients (Mantel-Cox χ = 8.31, P < 0.004). In analysis limited to children with JIA with polyarticular and oligoarticular disease, patients who received biologics >2 years after achieving remission had a higher probability of maintaining such remission off therapy (mean {\textpm} SD 18.64 {\textpm} 3.3 months versus 11.51 {\textpm} 2.7 months [P < 0.009]; Mantel-Cox χ = 9.06, P < 0.002). No other clinical variable was significantly associated with a long-lasting remission.

CONCLUSION: Children with oligoarticular and polyarticular JIA who stop treatment before 2 years from remission have a higher chance of relapsing after biologic withdrawal.

}, issn = {2151-4658}, doi = {10.1002/acr.23435}, author = {Simonini, Gabriele and Ferrara, Giovanna and Pontikaki, Irene and Scoccimarro, Erika and Giani, Teresa and Taddio, Andrea and Meroni, Pier Luigi and Cimaz, Rolando} } @article {10784, title = {Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Aug}, pages = {1112-1121}, abstract = {

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3\% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13\% of the variance in educational attainment and 7-10\% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0147-3}, author = {Lee, James J and Wedow, Robbee and Okbay, Aysu and Kong, Edward and Maghzian, Omeed and Zacher, Meghan and Nguyen-Viet, Tuan Anh and Bowers, Peter and Sidorenko, Julia and Karlsson Linn{\'e}r, Richard and Fontana, Mark Alan and Kundu, Tushar and Lee, Chanwook and Li, Hui and Li, Ruoxi and Royer, Rebecca and Timshel, Pascal N and Walters, Raymond K and Willoughby, Emily A and Yengo, Loic and Alver, Maris and Bao, Yanchun and Clark, David W and Day, Felix R and Furlotte, Nicholas A and Joshi, Peter K and Kemper, Kathryn E and Kleinman, Aaron and Langenberg, Claudia and M{\"a}gi, Reedik and Trampush, Joey W and Verma, Shefali Setia and Wu, Yang and Lam, Max and Zhao, Jing Hua and Zheng, Zhili and Boardman, Jason D and Campbell, Harry and Freese, Jeremy and Harris, Kathleen Mullan and Hayward, Caroline and Herd, Pamela and Kumari, Meena and Lencz, Todd and Luan, Jian{\textquoteright}an and Malhotra, Anil K and Metspalu, Andres and Milani, Lili and Ong, Ken K and Perry, John R B and Porteous, David J and Ritchie, Marylyn D and Smart, Melissa C and Smith, Blair H and Tung, Joyce Y and Wareham, Nicholas J and Wilson, James F and Beauchamp, Jonathan P and Conley, Dalton C and Esko, T{\~o}nu and Lehrer, Steven F and Magnusson, Patrik K E and Oskarsson, Sven and Pers, Tune H and Robinson, Matthew R and Thom, Kevin and Watson, Chelsea and Chabris, Christopher F and Meyer, Michelle N and Laibson, David I and Yang, Jian and Johannesson, Magnus and Koellinger, Philipp D and Turley, Patrick and Visscher, Peter M and Benjamin, Daniel J and Cesarini, David} } @article {10785, title = {Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Oct}, pages = {1412-1425}, abstract = {

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0205-x}, author = {Evangelou, Evangelos and Warren, Helen R and Mosen-Ansorena, David and Mifsud, Borbala and Pazoki, Raha and Gao, He and Ntritsos, Georgios and Dimou, Niki and Cabrera, Claudia P and Karaman, Ibrahim and Ng, Fu Liang and Evangelou, Marina and Witkowska, Katarzyna and Tzanis, Evan and Hellwege, Jacklyn N and Giri, Ayush and Velez Edwards, Digna R and Sun, Yan V and Cho, Kelly and Gaziano, J Michael and Wilson, Peter W F and Tsao, Philip S and Kovesdy, Csaba P and Esko, T{\~o}nu and M{\"a}gi, Reedik and Milani, Lili and Almgren, Peter and Boutin, Thibaud and Debette, St{\'e}phanie and Ding, Jun and Giulianini, Franco and Holliday, Elizabeth G and Jackson, Anne U and Li-Gao, Ruifang and Lin, Wei-Yu and Luan, Jian{\textquoteright}an and Mangino, Massimo and Oldmeadow, Christopher and Prins, Bram Peter and Qian, Yong and Sargurupremraj, Muralidharan and Shah, Nabi and Surendran, Praveen and Th{\'e}riault, S{\'e}bastien and Verweij, Niek and Willems, Sara M and Zhao, Jing-Hua and Amouyel, Philippe and Connell, John and de Mutsert, Ren{\'e}e and Doney, Alex S F and Farrall, Martin and Menni, Cristina and Morris, Andrew D and Noordam, Raymond and Par{\'e}, Guillaume and Poulter, Neil R and Shields, Denis C and Stanton, Alice and Thom, Simon and Abecasis, Goncalo and Amin, Najaf and Arking, Dan E and Ayers, Kristin L and Barbieri, Caterina M and Batini, Chiara and Bis, Joshua C and Blake, Tineka and Bochud, Murielle and Boehnke, Michael and Boerwinkle, Eric and Boomsma, Dorret I and Bottinger, Erwin P and Braund, Peter S and Brumat, Marco and Campbell, Archie and Campbell, Harry and Chakravarti, Aravinda and Chambers, John C and Chauhan, Ganesh and Ciullo, Marina and Cocca, Massimiliano and Collins, Francis and Cordell, Heather J and Davies, Gail and de Borst, Martin H and de Geus, Eco J and Deary, Ian J and Deelen, Joris and del Greco M, Fabiola and Demirkale, Cumhur Yusuf and D{\"o}rr, Marcus and Ehret, Georg B and Elosua, Roberto and Enroth, Stefan and Erzurumluoglu, A Mesut and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Franco, Oscar H and Gandin, Ilaria and Gasparini, Paolo and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Goel, Anuj and Gow, Alan J and Gudnason, Vilmundur and Guo, Xiuqing and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Harris, Sarah E and Hartman, Catharina A and Havulinna, Aki S and Hicks, Andrew A and Hofer, Edith and Hofman, Albert and Hottenga, Jouke-Jan and Huffman, Jennifer E and Hwang, Shih-Jen and Ingelsson, Erik and James, Alan and Jansen, Rick and J{\"a}rvelin, Marjo-Riitta and Joehanes, Roby and Johansson, {\r A}sa and Johnson, Andrew D and Joshi, Peter K and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Keavney, Bernard D and Khaw, Kay-Tee and Knekt, Paul and Knight, Joanne and Kolcic, Ivana and Kooner, Jaspal S and Koskinen, Seppo and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Laan, Maris and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liewald, David C M and Lin, Li and Lind, Lars and Lindgren, Cecilia M and Liu, Yongmei and Loos, Ruth J F and Lopez, Lorna M and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Mamasoula, Chrysovalanto and Marrugat, Jaume and Marten, Jonathan and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew P and Morrison, Alanna C and Munson, Peter J and Nalls, Mike A and Nandakumar, Priyanka and Nelson, Christopher P and Niiranen, Teemu and Nolte, Ilja M and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and O{\textquoteright}Reilly, Paul F and Org, Elin and Padmanabhan, Sandosh and Palmas, Walter and Palotie, Aarno and Pattie, Alison and Penninx, Brenda W J H and Perola, Markus and Peters, Annette and Polasek, Ozren and Pramstaller, Peter P and Nguyen, Quang Tri and Raitakari, Olli T and Ren, Meixia and Rettig, Rainer and Rice, Kenneth and Ridker, Paul M and Ried, Janina S and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rose, Lynda M and Rotter, Jerome I and Rudan, Igor and Ruggiero, Daniela and Saba, Yasaman and Sala, Cinzia F and Salomaa, Veikko and Samani, Nilesh J and Sarin, Antti-Pekka and Schmidt, Reinhold and Schmidt, Helena and Shrine, Nick and Siscovick, David and Smith, Albert V and Snieder, Harold and S{\~o}ber, Siim and Sorice, Rossella and Starr, John M and Stott, David J and Strachan, David P and Strawbridge, Rona J and Sundstr{\"o}m, Johan and Swertz, Morris A and Taylor, Kent D and Teumer, Alexander and Tobin, Martin D and Tomaszewski, Maciej and Toniolo, Daniela and Traglia, Michela and Trompet, Stella and Tuomilehto, Jaakko and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and Vaez, Ahmad and van der Most, Peter J and van Duijn, Cornelia M and Vergnaud, Anne-Claire and Verwoert, Germaine C and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Vuckovic, Dragana and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Wright, Alan F and Yao, Jie and Zemunik, Tatijana and Zhang, Weihua and Attia, John R and Butterworth, Adam S and Chasman, Daniel I and Conen, David and Cucca, Francesco and Danesh, John and Hayward, Caroline and Howson, Joanna M M and Laakso, Markku and Lakatta, Edward G and Langenberg, Claudia and Melander, Olle and Mook-Kanamori, Dennis O and Palmer, Colin N A and Risch, Lorenz and Scott, Robert A and Scott, Rodney J and Sever, Peter and Spector, Tim D and van der Harst, Pim and Wareham, Nicholas J and Zeggini, Eleftheria and Levy, Daniel and Munroe, Patricia B and Newton-Cheh, Christopher and Brown, Morris J and Metspalu, Andres and Hung, Adriana M and O{\textquoteright}Donnell, Christopher J and Edwards, Todd L and Psaty, Bruce M and Tzoulaki, Ioanna and Barnes, Michael R and Wain, Louise V and Elliott, Paul and Caulfield, Mark J} } @article {10420, title = {A genetic variant of NLRP1 gene is associated with asbestos body burden in patients with malignant pleural mesothelioma.}, journal = {J Toxicol Environ Health A}, volume = {81}, year = {2018}, month = {2018}, pages = {98-105}, abstract = {

The presence of asbestos bodies (ABs) in lung parenchyma is considered a histopathologic hallmark of past exposure to asbestos fibers, of which there was a population of longer fibers. The mechanisms underlying AB formation are complex, involving inflammatory responses and iron (Fe) metabolism. Thus, the responsiveness to AB formation is variable, with some individuals appearing to be poor AB formers. The aim of this study was to disclose the possible role of genetic variants of genes encoding inflammasome and iron metabolism proteins in the ability to form ABs in a population of 81 individuals from North East Italy, who died after having developed malignant pleural mesothelioma (MPM). This study included 86 genetic variants distributed in 10 genes involved in Fe metabolism and 7 genetic variants in two genes encoding for inflammasome molecules. Genotypes/haplotypes were compared according to the number of lung ABs. Data showed that the NLRP1 rs12150220 missense variant (H155L) was significantly correlated with numbers of ABs in MPM patients. Specifically, a low number of ABs was detected in individuals carrying the NLRP1 rs12150220 A/T genotype. Our findings suggest that the NLRP1 inflammasome might contribute in the development of lung ABs. It is postulated that the NLRP1 missense variant may be considered as one of the possible host genetic factors contributing to individual variability in coating efficiency, which needs to be taken when assessing occupational exposure to asbestos.

}, issn = {1528-7394}, doi = {10.1080/15287394.2017.1416911}, author = {Crovella, S and Moura, R R and Cappellani, S and Celsi, F and Trevisan, E and Schneider, M and Brollo, A and Nicastro, E M and Vita, F and Finotto, L and Zabucchi, G and Borelli, V} } @article {10786, title = {Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 Nov 01}, pages = {691-706}, abstract = {

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5~{\texttimes} 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0\% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.09.009}, author = {Ligthart, Symen and Vaez, Ahmad and V{\~o}sa, Urmo and Stathopoulou, Maria G and de Vries, Paul S and Prins, Bram P and van der Most, Peter J and Tanaka, Toshiko and Naderi, Elnaz and Rose, Lynda M and Wu, Ying and Karlsson, Robert and Barbalic, Maja and Lin, Honghuang and Pool, Ren{\'e} and Zhu, Gu and Mac{\'e}, Aur{\'e}lien and Sidore, Carlo and Trompet, Stella and Mangino, Massimo and Sabater-Lleal, Maria and Kemp, John P and Abbasi, Ali and Kacprowski, Tim and Verweij, Niek and Smith, Albert V and Huang, Tao and Marzi, Carola and Feitosa, Mary F and Lohman, Kurt K and Kleber, Marcus E and Milaneschi, Yuri and Mueller, Christian and Huq, Mahmudul and Vlachopoulou, Efthymia and Lyytik{\"a}inen, Leo-Pekka and Oldmeadow, Christopher and Deelen, Joris and Perola, Markus and Zhao, Jing Hua and Feenstra, Bjarke and Amini, Marzyeh and Lahti, Jari and Schraut, Katharina E and Fornage, Myriam and Suktitipat, Bhoom and Chen, Wei-Min and Li, Xiaohui and Nutile, Teresa and Malerba, Giovanni and Luan, Jian{\textquoteright}an and Bak, Tom and Schork, Nicholas and del Greco M, Fabiola and Thiering, Elisabeth and Mahajan, Anubha and Marioni, Riccardo E and Mihailov, Evelin and Eriksson, Joel and Ozel, Ayse Bilge and Zhang, Weihua and Nethander, Maria and Cheng, Yu-Ching and Aslibekyan, Stella and Ang, Wei and Gandin, Ilaria and Yengo, Loic and Portas, Laura and Kooperberg, Charles and Hofer, Edith and Rajan, Kumar B and Schurmann, Claudia and den Hollander, Wouter and Ahluwalia, Tarunveer S and Zhao, Jing and Draisma, Harmen H M and Ford, Ian and Timpson, Nicholas and Teumer, Alexander and Huang, Hongyan and Wahl, Simone and Liu, Yongmei and Huang, Jie and Uh, Hae-Won and Geller, Frank and Joshi, Peter K and Yanek, Lisa R and Trabetti, Elisabetta and Lehne, Benjamin and Vozzi, Diego and Verbanck, Marie and Biino, Ginevra and Saba, Yasaman and Meulenbelt, Ingrid and O{\textquoteright}Connell, Jeff R and Laakso, Markku and Giulianini, Franco and Magnusson, Patrik K E and Ballantyne, Christie M and Hottenga, Jouke Jan and Montgomery, Grant W and Rivadineira, Fernando and Rueedi, Rico and Steri, Maristella and Herzig, Karl-Heinz and Stott, David J and Menni, Cristina and Fr{\r a}nberg, Mattias and St Pourcain, Beate and Felix, Stephan B and Pers, Tune H and Bakker, Stephan J L and Kraft, Peter and Peters, Annette and Vaidya, Dhananjay and Delgado, Graciela and Smit, Johannes H and Gro{\ss}mann, Vera and Sinisalo, Juha and Sepp{\"a}l{\"a}, Ilkka and Williams, Stephen R and Holliday, Elizabeth G and Moed, Matthijs and Langenberg, Claudia and R{\"a}ikk{\"o}nen, Katri and Ding, Jingzhong and Campbell, Harry and Sale, Michele M and Chen, Yii-Der I and James, Alan L and Ruggiero, Daniela and Soranzo, Nicole and Hartman, Catharina A and Smith, Erin N and Berenson, Gerald S and Fuchsberger, Christian and Hernandez, Dena and Tiesler, Carla M T and Giedraitis, Vilmantas and Liewald, David and Fischer, Krista and Mellstr{\"o}m, Dan and Larsson, Anders and Wang, Yunmei and Scott, William R and Lorentzon, Matthias and Beilby, John and Ryan, Kathleen A and Pennell, Craig E and Vuckovic, Dragana and Balkau, Beverly and Concas, Maria Pina and Schmidt, Reinhold and Mendes de Leon, Carlos F and Bottinger, Erwin P and Kloppenburg, Margreet and Paternoster, Lavinia and Boehnke, Michael and Musk, A W and Willemsen, Gonneke and Evans, David M and Madden, Pamela A F and K{\"a}h{\"o}nen, Mika and Kutalik, Zolt{\'a}n and Zoledziewska, Magdalena and Karhunen, Ville and Kritchevsky, Stephen B and Sattar, Naveed and LaChance, Genevieve and Clarke, Robert and Harris, Tamara B and Raitakari, Olli T and Attia, John R and van Heemst, Diana and Kajantie, Eero and Sorice, Rossella and Gambaro, Giovanni and Scott, Robert A and Hicks, Andrew A and Ferrucci, Luigi and Standl, Marie and Lindgren, Cecilia M and Starr, John M and Karlsson, Magnus and Lind, Lars and Li, Jun Z and Chambers, John C and Mori, Trevor A and de Geus, Eco J C N and Heath, Andrew C and Martin, Nicholas G and Auvinen, Juha and Buckley, Brendan M and de Craen, Anton J M and Waldenberger, Melanie and Strauch, Konstantin and Meitinger, Thomas and Scott, Rodney J and McEvoy, Mark and Beekman, Marian and Bombieri, Cristina and Ridker, Paul M and Mohlke, Karen L and Pedersen, Nancy L and Morrison, Alanna C and Boomsma, Dorret I and Whitfield, John B and Strachan, David P and Hofman, Albert and Vollenweider, Peter and Cucca, Francesco and J{\"a}rvelin, Marjo-Riitta and Jukema, J Wouter and Spector, Tim D and Hamsten, Anders and Zeller, Tanja and Uitterlinden, Andr{\'e} G and Nauck, Matthias and Gudnason, Vilmundur and Qi, Lu and Grallert, Harald and Borecki, Ingrid B and Rotter, Jerome I and M{\"a}rz, Winfried and Wild, Philipp S and Lokki, Marja-Liisa and Boyle, Michael and Salomaa, Veikko and Melbye, Mads and Eriksson, Johan G and Wilson, James F and Penninx, Brenda W J H and Becker, Diane M and Worrall, Bradford B and Gibson, Greg and Krauss, Ronald M and Ciullo, Marina and Zaza, Gianluigi and Wareham, Nicholas J and Oldehinkel, Albertine J and Palmer, Lyle J and Murray, Sarah S and Pramstaller, Peter P and Bandinelli, Stefania and Heinrich, Joachim and Ingelsson, Erik and Deary, Ian J and M{\"a}gi, Reedik and Vandenput, Liesbeth and van der Harst, Pim and Desch, Karl C and Kooner, Jaspal S and Ohlsson, Claes and Hayward, Caroline and Lehtim{\"a}ki, Terho and Shuldiner, Alan R and Arnett, Donna K and Beilin, Lawrence J and Robino, Antonietta and Froguel, Philippe and Pirastu, Mario and Jess, Tine and Koenig, Wolfgang and Loos, Ruth J F and Evans, Denis A and Schmidt, Helena and Smith, George Davey and Slagboom, P Eline and Eiriksdottir, Gudny and Morris, Andrew P and Psaty, Bruce M and Tracy, Russell P and Nolte, Ilja M and Boerwinkle, Eric and Visvikis-Siest, Sophie and Reiner, Alex P and Gross, Myron and Bis, Joshua C and Franke, Lude and Franco, Oscar H and Benjamin, Emelia J and Chasman, Daniel I and Dupuis, Jos{\'e}e and Snieder, Harold and Dehghan, Abbas and Alizadeh, Behrooz Z} } @article {10444, title = {Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Jun}, pages = {834-848}, abstract = {

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0127-7}, author = {Tedja, Milly S and Wojciechowski, Robert and Hysi, Pirro G and Eriksson, Nicholas and Furlotte, Nicholas A and Verhoeven, Virginie J M and Iglesias, Adriana I and Meester-Smoor, Magda A and Tompson, Stuart W and Fan, Qiao and Khawaja, Anthony P and Cheng, Ching-Yu and H{\"o}hn, Ren{\'e} and Yamashiro, Kenji and Wenocur, Adam and Grazal, Clare and Haller, Toomas and Metspalu, Andres and Wedenoja, Juho and Jonas, Jost B and Wang, Ya Xing and Xie, Jing and Mitchell, Paul and Foster, Paul J and Klein, Barbara E K and Klein, Ronald and Paterson, Andrew D and Hosseini, S Mohsen and Shah, Rupal L and Williams, Cathy and Teo, Yik Ying and Tham, Yih Chung and Gupta, Preeti and Zhao, Wanting and Shi, Yuan and Saw, Woei-Yuh and Tai, E-Shyong and Sim, Xue Ling and Huffman, Jennifer E and Polasek, Ozren and Hayward, Caroline and Bencic, Goran and Rudan, Igor and Wilson, James F and Joshi, Peter K and Tsujikawa, Akitaka and Matsuda, Fumihiko and Whisenhunt, Kristina N and Zeller, Tanja and van der Spek, Peter J and Haak, Roxanna and Meijers-Heijboer, Hanne and van Leeuwen, Elisabeth M and Iyengar, Sudha K and Lass, Jonathan H and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Vingerling, Johannes R and Lehtim{\"a}ki, Terho and Raitakari, Olli T and Biino, Ginevra and Concas, Maria Pina and Schwantes-An, Tae-Hwi and Igo, Robert P and Cuellar-Partida, Gabriel and Martin, Nicholas G and Craig, Jamie E and Gharahkhani, Puya and Williams, Katie M and Nag, Abhishek and Rahi, Jugnoo S and Cumberland, Phillippa M and Delcourt, C{\'e}cile and Bellenguez, C{\'e}line and Ried, Janina S and Bergen, Arthur A and Meitinger, Thomas and Gieger, Christian and Wong, Tien Yin and Hewitt, Alex W and Mackey, David A and Simpson, Claire L and Pfeiffer, Norbert and P{\"a}rssinen, Olavi and Baird, Paul N and Vitart, Veronique and Amin, Najaf and van Duijn, Cornelia M and Bailey-Wilson, Joan E and Young, Terri L and Saw, Seang-Mei and Stambolian, Dwight and MacGregor, Stuart and Guggenheim, Jeremy A and Tung, Joyce Y and Hammond, Christopher J and Klaver, Caroline C W} } @article {10430, title = {Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 May}, pages = {652-656}, abstract = {

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6\% of red hair, 24.8\% of blond hair, and 26.1\% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0100-5}, author = {Hysi, Pirro G and Valdes, Ana M and Liu, Fan and Furlotte, Nicholas A and Evans, David M and Bataille, Veronique and Visconti, Alessia and Hemani, Gibran and McMahon, George and Ring, Susan M and Smith, George Davey and Duffy, David L and Zhu, Gu and Gordon, Scott D and Medland, Sarah E and Lin, Bochao D and Willemsen, Gonneke and Jan Hottenga, Jouke and Vuckovic, Dragana and Girotto, Giorgia and Gandin, Ilaria and Sala, Cinzia and Concas, Maria Pina and Brumat, Marco and Gasparini, Paolo and Toniolo, Daniela and Cocca, Massimiliano and Robino, Antonietta and Yazar, Seyhan and Hewitt, Alex W and Chen, Yan and Zeng, Changqing and Uitterlinden, Andr{\'e} G and Ikram, M Arfan and Hamer, Merel A and van Duijn, Cornelia M and Nijsten, Tamar and Mackey, David A and Falchi, Mario and Boomsma, Dorret I and Martin, Nicholas G and Hinds, David A and Kayser, Manfred and Spector, Timothy D} } @article {10426, title = {A genome-wide association study of corneal astigmatism: The CREAM Consortium.}, journal = {Mol Vis}, volume = {24}, year = {2018}, month = {2018}, pages = {127-142}, abstract = {

Purpose: To identify genes and genetic markers associated with corneal astigmatism.

Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression.

Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha () gene: top SNP: rs7673984, odds ratio=1.12 (95\% CI:1.08-1.16), p=5.55{\texttimes}10. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (), acid phosphatase 2, lysosomal (), and TNF alpha-induced protein 8 like 3 ().

Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the gene, gene-based analysis identified three novel candidate genes, , , and , that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

}, keywords = {Acid Phosphatase, Asian Continental Ancestry Group, Astigmatism, Claudins, Cohort Studies, Cornea, Corneal Diseases, European Continental Ancestry Group, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Odds Ratio, Polymorphism, Single Nucleotide, Receptor, Platelet-Derived Growth Factor alpha, Software}, issn = {1090-0535}, author = {Shah, Rupal L and Li, Qing and Zhao, Wanting and Tedja, Milly S and Tideman, J Willem L and Khawaja, Anthony P and Fan, Qiao and Yazar, Seyhan and Williams, Katie M and Verhoeven, Virginie J M and Xie, Jing and Wang, Ya Xing and Hess, Moritz and Nickels, Stefan and Lackner, Karl J and P{\"a}rssinen, Olavi and Wedenoja, Juho and Biino, Ginevra and Concas, Maria Pina and Uitterlinden, Andr{\'e} and Rivadeneira, Fernando and Jaddoe, Vincent W V and Hysi, Pirro G and Sim, Xueling and Tan, Nicholas and Tham, Yih-Chung and Sensaki, Sonoko and Hofman, Albert and Vingerling, Johannes R and Jonas, Jost B and Mitchell, Paul and Hammond, Christopher J and H{\"o}hn, Ren{\'e} and Baird, Paul N and Wong, Tien-Yin and Cheng, Chinfsg-Yu and Teo, Yik Ying and Mackey, David A and Williams, Cathy and Saw, Seang-Mei and Klaver, Caroline C W and Guggenheim, Jeremy A and Bailey-Wilson, Joan E} } @article {10744, title = {A Girl with Delayed Puberty and Bumpy Lips.}, journal = {J Pediatr}, volume = {203}, year = {2018}, month = {2018 12}, pages = {454-454.e1}, keywords = {Adolescent, Exons, Female, Genes, Dominant, Humans, Lip, Multiple Endocrine Neoplasia Type 2b, Neoplasm Metastasis, Puberty, Delayed, Thyroid Neoplasms, Thyroidectomy, Tongue}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2018.05.043}, author = {Andrade, Stefanny and Sirchia, Fabio and Faleschini, Elena and Barbi, Egidio} } @article {10436, title = {High-Throughput Sequencing of microRNAs in Glucocorticoid Sensitive Paediatric Inflammatory Bowel Disease Patients.}, journal = {Int J Mol Sci}, volume = {19}, year = {2018}, month = {2018 May 08}, abstract = {

The aim of this research was the identification of novel pharmacogenomic biomarkers for better understanding the complex gene regulation mechanisms underpinning glucocorticoid (GC) action in paediatric inflammatory bowel disease (IBD). This goal was achieved by evaluating high-throughput microRNA (miRNA) profiles during GC treatment, integrated with the assessment of expression changes in GC receptor (GR) heterocomplex genes. Furthermore, we tested the hypothesis that differentially expressed miRNAs could be directly regulated by GCs through investigating the presence of GC responsive elements (GREs) in their gene promoters. Ten IBD paediatric patients responding to GCs were enrolled. Peripheral blood was obtained at diagnosis (T0) and after four weeks of steroid treatment (T4). MicroRNA profiles were analyzed using next generation sequencing, and selected significantly differentially expressed miRNAs were validated by quantitative reverse transcription-polymerase chain reaction. In detail, 18 miRNAs were differentially expressed from T0 to T4, 16 of which were upregulated and 2 of which were downregulated. Out of these, three miRNAs (miR-144, miR-142, and miR-96) could putatively recognize the 3\’UTR of the GR gene and three miRNAs (miR-363, miR-96, miR-142) contained GREs sequences, thereby potentially enabling direct regulation by the GR. In conclusion, we identified miRNAs differently expressed during GC treatment and miRNAs which could be directly regulated by GCs in blood cells of young IBD patients. These results could represent a first step towards their translation as pharmacogenomic biomarkers.

}, keywords = {Adolescent, Biomarkers, Child, Female, Gene Expression Regulation, Glucocorticoids, High-Throughput Nucleotide Sequencing, Humans, Inflammatory Bowel Diseases, Male, MicroRNAs, Receptors, Glucocorticoid, Transcriptome}, issn = {1422-0067}, doi = {10.3390/ijms19051399}, author = {De Iudicibus, Sara and Lucaf{\`o}, Marianna and Vitulo, Nicola and Martelossi, Stefano and Zimbello, Rosanna and De Pascale, Fabio and Forcato, Claudio and Naviglio, Samuele and Di Silvestre, Alessia and Gerdol, Marco and Stocco, Gabriele and Valle, Giorgio and Ventura, Alessandro and Bramuzzo, Matteo and Decorti, Giuliana} } @article {10421, title = {Hypomorphic FANCA mutations correlate with mild mitochondrial and clinical phenotype in Fanconi anemia.}, journal = {Haematologica}, volume = {103}, year = {2018}, month = {2018 Mar}, pages = {417-426}, abstract = {

Fanconi anemia is a rare disease characterized by congenital malformations, aplastic anemia, and predisposition to cancer. Despite the consolidated role of the Fanconi anemia proteins in DNA repair, their involvement in mitochondrial function is emerging. The purpose of this work was to assess whether the mitochondrial phenotype, independent of genomic integrity, could correlate with patient phenotype. We evaluated mitochondrial and clinical features of 11 affected individuals homozygous or compound heterozygous for p.His913Pro and p.Arg951Gln/Trp, the two residues of FANCA that are more frequently affected in our cohort of patients. Although p.His913Pro and p.Arg951Gln proteins are stably expressed in cytoplasm, they are unable to migrate in the nucleus, preventing cells from repairing DNA. In these cells, the electron transfer between respiring complex I-III is reduced and the ATP/AMP ratio is impaired with defective ATP production and AMP accumulation. These activities are intermediate between those observed in wild-type and FANCA-/- cells, suggesting that the variants at residues His913 and Arg951 are hypomorphic mutations. Consistent with these findings, the clinical phenotype of most of the patients carrying these mutations is mild. These data further support the recent finding that the Fanconi anemia proteins play a role in mitochondria, and open up possibilities for genotype/phenotype studies based on novel mitochondrial criteria.

}, issn = {1592-8721}, doi = {10.3324/haematol.2017.176131}, author = {Bottega, Roberta and Nicchia, Elena and Cappelli, Enrico and Ravera, Silvia and De Rocco, Daniela and Faleschini, Michela and Corsolini, Fabio and Pierri, Filomena and Calvillo, Michaela and Russo, Giovanna and Casazza, Gabriella and Ramenghi, Ugo and Farruggia, Piero and Dufour, Carlo and Savoia, Anna} } @article {10802, title = {Influence of polymerization time on properties of dual-curing cements in combination with high translucency monolithic zirconia.}, journal = {J Prosthodont Res}, volume = {62}, year = {2018}, month = {2018 Oct}, pages = {468-472}, abstract = {

PURPOSE: The aim of this in vitro study was to assess conversion degree (DC), micro-hardness (MH) and bond strength of two dual-curing resin cements employed under translucent monolithic zirconia irradiated with different time protocols.

METHODS: 84 square shaped samples of 1mm thickness were prepared from high translucency zirconia blocks and divided into two groups (n=24) according to the cement employed: (1) Rely-X Ultimate; (2) Panavia SA. Each group was further divided into 3 subgroups (n=8) according to the irradiation time: (a) no light; (b) 20s; (c) 120s. Light curing was performed 60s after the sample was placed on the diamond support of a FT-IR spectrophotometer with a high power multiLED lamp. Final DC\% were calculated after 10min. After 24h, Vickers Test on the cement layer was performed. The same protocol was used to lute composite cylinders in order to evaluate microshear bond-strength test. ANOVA and Bonferroni tests were performed to find differences between MH and bond-strength to zirconia, while for DC\% the Scheirer-Ray-Hare two-way test was used.

RESULTS: The two cements reached higher DC\% in subgroup (b) and (c). As concern MH, statistics showed an increase in curing time was able to improve MH significantly. Bond-strength was not affected by irradiation time only for Panavia SA.

CONCLUSIONS: The first null hypothesis has to be rejected since DC\% and MH of the dual-cements tested were influenced by the curing time. The second null hypothesis is partially rejected since the bond strength was influenced by the curing time only for Rely-X Ultimate.

}, keywords = {Composite Resins, Dental Bonding, Dental Cements, Hardness, Lansoprazole, Materials Testing, Polymerization, Resins, Synthetic, Spectrophotometry, Time Factors, Zirconium}, issn = {2212-4632}, doi = {10.1016/j.jpor.2018.06.003}, author = {Alovisi, Mario and Scotti, Nicola and Comba, Allegra and Manzon, Elena and Farina, Elena and Pasqualini, Damiano and Michelotto Tempesta, Riccardo and Breschi, Lorenzo and Cadenaro, Milena} } @article {10429, title = {A Klinefelter boy with congenital adrenal hyperplasia: too much or too little androgens?}, journal = {Ital J Pediatr}, volume = {44}, year = {2018}, month = {2018 Apr 03}, pages = {43}, abstract = {

BACKGROUND: The simultaneous occurrence of Klinefelter Syndrome (KS) and Congenital Adrenal Hyperplasia (CAH) is an exceptional event: there are just three case reports (two children and a 51 years old man) describing males affected by both KS and 21OHD (21-hydroxylase deficiency) CAH, the first causing androgen deficiency, the latter leading to androgen excess.

CASE REPORT: We report the 4th case of association of KS and CAH in a young man with CAH with good androgen control and with normal secondary sex characteristics, whose Klinefelter syndrome was diagnosed because of reduced testicular volume. He was the first reported case of association of KS and CAH who started androgen replacement therapy in the pubertal age and whose pubertal development was described and followed up step by step.

CONCLUSION: In a boy with CAH and small testicular volume, it{\textquoteright}s important to consider that hypogonadism may be masked by the adrenal androgens excess and a karyotype should be performed once testicular adrenal rests have been ruled out.

}, keywords = {Adolescent, Adrenal Hyperplasia, Congenital, Androgens, Follow-Up Studies, Hormone Replacement Therapy, Humans, Klinefelter Syndrome, Male, Rare Diseases, Risk Assessment, Testis}, issn = {1824-7288}, doi = {10.1186/s13052-018-0485-x}, author = {Zanella, Giada and Tornese, Gianluca and Mascheroni, Elisabetta and Faleschini, Elena and Ventura, Alessandro and Barbi, Egidio} } @article {10427, title = {A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 03 01}, pages = {375-400}, abstract = {

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined \~{}18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5~{\texttimes} 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5~{\texttimes} 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

}, keywords = {Blood Pressure, Cohort Studies, Continental Population Groups, Diastole, Epistasis, Genetic, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reproducibility of Results, Smoking, Systole}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.01.015}, author = {Sung, Yun J and Winkler, Thomas W and de Las Fuentes, Lisa and Bentley, Amy R and Brown, Michael R and Kraja, Aldi T and Schwander, Karen and Ntalla, Ioanna and Guo, Xiuqing and Franceschini, Nora and Lu, Yingchang and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Marten, Jonathan and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Kilpel{\"a}inen, Tuomas O and Richard, Melissa A and Noordam, Raymond and Aslibekyan, Stella and Aschard, Hugues and Bartz, Traci M and Dorajoo, Rajkumar and Liu, Yongmei and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert Vernon and Tajuddin, Salman M and Tayo, Bamidele O and Warren, Helen R and Zhao, Wei and Zhou, Yanhua and Matoba, Nana and Sofer, Tamar and Alver, Maris and Amini, Marzyeh and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gandin, Ilaria and Gao, Chuan and Giulianini, Franco and Goel, Anuj and Harris, Sarah E and Hartwig, Fernando Pires and Horimoto, Andrea R V R and Hsu, Fang-Chi and Jackson, Anne U and K{\"a}h{\"o}nen, Mika and Kasturiratne, Anuradhani and Kuhnel, Brigitte and Leander, Karin and Lee, Wen-Jane and Lin, Keng-Hung and {\textquoteright}an Luan, Jian and McKenzie, Colin A and Meian, He and Nelson, Christopher P and Rauramaa, Rainer and Schupf, Nicole and Scott, Robert A and Sheu, Wayne H H and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and van der Most, Peter J and Varga, Tibor V and Wang, Heming and Wang, Yajuan and Ware, Erin B and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Afaq, Saima and Alfred, Tamuno and Amin, Najaf and Arking, Dan and Aung, Tin and Barr, R Graham and Bielak, Lawrence F and Boerwinkle, Eric and Bottinger, Erwin P and Braund, Peter S and Brody, Jennifer A and Broeckel, Ulrich and Cabrera, Claudia P and Cade, Brian and Caizheng, Yu and Campbell, Archie and Canouil, Micka{\"e}l and Chakravarti, Aravinda and Chauhan, Ganesh and Christensen, Kaare and Cocca, Massimiliano and Collins, Francis S and Connell, John M and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Debette, St{\'e}phanie and D{\"o}rr, Marcus and Duan, Qing and Eaton, Charles B and Ehret, Georg and Evangelou, Evangelos and Faul, Jessica D and Fisher, Virginia A and Forouhi, Nita G and Franco, Oscar H and Friedlander, Yechiel and Gao, He and Gigante, Bruna and Graff, Misa and Gu, C Charles and Gu, Dongfeng and Gupta, Preeti and Hagenaars, Saskia P and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hofman, Albert and Howard, Barbara V and Hunt, Steven and Irvin, Marguerite R and Jia, Yucheng and Joehanes, Roby and Justice, Anne E and Katsuya, Tomohiro and Kaufman, Joel and Kerrison, Nicola D and Khor, Chiea Chuen and Koh, Woon-Puay and Koistinen, Heikki A and Komulainen, Pirjo and Kooperberg, Charles and Krieger, Jose E and Kubo, Michiaki and Kuusisto, Johanna and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lewis, Cora E and Li, Yize and Lim, Sing Hui and Lin, Shiow and Liu, Ching-Ti and Liu, Jianjun and Liu, Jingmin and Liu, Kiang and Liu, Yeheng and Loh, Marie and Lohman, Kurt K and Long, Jirong and Louie, Tin and M{\"a}gi, Reedik and Mahajan, Anubha and Meitinger, Thomas and Metspalu, Andres and Milani, Lili and Momozawa, Yukihide and Morris, Andrew P and Mosley, Thomas H and Munson, Peter and Murray, Alison D and Nalls, Mike A and Nasri, Ubaydah and Norris, Jill M and North, Kari and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmas, Walter R and Palmer, Nicholette D and Pankow, James S and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Raitakari, Olli T and Renstrom, Frida and Rice, Treva K and Ridker, Paul M and Robino, Antonietta and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Sabanayagam, Charumathi and Salako, Babatunde L and Sandow, Kevin and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Seshadri, Sudha and Sever, Peter and Sitlani, Colleen M and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Tang, Hua and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and Waldenberger, Melanie and Wang, Lihua and Wang, Ya X and Wei, Wen Bin and Williams, Christine and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Yuan, Jian-Min and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Chen, Yii-Der Ida and de Faire, Ulf and Deary, Ian J and Esko, T{\~o}nu and Farrall, Martin and Forrester, Terrence and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Horta, Bernardo Lessa and Hung, Yi-Jen and Jonas, Jost B and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Lehtim{\"a}ki, Terho and Liang, Kae-Woei and Magnusson, Patrik K E and Newman, Anne B and Oldehinkel, Albertine J and Pereira, Alexandre C and Redline, Susan and Rettig, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zheng, Wei and Kamatani, Yoichiro and Laurie, Cathy C and Bouchard, Claude and Cooper, Richard S and Evans, Michele K and Gudnason, Vilmundur and Kardia, Sharon L R and Kritchevsky, Stephen B and Levy, Daniel and O{\textquoteright}Connell, Jeff R and Psaty, Bruce M and van Dam, Rob M and Sims, Mario and Arnett, Donna K and Mook-Kanamori, Dennis O and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and Fornage, Myriam and Rotimi, Charles N and Province, Michael A and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Loos, Ruth J F and Reiner, Alex P and Rotter, Jerome I and Zhu, Xiaofeng and Bierut, Laura J and Gauderman, W James and Caulfield, Mark J and Elliott, Paul and Rice, Kenneth and Munroe, Patricia B and Morrison, Alanna C and Cupples, L Adrienne and Rao, Dabeeru C and Chasman, Daniel I} } @article {10503, title = {MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study.}, journal = {Endocrine}, volume = {59}, year = {2018}, month = {2018 01}, pages = {203-208}, abstract = {

PURPOSE: Recently, mutations of makorin RING-finger protein 3 (MKRN3) have been described in familial central precocious puberty. Serum levels of this protein decline before the pubertal onset in healthy girls and boys. The aim of the study is to investigate MKRN3 circulating levels in patients with central precocious puberty.

METHODS: We performed an observational cross-sectional study. We enrolled 17 patients with central precocious puberty aged 7 years (range: 2-8 years) and breast development onset <8 years; 17 prepubertal control age-matched patients aged 6.3 years (2-8.2); and 10 pubertal stage-matched control patients aged 11.4 years (9-14). Serum values of MKRN3, gonadotropins, (17)estradiol and Anti-M{\"u}llerian Hormone were evaluated and the MKRN3 genotyped in central precocious puberty patients.

RESULTS: No MKRN3 mutation was found among central precocious puberty patients. MKRN3 levels were lower in patients with central precocious puberty compared to prepubertal age-matched ones (p: 0.0004) and comparable to those matched for pubertal stage. MKRN3 levels were inversely correlated to Body Mass Index Standard Deviations (r:-0.35; p:0.02), Luteinizing Hormone (r:-0.35; p:0.03), FSH (r:-0.37; p:0.02), and (17)estradiol (r: -0.36; p:0.02).

CONCLUSIONS: We showed that girls with central precocious puberty had lower peripheral levels of MKRN3 compared to age-matched pairs and that they negatively correlated to gonadotropins, estrogen, and BMI. Our findings support the MKRN3 involvement in central precocious puberty also in absence of deleterious mutations, although our sample size is small. In addition our data suggest the role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition.

}, keywords = {Adolescent, Adolescent Nutritional Physiological Phenomena, Anti-Mullerian Hormone, Case-Control Studies, Child, Child Nutritional Physiological Phenomena, Child, Preschool, Cross-Sectional Studies, Female, Follicle Stimulating Hormone, Gonadotropin-Releasing Hormone, Humans, Luteinizing Hormone, Pilot Projects, Puberty, Precocious, Ribonucleoproteins, Sexual Maturation}, issn = {1559-0100}, doi = {10.1007/s12020-017-1281-x}, author = {Grandone, Anna and Cirillo, Grazia and Sasso, Marcella and Capristo, Carlo and Tornese, Gianluca and Marzuillo, Pierluigi and Luongo, Caterina and Rosaria Umano, Giuseppina and Festa, Adalgisa and Coppola, Ruggero and Miraglia Del Giudice, Emanuele and Perrone, Laura} } @article {10817, title = {MKRN3 Levels in Girls with Central Precocious Puberty during GnRHa Treatment: A Longitudinal Study.}, journal = {Horm Res Paediatr}, volume = {90}, year = {2018}, month = {2018}, pages = {190-195}, abstract = {

BACKGROUND: Recently, mutations of makorin RING finger protein 3 (MKRN3) have been identified in familial central precocious puberty (CPP). Serum levels of this protein decline before the pubertal onset in healthy girls and boys and are lower in patients with CPP compared to prepubertal matched pairs. The aim of our study was to investigate longitudinal changes in circulating MKRN3 levels in patients with CPP before and during GnRH analogs (GnRHa) treatment.

METHODS: We performed a longitudinal prospective study. We enrolled 15 patients with CPP aged 7.2 years (range: 2-8) with age at breast development onset < 8 years and 12 control girls matched for the time from puberty onset (mean age 11.8 {\textpm} 1.2 years). Serum values of MKRN3, gonadotropins, and 17β-estradiol were evaluated before and during treatment with GnRHa (at 6 and 12 months). The MKRN3 gene was genotyped in CPP patients. In the girls from the control group, only basal levels were analyzed.

RESULTS: No MKRN3 mutations were found among CPP patients. MKRN3 levels declined significantly from baseline to 6 months of GnRHa treatment (p = 0.0007) and from 6 to 12 months of treatment (p = 0.003); MKRN3 levels at 6 months were significantly lower than in the control girls (p < 0.0001).

CONCLUSIONS: We showed that girls with CPP had a decline in peripheral levels of MKRN3 during GnRHa treatment. Our data suggest a suppression of MKRN3 by continuous pharmacological administration of GnRHa.

}, keywords = {Brain Diseases, Case-Control Studies, Child, Child, Preschool, Female, Follicle Stimulating Hormone, Genotype, Gonadotropin-Releasing Hormone, Humans, Longitudinal Studies, Luteinizing Hormone, Male, Puberty, Precocious, Ribonucleoproteins}, issn = {1663-2826}, doi = {10.1159/000493134}, author = {Grandone, Anna and Cirillo, Grazia and Sasso, Marcella and Tornese, Gianluca and Luongo, Caterina and Festa, Adalgisa and Marzuillo, Pierluigi and Miraglia Del Giudice, Emanuele} } @article {10821, title = {Needle-related pain and distress management during needle-related procedures in children with and without intellectual disability.}, journal = {Eur J Pediatr}, volume = {177}, year = {2018}, month = {2018 Dec}, pages = {1753-1760}, abstract = {

Children with intellectual disability frequently undergo needle-related procedures for diagnosis or treatment. Nevertheless, only a few studies deal with pain and distress management during the procedure in this population of children. This study aimed to investigate the number of anxiety and pain management techniques performed during needle procedure in children with intellectual disability (cases) compared to a population of children without intellectual disability (controls). This multicenter cohort study was performed from July 2016 to January 2018 in the pediatric ward of four urban hospitals in Italy. Eligible subjects were children with and without intellectual disability, from 4 to 17~years old, who needed venipuncture or intravenous cannulation for diagnosis or treatment. Use of topical anesthesia, distraction techniques, and physical or verbal comfort during procedures were recorded. Pain and anxiety scores were also recorded. Forty-seven cases and 94 controls were recruited. Three pain- and anxiety-relieving techniques were performed during the procedure in 12 (25\%) cases and in 10 controls (11\%); two techniques were performed in 23 (50\%) cases and in 26 (28\%) controls; 12 (25\%) cases and 52 (55\%) controls received only one.Conclusion: In this series, children with intellectual disability received significantly more relieving techniques, but experienced more pain and anxiety when compared to children without intellectual disability. What is Known: {\textbullet} Children with intellectual disability experience more episodes of pain than cognitively healthy ones, and almost 10\% of these episodes are due to medical procedures. What is New: {\textbullet} Children with intellectual disability despite receiving more relieving techniques during a needle-related procedure experienced more pain and anxiety when compared to healthy children.

}, keywords = {Adolescent, Anxiety, Child, Child, Preschool, Cohort Studies, Female, Humans, Intellectual Disability, Italy, Male, Pain Management, Pain Measurement, Pain, Procedural, Phlebotomy}, issn = {1432-1076}, doi = {10.1007/s00431-018-3237-4}, author = {Pascolo, Paola and Peri, Francesca and Montico, Marcella and Funaro, Mishelle and Parrino, Roberta and Vanadia, Francesca and Rusalen, Francesca and Vecchiato, Luca and Benini, Franca and Congedi, Sabrina and Barbi, Egidio and Cozzi, Giorgio} } @article {10446, title = {Non-invasive biomarkers of fetal brain development reflecting prenatal stress: An integrative multi-scale multi-species perspective on data collection and analysis.}, journal = {Neurosci Biobehav Rev}, year = {2018}, month = {2018 May 30}, abstract = {

Prenatal stress (PS) impacts early postnatal behavioural and cognitive development. This process of {\textquoteright}fetal programming{\textquoteright} is mediated by the effects of the prenatal experience on the developing hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). We derive a multi-scale multi-species approach to devising preclinical and clinical studies to identify early non-invasively available pre- and postnatal biomarkers of PS. The multiple scales include brain epigenome, metabolome, microbiome and the ANS activity gauged via an array of advanced non-invasively obtainable properties of fetal heart rate fluctuations. The proposed framework has the potential to reveal mechanistic links between maternal stress during pregnancy and changes across these physiological scales. Such biomarkers may hence be useful as early and non-invasive predictors of neurodevelopmental trajectories influenced by the PS as well as follow-up indicators of success of therapeutic interventions to correct such altered neurodevelopmental trajectories. PS studies must be conducted on multiple scales derived from concerted observations in multiple animal models and human cohorts performed in an interactive and iterative manner and deploying machine learning for data synthesis, identification and validation of the best non-invasive detection and follow-up biomarkers, a prerequisite for designing effective therapeutic interventions.

}, issn = {1873-7528}, doi = {10.1016/j.neubiorev.2018.05.026}, author = {Frasch, Martin G and Lobmaier, Silvia M and Stampalija, Tamara and Desplats, Paula and Pallar{\'e}s, Mar{\'\i}a Eugenia and Pastor, Ver{\'o}nica and Brocco, Marcela A and Wu, Hau-Tieng and Schulkin, Jay and Herry, Christophe L and Seely, Andrew J E and Metz, Gerlinde A S and Louzoun, Yoram and Antonelli, Marta C} } @article {10823, title = {Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0198166}, abstract = {

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Alcohol Drinking, Blood Pressure, Cohort Studies, Continental Population Groups, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, Young Adult}, issn = {1932-6203}, doi = {10.1371/journal.pone.0198166}, author = {Feitosa, Mary F and Kraja, Aldi T and Chasman, Daniel I and Sung, Yun J and Winkler, Thomas W and Ntalla, Ioanna and Guo, Xiuqing and Franceschini, Nora and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Marten, Jonathan and Musani, Solomon K and Li, Changwei and Bentley, Amy R and Brown, Michael R and Schwander, Karen and Richard, Melissa A and Noordam, Raymond and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Dorajoo, Rajkumar and Fisher, Virginia and Hartwig, Fernando P and Horimoto, Andrea R V R and Lohman, Kurt K and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Wojczynski, Mary K and Alver, Maris and Boissel, Mathilde and Cai, Qiuyin and Campbell, Archie and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Jackson, Anne U and K{\"a}h{\"o}nen, Mika and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Laguzzi, Federica and Luan, Jian{\textquoteright}an and Matoba, Nana and Nolte, Ilja M and Padmanabhan, Sandosh and Riaz, Muhammad and Rueedi, Rico and Robino, Antonietta and Said, M Abdullah and Scott, Robert A and Sofer, Tamar and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Varga, Tibor V and Vitart, Veronique and Wang, Yajuan and Ware, Erin B and Warren, Helen R and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Aung, Tin and Boerwinkle, Eric and Borecki, Ingrid and Broeckel, Ulrich and Brown, Morris and Brumat, Marco and Burke, Gregory L and Canouil, Micka{\"e}l and Chakravarti, Aravinda and Charumathi, Sabanayagam and Ida Chen, Yii-Der and Connell, John M and Correa, Adolfo and de Las Fuentes, Lisa and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Deng, Xuan and Ding, Jingzhong and Duan, Qing and Eaton, Charles B and Ehret, Georg and Eppinga, Ruben N and Evangelou, Evangelos and Faul, Jessica D and Felix, Stephan B and Forouhi, Nita G and Forrester, Terrence and Franco, Oscar H and Friedlander, Yechiel and Gandin, Ilaria and Gao, He and Ghanbari, Mohsen and Gigante, Bruna and Gu, C Charles and Gu, Dongfeng and Hagenaars, Saskia P and Hallmans, Goran and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Howard, Barbara V and Ikram, M Arfan and John, Ulrich and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Krieger, Jose E and Kritchevsky, Stephen B and Kubo, Michiaki and Kuusisto, Johanna and Lakka, Timo A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lewis, Cora E and Li, Yize and Lin, Shiow and Liu, Jianjun and Liu, Jingmin and Loh, Marie and Louie, Tin and M{\"a}gi, Reedik and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Momozawa, Yukihide and Nalls, Mike A and Nelson, Christopher P and Sotoodehnia, Nona and Norris, Jill M and O{\textquoteright}Connell, Jeff R and Palmer, Nicholette D and Perls, Thomas and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Poulter, Neil and Raffel, Leslie J and Raitakari, Olli T and Roll, Kathryn and Rose, Lynda M and Rosendaal, Frits R and Rotter, Jerome I and Schmidt, Carsten O and Schreiner, Pamela J and Schupf, Nicole and Scott, William R and Sever, Peter S and Shi, Yuan and Sidney, Stephen and Sims, Mario and Sitlani, Colleen M and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Stringham, Heather M and Tan, Nicholas Y Q and Tang, Hua and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Vollenweider, Peter and Waldenberger, Melanie and Wang, Lihua and Wang, Ya Xing and Wei, Wen Bin and Williams, Christine and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Deary, Ian J and Esko, T{\~o}nu and Farrall, Martin and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Jonas, Jost Bruno and Kamatani, Yoichiro and Kato, Norihiro and Kooner, Jaspal S and Kutalik, Zolt{\'a}n and Laakso, Markku and Laurie, Cathy C and Leander, Karin and Lehtim{\"a}ki, Terho and Study, Lifelines Cohort and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Polasek, Ozren and Porteous, David J and Rauramaa, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zheng, Wei and Bouchard, Claude and Christensen, Kaare and Evans, Michele K and Gudnason, Vilmundur and Horta, Bernardo L and Kardia, Sharon L R and Liu, Yongmei and Pereira, Alexandre C and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Gauderman, W James and Zhu, Xiaofeng and Mook-Kanamori, Dennis O and Fornage, Myriam and Rotimi, Charles N and Cupples, L Adrienne and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Kooperberg, Charles and Palmas, Walter and Rice, Kenneth and Morrison, Alanna C and Elliott, Paul and Caulfield, Mark J and Munroe, Patricia B and Rao, Dabeeru C and Province, Michael A and Levy, Daniel} } @article {10828, title = {Paediatric Home Artificial Nutrition in Italy: Report from 2016 Survey on Behalf of Artificial Nutrition Network of Italian Society for Gastroenterology, Hepatology and Nutrition (SIGENP).}, journal = {Nutrients}, volume = {10}, year = {2018}, month = {2018 Sep 16}, abstract = {

Home Artificial Nutrition (HAN) is a safe and efficacious technique that insures children{\textquoteright}s reintegration into the family, society and school. Epidemiological data on paediatric HAN in Italy are not available.

AIM: to detect the prevalence and incidence of Home Parenteral Nutrition (HPN) and Home Enteral Nutrition (HEN), either via tube or mouth, in Italy in 2016.

MATERIALS AND METHODS: a specific form was sent to all registered SIGENP members and investigators of local HAN centres, inviting them to provide the requested centre{\textquoteright}s data and demographics, underlying diseases and HAN characteristics of the patients.

RESULTS: we recorded 3403 Italian patients on HAN aged 0 to 19 years from 22 centres: 2277 HEN, 950 Oral Nutritional Supplements (ONS) and 179 HPN programs. The prevalence of HEN (205 pts/million inhabitants) and HPN (16 pts/million inhabitants) has dramatically increased in Italy in the last 9 years. Neurodisabling conditions were the first indication for HEN by tube or mouth while HPN is mainly requested in digestive disorders.

CONCLUSIONS: HAN is a widespread and rapidly growing treatment in Italy, as well as in other European countries. Awareness of its extent and characteristics helps improving HAN service and patients{\textquoteright} quality of life.

}, keywords = {Adolescent, Age Factors, Child, Child Nutritional Physiological Phenomena, Child, Preschool, Enteral Nutrition, Female, Health Care Surveys, Home Care Services, Humans, Infant, Infant, Newborn, Italy, Male, Nutritional Status, Parenteral Nutrition, Home, Pediatrics, Time Factors, Young Adult}, issn = {2072-6643}, doi = {10.3390/nu10091311}, author = {Lezo, Antonella and Capriati, Teresa and Spagnuolo, Maria Immacolata and Lacitignola, Laura and Goreva, Irina and Di Leo, Grazia and Cecchi, Nicola and Gandullia, Paolo and Amarri, Sergio and Forchielli, Maria Luisa and Dipasquale, Valeria and Parma, Barbara and Gatti, Simona and Ravaioli, Elisa and Salvatore, Silvia and Mainetti, Martina and Norsa, Lorenzo and Pellegrino, Maristella and Fornaro, Martina and Fiorito, Valentina and Lanari, Marcello and Giaquinto, Ester and Verduci, Elvira and Baldassarre, Maria Elisabetta and Diamanti, Antonella} } @article {10830, title = {Pathological Significance and Prognostic Value of Surfactant Protein D in Cancer.}, journal = {Front Immunol}, volume = {9}, year = {2018}, month = {2018}, pages = {1748}, abstract = {

Surfactant protein D (SP-D) is a pattern recognition molecule belonging to the Collectin (collagen-containing C-type lectin) family that has pulmonary as well as extra-pulmonary existence. In the lungs, it is a well-established opsonin that can agglutinate a range of microbes, and enhance their clearance phagocytosis and super-oxidative burst. It can interfere with allergen-IgE interaction and suppress basophil and mast cell activation. However, it is now becoming evident that SP-D is likely to be an innate immune surveillance molecule against tumor development. SP-D has been shown to induce apoptosis in sensitized eosinophils derived from allergic patients and a leukemic cell line p53 pathway. Recently, SP-D has been shown to suppress lung cancer progression interference with the epidermal growth factor signaling. In addition, a truncated form of recombinant human SP-D has been reported to induce apoptosis in pancreatic adenocarcinoma Fas-mediated pathway in a p53-independent manner. To further establish a correlation between SP-D presence/levels and normal and cancer tissues, we performed a bioinformatics analysis, using Oncomine dataset and the survival analysis platforms Kaplan-Meier plotter, to assess if SP-D can serve as a potential prognostic marker for human lung cancer, in addition to human gastric, breast, and ovarian cancers. We also analyzed immunohistochemically the presence of SP-D in normal and tumor human tissues. We conclude that (1) in the lung, gastric, and breast cancers, there is a lower expression of SP-D than normal tissues; (2) in ovarian cancer, there is a higher expression of SP-D than normal tissue; and (3) in lung cancer, the presence of SP-D could be associated with a favorable prognosis. On the contrary, at non-pulmonary sites such as gastric, breast, and ovarian cancers, the presence of SP-D could be associated with unfavorable prognosis. Correlation between the levels of SP-D and overall survival requires further investigation. Our analysis involves a large number of dataset; therefore, any trend observed is reliable. Despite apparent complexity within the results, it is evident that cancer tissues that produce less levels of SP-D compared to their normal tissue counterparts are probably less susceptible to SP-D-mediated immune surveillance mechanisms infiltrating immune cells.

}, issn = {1664-3224}, doi = {10.3389/fimmu.2018.01748}, author = {Mangogna, Alessandro and Belmonte, Beatrice and Agostinis, Chiara and Ricci, Giuseppe and Gulino, Alessandro and Ferrara, Ines and Zanconati, Fabrizio and Tripodo, Claudio and Romano, Federico and Kishore, Uday and Bulla, Roberta} } @article {10831, title = {Pharmacogenetics of treatments for inflammatory bowel disease.}, journal = {Expert Opin Drug Metab Toxicol}, volume = {14}, year = {2018}, month = {2018 Dec}, pages = {1209-1223}, abstract = {

INTRODUCTION: Inflammatory bowel disease is a chronic inflammation of the gut whose pathogenesis is still unclear. Although no curative therapy is currently available, a number of drugs are used in induction and maintenance therapy; however, for most of these drugs, a high inter-individual variability in response is observed. Among the factors of this variability, genetics plays an important role. Areas covered: This review summarizes the results of pharmacogenetic studies, considering the most important drugs used and in particular aminosalycilates, glucocorticoids, thiopurines, monoclonal antibodies and thalidomide. Most studies used a candidate gene approach, even if significant breakthroughs have been obtained recently from applying genome-wide studies. When available, also investigations considering epigenetics and pharmacogenetic dosing guidelines have been included. Expert opinion: Only for thiopurines, genetic markers identified as predictors of efficacy or adverse events have allowed the development of dosing guidelines. For the other drugs, encouraging results are available and great expectations rely on the study of epigenetics and integration with pharmacokinetic information, especially useful for biologics. However, to improve therapy of IBD patients with these drugs, for implementation in the clinics of pharmacogenetics, informatic clinical decision support systems and training about pharmacogenetics of health providers are needed.

}, keywords = {Dose-Response Relationship, Drug, Epigenesis, Genetic, Gastrointestinal Agents, Genetic Markers, Genetic Predisposition to Disease, Humans, Inflammatory Bowel Diseases, Pharmacogenetics}, issn = {1744-7607}, doi = {10.1080/17425255.2018.1551876}, author = {Lucaf{\`o}, Marianna and Franca, Raffaella and Selvestrel, Davide and Curci, Debora and Pugnetti, Letizia and Decorti, Giuliana and Stocco, Gabriele} } @article {10832, title = {Photobiomodulation at Multiple Wavelengths Differentially Modulates Oxidative Stress and .}, journal = {Oxid Med Cell Longev}, volume = {2018}, year = {2018}, month = {2018}, pages = {6510159}, abstract = {

Photobiomodulation (PBM) is emerging as an effective strategy for the management of multiple inflammatory conditions, including oral mucositis (OM) in cancer patients who receive chemotherapy or radiotherapy. Still, the poor understanding of the mechanisms by which the light interacts with biological tissues and the heterogeneity of light sources and protocols employed worldwide significantly limits its applicability. Reactive oxygen species (ROS) are massively generated during the early phases of OM and play a major role in the pathogenesis of inflammation in general. Here, we report the results of a clinical and experimental study, aimed at evaluating the effect of laser light at different wavelengths on oxidative stress in oncologic patients suffering from OM and in two cell types abundantly present within the inflamed oral mucosa, neutrophil polymorphonuclear (PMN) granulocytes, and keratinocytes. In addition to standard ROS detection methods, we exploited a roGFP2-Orp1 genetically encoded sensor, allowing specific, quantitative, and dynamic imaging of redox events in living cells in response to oxidative stress and PBM. We found that the various wavelengths differentially modulate ROS production. In particular, the 660 nm laser light increases ROS production when applied either before or after an oxidative stimulus. In contrast, the 970 nm laser light exerted a moderate antioxidant activity both in the saliva of OM patients and in both cell types. The most marked reduction in the levels of ROS was detected in cells exposed either to the 800 nm laser light or to the combination of the three wavelengths. Overall, our study demonstrates that PBM exerts different effects on the redox state of both PMNs and keratinocytes depending on the used wavelength and prompts the validation of a multiwavelength protocol in the clinical settings.

}, keywords = {Adult, Aged, Aged, 80 and over, Female, Humans, Keratinocytes, Lasers, Semiconductor, Low-Level Light Therapy, Male, Middle Aged, Neutrophils, Oxidation-Reduction, Oxidative Stress, Stomatitis}, issn = {1942-0994}, doi = {10.1155/2018/6510159}, author = {Rupel, Katia and Zupin, Luisa and Colliva, Andrea and Kamada, Anselmo and Poropat, Augusto and Ottaviani, Giulia and Gobbo, Margherita and Fanfoni, Lidia and Gratton, Rossella and Santoro, Massimo and Di Lenarda, Roberto and Biasotto, Matteo and Zacchigna, Serena} } @article {10834, title = {Potential use of MCR-ALS for the identification of coeliac-related biochemical changes in hyperspectral Raman maps from pediatric intestinal biopsies.}, journal = {Integr Biol (Camb)}, volume = {10}, year = {2018}, month = {2018 06 18}, pages = {356-363}, abstract = {

Raman hyperspectral imaging is an emerging practice in biological and biomedical research for label free analysis of tissues and cells. Using this method, both spatial distribution and spectral information of analyzed samples can be obtained. The current study reports the first Raman microspectroscopic characterisation of colon tissues from patients with Coeliac Disease (CD). The aim was to assess if Raman imaging coupled with hyperspectral multivariate image analysis is capable of detecting the alterations in the biochemical composition of intestinal tissues associated with CD. The analytical approach was based on a multi-step methodology: duodenal biopsies from healthy and coeliac patients were measured and processed with Multivariate Curve Resolution Alternating Least Squares (MCR-ALS). Based on the distribution maps and the pure spectra of the image constituents obtained from MCR-ALS, interesting biochemical differences between healthy and coeliac patients has been derived. Noticeably, a reduced distribution of complex lipids in the pericryptic space, and a different distribution and abundance of proteins rich in beta-sheet structures was found in CD patients. The output of the MCR-ALS analysis was then used as a starting point for two clustering algorithms (k-means clustering and hierarchical clustering methods). Both methods converged with similar results providing precise segmentation over multiple Raman images of studied tissues.

}, issn = {1757-9708}, doi = {10.1039/c8ib00028j}, author = {Fornasaro, Stefano and Vicario, Annalisa and De Leo, Luigina and Bonifacio, Alois and Not, Tarcisio and Sergo, Valter} } @article {10835, title = {PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 07 25}, pages = {2904}, abstract = {

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

}, keywords = {Atrial Function, Atrioventricular Node, Electrocardiography, Electrophysiological Phenomena, Female, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Mutation, Missense, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-018-04766-9}, author = {van Setten, Jessica and Brody, Jennifer A and Jamshidi, Yalda and Swenson, Brenton R and Butler, Anne M and Campbell, Harry and Del Greco, Fabiola M and Evans, Daniel S and Gibson, Quince and Gudbjartsson, Daniel F and Kerr, Kathleen F and Krijthe, Bouwe P and Lyytik{\"a}inen, Leo-Pekka and M{\"u}ller, Christian and M{\"u}ller-Nurasyid, Martina and Nolte, Ilja M and Padmanabhan, Sandosh and Ritchie, Marylyn D and Robino, Antonietta and Smith, Albert V and Steri, Maristella and Tanaka, Toshiko and Teumer, Alexander and Trompet, Stella and Ulivi, Sheila and Verweij, Niek and Yin, Xiaoyan and Arnar, David O and Asselbergs, Folkert W and Bader, Joel S and Barnard, John and Bis, Josh and Blankenberg, Stefan and Boerwinkle, Eric and Bradford, Yuki and Buckley, Brendan M and Chung, Mina K and Crawford, Dana and den Hoed, Marcel and Denny, Josh C and Dominiczak, Anna F and Ehret, Georg B and Eijgelsheim, Mark and Ellinor, Patrick T and Felix, Stephan B and Franco, Oscar H and Franke, Lude and Harris, Tamara B and Holm, Hilma and Ilaria, Gandin and Iorio, Annamaria and K{\"a}h{\"o}nen, Mika and Kolcic, Ivana and Kors, Jan A and Lakatta, Edward G and Launer, Lenore J and Lin, Honghuang and Lin, Henry J and Loos, Ruth J F and Lubitz, Steven A and Macfarlane, Peter W and Magnani, Jared W and Leach, Irene Mateo and Meitinger, Thomas and Mitchell, Braxton D and Munzel, Thomas and Papanicolaou, George J and Peters, Annette and Pfeufer, Arne and Pramstaller, Peter P and Raitakari, Olli T and Rotter, Jerome I and Rudan, Igor and Samani, Nilesh J and Schlessinger, David and Silva Aldana, Claudia T and Sinner, Moritz F and Smith, Jonathan D and Snieder, Harold and Soliman, Elsayed Z and Spector, Timothy D and Stott, David J and Strauch, Konstantin and Tarasov, Kirill V and Thorsteinsdottir, Unnur and Uitterlinden, Andr{\'e} G and Van Wagoner, David R and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Jan Westra, Harm and Wild, Philipp S and Zeller, Tanja and Alonso, Alvaro and Avery, Christy L and Bandinelli, Stefania and Benjamin, Emelia J and Cucca, Francesco and D{\"o}rr, Marcus and Ferrucci, Luigi and Gasparini, Paolo and Gudnason, Vilmundur and Hayward, Caroline and Heckbert, Susan R and Hicks, Andrew A and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and Lehtim{\"a}ki, Terho and Liu, Yongmei and Munroe, Patricia B and Parsa, Afshin and Polasek, Ozren and Psaty, Bruce M and Roden, Dan M and Schnabel, Renate B and Sinagra, Gianfranco and Stefansson, Kari and Stricker, Bruno H and van der Harst, Pim and van Duijn, Cornelia M and Wilson, James F and Gharib, Sina A and de Bakker, Paul I W and Isaacs, Aaron and Arking, Dan E and Sotoodehnia, Nona} } @article {10845, title = {Rothmund-Thomson Syndrome: Insights from New Patients on the Genetic Variability Underpinning Clinical Presentation and Cancer Outcome.}, journal = {Int J Mol Sci}, volume = {19}, year = {2018}, month = {2018 Apr 06}, abstract = {

Biallelic mutations in gene, a caretaker of the genome, cause Rothmund-Thomson type-II syndrome (RTS-II) and confer increased cancer risk if they damage the helicase domain. We describe five families exemplifying clinical and allelic heterogeneity of RTS-II, and report the effect of pathogenic variants by predictions and transcripts analyses. Complete phenotype of patients $\#$39 and $\#$42 whose affected siblings developed osteosarcoma correlates with their c.[1048_1049del], c.[1878+32_1878+55del] and c.[1568G>C;1573delT], c.[3021_3022del] variants which damage the helicase domain. Literature survey highlights enrichment of these variants affecting the helicase domain in patients with cancer outcome raising the issue of strict oncological surveillance. Conversely, patients $\#$29 and $\#$19 have a mild phenotype and carry, respectively, the unreported homozygous c.3265G>T and c.3054A>G variants, both sparing the helicase domain. Finally, despite matching several criteria for RTS clinical diagnosis, patient $\#$38 is heterozygous for c.2412_2414del; no pathogenic CNVs out of those evidenced by high-resolution CGH-array, emerged as contributors to her phenotype.

}, keywords = {Adolescent, Adult, Cell Line, Tumor, Child, Female, Homozygote, Humans, Male, Mutation, Pedigree, Phenotype, RecQ Helicases, Rothmund-Thomson Syndrome}, issn = {1422-0067}, doi = {10.3390/ijms19041103}, author = {Colombo, Elisa A and Locatelli, Andrea and Cubells S{\'a}nchez, Laura and Romeo, Sara and Elcioglu, Nursel H and Maystadt, Isabelle and Esteve Mart{\'\i}nez, Altea and Sironi, Alessandra and Fontana, Laura and Finelli, Palma and Gervasini, Cristina and Pecile, Vanna and Larizza, Lidia} } @article {10543, title = {Ultrasound-guided genitofemoral nerve block for inguinal hernia repair in the male adult: a randomized controlled pilot study.}, journal = {Minerva Anestesiol}, volume = {84}, year = {2018}, month = {2018 Feb}, pages = {189-195}, abstract = {

BACKGROUND: Ultrasound-guided (USG) ilioinguinal/iliohypogastric nerve (II/IHN) block is a widely validated anesthetic technique for inguinal herniorrhaphy. As the spermatic cord, scrotum, and adjacent thigh receive sensory innervation from the genital branch of genitofemoral nerve (GFN), the addition of GFN block has been suggested to improve the quality of perioperative anesthesia and analgesia. The aim of this study is to compare GFN block plus II/IHN block with II/IHN block alone for intraoperative anesthesia and post-operative pain management.

METHODS: We enrolled 80, ASA I-III, male adults scheduled for elective open herniorrhaphy. Patients were randomized to receive either USG II/IHN plus GFN block (Case Group) or USG II/IHN block alone (Control Group). The outcome measures were the assessment of postoperative VAS scores on coughing and the adequacy of anesthesia, measured with intraoperative requirement for extra local anesthetic (LA) infiltration and number of patients needing systemic sedation.

RESULTS: The requirement of intraoperative additional doses of LA was significantly lower in the Case Group (median LA volume administered by the surgeon: 13.8{\textpm}5.6 mL vs. 20.7{\textpm}9.1 mL, P<0.05). Two patients in the Control Group needed systemic sedation. VAS scores at 15 minutes, 30 minutes, 1 hour, 2 hours, pre-discharge, and 24 hours were significantly lower in the Case Group (P<0.005). Four cases of femoral nerve block were reported, three in the Control Group, one in the Case Group (2.2\% vs. 7.7\%, P>0.05).

CONCLUSIONS: The combination of GFN block and II/IHN block is associated with lower postoperative VAS scores and lower doses of intraoperative additional LA.

}, issn = {1827-1596}, doi = {10.23736/S0375-9393.17.11948-6}, author = {Frassanito, Luciano and Zanfini, Bruno A and Pitoni, Sara and Germini, Paolo and Del Vicario, Miryam and Draisci, Gaetano} } @article {10417, title = {An unusual unilateral breast enlargement in a prepubertal girl.}, journal = {Arch Dis Child}, volume = {103}, year = {2018}, month = {2018 May}, pages = {451}, issn = {1468-2044}, doi = {10.1136/archdischild-2017-313215}, author = {Pavan, Matteo and Faleschini, Elena and Tornese, Gianluca and Zandon{\`a}, Lorenzo and Ventura, Alessandro} } @article {10854, title = {What is known about deferasirox chelation therapy in pediatric HSCT recipients: two case reports of metabolic acidosis.}, journal = {Ther Clin Risk Manag}, volume = {14}, year = {2018}, month = {2018}, pages = {1649-1655}, abstract = {

To date, in pediatric field, various hematological malignancies are increasingly treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Iron overload and systemic siderosis often occur in this particular cohort of patients and are associated with poor prognosis. We describe herein the case of two allo-HSCT patients, on treatment with deferasirox; they showed histopathological elements compatible with venoocclusive disease or vanishing bile duct syndrome in ductopenic evolution before deferasirox started. The first patient developed drug-induced liver damage with metabolic acidosis and the second one a liver impairment with Fanconi syndrome. After withdrawing deferasirox treatment, both patients showed improvement. Measurements of drug plasma concentrations were performed by HPLC assay. The reduction and consequent disappearance of symptoms after the suspension of deferasirox substantiate its role in inducing hepatic damage, probably enabling the diagnosis of drug-induced liver damage. But the difficulties in diagnosing drug-related toxicity must be underlined, especially in compromised subjects. For these reasons, in patients requiring iron-chelating therapy, close and careful drug therapeutic monitoring is strongly recommended.

}, issn = {1176-6336}, doi = {10.2147/TCRM.S170761}, author = {Fucile, Carmen and Mattioli, Francesca and Marini, Valeria and Gregori, Massimo and Sonzogni, Aurelio and Martelli, Antonietta and Maximova, Natalia} } @article {10481, title = {1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 04 28}, pages = {45040}, abstract = {

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5\% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 {\texttimes} 10 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

}, keywords = {Computational Biology, Gene Frequency, Genetic Loci, Genome, Human, Genome-Wide Association Study, Genotyping Techniques, Humans, Kidney, Polymorphism, Single Nucleotide}, issn = {2045-2322}, doi = {10.1038/srep45040}, author = {Gorski, Mathias and van der Most, Peter J and Teumer, Alexander and Chu, Audrey Y and Li, Man and Mijatovic, Vladan and Nolte, Ilja M and Cocca, Massimiliano and Taliun, Daniel and Gomez, Felicia and Li, Yong and Tayo, Bamidele and Tin, Adrienne and Feitosa, Mary F and Aspelund, Thor and Attia, John and Biffar, Reiner and Bochud, Murielle and Boerwinkle, Eric and Borecki, Ingrid and Bottinger, Erwin P and Chen, Ming-Huei and Chouraki, Vincent and Ciullo, Marina and Coresh, Josef and Cornelis, Marilyn C and Curhan, Gary C and d{\textquoteright}Adamo, Adamo Pio and Dehghan, Abbas and Dengler, Laura and Ding, Jingzhong and Eiriksdottir, Gudny and Endlich, Karlhans and Enroth, Stefan and Esko, T{\~o}nu and Franco, Oscar H and Gasparini, Paolo and Gieger, Christian and Girotto, Giorgia and Gottesman, Omri and Gudnason, Vilmundur and Gyllensten, Ulf and Hancock, Stephen J and Harris, Tamara B and Helmer, Catherine and H{\"o}llerer, Simon and Hofer, Edith and Hofman, Albert and Holliday, Elizabeth G and Homuth, Georg and Hu, Frank B and Huth, Cornelia and Hutri-K{\"a}h{\"o}nen, Nina and Hwang, Shih-Jen and Imboden, Medea and Johansson, {\r A}sa and K{\"a}h{\"o}nen, Mika and K{\"o}nig, Wolfgang and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kumar, Ashish and Kutalik, Zolt{\'a}n and Lambert, Jean-Charles and Launer, Lenore J and Lehtim{\"a}ki, Terho and de Borst, Martin and Navis, Gerjan and Swertz, Morris and Liu, Yongmei and Lohman, Kurt and Loos, Ruth J F and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and McEvoy, Mark A and Meisinger, Christa and Meitinger, Thomas and Metspalu, Andres and Metzger, Marie and Mihailov, Evelin and Mitchell, Paul and Nauck, Matthias and Oldehinkel, Albertine J and Olden, Matthias and Wjh Penninx, Brenda and Pistis, Giorgio and Pramstaller, Peter P and Probst-Hensch, Nicole and Raitakari, Olli T and Rettig, Rainer and Ridker, Paul M and Rivadeneira, Fernando and Robino, Antonietta and Rosas, Sylvia E and Ruderfer, Douglas and Ruggiero, Daniela and Saba, Yasaman and Sala, Cinzia and Schmidt, Helena and Schmidt, Reinhold and Scott, Rodney J and Sedaghat, Sanaz and Smith, Albert V and Sorice, Rossella and Stengel, B{\'e}n{\'e}dicte and Stracke, Sylvia and Strauch, Konstantin and Toniolo, Daniela and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Viikari, Jorma S and V{\"o}lker, Uwe and Vollenweider, Peter and V{\"o}lzke, Henry and Vuckovic, Dragana and Waldenberger, Melanie and Jin Wang, Jie and Yang, Qiong and Chasman, Daniel I and Tromp, Gerard and Snieder, Harold and Heid, Iris M and Fox, Caroline S and K{\"o}ttgen, Anna and Pattaro, Cristian and B{\"o}ger, Carsten A and Fuchsberger, Christian} } @article {10549, title = {ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study.}, journal = {Ann Rheum Dis}, volume = {76}, year = {2017}, month = {2017 Oct}, pages = {1648-1656}, abstract = {

OBJECTIVES: To analyse the prevalence of mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study.

METHODS: Direct sequencing of was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor.

RESULTS: Biallelic homozygous or compound heterozygous mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect.

CONCLUSIONS: DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.

}, keywords = {Adenosine Deaminase, Adolescent, Age of Onset, Case-Control Studies, Child, Child, Preschool, DNA Mutational Analysis, Female, Heterozygote, Homozygote, Humans, Immunoglobulins, Immunosuppressive Agents, Infant, Intercellular Signaling Peptides and Proteins, Italy, Livedo Reticularis, Male, Pedigree, Polyarteritis Nodosa, Stroke, Thalidomide, Tumor Necrosis Factor-alpha, Young Adult}, issn = {1468-2060}, doi = {10.1136/annrheumdis-2016-210802}, author = {Caorsi, Roberta and Penco, Federica and Grossi, Alice and Insalaco, Antonella and Omenetti, Alessia and Alessio, Maria and Conti, Giovanni and Marchetti, Federico and Picco, Paolo and Tommasini, Alberto and Martino, Silvana and Malattia, Clara and Gallizi, Romina and Podda, Rosa Anna and Salis, Annalisa and Falcini, Fernanda and Schena, Francesca and Garbarino, Francesca and Morreale, Alessia and Pardeo, Manuela and Ventrici, Claudia and Passarelli, Chiara and Zhou, Qing and Severino, Mariasavina and Gandolfo, Carlo and Damonte, Gianluca and Martini, Alberto and Ravelli, Angelo and Aksentijevich, Ivona and Ceccherini, Isabella and Gattorno, Marco} } @article {8506, title = {Amniocentesis and chorionic villus sampling in HIV-infected pregnant women: a multicentre case series.}, journal = {BJOG}, volume = {124}, year = {2017}, month = {2017 Jul}, pages = {1218-1223}, abstract = {

OBJECTIVES: To assess in pregnant women with HIV the rates of amniocentesis and chorionic villus sampling (CVS), and the outcomes associated with such procedures.

DESIGN: Observational study. Data from the Italian National Program on Surveillance on Antiretroviral Treatment in Pregnancy were used.

SETTING: University and hospital clinics.

POPULATION: Pregnant women with HIV.

METHODS: Temporal trends were analysed by analysis of variance and by the Chi-square test for trend. Quantitative variables were compared by Student{\textquoteright}s t-test and categorical data by the Chi-square test, with odds ratios and 95\% confidence intervals calculated.

MAIN OUTCOME MEASURES: Rate of invasive testing, intrauterine death, HIV transmission.

RESULTS: Between 2001 and 2015, among 2065 pregnancies in women with HIV, 113 (5.5\%) had invasive tests performed. The procedures were conducted under antiretroviral treatment in 99 cases (87.6\%), with a significant increase over time in the proportion of tests performed under highly active antiretroviral therapy (HAART) (100\% in 2011-2015). Three intrauterine deaths were observed (2.6\%), and 14 pregnancies were terminated because of fetal anomalies. Among 96 live newborns, eight had no information available on HIV status. Among the remaining 88 cases with either amniocentesis (n = 75), CVS (n = 12), or both (n = 1), two HIV transmissions occurred (2.3\%). No HIV transmission occurred among the women who were on HAART at the time of invasive testing, and none after 2005.

CONCLUSIONS: The findings reinforce the assumption that invasive prenatal testing does not increase the risk of HIV vertical transmission among pregnant women under suppressive antiretroviral treatment.

TWEETABLE ABSTRACT: No HIV transmission occurred among women who underwent amniocentesis or CVS under effective anti-HIV regimens.

}, keywords = {Adult, Amniocentesis, Analysis of Variance, Anti-Retroviral Agents, Chi-Square Distribution, Chorionic Villi Sampling, Female, Fetal Death, HIV Infections, Humans, Infectious Disease Transmission, Vertical, Odds Ratio, Pregnancy, Pregnancy Complications, Infectious}, issn = {1471-0528}, doi = {10.1111/1471-0528.14183}, author = {Floridia, M and Masuelli, G and Meloni, A and Cetin, I and Tamburrini, E and Cavaliere, A F and Dalzero, S and Sansone, M and Alberico, S and Guerra, B and Spinillo, A and Chiad{\`o} Fiorio Tin, M and Ravizza, M} } @article {10572, title = { and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.}, journal = {J Am Soc Nephrol}, volume = {28}, year = {2017}, month = {2017 Mar}, pages = {981-994}, abstract = {

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7{\texttimes}10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4{\texttimes}10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

}, keywords = {Animals, Exome, Genetic Loci, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins, Son of Sevenless Proteins, Zebrafish}, issn = {1533-3450}, doi = {10.1681/ASN.2016020131}, author = {Li, Man and Li, Yong and Weeks, Olivia and Mijatovic, Vladan and Teumer, Alexander and Huffman, Jennifer E and Tromp, Gerard and Fuchsberger, Christian and Gorski, Mathias and Lyytik{\"a}inen, Leo-Pekka and Nutile, Teresa and Sedaghat, Sanaz and Sorice, Rossella and Tin, Adrienne and Yang, Qiong and Ahluwalia, Tarunveer S and Arking, Dan E and Bihlmeyer, Nathan A and B{\"o}ger, Carsten A and Carroll, Robert J and Chasman, Daniel I and Cornelis, Marilyn C and Dehghan, Abbas and Faul, Jessica D and Feitosa, Mary F and Gambaro, Giovanni and Gasparini, Paolo and Giulianini, Franco and Heid, Iris and Huang, Jinyan and Imboden, Medea and Jackson, Anne U and Jeff, Janina and Jhun, Min A and Katz, Ronit and Kifley, Annette and Kilpel{\"a}inen, Tuomas O and Kumar, Ashish and Laakso, Markku and Li-Gao, Ruifang and Lohman, Kurt and Lu, Yingchang and M{\"a}gi, Reedik and Malerba, Giovanni and Mihailov, Evelin and Mohlke, Karen L and Mook-Kanamori, Dennis O and Robino, Antonietta and Ruderfer, Douglas and Salvi, Erika and Schick, Ursula M and Schulz, Christina-Alexandra and Smith, Albert V and Smith, Jennifer A and Traglia, Michela and Yerges-Armstrong, Laura M and Zhao, Wei and Goodarzi, Mark O and Kraja, Aldi T and Liu, Chunyu and Wessel, Jennifer and Boerwinkle, Eric and Borecki, Ingrid B and Bork-Jensen, Jette and Bottinger, Erwin P and Braga, Daniele and Brandslund, Ivan and Brody, Jennifer A and Campbell, Archie and Carey, David J and Christensen, Cramer and Coresh, Josef and Crook, Errol and Curhan, Gary C and Cusi, Daniele and de Boer, Ian H and de Vries, Aiko P J and Denny, Joshua C and Devuyst, Olivier and Dreisbach, Albert W and Endlich, Karlhans and Esko, T{\~o}nu and Franco, Oscar H and Fulop, Tibor and Gerhard, Glenn S and Gl{\"u}mer, Charlotte and Gottesman, Omri and Grarup, Niels and Gudnason, Vilmundur and Hansen, Torben and Harris, Tamara B and Hayward, Caroline and Hocking, Lynne and Hofman, Albert and Hu, Frank B and Husemoen, Lise Lotte N and Jackson, Rebecca D and J{\o}rgensen, Torben and J{\o}rgensen, Marit E and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and K{\"o}nig, Wolfgang and Kooperberg, Charles and Kriebel, Jennifer and Launer, Lenore J and Lauritzen, Torsten and Lehtim{\"a}ki, Terho and Levy, Daniel and Linksted, Pamela and Linneberg, Allan and Liu, Yongmei and Loos, Ruth J F and Lupo, Antonio and Meisinger, Christine and Melander, Olle and Metspalu, Andres and Mitchell, Paul and Nauck, Matthias and N{\"u}rnberg, Peter and Orho-Melander, Marju and Parsa, Afshin and Pedersen, Oluf and Peters, Annette and Peters, Ulrike and Polasek, Ozren and Porteous, David and Probst-Hensch, Nicole M and Psaty, Bruce M and Qi, Lu and Raitakari, Olli T and Reiner, Alex P and Rettig, Rainer and Ridker, Paul M and Rivadeneira, Fernando and Rossouw, Jacques E and Schmidt, Frank and Siscovick, David and Soranzo, Nicole and Strauch, Konstantin and Toniolo, Daniela and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Velayutham, Dinesh and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wang, Jie Jin and Weir, David R and Witte, Daniel and Kuivaniemi, Helena and Fox, Caroline S and Franceschini, Nora and Goessling, Wolfram and K{\"o}ttgen, Anna and Chu, Audrey Y} } @article {10527, title = {Association between thyroid hormones and TRAIL.}, journal = {Clin Biochem}, volume = {50}, year = {2017}, month = {2017 Nov}, pages = {972-976}, abstract = {

INTRODUCTION: Recent studies suggest that a circulating protein called TRAIL (TNF-related apoptosis-inducing ligand) might have a role in the regulation of body weight and metabolism. Interestingly, thyroid hormones seem to increase TRAIL tissue expression. This study aimed at evaluating whether overt thyroid disorders affected circulating TRAIL levels.

METHODS: TRAIL circulating levels were measured in euthyroid, hyperthyroid, and hypothyroid patients before and after thyroid function normalization. Univariate and multivariate analyses were performed to evaluate the correlation between thyroid hormones and TRAIL. Then, the stimulatory effect of both triiodothyronine (T3) and thyroxine (T4) on TRAIL was evaluated in vitro on peripheral blood mononuclear cells.

RESULTS: Circulating levels of TRAIL significantly increased in hyperthyroid and decreased in hypothyroid patients as compared to controls. Once thyroid function was restored, TRAIL levels normalized. There was an independent association between TRAIL and both fT3 and fT4. Consistent with these findings, T3 and T4 stimulated TRAIL release in vitro.

CONCLUSION: Here we show that thyroid hormones are associated with TRAIL expression in vivo and stimulate TRAIL expression in vitro. Given the overlap between the metabolic effects of thyroid hormones and TRAIL, this work sheds light on the possibility that TRAIL might be one of the molecules mediating thyroid hormones peripheral effects.

}, keywords = {Aged, Female, Gene Expression Regulation, Humans, Hyperthyroidism, Hypothyroidism, Leukocytes, Mononuclear, Male, Middle Aged, Thyroxine, TNF-Related Apoptosis-Inducing Ligand, Triiodothyronine}, issn = {1873-2933}, doi = {10.1016/j.clinbiochem.2017.05.011}, author = {Bernardi, Stella and Bossi, Fleur and Toffoli, Barbara and Giudici, Fabiola and Bramante, Alessandra and Furlanis, Giulia and Stenner, Elisabetta and Secchiero, Paola and Zauli, Giorgio and Carretta, Renzo and Fabris, Bruno} } @article {10525, title = {Autoimmune neutropenia of childhood secondary to other autoimmune disorders: Data from the Italian neutropenia registry.}, journal = {Am J Hematol}, volume = {92}, year = {2017}, month = {2017 Sep}, pages = {E546-E549}, keywords = {Autoimmune Diseases, Child, Disease Susceptibility, Female, Humans, Immunoglobulins, Intravenous, Immunosuppressive Agents, Infant, Newborn, Infant, Premature, Infant, Premature, Diseases, Italy, Male, Neutropenia, Prevalence, Registries}, issn = {1096-8652}, doi = {10.1002/ajh.24803}, author = {Farruggia, Piero and Puccio, Giuseppe and Fioredda, Francesca and Lanza, Tiziana and Porretti, Laura and Ramenghi, Ugo and Barone, Angelica and Bonanomi, Sonia and Finocchi, Andrea and Ghilardi, Roberta and Ladogana, Saverio and Marra, Nicoletta and Martire, Baldassare and Notarangelo, Lucia Dora and Onofrillo, Daniela and Pillon, Marta and Russo, Giovanna and Lo Valvo, Laura and Serafinelli, Jessica and Tucci, Fabio and Zunica, Fiammetta and Verzegnassi, Federico and Dufour, Carlo} } @article {10524, title = {Child and Adolescent Health From 1990 to 2015: Findings From the Global Burden of Diseases, Injuries, and Risk Factors 2015 Study.}, journal = {JAMA Pediatr}, volume = {171}, year = {2017}, month = {2017 Jun 01}, pages = {573-592}, abstract = {

Importance: Comprehensive and timely monitoring of disease burden in all age groups, including children and adolescents, is essential for improving population health.

Objective: To quantify and describe levels and trends of mortality and nonfatal health outcomes among children and adolescents from 1990 to 2015 to provide a framework for policy discussion.

Evidence Review: Cause-specific mortality and nonfatal health outcomes were analyzed for 195 countries and territories by age group, sex, and year from 1990 to 2015 using standardized approaches for data processing and statistical modeling, with subsequent analysis of the findings to describe levels and trends across geography and time among children and adolescents 19 years or younger. A composite indicator of income, education, and fertility was developed (Socio-demographic Index [SDI]) for each geographic unit and year, which evaluates the historical association between SDI and health loss.

Findings: Global child and adolescent mortality decreased from 14.18 million (95\% uncertainty interval [UI], 14.09 million to 14.28 million) deaths in 1990 to 7.26 million (95\% UI, 7.14 million to 7.39 million) deaths in 2015, but progress has been unevenly distributed. Countries with a lower SDI had a larger proportion of mortality burden (75\%) in 2015 than was the case in 1990 (61\%). Most deaths in 2015 occurred in South Asia and sub-Saharan Africa. Global trends were driven by reductions in mortality owing to infectious, nutritional, and neonatal disorders, which in the aggregate led to a relative increase in the importance of noncommunicable diseases and injuries in explaining global disease burden. The absolute burden of disability in children and adolescents increased 4.3\% (95\% UI, 3.1\%-5.6\%) from 1990 to 2015, with much of the increase owing to population growth and improved survival for children and adolescents to older ages. Other than infectious conditions, many top causes of disability are associated with long-term sequelae of conditions present at birth (eg, neonatal disorders, congenital birth defects, and hemoglobinopathies) and complications of a variety of infections and nutritional deficiencies. Anemia, developmental intellectual disability, hearing loss, epilepsy, and vision loss are important contributors to childhood disability that can arise from multiple causes. Maternal and reproductive health remains a key cause of disease burden in adolescent females, especially in lower-SDI countries. In low-SDI countries, mortality is the primary driver of health loss for children and adolescents, whereas disability predominates in higher-SDI locations; the specific pattern of epidemiological transition varies across diseases and injuries.

Conclusions and Relevance: Consistent international attention and investment have led to sustained improvements in causes of health loss among children and adolescents in many countries, although progress has been uneven. The persistence of infectious diseases in some countries, coupled with ongoing epidemiologic transition to injuries and noncommunicable diseases, require all countries to carefully evaluate and implement appropriate strategies to maximize the health of their children and adolescents and for the international community to carefully consider which elements of child and adolescent health should be monitored.

}, keywords = {Adolescent, Adolescent Health, Age Factors, Cause of Death, Child, Child Health, Child Mortality, Disabled Children, Female, Global Burden of Disease, Global Health, Humans, Male, Pregnancy, Pregnancy Complications, Risk Factors, Sex Factors, Wounds and Injuries}, issn = {2168-6211}, doi = {10.1001/jamapediatrics.2017.0250}, author = {Kassebaum, Nicholas and Kyu, Hmwe Hmwe and Zoeckler, Leo and Olsen, Helen Elizabeth and Thomas, Katie and Pinho, Christine and Bhutta, Zulfiqar A and Dandona, Lalit and Ferrari, Alize and Ghiwot, Tsegaye Tewelde and Hay, Simon I and Kinfu, Yohannes and Liang, Xiaofeng and Lopez, Alan and Malta, Deborah Carvalho and Mokdad, Ali H and Naghavi, Mohsen and Patton, George C and Salomon, Joshua and Sartorius, Benn and Topor-Madry, Roman and Vollset, Stein Emil and Werdecker, Andrea and Whiteford, Harvey A and Abate, Kalkidan Hasen and Abbas, Kaja and Damtew, Solomon Abrha and Ahmed, Muktar Beshir and Akseer, Nadia and Al-Raddadi, Rajaa and Alemayohu, Mulubirhan Assefa and Altirkawi, Khalid and Abajobir, Amanuel Alemu and Amare, Azmeraw T and Antonio, Carl A T and Arnl{\"o}v, Johan and Artaman, Al and Asayesh, Hamid and Avokpaho, Euripide Frinel G Arthur and Awasthi, Ashish and Ayala Quintanilla, Beatriz Paulina and Bacha, Umar and Betsu, Balem Demtsu and Barac, Aleksandra and B{\"a}rnighausen, Till Winfried and Baye, Estifanos and Bedi, Neeraj and Bensenor, Isabela M and Berhane, Adugnaw and Bernabe, Eduardo and Bernal, Oscar Alberto and Beyene, Addisu Shunu and Biadgilign, Sibhatu and Bikbov, Boris and Boyce, Cheryl Anne and Brazinova, Alexandra and Hailu, Gessessew Bugssa and Carter, Austin and Casta{\~n}eda-Orjuela, Carlos A and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and Charlson, Fiona J and Chitheer, Abdulaal A and Choi, Jee-Young Jasmine and Ciobanu, Liliana G and Crump, John and Dandona, Rakhi and Dellavalle, Robert P and Deribew, Amare and deVeber, Gabrielle and Dicker, Daniel and Ding, Eric L and Dubey, Manisha and Endries, Amanuel Yesuf and Erskine, Holly E and Faraon, Emerito Jose Aquino and Faro, Andre and Farzadfar, Farshad and Fernandes, Joao C and Fijabi, Daniel Obadare and Fitzmaurice, Christina and Fleming, Thomas D and Flor, Luisa Sorio and Foreman, Kyle J and Franklin, Richard C and Fraser, Maya S and Frostad, Joseph J and Fullman, Nancy and Gebregergs, Gebremedhin Berhe and Gebru, Alemseged Aregay and Geleijnse, Johanna M and Gibney, Katherine B and Gidey Yihdego, Mahari and Ginawi, Ibrahim Abdelmageem Mohamed and Gishu, Melkamu Dedefo and Gizachew, Tessema Assefa and Glaser, Elizabeth and Gold, Audra L and Goldberg, Ellen and Gona, Philimon and Goto, Atsushi and Gugnani, Harish Chander and Jiang, Guohong and Gupta, Rajeev and Tesfay, Fisaha Haile and Hankey, Graeme J and Havmoeller, Rasmus and Hijar, Martha and Horino, Masako and Hosgood, H Dean and Hu, Guoqing and Jacobsen, Kathryn H and Jakovljevic, Mihajlo B and Jayaraman, Sudha P and Jha, Vivekanand and Jibat, Tariku and Johnson, Catherine O and Jonas, Jost and Kasaeian, Amir and Kawakami, Norito and Keiyoro, Peter N and Khalil, Ibrahim and Khang, Young-Ho and Khubchandani, Jagdish and Ahmad Kiadaliri, Aliasghar A and Kieling, Christian and Kim, Daniel and Kissoon, Niranjan and Knibbs, Luke D and Koyanagi, Ai and Krohn, Kristopher J and Kuate Defo, Barthelemy and Kucuk Bicer, Burcu and Kulikoff, Rachel and Kumar, G Anil and Lal, Dharmesh Kumar and Lam, Hilton Y and Larson, Heidi J and Larsson, Anders and Laryea, Dennis Odai and Leung, Janni and Lim, Stephen S and Lo, Loon-Tzian and Lo, Warren D and Looker, Katharine J and Lotufo, Paulo A and Magdy Abd El Razek, Hassan and Malekzadeh, Reza and Markos Shifti, Desalegn and Mazidi, Mohsen and Meaney, Peter A and Meles, Kidanu Gebremariam and Memiah, Peter and Mendoza, Walter and Abera Mengistie, Mubarek and Mengistu, Gebremichael Welday and Mensah, George A and Miller, Ted R and Mock, Charles and Mohammadi, Alireza and Mohammed, Shafiu and Monasta, Lorenzo and Mueller, Ulrich and Nagata, Chie and Naheed, Aliya and Nguyen, Grant and Nguyen, Quyen Le and Nsoesie, Elaine and Oh, In-Hwan and Okoro, Anselm and Olusanya, Jacob Olusegun and Olusanya, Bolajoko O and Ortiz, Alberto and Paudel, Deepak and Pereira, David M and Perico, Norberto and Petzold, Max and Phillips, Michael Robert and Polanczyk, Guilherme V and Pourmalek, Farshad and Qorbani, Mostafa and Rafay, Anwar and Rahimi-Movaghar, Vafa and Rahman, Mahfuzar and Rai, Rajesh Kumar and Ram, Usha and Rankin, Zane and Remuzzi, Giuseppe and Renzaho, Andre M N and Roba, Hirbo Shore and Rojas-Rueda, David and Ronfani, Luca and Sagar, Rajesh and Sanabria, Juan Ramon and Kedir Mohammed, Muktar Sano and Santos, Itamar S and Satpathy, Maheswar and Sawhney, Monika and Sch{\"o}ttker, Ben and Schwebel, David C and Scott, James G and Sepanlou, Sadaf G and Shaheen, Amira and Shaikh, Masood Ali and She, June and Shiri, Rahman and Shiue, Ivy and Sigfusdottir, Inga Dora and Singh, Jasvinder and Silpakit, Naris and Smith, Alison and Sreeramareddy, Chandrashekhar and Stanaway, Jeffrey D and Stein, Dan J and Steiner, Caitlyn and Sufiyan, Muawiyyah Babale and Swaminathan, Soumya and Tabar{\'e}s-Seisdedos, Rafael and Tabb, Karen M and Tadese, Fentaw and Tavakkoli, Mohammad and Taye, Bineyam and Teeple, Stephanie and Tegegne, Teketo Kassaw and Temam Shifa, Girma and Terkawi, Abdullah Sulieman and Thomas, Bernadette and Thomson, Alan J and Tobe-Gai, Ruoyan and Tonelli, Marcello and Tran, Bach Xuan and Troeger, Christopher and Ukwaja, Kingsley N and Uthman, Olalekan and Vasankari, Tommi and Venketasubramanian, Narayanaswamy and Vlassov, Vasiliy Victorovich and Weiderpass, Elisabete and Weintraub, Robert and Gebrehiwot, Solomon Weldemariam and Westerman, Ronny and Williams, Hywel C and Wolfe, Charles D A and Woodbrook, Rachel and Yano, Yuichiro and Yonemoto, Naohiro and Yoon, Seok-Jun and Younis, Mustafa Z and Yu, Chuanhua and Zaki, Maysaa El Sayed and Zegeye, Elias Asfaw and Zuhlke, Liesl Joanna and Murray, Christopher J L and Vos, Theo} } @article {10482, title = {Circulating osteoprotegerin is associated with chronic kidney disease in hypertensive patients.}, journal = {BMC Nephrol}, volume = {18}, year = {2017}, month = {2017 Jul 06}, pages = {219}, abstract = {

BACKGROUND: Osteoprotegerin (OPG) is a glycoprotein that plays an important regulatory role in the skeletal, vascular, and immune system. It has been shown that OPG predicts chronic kidney disease (CKD) in diabetic patients. We hypothesized that OPG could be a risk marker of CKD development also in non-diabetic hypertensive patients.

METHODS: A case-control study was carried out to measure circulating OPG levels in 42 hypertensive patients with CKD and in 141 hypertensive patients without CKD. A potential relationship between OPG and the presence of CKD was investigated and a receiver-operating characteristic (ROC) curve was designed thereafter to identify a cut-off value of OPG that best explained the presence of CKD. Secondly, to evaluate whether OPG increase could affect the kidney, 18 C57BL/6J mice were randomized to be treated with saline or recombinant OPG every 3~weeks for 12~weeks.

RESULTS: Circulating OPG levels were significantly higher in hypertensive patients with CKD, and there was a significant inverse association between OPG and renal function, that was independent from other variables. ROC analysis showed that OPG levels had a high statistically predictive value on CKD in hypertensive patients, which was greater than that of hypertension. The OPG best cut-off value associated with CKD was 1109.19~ng/L. In the experimental study, OPG delivery significantly increased the gene expression of pro-inflammatory and pro-fibrotic mediators, as well as the glomerular nitrosylation of proteins.

CONCLUSIONS: This study shows that OPG is associated with CKD in hypertensive patients, where it might have a higher predictive value than that of hypertension for CKD development. Secondly, we found that OPG delivery significantly increased the expression of molecular pathways involved in kidney damage. Further longitudinal studies are needed not only to evaluate whether OPG predicts CKD development but also to clarify whether OPG should be considered a risk factor for CKD.

}, keywords = {Aged, Animals, Biomarkers, Case-Control Studies, Female, Follow-Up Studies, Humans, Hypertension, Male, Mice, Mice, Inbred C57BL, Middle Aged, Osteoprotegerin, Random Allocation, Renal Insufficiency, Chronic}, issn = {1471-2369}, doi = {10.1186/s12882-017-0625-3}, author = {Bernardi, Stella and Toffoli, Barbara and Bossi, Fleur and Candido, Riccardo and Stenner, Elisabetta and Carretta, Renzo and Barbone, Fabio and Fabris, Bruno} } @article {10474, title = {Cubosomes for in vivo fluorescence lifetime imaging.}, journal = {Nanotechnology}, volume = {28}, year = {2017}, month = {2017 Feb 03}, pages = {055102}, abstract = {

Herein we provided the first proof of principle for in vivo fluorescence optical imaging application using monoolein-based cubosomes in a healthy mouse animal model. This formulation, administered at a non-cytotoxic concentration, was capable of providing both exogenous contrast for NIR fluorescence imaging with very high efficiency and chemospecific information upon lifetime analysis. Time-resolved measurements of fluorescence after the intravenous injection of cubosomes revealed that the dye rapidly accumulated mainly in the liver, while lifetimes profiles obtained in vivo allowed for discriminating between free dye or dye embedded within the cubosome nanostructure after injection.

}, keywords = {Animals, Carbocyanines, Cell Survival, Drug Compounding, Erythrocytes, Female, Fluorescent Dyes, Glycerides, Humans, Injections, Intravenous, Liposomes, Liver, Mice, Mice, Inbred BALB C, Nanoparticles, NIH 3T3 Cells, Optical Imaging, Particle Size, Spectroscopy, Near-Infrared, Time-Lapse Imaging}, issn = {1361-6528}, doi = {10.1088/1361-6528/28/5/055102}, author = {Biffi, Stefania and Andolfi, Laura and Caltagirone, Claudia and Garrovo, Chiara and Falchi, Angela M and Lippolis, Vito and Lorenzon, Andrea and Macor, Paolo and Meli, Valeria and Monduzzi, Maura and Obiols-Rabasa, Marc and Petrizza, Luca and Prodi, Luca and Rosa, Antonella and Schmidt, Judith and Talmon, Yeshayahu and Murgia, Sergio} } @article {10539, title = {Diagnosis and management of newly diagnosed childhood autoimmune haemolytic anaemia. Recommendations from the Red Cell Study Group of the Paediatric Haemato-Oncology Italian Association.}, journal = {Blood Transfus}, volume = {15}, year = {2017}, month = {2017 May}, pages = {259-267}, abstract = {

Autoimmune haemolytic anaemia is an uncommon disorder to which paediatric haematology centres take a variety of diagnostic and therapeutic approaches. The Red Cell Working Group of the Italian Association of Paediatric Onco-haematology (Associazione Italiana di Ematologia ed Oncologia Pediatrica, AIEOP) developed this document in order to collate expert opinions on the management of newly diagnosed childhood autoimmune haemolytic anaemia.The diagnostic process includes the direct and indirect antiglobulin tests; recommendations are given regarding further diagnostic tests, specifically in the cases that the direct and indirect antiglobulin tests are negative. Clear-cut definitions of clinical response are stated. Specific recommendations for treatment include: dosage of steroid therapy and tapering modality for warm autoimmune haemolytic anaemia; the choice of rituximab as first-line therapy for the rare primary transfusion-dependent cold autoimmune haemolytic anaemia; the indications for supportive therapy; the need for switching to second-line therapy. Each statement is provided with a score expressing the level of appropriateness and the agreement among participants.

}, keywords = {Anemia, Hemolytic, Autoimmune, Blood Transfusion, Child, Coombs Test, Disease Management, Hematology, Humans, Immunoglobulin M, Italy, Pediatrics, Societies, Medical, Steroids}, issn = {1723-2007}, doi = {10.2450/2016.0072-16}, author = {Ladogana, Saverio and Maruzzi, Matteo and Samperi, Piera and Perrotta, Silverio and Del Vecchio, Giovanni C and Notarangelo, Lucia D and Farruggia, Piero and Verzegnassi, Federico and Masera, Nicoletta and Saracco, Paola and Fasoli, Silvia and Miano, Maurizio and Girelli, Gabriella and Barcellini, Wilma and Zanella, Alberto and Russo, Giovanna} } @article {10497, title = {Dynamic quadripolar radiofrequency treatment of vaginal laxity/menopausal vulvo-vaginal atrophy: 12-month efficacy and safety.}, journal = {Minerva Ginecol}, volume = {69}, year = {2017}, month = {2017 Aug}, pages = {342-349}, abstract = {

BACKGROUND: Twelve-month extension of a previous spontaneous exploratory study investigating safety and efficacy of a new low-energy dynamic quadripolar radiofrequency (DQRF) device in: A) premenopausal women with symptoms of vaginal laxity, with special reference to dysuria, urinary incontinence and unsatisfactory sexual life (vaginal laxity arm of the study); B) postmenopausal women with vulvovaginal atrophy/genitourinary syndrome of menopause (VVA/GSM) and VVA/GSM-related symptoms (VVA/GSM arm of the study). DQRF treatment schedule in both study arms: 4 to 6 procedures of 15 to 20 min every 14 days (vaginal laxity, range 12-17 days; VVA/GSM, range 13-16). Operative temperatures in vaginal target tissues during procedure: vaginal laxity, 42 {\textdegree}C (range 40-43 {\textdegree}C); VVA/GSM, 40 {\textdegree}C (range 40-42 {\textdegree}C).

METHODS: In the vaginal laxity arm of the study, 25 women with subjective sensation of vaginal introital laxity (very to slightly loose). Assessment of urinary incontinence, satisfaction with sexual relationship and contribution of pelvic organ prolapse: Vaginal Laxity Questionnaire (VLQ, Italian certified translation) and short form of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12, Italian certified translation). Further evaluation of sexual gratification: Sexual Satisfaction Questionnaire (SSQ). In the VVA/GSM arm of the study, 32 women with objective evidence of VVA and vaginal dryness and/or dyspareunia as most bothersome symptoms. Assessment of VVA/GSM symptoms and overall satisfaction with sexual life: specifically designed 10-cm visual analogue scales.

RESULTS: All 4 to 6 planned DQRF sessions were well tolerated in both the vaginal laxity and VVA/GSM arms of the study, with no troubling pain, thermal injury or other immediate adverse effects during all the procedures. All screened women completed the planned DQRF treatment sessions in both arms of the extension study. There was no participant attrition with only a few occasionally missing visits over the 12-month follow-up period. Improvements were rapid in self-perception of introital looseness and related symptoms like dysuria/urinary incontinence and unrewarding sexual relationship (vaginal laxity patients) and atrophy-related symptoms including painful and unsatisfactory sexual activity (VVA/GSM patients). Participating women consistently reported wide-spectrum strong clinical improvements by the end of the planned DQRF sessions. Clinical improvements remained steady for the whole follow-up period in postmenopausal women; a statistically non-significant tendency to slight deterioration in VLQ, PISQ-12 and SSQ mean scores was detected after 6 to 9 months of follow-up in the vaginal laxity arm of the study.

CONCLUSIONS: Safety was excellent during all DQRF procedures and over the 12 months following the end of the treatment sessions. VLQ, PISQ-12 and SSQ scores (women with vaginal laxity), VAS self-evaluation of VVA/GSM symptoms and overall satisfaction with sexual life (women with VVA/GSM symptoms) improved rapidly, reaching almost normal levels by the last DQRF session and suggesting rapid, but also persistent, vaginal rejuvenation in both indications. A late tendency to some slight deterioration in women treated for vaginal laxity suggests such women might benefit from new DQRF treatments 6 to 9 months after the previous cycle.

}, keywords = {Adult, Atrophy, Dyspareunia, Electric Stimulation Therapy, Female, Follow-Up Studies, Humans, Italy, Middle Aged, Orgasm, Patient Satisfaction, Pelvic Organ Prolapse, Postmenopause, Premenopause, Sexual Behavior, Surveys and Questionnaires, Time Factors, Treatment Outcome, Urinary Incontinence, Vagina, Vaginal Diseases, Vulva}, issn = {1827-1650}, doi = {10.23736/S0026-4784.17.04072-2}, author = {Vicariotto, Franco and De Seta, Francesco and Faoro, Valentina and Raichi, Mauro} } @article {10514, title = {Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations.}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {2017 06 23}, pages = {15927}, abstract = {

The genetic features of isolated populations can boost power in complex-trait association studies, and an in-depth understanding of how their genetic variation has been shaped by their demographic history can help leverage these advantageous characteristics. Here, we perform a comprehensive investigation using 3,059 newly generated low-depth whole-genome sequences from eight European isolates and two matched general populations, together with published data from the 1000 Genomes Project and UK10K. Sequencing data give deeper and richer insights into population demography and genetic characteristics than genotype-chip data, distinguishing related populations more effectively and allowing their functional variants to be studied more fully. We demonstrate relaxation of purifying selection in the isolates, leading to enrichment of rare and low-frequency functional variants, using novel statistics, DVxy and SVxy. We also develop an isolation-index (Isx) that predicts the overall level of such key genetic characteristics and can thus help guide population choice in future complex-trait association studies.

}, keywords = {European Continental Ancestry Group, Gene Frequency, Genetic Variation, Genetics, Population, Genome, Human, Humans, Polymorphism, Single Nucleotide, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/ncomms15927}, author = {Xue, Yali and Mezzavilla, Massimo and Haber, Marc and McCarthy, Shane and Chen, Yuan and Narasimhan, Vagheesh and Gilly, Arthur and Ayub, Qasim and Colonna, Vincenza and Southam, Lorraine and Finan, Christopher and Massaia, Andrea and Chheda, Himanshu and Palta, Priit and Ritchie, Graham and Asimit, Jennifer and Dedoussis, George and Gasparini, Paolo and Palotie, Aarno and Ripatti, Samuli and Soranzo, Nicole and Toniolo, Daniela and Wilson, James F and Durbin, Richard and Tyler-Smith, Chris and Zeggini, Eleftheria} } @article {10460, title = {Epratuzumab and Blinatumomab as Therapeutic Antibodies for Treatment of Pediatric Acute Lymphoblastic Leukemia: Current Status and Future Perspectives.}, journal = {Curr Med Chem}, volume = {24}, year = {2017}, month = {2017}, pages = {1050-1065}, abstract = {

BACKGROUND: More than 85\% of children affected by acute lymphoblastic leukemia (ALL) are successfully treated; however relapse remains a remarkable clinical concern, with 50-60\% of relapsing patients facing a fatal outcome. Management of relapsed patients includes standardized intensive risk-adapted regimens based on conventional drugs, and hematopoietic stem cells transplantation for patients with unfavourable features. Biological drugs, in particular the monoclonal antibody epratuzumab and the bi-functional recombinant single chain peptide blinatumomab, have been recently recognized as novel potential agents to be integrated in salvage ALL therapy to further improve rescue outcome.

METHODS: A systematic search of peer-reviewed scientific literature and clinical trials in public databases has been carried out. Both clinical and pre-clinical studies have been included to summarize recent evidence on epratuzumab and blinatumomab for salvage ALL therapy.

RESULTS: Sixty-two papers and 25 clinical trials were included. Although not all patients responded properly to these agents, their use in relapsed and refractory pediatric ALL seems promising.

CONCLUSION: Phase 3 studies have recently begun and more consistent results about epratuzumab and blinatumomab safety and efficacy in comparison to conventional therapies are expected in the next years. Epratuzumab seems safe in the dosing scheme proposed in ALL, but its efficacy over the conventional chemotherapy is still questionable. Blinatumomab has shown promising results in high risk cases such as elder adult patients and conclusive studies on pediatric ALL are needed. Patient inter-individual variability to these agents has not been investigated in depth, but this issue needs to be addressed, in particular for blinatumomab.

}, keywords = {Antibodies, Bispecific, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Child, Clinical Trials as Topic, Half-Life, Humans, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Sialic Acid Binding Ig-like Lectin 2}, issn = {1875-533X}, doi = {10.2174/0929867324666170113105733}, author = {Franca, Raffaella and Favretto, Diego and Granzotto, Marilena and Decorti, Giuliana and Rabusin, Marco and Stocco, Gabriele} } @article {10540, title = {Essure Permanent Birth Control, Effectiveness and Safety: An~Italian 11-Year Survey.}, journal = {J Minim Invasive Gynecol}, volume = {24}, year = {2017}, month = {2017 May - Jun}, pages = {640-645}, abstract = {

STUDY OBJECTIVE: To describe safety, tolerability, and effectiveness results through a minimum 2-year follow-up of patients who underwent permanent sterilization with the Essure insert.

DESIGN: A retrospective multicenter study (Canadian Task Force classification II2).

SETTING: Seven general hospitals and 4 clinical teaching centers in Italy.

PATIENTS: A total of 1968 women, mean age 39.5~years (range, 23-48~years) who underwent office hysteroscopic sterilization using the Essure insert between April 1, 2003, and December 30,~2014.

INTERVENTION: The women underwent office hysteroscopic bilateral Essure insert placement, with satisfactory device location and tube occlusion based on hysterosalpingography or hysterosalpingo-contrast sonography (HyCoSy).

MEASUREMENTS AND MAIN RESULTS: Placement rate, successful bilateral tubal occlusion, perioperative adverse events, early postoperative (during the first 3~months of follow-up), and late complications were evaluated. Satisfactory insertion was accomplished in 97.2\% of women and, in 4, perforation and 1 expulsion were detected during hysterosalpingography. Three unintended pregnancies occurred before the 3-month confirmation test. Two pregnancies were reported among women relying on the Essure inserts. Postprocedure pain was minimal and brief; in 9 women, pelvic pain became intractable, necessitating removal of the devices via laparoscopy. On telephone interviews, overall satisfaction was rated as "very satisfied" by the majority of women (97.6\%), and no long-term adverse events were reported.

CONCLUSION: The findings from this extended Italian survey further support the effectiveness, tolerability, and satisfaction of Essure hysteroscopic sterilization when motivated women are selected and well informed of the potential risks of the device. Moreover, the results do not demonstrate an increased incidence of complications and pregnancies associated with long-term Essure use. Patients with a known hypersensitivity to nickel may be less suitable candidates for the Essure insert.

}, keywords = {Adult, Fallopian Tubes, Female, Follow-Up Studies, Humans, Hypersensitivity, Hysterosalpingography, Hysteroscopy, Italy, Laparoscopy, Middle Aged, Nickel, Pain, Pregnancy, Pregnancy, Unplanned, Retrospective Studies, Sterilization, Reproductive, Sterilization, Tubal, Surveys and Questionnaires, Young Adult}, issn = {1553-4669}, doi = {10.1016/j.jmig.2017.02.004}, author = {Franchini, Mario and Zizolfi, Brunella and Coppola, Carmela and Bergamini, Valentino and Bonin, Cecilia and Borsellino, Giovanni and Busato, Enrico and Calabrese, Stefania and Calzolari, Stefano and Fantin, Gian Piero and Giarr{\`e}, Giovanna and Litta, Piero and Luerti, Massimo and Mangino, Francesco Paolo and Marchino, Gian Luigi and Molinari, Maria Antonietta and Scatena, Elisa and Scrimin, Federica and Telloli, Paolo and Di Spiezio Sardo, Attilio} } @article {10584, title = {Fetal monitoring indications for delivery and 2-year outcome in 310 infants with fetal growth restriction delivered before 32 weeks{\textquoteright} gestation in the TRUFFLE study.}, journal = {Ultrasound Obstet Gynecol}, volume = {50}, year = {2017}, month = {2017 Sep}, pages = {347-352}, abstract = {

OBJECTIVE: In the TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe) study on the outcome of early fetal growth restriction, women were allocated to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate (FHR) short-term variation (STV) on cardiotocography (CTG); (2) early changes in fetal ductus venosus (DV) waveform (DV-p95); and (3) late changes in fetal DV waveform (DV-no-A). However, many infants per monitoring protocol were delivered because of safety-net criteria, for maternal or other fetal indications, or after 32 weeks of gestation when the protocol was no longer applied. The objective of the present posthoc subanalysis was to investigate the indications for delivery in relation to 2-year outcome in infants delivered before 32 weeks to further refine management proposals.

METHODS: We included all 310 cases of the TRUFFLE study with known outcome at 2 years{\textquoteright} corrected age and seven fetal deaths, excluding seven cases with inevitable perinatal death. Data were analyzed according to the allocated fetal monitoring strategy in combination with the indication for delivery.

RESULTS: Overall, only 32\% of liveborn infants were delivered according to the specified monitoring parameter for indication for delivery; 38\% were delivered because of safety-net criteria, 15\% for other fetal reasons and 15\% for maternal reasons. In the CTG-STV group, 51\% of infants were delivered because of reduced STV. In the DV-p95 group, 34\% of infants were delivered because of abnormal DV and, in the DV-no-A group, only 10\% of infants were delivered accordingly. The majority of infants in the DV groups were delivered for the safety-net criterion of spontaneous decelerations in FHR. Two-year intact survival was highest in the DV groups combined compared with the CTG-STV group (P = 0.05 for live births only, P = 0.21 including fetal death), with no difference between DV groups. A poorer outcome in the CTG-STV group was restricted to infants delivered because of FHR decelerations in the safety-net subgroup. Infants delivered because of maternal reasons had the highest birth weight and a non-significantly higher intact survival.

CONCLUSIONS: In this subanalysis of infants delivered before 32 weeks, the majority were delivered for reasons other than the allocated monitoring strategy indication. Since, in the DV group, CTG-STV criteria were used as a safety net but in the CTG-STV group, no DV safety-net criteria were applied, we speculate that the slightly poorer outcome in the CTG-STV group might be explained by the absence of DV data. The optimal timing of delivery of fetuses with early intrauterine growth restriction may therefore be best determined by monitoring them longitudinally, with both DV and CTG monitoring. Copyright {\textcopyright} 2016 ISUOG. Published by John Wiley \& Sons Ltd.

}, keywords = {Cardiotocography, Delivery, Obstetric, Female, Fetal Growth Retardation, Fetal Monitoring, Fetus, Gestational Age, Humans, Infant, Newborn, Male, Netherlands, Pregnancy, Pregnancy Outcome, Pulsatile Flow, Survival Analysis, Ultrasonography, Prenatal, Umbilical Arteries}, issn = {1469-0705}, doi = {10.1002/uog.17361}, author = {Visser, G H A and Bilardo, C M and Derks, J B and Ferrazzi, E and Fratelli, N and Frusca, T and Ganzevoort, W and Lees, C C and Napolitano, R and Todros, T and Wolf, H and Hecher, K} } @article {10511, title = {Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Mar}, pages = {403-415}, abstract = {

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

}, keywords = {Adult, Blood Pressure, Cardiovascular Diseases, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.3768}, author = {Warren, Helen R and Evangelou, Evangelos and Cabrera, Claudia P and Gao, He and Ren, Meixia and Mifsud, Borbala and Ntalla, Ioanna and Surendran, Praveen and Liu, Chunyu and Cook, James P and Kraja, Aldi T and Drenos, Fotios and Loh, Marie and Verweij, Niek and Marten, Jonathan and Karaman, Ibrahim and Lepe, Marcelo P Segura and O{\textquoteright}Reilly, Paul F and Knight, Joanne and Snieder, Harold and Kato, Norihiro and He, Jiang and Tai, E Shyong and Said, M Abdullah and Porteous, David and Alver, Maris and Poulter, Neil and Farrall, Martin and Gansevoort, Ron T and Padmanabhan, Sandosh and M{\"a}gi, Reedik and Stanton, Alice and Connell, John and Bakker, Stephan J L and Metspalu, Andres and Shields, Denis C and Thom, Simon and Brown, Morris and Sever, Peter and Esko, T{\~o}nu and Hayward, Caroline and van der Harst, Pim and Saleheen, Danish and Chowdhury, Rajiv and Chambers, John C and Chasman, Daniel I and Chakravarti, Aravinda and Newton-Cheh, Christopher and Lindgren, Cecilia M and Levy, Daniel and Kooner, Jaspal S and Keavney, Bernard and Tomaszewski, Maciej and Samani, Nilesh J and Howson, Joanna M M and Tobin, Martin D and Munroe, Patricia B and Ehret, Georg B and Wain, Louise V} } @article {10556, title = {Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Jun}, pages = {834-841}, abstract = {

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to \~{}370,000 women, we identify 389 independent signals (P < 5 {\texttimes} 10) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain \~{}7.4\% of the population variance in age at menarche, corresponding to \~{}25\% of the estimated heritability. We implicate \~{}250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

}, keywords = {Adolescent, Age Factors, Body Mass Index, Databases, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomic Imprinting, Humans, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Neoplasms, Polymorphism, Single Nucleotide, Puberty, Quantitative Trait Loci, Ribonucleoproteins, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.3841}, author = {Day, Felix R and Thompson, Deborah J and Helgason, Hannes and Chasman, Daniel I and Finucane, Hilary and Sulem, Patrick and Ruth, Katherine S and Whalen, Sean and Sarkar, Abhishek K and Albrecht, Eva and Altmaier, Elisabeth and Amini, Marzyeh and Barbieri, Caterina M and Boutin, Thibaud and Campbell, Archie and Demerath, Ellen and Giri, Ayush and He, Chunyan and Hottenga, Jouke J and Karlsson, Robert and Kolcic, Ivana and Loh, Po-Ru and Lunetta, Kathryn L and Mangino, Massimo and Marco, Brumat and McMahon, George and Medland, Sarah E and Nolte, Ilja M and Noordam, Raymond and Nutile, Teresa and Paternoster, Lavinia and Perjakova, Natalia and Porcu, Eleonora and Rose, Lynda M and Schraut, Katharina E and Segr{\`e}, Ayellet V and Smith, Albert V and Stolk, Lisette and Teumer, Alexander and Andrulis, Irene L and Bandinelli, Stefania and Beckmann, Matthias W and Benitez, Javier and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bojesen, Stig E and Bolla, Manjeet K and Brand, Judith S and Brauch, Hiltrud and Brenner, Hermann and Broer, Linda and Br{\"u}ning, Thomas and Buring, Julie E and Campbell, Harry and Catamo, Eulalia and Chanock, Stephen and Chenevix-Trench, Georgia and Corre, Tanguy and Couch, Fergus J and Cousminer, Diana L and Cox, Angela and Crisponi, Laura and Czene, Kamila and Davey Smith, George and de Geus, Eco J C N and de Mutsert, Ren{\'e}e and De Vivo, Immaculata and Dennis, Joe and Devilee, Peter and Dos-Santos-Silva, Isabel and Dunning, Alison M and Eriksson, Johan G and Fasching, Peter A and Fern{\'a}ndez-Rhodes, Lindsay and Ferrucci, Luigi and Flesch-Janys, Dieter and Franke, Lude and Gabrielson, Marike and Gandin, Ilaria and Giles, Graham G and Grallert, Harald and Gudbjartsson, Daniel F and Guenel, Pascal and Hall, Per and Hallberg, Emily and Hamann, Ute and Harris, Tamara B and Hartman, Catharina A and Heiss, Gerardo and Hooning, Maartje J and Hopper, John L and Hu, Frank and Hunter, David J and Ikram, M Arfan and Im, Hae Kyung and J{\"a}rvelin, Marjo-Riitta and Joshi, Peter K and Karasik, David and Kellis, Manolis and Kutalik, Zolt{\'a}n and LaChance, Genevieve and Lambrechts, Diether and Langenberg, Claudia and Launer, Lenore J and Laven, Joop S E and Lenarduzzi, Stefania and Li, Jingmei and Lind, Penelope A and Lindstr{\"o}m, Sara and Liu, Yongmei and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Mannermaa, Arto and Mbarek, Hamdi and McCarthy, Mark I and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Metspalu, Andres and Michailidou, Kyriaki and Milani, Lili and Milne, Roger L and Montgomery, Grant W and Mulligan, Anna M and Nalls, Mike A and Navarro, Pau and Nevanlinna, Heli and Nyholt, Dale R and Oldehinkel, Albertine J and O{\textquoteright}Mara, Tracy A and Padmanabhan, Sandosh and Palotie, Aarno and Pedersen, Nancy and Peters, Annette and Peto, Julian and Pharoah, Paul D P and Pouta, Anneli and Radice, Paolo and Rahman, Iffat and Ring, Susan M and Robino, Antonietta and Rosendaal, Frits R and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Sala, Cinzia F and Schmidt, Marjanka K and Scott, Robert A and Shah, Mitul and Sorice, Rossella and Southey, Melissa C and Sovio, Ulla and Stampfer, Meir and Steri, Maristella and Strauch, Konstantin and Tanaka, Toshiko and Tikkanen, Emmi and Timpson, Nicholas J and Traglia, Michela and Truong, Therese and Tyrer, Jonathan P and Uitterlinden, Andr{\'e} G and Edwards, Digna R Velez and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Wang, Qin and Widen, Elisabeth and van Dijk, Ko Willems and Willemsen, Gonneke and Winqvist, Robert and Wolffenbuttel, Bruce H R and Zhao, Jing Hua and Zoledziewska, Magdalena and Zygmunt, Marek and Alizadeh, Behrooz Z and Boomsma, Dorret I and Ciullo, Marina and Cucca, Francesco and Esko, T{\~o}nu and Franceschini, Nora and Gieger, Christian and Gudnason, Vilmundur and Hayward, Caroline and Kraft, Peter and Lawlor, Debbie A and Magnusson, Patrik K E and Martin, Nicholas G and Mook-Kanamori, Dennis O and Nohr, Ellen A and Polasek, Ozren and Porteous, David and Price, Alkes L and Ridker, Paul M and Snieder, Harold and Spector, Tim D and St{\"o}ckl, Doris and Toniolo, Daniela and Ulivi, Sheila and Visser, Jenny A and V{\"o}lzke, Henry and Wareham, Nicholas J and Wilson, James F and Spurdle, Amanda B and Thorsteindottir, Unnur and Pollard, Katherine S and Easton, Douglas F and Tung, Joyce Y and Chang-Claude, Jenny and Hinds, David and Murray, Anna and Murabito, Joanne M and Stefansson, Kari and Ong, Ken K and Perry, John R B} } @article {10585, title = {Guidelines of the Italian Society of Videosurgery in Infancy for the minimally invasive treatment of the esophageal atresia.}, journal = {Pediatr Med Chir}, volume = {39}, year = {2017}, month = {2017 Oct 04}, pages = {166}, abstract = {

Not available.

}, keywords = {Esophageal Atresia, Humans, Infant, Minimally Invasive Surgical Procedures, Video-Assisted Surgery}, issn = {2420-7748}, doi = {10.4081/pmc.2017.166}, author = {Chiarenza, Salvatore Fabio and Conighi, Maria Luisa and Conforti, Andrea and Esposito, Ciro and Escolino, Maria and Beretta, Fabio and Cheli, Maurizio and Di Benedetto, Vincenzo and Scuderi, Maria Grazia and Casadio, Giovanni and Marzaro, Maurizio and Fascetti, Leon Francesco and Vella, Claudio and Bleve, Cosimo and Codric, Daniela and Caione, Paolo and Bagolan, Pietro} } @article {10586, title = {Guidelines of the Italian Society of Videosurgery in Infancy for the minimally invasive treatment of the ureteropelvic-junction obstruction.}, journal = {Pediatr Med Chir}, volume = {39}, year = {2017}, month = {2017 Oct 04}, pages = {174}, abstract = {

Not available.

}, keywords = {Humans, Infant, Kidney Pelvis, Minimally Invasive Surgical Procedures, Ureteral Obstruction, Video-Assisted Surgery}, issn = {2420-7748}, doi = {10.4081/pmc.2017.174}, author = {Chiarenza, Salvatore Fabio and Bleve, Cosimo and Esposito, Ciro and Escolino, Maria and Beretta, Fabio and Cheli, Maurizio and Di Benedetto, Vincenzo and Scuderi, Maria Grazia and Casadio, Giovanni and Marzaro, Maurizio and Fascetti, Leon Francesco and Bagolan, Pietro and Vella, Claudio and Conighi, Maria Luisa and Codric, Daniela and Nappo, Simona and Caione, Paolo} } @article {10459, title = {HLA-G regulatory polymorphisms are associated with susceptibility to HCV infection.}, journal = {HLA}, volume = {89}, year = {2017}, month = {2017 03}, pages = {135-142}, abstract = {

BACKGROUND: Hepatitis C virus (HCV) is able to bypass the immune system modulating innate and adaptive immune response and blocking T helper 1 (Th1) cell production. Because the human leukocyte antigen (HLA)-G molecule has immunomodulatory properties inhibiting the function and production of natural killer and cytotoxic lymphocyte T cells, as well as promoting shift from Th1 toward Th2 response, we hypothesized its involvement in susceptibility to HCV infection.

MATERIALS AND METHODS: Considering that HLA-G mRNA expression has been reported to be under genetic control, an association study was conducted analyzing 800 base pairs upstream the ATG at the 5{\textquoteright}upstream regulator region (URR) and 850 base pairs from ATG to exon 3 and the 3{\textquoteright}untranslated region (UTR) of HLA-G gene in Italian HCV-positive patients and uninfected controls.

RESULTS: Four 5{\textquoteright}URR polymorphisms (-725C>G>T, -509C>G, -400G>A and -398G>A), 7 polymorphisms at coding region (+15G>A, +36G>A, +243G>A, insC506, 531G>C, delA615 and 685G>A), the +644G>T polymorphism, and 1 haplotype (TTGTTCCIGAC) showed different frequency distributions between HCV patients and uninfected controls.

CONCLUSION: The results from our study suggest a possible involvement of HLA-G in the risk modulation toward HCV infection.

}, keywords = {3{\textquoteright} Untranslated Regions, 5{\textquoteright} Untranslated Regions, Adult, Aged, Aged, 80 and over, Alleles, Case-Control Studies, Exons, Female, Gene Expression, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Haplotypes, Hepacivirus, Hepatitis C, HLA-G Antigens, Humans, Italy, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk, Th1 Cells}, issn = {2059-2310}, doi = {10.1111/tan.12959}, author = {Catamo, E and Zupin, L and Freato, N and Polesello, V and Celsi, F and Croc{\`e}, S L and Masutti, F and Pozzato, G and Segat, L and Crovella, S} } @article {10588, title = {How to monitor pregnancies complicated by fetal growth restriction and delivery before 32 weeks: post-hoc analysis of TRUFFLE study.}, journal = {Ultrasound Obstet Gynecol}, volume = {49}, year = {2017}, month = {2017 Jun}, pages = {769-777}, abstract = {

OBJECTIVES: In the recent TRUFFLE study, it appeared that, in pregnancies complicated by fetal growth restriction (FGR) between 26 and 32 weeks{\textquoteright} gestation, monitoring of the fetal ductus venosus (DV) waveform combined with computed cardiotocography (CTG) to determine timing of delivery increased the chance of infant survival without neurological impairment. However, concerns with the interpretation were raised, as DV monitoring appeared to be associated with a non-significant increase in fetal death, and some infants were delivered after 32 weeks, at which time the study protocol no longer applied. This secondary sensitivity analysis of the TRUFFLE study focuses on women who delivered before 32 completed weeks{\textquoteright} gestation and analyzes in detail the cases of fetal death.

METHODS: Monitoring data of 317 pregnancies with FGR that delivered before 32 weeks were analyzed, excluding those with absent outcome data or inevitable perinatal death. Women were allocated randomly to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate short-term variation (STV) on CTG; (2) early changes in fetal DV waveform; and (3) late changes in fetal DV waveform. Primary outcome was 2-year survival without neurological impairment. The association of the last monitoring data before delivery and infant outcome was assessed by multivariable analysis.

RESULTS: Two-year survival without neurological impairment occurred more often in the two DV groups (both 83\%) than in the CTG-STV group (77\%), however, the difference was not statistically significant (P = 0.21). Among the surviving infants in the DV groups, 93\% were free of neurological impairment vs 85\% of surviving infants in the CTG-STV group (P = 0.049). All fetal deaths (n = 7) occurred in the groups with DV monitoring. Of the monitoring parameters obtained shortly before fetal death in these seven cases, an abnormal CTG was observed in only one case. Multivariable regression analysis of factors at study entry demonstrated that a later gestational age, higher estimated fetal weight-to-50 percentile ratio and lower umbilical artery pulsatility index (PI)/fetal middle cerebral artery-PI ratio were significantly associated with normal outcome. Allocation to DV monitoring had a smaller effect on outcome, but remained in the model (P < 0.1). Abnormal fetal arterial Doppler before delivery was significantly associated with adverse outcome in the CTG-STV group. In contrast, abnormal DV flow was the only monitoring parameter associated with adverse outcome in the DV groups, while fetal arterial Doppler, STV below the cut-off used in the CTG-STV group and recurrent decelerations in fetal heart rate were not.

CONCLUSIONS: In accordance with the findings of the TRUFFLE study on monitoring and intervention management of very preterm FGR, we found that the proportion of infants surviving without neuroimpairment was not significantly different when the decision for delivery was based on changes in DV waveform vs reduced STV on CTG. The uneven distribution of fetal deaths towards the DV groups was probably a chance effect, and neurological outcome was better among surviving children in these groups. Before 32 weeks, delaying delivery until abnormalities in DV-PI or STV and/or recurrent decelerations in fetal heat rate occur, as defined by the study protocol, is likely to be safe and possibly benefits long-term outcome. Copyright {\textcopyright} 2017 ISUOG. Published by John Wiley \& Sons Ltd.

}, keywords = {Adult, Cardiotocography, Central Nervous System Diseases, Child, Preschool, Female, Fetal Growth Retardation, Fetal Membranes, Premature Rupture, Gestational Age, Heart Rate, Fetal, Humans, Infant, Infant, Extremely Premature, Male, Middle Cerebral Artery, Pregnancy, Pulsatile Flow, Survival Analysis, Treatment Outcome, Ultrasonography, Prenatal, Uterine Artery}, issn = {1469-0705}, doi = {10.1002/uog.17433}, author = {Ganzevoort, W and Mensing Van Charante, N and Thilaganathan, B and Prefumo, F and Arabin, B and Bilardo, C M and Brezinka, C and Derks, J B and Diemert, A and Duvekot, J J and Ferrazzi, E and Frusca, T and Hecher, K and Marlow, N and Martinelli, P and Ostermayer, E and Papageorghiou, A T and Schlembach, D and Schneider, K T M and Todros, T and Valcamonico, A and Visser, G H A and Van Wassenaer-Leemhuis, A and Lees, C C and Wolf, H} } @article {10542, title = {Identification of proteins with different abundance associated with cell migration and proliferation in leiomyoma interstitial fluid by proteomics.}, journal = {Oncol Lett}, volume = {13}, year = {2017}, month = {2017 May}, pages = {3912-3920}, abstract = {

Uterine leiomyoma is the most common female reproductive tract benign tumor. Little is known about protein composition and changes in the leiomyoma interstitial fluid (IF). The present study focused on changes in protein abundance in the IF of leiomyoma. Leiomyoma IFs and adjacent myometrial IFs were obtained and analyzed by two-dimensional electrophoresis (2-DE) coupled with mass spectrometry and western blotting for 2-DE data validation. A total of 25 unique proteins were observed to change significantly (P<0.05). Of these proteins with different abundance, 22 had not been previously identified in leiomyoma IF. analysis predicted that three of these proteins were secreted via classical mechanisms, while 22 were secreted via non-classical mechanisms. Ingenuity Pathway Analysis identified 17 proteins associated with cellular migration and proliferation. Among these, phosphoglycerate mutase 1 had not been previously associated with leiomyoma. The abundance of seven proteins was further validated by western blotting. A comparative proteomic approach identified a number of proteins associated with cellular migration and proliferation, with changes in abundance in IF likely to be involved in tumor development. Further studies will be required to investigate the role of these proteins in leiomyoma IF and their possible association with tumor development and growth.

}, issn = {1792-1074}, doi = {10.3892/ol.2017.5943}, author = {Ura, Blendi and Scrimin, Federica and Franchin, Cinzia and Arrigoni, Giorgio and Licastro, Danilo and Monasta, Lorenzo and Ricci, Giuseppe} } @article {10564, title = {Impaired fasting glucose and impaired glucose tolerance in children and adolescents with overweight/obesity.}, journal = {J Endocrinol Invest}, volume = {40}, year = {2017}, month = {2017 Apr}, pages = {409-416}, abstract = {

OBJECTIVE: To investigate in a large sample of overweight/obese (OW/OB) children and adolescents the prevalence of prediabetic phenotypes such as impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), and to assess their association with cardiometabolic risk (CMR) factors including hepatic steatosis (HS).

METHODS: Population data were obtained from the CARdiometabolic risk factors in children and adolescents in ITALY study. Between 2003 and 2013, 3088 youths (972 children and 2116 adolescents) received oral glucose tolerance test (OGTT) and were included in the study. In 798 individuals, abdominal ultrasound for identification of HS was available.

RESULTS: The prevalence of IFG (3.2 vs. 3.3\%) and IGT (4.6 vs. 5.0\%) was similar between children and adolescents. Children with isolated IGT had a 2-11 fold increased risk of high LDL-C, non-HDL-C, Tg/HDL-C ratio, and low insulin sensitivity, when compared to those with normal glucose tolerance (NGT). No significant association of IFG with any CMR factor was found in children. Among adolescents, IGT subjects, and to a lesser extent those with IFG, showed a worse CMR profile compared to NGT subgroup. In the overall sample, IGT phenotype showed a twofold increased risk of HS compared to NGT subgroup.

CONCLUSIONS: Our study shows an unexpected similar prevalence of IFG and IGT between children and adolescents with overweight/obesity. The IGT phenotype was associated with a worse CMR profile in both children and adolescents. Phenotyping prediabetes conditions by OGTT should be done as part of prediction and prevention of cardiometabolic diseases in OW/OB youth since early childhood.

}, keywords = {Adolescent, Blood Glucose, Case-Control Studies, Child, Fasting, Female, Glucose Intolerance, Glucose Tolerance Test, Humans, Insulin, Insulin Resistance, Italy, Male, Obesity, Overweight, Prediabetic State, Prevalence}, issn = {1720-8386}, doi = {10.1007/s40618-016-0576-8}, author = {Di Bonito, P and Pacifico, L and Chiesa, C and Valerio, G and Miraglia Del Giudice, E and Maffeis, C and Morandi, A and Invitti, C and Licenziati, M R and Loche, S and Tornese, G and Franco, F and Manco, M and Baroni, M G} } @article {10502, title = {Imported arboviral infections in Italy, July 2014-October 2015: a National Reference Laboratory report.}, journal = {BMC Infect Dis}, volume = {17}, year = {2017}, month = {2017 03 16}, pages = {216}, abstract = {

BACKGROUND: Imported cases of infections due to Dengue (DENV) and Chikungunya (CHIKV) viruses and, more recently, Zika virus (ZIKV) are commonly reported among travelers returning from endemic regions. In areas where potentially competent vectors are present, the risk of autochthonous transmission of these vector-borne pathogens is relatively high. Laboratory surveillance is crucial to rapidly detect imported cases in order to reduce the risk of transmission. This study describes the laboratory activity performed by the National Reference Laboratory for Arboviruses (NRLA) at the Italian National Institute of Health in the period from July 2014 to October 2015.

METHODS: Samples from 180 patients visited/hospitalized with a suspected DENV/CHIKV/ZIKV infection were sent to the NRLA from several Italian Hospitals and from Regional Reference Laboratories for Arboviruses, in agreement with the National Plan on human surveillance of vector-borne diseases. Both serological (ELISA IgM test and Plaque Reduction Neutralization Test-PRNT) and molecular assays (Real Time PCR tests, RT-PCR plus nested PCR and sequencing of positive samples) were performed.

RESULTS: DENV infection was the most frequently diagnosed (80 confirmed/probable cases), and all four genotypes were detected. However, an increase in imported CHIKV cases (41 confirmed/probable cases) was observed, along with the detection of the first ZIKV cases (4 confirmed cases), as a consequence of the recent spread of both CHIKV and ZIKV in the Americas.

CONCLUSIONS: Main diagnostic issues highlighted in our study are sensitivity limitations of molecular tests, and the importance of PRNT to confirm serological results for differential diagnosis of Arboviruses. The continuous evaluation of diagnostic strategy, and the implementation of laboratories networks involved in surveillance activities is essential to ensure correct diagnosis, and to improve the preparedness for a rapid and proper identification of viral threats.

}, keywords = {Chikungunya Fever, Chikungunya virus, Dengue, Dengue Virus, Disease Outbreaks, Female, Genotype, Humans, Italy, Male, Molecular Diagnostic Techniques, Population Surveillance, Public Health, Travel, Young Adult, Zika Virus, Zika Virus Infection}, issn = {1471-2334}, doi = {10.1186/s12879-017-2320-1}, author = {Fortuna, Claudia and Remoli, Maria Elena and Rizzo, Caterina and Benedetti, Eleonora and Fiorentini, Cristiano and Bella, Antonino and Argentini, Claudio and Farchi, Francesca and Castilletti, Concetta and Capobianchi, Maria Rosaria and Zammarchi, Lorenzo and Bartoloni, Alessandro and Zanchetta, Nadia and Gismondo, Maria Rita and Nelli, Luca Ceccherini and Vitale, Giustina and Baldelli, Franco and D{\textquoteright}Agaro, Pierlanfranco and Sodano, Giuseppe and Rezza, Giovanni and Venturi, Giulietta} } @article {10555, title = {Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial.}, journal = {Lancet}, volume = {389}, year = {2017}, month = {2017 03 04}, pages = {909-916}, abstract = {

BACKGROUND: Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy.

METHODS: We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70.

FINDINGS: Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32\%) patients assigned to intra-articular corticosteroids alone and 39 (37\%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0{\textperiodcentered}48). Adverse events were recorded for 20 (17\%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event.

INTERPRETATION: Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis.

FUNDING: Italian Agency of Drug Evaluation.

}, keywords = {Adrenal Cortex Hormones, Arthritis, Juvenile, Humans, Injections, Intra-Articular, Italy, Methotrexate, Prospective Studies, Treatment Outcome}, issn = {1474-547X}, doi = {10.1016/S0140-6736(17)30065-X}, author = {Ravelli, Angelo and Dav{\`\i}, Sergio and Bracciolini, Giulia and Pistorio, Angela and Consolaro, Alessandro and van Dijkhuizen, Evert Hendrik Pieter and Lattanzi, Bianca and Filocamo, Giovanni and Verazza, Sara and Gerloni, Valeria and Gattinara, Maurizio and Pontikaki, Irene and Insalaco, Antonella and De Benedetti, Fabrizio and Civino, Adele and Presta, Giuseppe and Breda, Luciana and Marzetti, Valentina and Pastore, Serena and Magni-Manzoni, Silvia and Maggio, Maria Cristina and Garofalo, Franco and Rigante, Donato and Gattorno, Marco and Malattia, Clara and Picco, Paolo and Viola, Stefania and Lanni, Stefano and Ruperto, Nicolino and Martini, Alberto} } @article {10492, title = {ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development.}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 02 08}, pages = {42170}, abstract = {

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 {\texttimes} 10). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 {\texttimes} 10. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.

}, keywords = {Animals, Bladder Exstrophy, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Genetic Predisposition to Disease, Humans, Larva, LIM-Homeodomain Proteins, Mesoderm, Mice, Organogenesis, Polymorphism, Single Nucleotide, Pronephros, Protein Isoforms, Transcription Factors, Urinary Tract, Zebrafish}, issn = {2045-2322}, doi = {10.1038/srep42170}, author = {Zhang, Rong and Knapp, Michael and Suzuki, Kentaro and Kajioka, Daiki and Schmidt, Johanna M and Winkler, Jonas and Yilmaz, {\"O}znur and Pleschka, Michael and Cao, Jia and Kockum, Christina Clementson and Barker, Gillian and Holmdahl, Gundela and Beaman, Glenda and Keene, David and Woolf, Adrian S and Cervellione, Raimondo M and Cheng, Wei and Wilkins, Simon and Gearhart, John P and Sirchia, Fabio and Di Grazia, Massimo and Ebert, Anne-Karolin and R{\"o}sch, Wolfgang and Ellinger, J{\"o}rg and Jenetzky, Ekkehart and Zwink, Nadine and Feitz, Wout F and Marcelis, Carlo and Schumacher, Johannes and Martin{\'o}n-Torres, Federico and Hibberd, Martin Lloyd and Khor, Chiea Chuen and Heilmann-Heimbach, Stefanie and Barth, Sandra and Boyadjiev, Simeon A and Brusco, Alfredo and Ludwig, Michael and Newman, William and Nordenskj{\"o}ld, Agneta and Yamada, Gen and Odermatt, Benjamin and Reutter, Heiko} } @article {10483, title = {The Italian Society for Pediatric Nephrology (SINePe) consensus document on the management of nephrotic syndrome in children: Part I - Diagnosis and treatment of the first episode and the first relapse.}, journal = {Ital J Pediatr}, volume = {43}, year = {2017}, month = {2017 Apr 21}, pages = {41}, abstract = {

This consensus document is aimed at providing an updated, multidisciplinary overview on the diagnosis and treatment of pediatric nephrotic syndrome (NS) at first presentation. It is the first consensus document of its kind to be produced by all the pediatric nephrology centres in Italy, in line with what is already present in other countries such as France, Germany and the USA. It is based on the current knowledge surrounding the symptomatic and steroid treatment of NS, with a view to providing the basis for a separate consensus document on the treatment of relapses. NS is one of the most common pediatric glomerular diseases, with an incidence of around 2-7 cases per 100000 children per year. Corticosteroids are the mainstay of treatment, but the optimal therapeutic regimen for managing childhood idiopathic NS is still under debate. In Italy, shared treatment guidelines were lacking and, consequently, the choice of steroid regimen was based on the clinical expertise of each individual unit. On the basis of the 2015 Cochrane systematic review, KDIGO Guidelines and more recent data from the literature, this working group, with the contribution of all the pediatric nephrology centres in Italy and on the behalf of the Italian Society of Pediatric Nephrology, has produced a shared steroid protocol that will be useful for National Health System hospitals and pediatricians. Investigations at initial presentation and the principal causes of NS to be screened are suggested. In the early phase of the disease, symptomatic treatment is also important as many severe complications can occur which are either directly related to the pathophysiology of the underlying NS or to the steroid treatment itself. To date, very few studies have been published on the prophylaxis and treatment of these early complications, while recommendations are either lacking or conflicting. This consensus provides indications for the prevention, early recognition and treatment of these complications (management of edema and hypovolemia, therapy and prophylaxis of infections and thromboembolic events). Finally, recommendations about the clinical definition of steroid resistance and its initial diagnostic management, as well as indications for renal biopsy are provided.

}, keywords = {Adrenal Cortex Hormones, Child, Child, Preschool, Consensus, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Italy, Male, Nephrotic Syndrome, Practice Guidelines as Topic, Prognosis, Recurrence, Retreatment, Societies, Medical, Survival Rate, Treatment Outcome}, issn = {1824-7288}, doi = {10.1186/s13052-017-0356-x}, author = {Pasini, Andrea and Benetti, Elisa and Conti, Giovanni and Ghio, Luciana and Lepore, Marta and Massella, Laura and Molino, Daniela and Peruzzi, Licia and Emma, Francesco and Fede, Carmelo and Trivelli, Antonella and Maringhini, Silvio and Materassi, Marco and Messina, Giovanni and Montini, Giovanni and Murer, Luisa and Pecoraro, Carmine and Pennesi, Marco} } @article {10484, title = {Longitudinal Responses to Weighing and Bathing Procedures in Preterm Infants.}, journal = {J Perinat Neonatal Nurs}, volume = {31}, year = {2017}, month = {2017 Jan/Mar}, pages = {67-74}, abstract = {

Knowledge of the effects of nursing-induced stress on short-term outcomes in preterm infants is limited. Effects of 2 standard nursing procedures-weighing and bathing-on autonomic and motor stability of preterm infants were studied during their hospitalization. Outcomes were evaluated during and after the procedures. Eleven preterm infants were observed between 32 and 35 weeks{\textquoteright} postmenstrual age (PMA) (postnatal days range: 4-63). Neonatal responses were assessed according to the Synactive Theory of Development and nursing was performed taking into account Newborn Individualized Developmental Care and Assessment Program (NIDCAP) principles. Effects of the studied nursing procedures on infants{\textquoteright} stability during and after their execution were evaluated by nonparametric statistics. During monitored procedures, stress responses in autonomic and motor systems were observed at all PMAs. However, after 32 weeks{\textquoteright} PMA, preterm infants also showed an autonomic and motor stability recovery 5 minutes after procedure completion. Contrary to our hypothesis, preterm infants showed to be stressed by weighing and bathing procedures up to 35 weeks{\textquoteright} PMA. However, if facilitated and supported after nursing conclusion by interventions such as swaddling and nesting, according to NIDCAP principles, they recovered autonomic and motor stability by 5 minutes after ending procedures.

}, keywords = {Baths, Body Weight, Female, Humans, Infant Behavior, Infant Care, Infant, Newborn, Infant, Premature, Male, Neonatal Nursing}, issn = {1550-5073}, doi = {10.1097/JPN.0000000000000228}, author = {Bembich, Stefano and Fiani, Giulia and Strajn, Tamara and Sanesi, Cecilia and Demarini, Sergio and Sanson, Gianfranco} } @article {10589, title = {Longitudinal study of computerized cardiotocography in early fetal growth restriction.}, journal = {Ultrasound Obstet Gynecol}, volume = {50}, year = {2017}, month = {2017 Jul}, pages = {71-78}, abstract = {

OBJECTIVES: To explore whether, in early fetal growth restriction (FGR), the longitudinal pattern of fetal heart rate (FHR) short-term variation (STV) can be used to identify imminent fetal distress and whether abnormalities of FHR recordings are associated with 2-year infant outcome.

METHODS: The original TRUFFLE study assessed whether, in early FGR, delivery based on ductus venosus (DV) Doppler pulsatility index (PI), in combination with safety-net criteria of very low STV on cardiotocography (CTG) and/or recurrent FHR decelerations, could improve 2-year infant survival without neurological impairment in comparison with delivery based on CTG monitoring only. This was a secondary analysis of women who delivered before 32 weeks and had consecutive STV data recorded > 3 days before delivery and known infant outcome at 2 years of age. Women who received corticosteroids within 3 days of delivery were excluded. Individual regression line algorithms of all STV values, except the last one before delivery, were calculated. Life tables and Cox regression analysis were used to calculate the daily risk for low STV or very low STV and/or FHR decelerations (below DV group safety-net criteria) and to assess which parameters were associated with this risk. Furthermore, it was assessed whether STV pattern, last STV value or recurrent FHR decelerations were associated with 2-year infant outcome.

RESULTS: One hundred and forty-nine women from the original TRUFFLE study met the inclusion criteria. Using the individual STV regression lines, prediction of a last STV below the cut-off used by the CTG monitoring group had sensitivity of 42\% and specificity of 91\%. For each day after study inclusion, the median risk for low STV (CTG group cut-off) was 4\% (interquartile range (IQR), 2-7\%) and for very low STV and/or recurrent FHR decelerations (below DV group safety-net criteria) was 5\% (IQR, 4-7\%). Measures of STV pattern, fetal Doppler (arterial or venous), birth-weight multiples of the median and gestational age did not usefully improve daily risk prediction. There was no association of STV regression coefficients, a low last STV and/or recurrent FHR decelerations with short- or long-term infant outcomes.

CONCLUSION: The TRUFFLE study showed that a strategy of DV monitoring with safety-net criteria of very low STV and/or recurrent FHR decelerations for delivery indication could increase 2-year infant survival without neurological impairment. This post-hoc analysis demonstrates that, in early FGR, the daily risk of abnormal CTG, as defined by the DV group safety-net criteria, is 5\%, and that prediction is not possible. This supports the rationale for CTG monitoring more often than daily in these high-risk fetuses. Low STV and/or recurrent FHR decelerations were not associated with adverse infant outcome and it appears safe to delay intervention until such abnormalities occur, as long as DV-PI is within normal range. Copyright {\textcopyright} 2016 ISUOG. Published by John Wiley \& Sons Ltd.

}, keywords = {Adult, Cardiotocography, Child, Preschool, Female, Fetal Growth Retardation, Fetal Heart, Heart Rate, Fetal, Humans, Infant, Infant, Newborn, Longitudinal Studies, Middle Cerebral Artery, Pregnancy, Pregnancy Outcome, Pulsatile Flow, Survival Analysis, Ultrasonography, Prenatal}, issn = {1469-0705}, doi = {10.1002/uog.17215}, author = {Wolf, H and Arabin, B and Lees, C C and Oepkes, D and Prefumo, F and Thilaganathan, B and Todros, T and Visser, G H A and Bilardo, C M and Derks, J B and Diemert, A and Duvekot, J J and Ferrazzi, E and Frusca, T and Hecher, K and Marlow, N and Martinelli, P and Ostermayer, E and Papageorghiou, A T and Scheepers, H C J and Schlembach, D and Schneider, K T M and Valcamonico, A and Van Wassenaer-Leemhuis, A and Ganzevoort, W} } @article {10504, title = {Multicentric Case-Control Study on Azathioprine Dose and Pharmacokinetics in Early-onset Pediatric Inflammatory Bowel Disease.}, journal = {Inflamm Bowel Dis}, volume = {23}, year = {2017}, month = {2017 04}, pages = {628-634}, abstract = {

BACKGROUND: Early-onset inflammatory bowel disease (IBD) is generally aggressive, with a high probability of complications and need of surgery. Despite the introduction of highly effective biological drugs, treatment with azathioprine continues to be important even for early-onset IBD; however, in these patients azathioprine response seems to be reduced. This study evaluated azathioprine doses, metabolite concentrations, and their associations with patients{\textquoteright} age in children with IBD treated at 6 tertiary pediatric referral centers.

METHODS: Azathioprine doses, metabolites, and clinical effects were assessed after at least 3 months of therapy in 17 early-onset (age < 6 yr, cases) and 51 nonearly-onset (aged > 12 and <18 yrs, controls) patients with IBD. Azathioprine dose was titrated on therapeutic efficacy (response and adverse effects). Azathioprine metabolites and thiopurine methyltransferase activity were determined by high-performance liquid chromatography with ultra violet-vis detection (HPLC-UV) methods.

RESULTS: Frequency of patients in remission was similar among early-onset and control groups, respectively (82\% and 84\%, P value = 0.72). Early-onset patients required higher doses of azathioprine (median 2.7 versus 2.0 mg{\textperiodcentered}kg{\textperiodcentered}d, P value = 1.1 {\texttimes} 10). Different doses resulted in comparable azathioprine active thioguanine nucleotide metabolite concentrations (median 263 versus 366 pmol/8 {\texttimes} 10 erythrocytes, P value = 0.41) and methylmercaptopurine nucleotide concentrations (median 1455 versus 1532 pmol/8 {\texttimes} 10 erythrocytes, P value = 0.60). Lower ratios between thioguanine nucleotide metabolites and azathioprine doses were found in early-onset patients (median 98 versus 184 pmol/8 {\texttimes} 10 erythrocytes{\textperiodcentered}mg{\textperiodcentered}kg{\textperiodcentered}d, P value = 0.017). Interestingly, early-onset patients presented also higher thiopurine methyltransferase activity (median 476 versus 350 nmol methylmercaptopurine/mg hemoglobin/h, P-value = 0.046).

CONCLUSIONS: This study demonstrated that patients with early-onset IBD present increased inactivating azathioprine metabolism, likely because of elevated activity of the enzyme thiopurine methyltransferase.

}, keywords = {Adolescent, Age of Onset, Antimetabolites, Azathioprine, Case-Control Studies, Child, Child, Preschool, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Erythrocytes, Female, Guanine Nucleotides, Humans, Inflammatory Bowel Diseases, Male, Mercaptopurine, Methyltransferases, Thioguanine}, issn = {1536-4844}, doi = {10.1097/MIB.0000000000001051}, author = {Stocco, Gabriele and Martelossi, Stefano and Arrigo, Serena and Barabino, Arrigo and Aloi, Marina and Martinelli, Massimo and Miele, Erasmo and Knafelz, Daniela and Romano, Claudio and Naviglio, Samuele and Favretto, Diego and Cuzzoni, Eva and Franca, Raffaella and Decorti, Giuliana and Ventura, Alessandro} } @article {10576, title = {Natalizumab treatment of multiple sclerosis: new insights.}, journal = {Immunotherapy}, volume = {9}, year = {2017}, month = {2017 01}, pages = {157-171}, abstract = {

Natalizumab is a monoclonal antibody directed against the α4 chain of the very late activating antigen 4 and α4β7 integrins, present on the leukocytes surface, used as monotherapy for the treatment of relapsing-remitting multiple sclerosis. It substantially reduces relapse rate and the accumulation of disability, but its use is associated with a very adverse event, that is the development of progressive multifocal leukoencephalopathy, a fatal demyelinating disease of the CNS, due to the lytic replication of the human polyomavirus JC. The main focus of the review is to describe the newest insights on natalizumab, its current use in the clinical practice, the natalizumab-treated patients{\textquoteright} management and the risk stratification related to the progressive multifocal leukoencephalopathy development.

}, keywords = {Animals, Drug-Related Side Effects and Adverse Reactions, Humans, Immunotherapy, Integrin alpha Chains, Integrin alpha4, Integrin beta Chains, JC Virus, Leukoencephalopathy, Progressive Multifocal, Multiple Sclerosis, Relapsing-Remitting, Natalizumab, Risk, Virus Activation, Virus Replication}, issn = {1750-7448}, doi = {10.2217/imt-2016-0113}, author = {Delbue, Serena and Comar, Manola and Ferrante, Pasquale} } @article {10554, title = {Neuroimaging Changes in Menkes Disease, Part 1.}, journal = {AJNR Am J Neuroradiol}, volume = {38}, year = {2017}, month = {2017 Oct}, pages = {1850-1857}, abstract = {

Menkes disease is a rare multisystem X-linked disorder of copper metabolism. Despite an early, severe, and progressive neurologic involvement, our knowledge of brain involvement remains unsatisfactory. The first part of this retrospective and review MR imaging study aims to define the frequency rate, timing, imaging features, and evolution of intracranial vascular and white matter changes. According to our analysis, striking but also poorly evolutive vascular abnormalities characterize the very early phases of disease. After the first months, myelination delay becomes evident, often in association with protean focal white matter lesions, some of which reveal an age-specific brain vulnerability. In later phases of the disease, concomitant progressive neurodegeneration might hinder the myelination progression. The currently enriched knowledge of neuroradiologic finding evolution provides valuable clues for early diagnosis, identifies possible MR imaging biomarkers of new treatment efficacy, and improves our comprehension of possible mechanisms of brain injury in Menkes disease.

}, keywords = {Brain, Disease Progression, Female, Humans, Magnetic Resonance Imaging, Male, Menkes Kinky Hair Syndrome, Neuroimaging, Retrospective Studies, White Matter}, issn = {1936-959X}, doi = {10.3174/ajnr.A5186}, author = {Manara, R and D{\textquoteright}Agata, L and Rocco, M C and Cusmai, R and Freri, E and Pinelli, L and Darra, F and Procopio, E and Mardari, R and Zanus, C and Di Rosa, G and Soddu, C and Severino, M and Ermani, M and Longo, D and Sartori, S} } @article {10512, title = {Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.}, journal = {Hypertension}, year = {2017}, month = {2017 Jul 24}, abstract = {

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near , , , , , and , and provide new replication evidence for a further 2 signals in and Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.117.09438}, author = {Wain, Louise V and Vaez, Ahmad and Jansen, Rick and Joehanes, Roby and van der Most, Peter J and Erzurumluoglu, A Mesut and O{\textquoteright}Reilly, Paul F and Cabrera, Claudia P and Warren, Helen R and Rose, Lynda M and Verwoert, Germaine C and Hottenga, Jouke-Jan and Strawbridge, Rona J and Esko, T{\~o}nu and Arking, Dan E and Hwang, Shih-Jen and Guo, Xiuqing and Kutalik, Zolt{\'a}n and Trompet, Stella and Shrine, Nick and Teumer, Alexander and Ried, Janina S and Bis, Joshua C and Smith, Albert V and Amin, Najaf and Nolte, Ilja M and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Wareham, Nicholas J and Hofer, Edith and Joshi, Peter K and Kristiansson, Kati and Traglia, Michela and Havulinna, Aki S and Goel, Anuj and Nalls, Mike A and S{\~o}ber, Siim and Vuckovic, Dragana and Luan, Jian{\textquoteright}an and del Greco M, Fabiola and Ayers, Kristin L and Marrugat, Jaume and Ruggiero, Daniela and Lopez, Lorna M and Niiranen, Teemu and Enroth, Stefan and Jackson, Anne U and Nelson, Christopher P and Huffman, Jennifer E and Zhang, Weihua and Marten, Jonathan and Gandin, Ilaria and Harris, Sarah E and Zemunik, Tatijana and Lu, Yingchang and Evangelou, Evangelos and Shah, Nabi and de Borst, Martin H and Mangino, Massimo and Prins, Bram P and Campbell, Archie and Li-Gao, Ruifang and Chauhan, Ganesh and Oldmeadow, Christopher and Abecasis, Goncalo and Abedi, Maryam and Barbieri, Caterina M and Barnes, Michael R and Batini, Chiara and Beilby, John and Blake, Tineka and Boehnke, Michael and Bottinger, Erwin P and Braund, Peter S and Brown, Morris and Brumat, Marco and Campbell, Harry and Chambers, John C and Cocca, Massimiliano and Collins, Francis and Connell, John and Cordell, Heather J and Damman, Jeffrey J and Davies, Gail and de Geus, Eco J and de Mutsert, Ren{\'e}e and Deelen, Joris and Demirkale, Yusuf and Doney, Alex S F and D{\"o}rr, Marcus and Farrall, Martin and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Gao, He and Giedraitis, Vilmantas and Gieger, Christian and Giulianini, Franco and Gow, Alan J and Hamsten, Anders and Harris, Tamara B and Hofman, Albert and Holliday, Elizabeth G and Hui, Jennie and J{\"a}rvelin, Marjo-Riitta and Johansson, {\r A}sa and Johnson, Andrew D and Jousilahti, Pekka and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Khaw, Kay-Tee and Kolcic, Ivana and Koskinen, Seppo and Langenberg, Claudia and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Liewald, David C M and Lin, Li and Lind, Lars and Mach, Fran{\c c}ois and Mamasoula, Chrysovalanto and Menni, Cristina and Mifsud, Borbala and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew D and Morrison, Alanna C and Munson, Peter J and Nandakumar, Priyanka and Nguyen, Quang Tri and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and Org, Elin and Padmanabhan, Sandosh and Palotie, Aarno and Par{\'e}, Guillaume and Pattie, Alison and Penninx, Brenda W J H and Poulter, Neil and Pramstaller, Peter P and Raitakari, Olli T and Ren, Meixia and Rice, Kenneth and Ridker, Paul M and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rotter, Jerome I and Rudan, Igor and Saba, Yasaman and Saint Pierre, Aude and Sala, Cinzia F and Sarin, Antti-Pekka and Schmidt, Reinhold and Scott, Rodney and Seelen, Marc A and Shields, Denis C and Siscovick, David and Sorice, Rossella and Stanton, Alice and Stott, David J and Sundstr{\"o}m, Johan and Swertz, Morris and Taylor, Kent D and Thom, Simon and Tzoulaki, Ioanna and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and Vollenweider, Peter and Wild, Sarah and Willemsen, Gonneke and Wright, Alan F and Yao, Jie and Th{\'e}riault, S{\'e}bastien and Conen, David and Attia, John and Sever, Peter and Debette, St{\'e}phanie and Mook-Kanamori, Dennis O and Zeggini, Eleftheria and Spector, Tim D and van der Harst, Pim and Palmer, Colin N A and Vergnaud, Anne-Claire and Loos, Ruth J F and Polasek, Ozren and Starr, John M and Girotto, Giorgia and Hayward, Caroline and Kooner, Jaspal S and Lindgren, Cecila M and Vitart, Veronique and Samani, Nilesh J and Tuomilehto, Jaakko and Gyllensten, Ulf and Knekt, Paul and Deary, Ian J and Ciullo, Marina and Elosua, Roberto and Keavney, Bernard D and Hicks, Andrew A and Scott, Robert A and Gasparini, Paolo and Laan, Maris and Liu, Yongmei and Watkins, Hugh and Hartman, Catharina A and Salomaa, Veikko and Toniolo, Daniela and Perola, Markus and Wilson, James F and Schmidt, Helena and Zhao, Jing Hua and Lehtim{\"a}ki, Terho and van Duijn, Cornelia M and Gudnason, Vilmundur and Psaty, Bruce M and Peters, Annette and Rettig, Rainer and James, Alan and Jukema, J Wouter and Strachan, David P and Palmas, Walter and Metspalu, Andres and Ingelsson, Erik and Boomsma, Dorret I and Franco, Oscar H and Bochud, Murielle and Newton-Cheh, Christopher and Munroe, Patricia B and Elliott, Paul and Chasman, Daniel I and Chakravarti, Aravinda and Knight, Joanne and Morris, Andrew P and Levy, Daniel and Tobin, Martin D and Snieder, Harold and Caulfield, Mark J and Ehret, Georg B} } @article {10499, title = {A Novel Panel of Serum Biomarkers for MPM Diagnosis.}, journal = {Dis Markers}, volume = {2017}, year = {2017}, month = {2017}, pages = {3510984}, abstract = {

Exposure to asbestos is the main cause of malignant pleural mesothelioma (MPM), a highly aggressive cancer of the pleura. Since the only tools for early detection are based on radiological tests, some authors focused on serum markers (i.e., mesothelin). The aim of this study was the evaluation of new serum biomarkers to be used individually or in combination, in order to improve the outcome of patients whose disease would be diagnosed at an earlier stage. Serum and plasma were available from 43 subjects previously exposed to asbestos and 27 MPM patients, all being epithelioid type. All the new markers found differentially expressed in MPM and healthy subjects, by proteomic and genomic approaches, have been validated in the serum by the use of specific ELISA. The combined approach, using tools of genomics and proteomics, is found to be highly innovative for this type of disease and led to the identification of new serum markers in the diagnosis of MPM. These results, if confirmed in a larger series, may have a strong impact in this area, because early detection of this cancer in people at high risk could significantly improve the course of the disease and the clinical approach to an individualized therapy.

}, keywords = {Aged, Biomarkers, Tumor, Blood Proteins, Case-Control Studies, Female, Humans, Lung Neoplasms, Male, Mesothelioma, Middle Aged, Proteome}, issn = {1875-8630}, doi = {10.1155/2017/3510984}, author = {Bonotti, A and Foddis, R and Landi, S and Melaiu, O and De Santi, C and Giusti, L and Donadio, E and Ciregia, F and Mazzoni, M R and Lucacchini, A and Bovenzi, M and Comar, M and Pantani, E and Pistelli, A and Cristaudo, A} } @article {10569, title = {Pediatric Ovarian Torsion and its Recurrence: A Multicenter Study.}, journal = {J Pediatr Adolesc Gynecol}, volume = {30}, year = {2017}, month = {2017 Jun}, pages = {413-417}, abstract = {

STUDY OBJECTIVE: To report results of a retrospective multicentric Italian survey concerning the management of pediatric ovarian torsion (OT) and its recurrence.

DESIGN: Multicenter retrospective cohort study.

SETTING: Italian Units of Pediatric Surgery.

PARTICIPANTS: Participants were female aged 1-14~years of age with surgically diagnosed OT between 2004 and~2014.

INTERVENTIONS: Adnexal detorsion, adnexectomy, mass excision using laparoscopy or laparotomy. Different kinds of oophoropexy (OPY) for OT or recurrence, respectively.

MAIN OUTCOME MEASURES: A total of 124 questionnaires were returned and analyzed to understand the current management of pediatric OT and its recurrence. The questionnaires concerned patient age, presence of menarche, OT site, presence and type of mass, performed procedure, OPY technique adopted, intra- and postoperative complications, recurrence and site, procedure performed for recurrence, OPY technique for recurrence, and 1~year follow-up of detorsed ovaries.

RESULTS: Mean age at surgery was 9.79~{\textpm}~3.54~years. Performed procedures were open adnexectomy (52 of 125; 41.6\%), laparoscopic adnexectomy~(25 of 125; 20\%), open detorsion (10 of 125; 8\%), and laparoscopic detorsion (38 of 125; 30.4\%). Recurrence occurred in 15 of 125 cases (12\%) and resulted as~significant (P~=~.012) if associated with a normal ovary at the first episode of torsion. Recurrence occurred only in 1 of 19 cases after OPY (5.2\%). Ultrasonographic results of detorsed ovaries were not significant whether an OPY was performed or not (P~=~1.00).

CONCLUSION: Unfortunately, oophorectomy and open technique are still widely adopted even if not advised. Recurrence is not rare and the risk is greater in patients without ovarian masses. OPY does not adversely affect ultrasonographic results at 1~year. When possible OPY should be performed at the first episode of OT.

}, keywords = {Adolescent, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Italy, Laparoscopy, Laparotomy, Menarche, Ovarian Diseases, Ovariectomy, Postoperative Complications, Recurrence, Retrospective Studies, Surveys and Questionnaires, Torsion Abnormality}, issn = {1873-4332}, doi = {10.1016/j.jpag.2016.11.008}, author = {Bertozzi, Mirko and Esposito, Ciro and Vella, Claudio and Briganti, Vito and Zampieri, Nicola and Codrich, Daniela and Ubertazzi, Michele and Trucchi, Alessandro and Magrini, Elisa and Battaglia, Sonia and Bini, Vittorio and Conighi, Maria Luisa and Gulia, Caterina and Farina, Alessandra and Camoglio, Francesco Saverio and Rigamonti, Waifro and Gamba, Piergiorgio and Riccipetitoni, Giovanna and Chiarenza, Salvatore Fabio and Inserra, Alessandro and Appignani, Antonino} } @article {10500, title = {Phenotypic expression of 19q13.32 microdeletions: Report of a new patient and review of the literature.}, journal = {Am J Med Genet A}, year = {2017}, month = {2017 Apr 14}, abstract = {

The phenotypic manifestations of microdeletions in the 19q13.32 region are still poorly known. In this paper we report a patient who presented with hypotonia, developmental delay, facial dysmorphism, micrognathia, kyphoscoliosis, and buried penis. Chromosomal microarray revealed an interstitial 327 kb de novo microdeletion in the 19q13.32 region comprising eight genes (ARGHAP35, NPAS1, TMEM160, ZC3H4, SAE1, BBC3, MIR3190, and MIR3191). Previously reported cases of microdeletions in the 19q13.32 region were reviewed and compared to our patient, highlighting the common features of a possible 19q13.32 microdeletion syndrome.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38256}, author = {Travan, Laura and Naviglio, Samuele and De Cunto, Angela and Pellegrin, Andrea and Pecile, Vanna and Spinelli, Alessandro Mauro and Cappellani, Stefania and Faletra, Flavio} } @article {10507, title = {Pregnant with HIV before age 25: data from a large national study in Italy, 2001-2016.}, journal = {Epidemiol Infect}, volume = {145}, year = {2017}, month = {2017 08}, pages = {2360-2365}, abstract = {

Young pregnant women with HIV may be at significant risk of unplanned pregnancy, lower treatment coverage, and other adverse pregnancy outcomes. In a large cohort of pregnant women with HIV in Italy, among 2979 pregnancies followed in 2001-2016, 9{\textperiodcentered}0\% were in women <25 years, with a significant increase over time (2001-2005: 7{\textperiodcentered}0\%; 2006-2010: 9{\textperiodcentered}1\%; 2011-2016: 12{\textperiodcentered}2\%, P < 0{\textperiodcentered}001). Younger women had a lower rate of planned pregnancy (23{\textperiodcentered}2\% vs. 37{\textperiodcentered}7\%, odds ratio (OR) 0{\textperiodcentered}50, 95\% confidence interval (CI) 0{\textperiodcentered}36-0{\textperiodcentered}69), were more frequently diagnosed with HIV in pregnancy (46{\textperiodcentered}5\% vs. 20{\textperiodcentered}9\%, OR 3{\textperiodcentered}29, 95\% CI 2{\textperiodcentered}54-4{\textperiodcentered}25), and, if already diagnosed with HIV before pregnancy, were less frequently on antiretroviral treatment at conception (<25 years: 56{\textperiodcentered}3\%; ⩾25 years: 69{\textperiodcentered}0\%, OR 0{\textperiodcentered}58, 95\% CI 0{\textperiodcentered}41-0{\textperiodcentered}81). During pregnancy, treatment coverage was almost universal in both age groups (98{\textperiodcentered}5\% vs. 99{\textperiodcentered}3\%), with no differences in rate of HIV viral suppression at third trimester and adverse pregnancy outcomes. The data show that young women represent a growing proportion of pregnant women with HIV, and are significantly more likely to have unplanned pregnancy, undiagnosed HIV infection, and lower treatment coverage at conception. During pregnancy, antiretroviral treatment, HIV suppression, and pregnancy outcomes are similar compared with older women. Earlier intervention strategies may provide additional benefits in the quality of care for women with HIV.

}, keywords = {Adolescent, Cohort Studies, Female, HIV Infections, Humans, Italy, Odds Ratio, Pregnancy, Young Adult}, issn = {1469-4409}, doi = {10.1017/S0950268817001340}, author = {Floridia, M and Masuelli, G and Tamburrini, E and Cetin, I and Liuzzi, G and Martinelli, P and Guaraldi, G and Spinillo, A and Vimercati, A and Maso, G and Pinnetti, C and Frisina, V and Dalzero, S and Ravizza, M} } @article {10561, title = {Preoperative Serum Human Epididymis Protein 4 Levels in Early Stage Endometrial Cancer: A Prospective Study.}, journal = {Int J Gynecol Cancer}, volume = {27}, year = {2017}, month = {2017 07}, pages = {1200-1205}, abstract = {

OBJECTIVE: The aim of the study was to evaluate the prognostic value of human epididymis protein 4 (HE4) and cancer antigen 125 markers with pathological prognostic factor to complete the preoperative clinical panel and help the treatment planning.

METHODS: This prospective multicenter study was conducted in 2 gynecologic oncology centers between 2012 and 2014 (Institute for Maternal and Child Health IRCCS Burlo Garofolo in Trieste and Catholic University of the Sacred Heart in Rome, Italy). We enrolled 153 patients diagnosed with clinical early (International Federation of Gynecology and Obstetrics stages I-II) type I endometrial cancer.

RESULTS: Human epididymis protein 4 levels seemed to be strictly related to age (P < 0.001) and menopausal status (P < 0.002). Compared with myometrial invasion (MI), the HE4 values were significantly higher in case of invasion of greater than 50\% of the thickness: MI of greater than 50\%, median of 94.85 pmol/L (38.3-820.8 pmol/L), versus MI of less than 50\%, median of 65.65 pmol/L (25.1-360.2 pmol/L), (P < 0.001). The HE4 levels increase significantly with increasing tumor size: diameter of larger than 2 cm, median of 86.9 pmol/L (35.8-820.8 pmol/L), versus diameter of smaller than 2 cm, median of 52.2 pmol/L (33.3-146.8 pmol/L), (P < 0.001). In our population, HE4 did not correlate with the histological grade, endometrial cancer type I versus type II (P = 0.86), the lymphovascular infiltration (P = 0.12), and the cervical invasion (P = 0.6). We established a new variable, considering 3 high-risk tumor features: MI of greater than 50\% and/or histological G3 and/or type II. Human epididymis protein 4 levels significantly increase in high-risk tumors (high risk HE4, 93.6 pmol/L vs low-medium risk, 65.5 pmol/L; P < 0.001).

CONCLUSIONS: A preoperative HE4 evaluation could help stratify patients with deep invasion and/or metastatic disease and is correlated with other relevant prognostic factors to be considered to tailor an adequate surgical strategy.

}, keywords = {Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Endometrial Neoplasms, Female, Humans, Middle Aged, Neoplasm Staging, Preoperative Care, Prognosis, Prospective Studies, Proteins}, issn = {1525-1438}, doi = {10.1097/IGC.0000000000001015}, author = {Fanfani, Francesco and Restaino, Stefano and Cicogna, Stefania and Petrillo, Marco and Montico, Marcella and Perrone, Emanuele and Radillo, Oriano and De Leo, Rossella and Ceccarello, Matteo and Scambia, Giovanni and Ricci, Giuseppe} } @article {10493, title = {Rare and low-frequency coding variants alter human adult height.}, journal = {Nature}, volume = {542}, year = {2017}, month = {2017 02 09}, pages = {186-190}, abstract = {

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8\%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

}, keywords = {ADAMTS Proteins, Adult, Alleles, Body Height, Cell Adhesion Molecules, Female, Gene Frequency, Genetic Variation, Genome, Human, Glycoproteins, Glycosaminoglycans, Hedgehog Proteins, Humans, Intercellular Signaling Peptides and Proteins, Interferon Regulatory Factors, Interleukin-11 Receptor alpha Subunit, Male, Multifactorial Inheritance, NADPH Oxidase 4, NADPH Oxidases, Phenotype, Pregnancy-Associated Plasma Protein-A, Procollagen N-Endopeptidase, Proteoglycans, Proteolysis, Receptors, Androgen, Somatomedins}, issn = {1476-4687}, doi = {10.1038/nature21039}, author = {Marouli, Eirini and Graff, Mariaelisa and Medina-Gomez, Carolina and Lo, Ken Sin and Wood, Andrew R and Kjaer, Troels R and Fine, Rebecca S and Lu, Yingchang and Schurmann, Claudia and Highland, Heather M and R{\"u}eger, Sina and Thorleifsson, Gudmar and Justice, Anne E and Lamparter, David and Stirrups, Kathleen E and Turcot, Val{\'e}rie and Young, Kristin L and Winkler, Thomas W and Esko, T{\~o}nu and Karaderi, Tugce and Locke, Adam E and Masca, Nicholas G D and Ng, Maggie C Y and Mudgal, Poorva and Rivas, Manuel A and Vedantam, Sailaja and Mahajan, Anubha and Guo, Xiuqing and Abecasis, Goncalo and Aben, Katja K and Adair, Linda S and Alam, Dewan S and Albrecht, Eva and Allin, Kristine H and Allison, Matthew and Amouyel, Philippe and Appel, Emil V and Arveiler, Dominique and Asselbergs, Folkert W and Auer, Paul L and Balkau, Beverley and Banas, Bernhard and Bang, Lia E and Benn, Marianne and Bergmann, Sven and Bielak, Lawrence F and Bl{\"u}her, Matthias and Boeing, Heiner and Boerwinkle, Eric and B{\"o}ger, Carsten A and Bonnycastle, Lori L and Bork-Jensen, Jette and Bots, Michiel L and Bottinger, Erwin P and Bowden, Donald W and Brandslund, Ivan and Breen, Gerome and Brilliant, Murray H and Broer, Linda and Burt, Amber A and Butterworth, Adam S and Carey, David J and Caulfield, Mark J and Chambers, John C and Chasman, Daniel I and Chen, Yii-Der Ida and Chowdhury, Rajiv and Christensen, Cramer and Chu, Audrey Y and Cocca, Massimiliano and Collins, Francis S and Cook, James P and Corley, Janie and Galbany, Jordi Corominas and Cox, Amanda J and Cuellar-Partida, Gabriel and Danesh, John and Davies, Gail and de Bakker, Paul I W and de Borst, Gert J and de Denus, Simon and de Groot, Mark C H and de Mutsert, Ren{\'e}e and Deary, Ian J and Dedoussis, George and Demerath, Ellen W and den Hollander, Anneke I and Dennis, Joe G and Di Angelantonio, Emanuele and Drenos, Fotios and Du, Mengmeng and Dunning, Alison M and Easton, Douglas F and Ebeling, Tapani and Edwards, Todd L and Ellinor, Patrick T and Elliott, Paul and Evangelou, Evangelos and Farmaki, Aliki-Eleni and Faul, Jessica D and Feitosa, Mary F and Feng, Shuang and Ferrannini, Ele and Ferrario, Marco M and Ferri{\`e}res, Jean and Florez, Jose C and Ford, Ian and Fornage, Myriam and Franks, Paul W and Frikke-Schmidt, Ruth and Galesloot, Tessel E and Gan, Wei and Gandin, Ilaria and Gasparini, Paolo and Giedraitis, Vilmantas and Giri, Ayush and Girotto, Giorgia and Gordon, Scott D and Gordon-Larsen, Penny and Gorski, Mathias and Grarup, Niels and Grove, Megan L and Gudnason, Vilmundur and Gustafsson, Stefan and Hansen, Torben and Harris, Kathleen Mullan and Harris, Tamara B and Hattersley, Andrew T and Hayward, Caroline and He, Liang and Heid, Iris M and Heikkil{\"a}, Kauko and Helgeland, {\O}yvind and Hernesniemi, Jussi and Hewitt, Alex W and Hocking, Lynne J and Hollensted, Mette and Holmen, Oddgeir L and Hovingh, G Kees and Howson, Joanna M M and Hoyng, Carel B and Huang, Paul L and Hveem, Kristian and Ikram, M Arfan and Ingelsson, Erik and Jackson, Anne U and Jansson, Jan-H{\r a}kan and Jarvik, Gail P and Jensen, Gorm B and Jhun, Min A and Jia, Yucheng and Jiang, Xuejuan and Johansson, Stefan and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Jousilahti, Pekka and Jukema, J Wouter and Kahali, Bratati and Kahn, Ren{\'e} S and K{\"a}h{\"o}nen, Mika and Kamstrup, Pia R and Kanoni, Stavroula and Kaprio, Jaakko and Karaleftheri, Maria and Kardia, Sharon L R and Karpe, Fredrik and Kee, Frank and Keeman, Renske and Kiemeney, Lambertus A and Kitajima, Hidetoshi and Kluivers, Kirsten B and Kocher, Thomas and Komulainen, Pirjo and Kontto, Jukka and Kooner, Jaspal S and Kooperberg, Charles and Kovacs, Peter and Kriebel, Jennifer and Kuivaniemi, Helena and K{\"u}ry, S{\'e}bastien and Kuusisto, Johanna and La Bianca, Martina and Laakso, Markku and Lakka, Timo A and Lange, Ethan M and Lange, Leslie A and Langefeld, Carl D and Langenberg, Claudia and Larson, Eric B and Lee, I-Te and Lehtim{\"a}ki, Terho and Lewis, Cora E and Li, Huaixing and Li, Jin and Li-Gao, Ruifang and Lin, Honghuang and Lin, Li-An and Lin, Xu and Lind, Lars and Lindstr{\"o}m, Jaana and Linneberg, Allan and Liu, Yeheng and Liu, Yongmei and Lophatananon, Artitaya and Luan, Jian{\textquoteright}an and Lubitz, Steven A and Lyytik{\"a}inen, Leo-Pekka and Mackey, David A and Madden, Pamela A F and Manning, Alisa K and M{\"a}nnist{\"o}, Satu and Marenne, Ga{\"e}lle and Marten, Jonathan and Martin, Nicholas G and Mazul, Angela L and Meidtner, Karina and Metspalu, Andres and Mitchell, Paul and Mohlke, Karen L and Mook-Kanamori, Dennis O and Morgan, Anna and Morris, Andrew D and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Munroe, Patricia B and Nalls, Mike A and Nauck, Matthias and Nelson, Christopher P and Neville, Matt and Nielsen, Sune F and Nikus, Kjell and Nj{\o}lstad, P{\r a}l R and Nordestgaard, B{\o}rge G and Ntalla, Ioanna and O{\textquoteright}Connel, Jeffrey R and Oksa, Heikki and Loohuis, Loes M Olde and Ophoff, Roel A and Owen, Katharine R and Packard, Chris J and Padmanabhan, Sandosh and Palmer, Colin N A and Pasterkamp, Gerard and Patel, Aniruddh P and Pattie, Alison and Pedersen, Oluf and Peissig, Peggy L and Peloso, Gina M and Pennell, Craig E and Perola, Markus and Perry, James A and Perry, John R B and Person, Thomas N and Pirie, Ailith and Polasek, Ozren and Posthuma, Danielle and Raitakari, Olli T and Rasheed, Asif and Rauramaa, Rainer and Reilly, Dermot F and Reiner, Alex P and Renstrom, Frida and Ridker, Paul M and Rioux, John D and Robertson, Neil and Robino, Antonietta and Rolandsson, Olov and Rudan, Igor and Ruth, Katherine S and Saleheen, Danish and Salomaa, Veikko and Samani, Nilesh J and Sandow, Kevin and Sapkota, Yadav and Sattar, Naveed and Schmidt, Marjanka K and Schreiner, Pamela J and Schulze, Matthias B and Scott, Robert A and Segura-Lepe, Marcelo P and Shah, Svati and Sim, Xueling and Sivapalaratnam, Suthesh and Small, Kerrin S and Smith, Albert Vernon and Smith, Jennifer A and Southam, Lorraine and Spector, Timothy D and Speliotes, Elizabeth K and Starr, John M and Steinthorsdottir, Valgerdur and Stringham, Heather M and Stumvoll, Michael and Surendran, Praveen and {\textquoteright}t Hart, Leen M and Tansey, Katherine E and Tardif, Jean-Claude and Taylor, Kent D and Teumer, Alexander and Thompson, Deborah J and Thorsteinsdottir, Unnur and Thuesen, Betina H and T{\"o}njes, Anke and Tromp, Gerard and Trompet, Stella and Tsafantakis, Emmanouil and Tuomilehto, Jaakko and Tybjaerg-Hansen, Anne and Tyrer, Jonathan P and Uher, Rudolf and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and van der Laan, Sander W and Van Der Leij, Andries R and van Duijn, Cornelia M and van Schoor, Natasja M and van Setten, Jessica and Varbo, Anette and Varga, Tibor V and Varma, Rohit and Edwards, Digna R Velez and Vermeulen, Sita H and Vestergaard, Henrik and Vitart, Veronique and Vogt, Thomas F and Vozzi, Diego and Walker, Mark and Wang, Feijie and Wang, Carol A and Wang, Shuai and Wang, Yiqin and Wareham, Nicholas J and Warren, Helen R and Wessel, Jennifer and Willems, Sara M and Wilson, James G and Witte, Daniel R and Woods, Michael O and Wu, Ying and Yaghootkar, Hanieh and Yao, Jie and Yao, Pang and Yerges-Armstrong, Laura M and Young, Robin and Zeggini, Eleftheria and Zhan, Xiaowei and Zhang, Weihua and Zhao, Jing Hua and Zhao, Wei and Zhao, Wei and Zheng, He and Zhou, Wei and Rotter, Jerome I and Boehnke, Michael and Kathiresan, Sekar and McCarthy, Mark I and Willer, Cristen J and Stefansson, Kari and Borecki, Ingrid B and Liu, Dajiang J and North, Kari E and Heard-Costa, Nancy L and Pers, Tune H and Lindgren, Cecilia M and Oxvig, Claus and Kutalik, Zolt{\'a}n and Rivadeneira, Fernando and Loos, Ruth J F and Frayling, Timothy M and Hirschhorn, Joel N and Deloukas, Panos and Lettre, Guillaume} } @article {10575, title = {Rate, correlates and outcomes of repeat pregnancy in HIV-infected women.}, journal = {HIV Med}, volume = {18}, year = {2017}, month = {2017 07}, pages = {440-443}, abstract = {

OBJECTIVES: The aim of the study was to assess the rate, determinants, and outcomes of repeat pregnancies in women with HIV infection.

METHODS: Data from a national study of pregnant women with HIV infection were used. Main outcomes were preterm delivery, low birth weight, CD4 cell count and HIV plasma viral load.

RESULTS: The rate of repeat pregnancy among 3007 women was 16.2\%. Women with a repeat pregnancy were on average younger than those with a single pregnancy (median age 30 vs. 33 years, respectively), more recently diagnosed with HIV infection (median time since diagnosis 25 vs. 51 months, respectively), and more frequently of foreign origin [odds ratio (OR) 1.36; 95\% confidence interval (CI) 1.10-1.68], diagnosed with HIV infection in the current pregnancy (OR: 1.69; 95\% CI: 1.35-2.11), and at their first pregnancy (OR: 1.33; 95\% CI: 1.06-1.66). In women with sequential pregnancies, compared with the first pregnancy, several outcomes showed a significant improvement in the second pregnancy, with a higher rate of antiretroviral treatment at conception (39.0 vs. 65.4\%, respectively), better median maternal weight at the start of pregnancy (60 vs. 61 kg, respectively), a higher rate of end-of-pregnancy undetectable HIV RNA (60.7 vs. 71.6\%, respectively), a higher median birth weight (2815 vs. 2885 g, respectively), lower rates of preterm delivery (23.0 vs. 17.7\%, respectively) and of low birth weight (23.4 vs. 15.4\%, respectively), and a higher median CD4 cell count (+47 cells/μL), with almost no clinical progression to Centers for Disease Control and Prevention stage C (CDC-C) HIV disease (0.3\%). The second pregnancy was significantly more likely to end in voluntary termination than the first pregnancy (11.4 vs. 6.1\%, respectively).

CONCLUSIONS: Younger and foreign women were more likely to have a repeat pregnancy; in women with sequential pregnancies, the second pregnancy was characterized by a significant improvement in several outcomes, suggesting that women with HIV infection who desire multiple children may proceed safely and confidently with subsequent pregnancies.

}, keywords = {Adult, Anti-HIV Agents, CD4 Lymphocyte Count, Emigrants and Immigrants, Female, HIV Infections, HIV-1, Humans, Infant, Low Birth Weight, Pregnancy, Premature Birth, Viral Load}, issn = {1468-1293}, doi = {10.1111/hiv.12473}, author = {Floridia, M and Tamburrini, E and Masuelli, G and Martinelli, P and Spinillo, A and Liuzzi, G and Vimercati, A and Alberico, S and Maccabruni, A and Pinnetti, C and Frisina, V and Dalzero, S and Ravizza, M} } @article {10491, title = {Review on the role of the human Polyomavirus JC in the development of tumors.}, journal = {Infect Agent Cancer}, volume = {12}, year = {2017}, month = {2017}, pages = {10}, abstract = {

Almost one fifth of human cancers worldwide are associated with infectious agents, either bacteria or viruses, and this makes the possible association between infections and tumors a relevant research issue. We focused our attention on the human Polyomavirus JC (JCPyV), that is a small, naked DNA virus, belonging to the family. It is the recognized etiological agent of the Progressive Multifocal Leukoencephalopathy (PML), a fatal demyelinating disease, occurring in immunosuppressed individuals. JCPyV is able to induce cell transformation in vitro when infecting non-permissive cells, that do not support viral replication and JCPyV inoculation into small animal models and non human primates drives to tumor formation. The molecular mechanisms involved in JCPyV oncogenesis have been extensively studied: the main oncogenic viral protein is the large tumor antigen (T-Ag), that is able to bind, among other cellular factors, both Retinoblastoma protein (pRb) and p53 and to dysregulate the cell cycle, but also the early proteins small tumor antigen (t-Ag) and Agnoprotein appear to cooperate in the process of cell transformation. Consequently, it is not surprising that JCPyV genomic sequences and protein expression have been detected in Central Nervous System (CNS) tumors and colon cancer and an association between this virus and several brain and non CNS-tumors has been proposed. However, the significances of these findings are under debate because there is still insufficient evidence of a casual association between JCPyV and solid cancer development. In this paper we summarized and critically analyzed the published literature, in order to describe the current knowledge on the possible role of JCPyV in the development of human tumors.

}, issn = {1750-9378}, doi = {10.1186/s13027-017-0122-0}, author = {Delbue, Serena and Comar, Manola and Ferrante, Pasquale} } @article {10551, title = {Risk of hospitalisation after early-revisit in the emergency department.}, journal = {J Paediatr Child Health}, volume = {53}, year = {2017}, month = {2017 Sep}, pages = {850-854}, abstract = {

AIM: Early-revisits are frequent in the paediatric emergency department (ED) setting, but few data are available about early-revisited patients. The aim of this study was to investigate the hospitalisation rate of a population of early-revisited patients and to detect if an early-revisited patient was at risk of a more severe disease.

METHODS: Between June 2014 and January 2015, we conducted a retrospective cohort study, considering all patients presented to the ED of a tertiary level children{\textquoteright}s hospital in Italy. We selected all patients who were revisited within 72 h from the initial visit (study cohort), while all other patients accessed in the same period were considered the control cohort. The two cohorts were compared for age, gender, triage category, hospitalisation rate, diagnosis at admission and hospital length of stay.

RESULTS: In the study period, we reviewed 10 750 visits, of which 430 (4\%) were unplanned revisits for the same chief complaint within 72 h from the initial visit. Hospitalisation rate of early-revisited patients was significantly higher compared to control patients (8.4 vs. 2.9\%). Hospitalisation rate increases in parallel with the number of revisits, but in many cases, it was not directly related to a worst triage category, neither to a longer hospital length of stay.

CONCLUSION: Early revisited patients in the ED had a significantly higher risk of hospitalisation, but this risk was only partially related to their clinical conditions.

}, keywords = {Adolescent, Child, Child, Preschool, Emergency Service, Hospital, Female, Hospitalization, Humans, Infant, Italy, Male, Retrospective Studies, Risk Assessment, Tertiary Care Centers, Time Factors}, issn = {1440-1754}, doi = {10.1111/jpc.13561}, author = {Cozzi, Giorgio and Ghirardo, Sergio and Fiorese, Ilaria and Proietti, Ilaria and Monasta, Lorenzo and Minute, Marta and Barbi, Egidio and Calligaris, Lorenzo} } @article {10466, title = {Subclinical alteration of the cervical-vaginal microbiome in women with idiopathic infertility.}, journal = {J Cell Physiol}, volume = {232}, year = {2017}, month = {2017 Jul}, pages = {1681-1688}, abstract = {

Biomarkers have a wide application in research and clinic, they help to choose the correct treatment for diseases. Recent studies, addressing the vaginal microbiome using next generation sequencing (NGS), reported the involvement of bacterial species in infertility. We compared the vaginal microbiome of idiopathic infertile women with that of healthy, including bacterial vaginosis affected women and non-idiopathic infertile women, to identify bacterial species suitable as biomarkers. Information on microorganisms was obtained from the V3-16S rDNA sequencing of cervical-vaginal fluids of 96 women using the Ion Torrent platform. Data were processed with QIIME and classified against the Vaginal 16S rDNA Reference Database. The analysis revealed a significant beta-diversity variation (p < 0.001) between the four groups included in the study. L. iners, L. crispatus, and L. gasseri distinguished idiopathic infertile women from the other groups. In these women, a microbial profile similar to that observed in bacterial vaginosis women has been detected. Our results suggest that the quantitative assessment and identification of specific microorganisms of the cervical-vaginal microflora could increase the accuracy of available tools for the diagnosis of infertility and improve the adoption of therapeutic protocols.

}, keywords = {Adult, Biodiversity, Cervix Uteri, Cohort Studies, Demography, Female, Humans, Infertility, Female, Microbiota, Species Specificity, Vagina, Vaginosis, Bacterial}, issn = {1097-4652}, doi = {10.1002/jcp.25806}, author = {Campisciano, Giuseppina and Florian, Fiorella and D{\textquoteright}Eustacchio, Angela and Stankovi{\'c}, David and Ricci, Giuseppe and De Seta, Francesco and Comar, Manola} } @article {10550, title = {Synthesis of Lipophilic Core-Shell FeO@SiO@Au Nanoparticles and Polymeric Entrapment into Nanomicelles: A Novel Nanosystem for in Vivo Active Targeting and Magnetic Resonance-Photoacoustic Dual Imaging.}, journal = {Bioconjug Chem}, volume = {28}, year = {2017}, month = {2017 05 17}, pages = {1382-1390}, abstract = {

In this work, iron/silica/gold core-shell nanoparticles (FeO@SiO@Au NPs) characterized by magnetic and optical properties have been synthesized to obtain a promising theranostic platform. To improve their biocompatibility, the obtained multilayer nanoparticles have been entrapped in polymeric micelles, decorated with folic acid moieties, and tested in vivo for photoacoustic and magnetic resonance imaging detection of ovarian cancer.

}, keywords = {Animals, Cell Proliferation, Female, Ferric Compounds, Folic Acid, Gold, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Magnetite Nanoparticles, Mice, Mice, Inbred BALB C, Mice, Nude, Micelles, Multimodal Imaging, Ovarian Neoplasms, Photoacoustic Techniques, Polymers, Silicon Dioxide, Tumor Cells, Cultured, Xenograft Model Antitumor Assays}, issn = {1520-4812}, doi = {10.1021/acs.bioconjchem.7b00076}, author = {Monaco, Ilaria and Arena, Francesca and Biffi, Stefania and Locatelli, Erica and Bortot, Barbara and La Cava, Francesca and Marini, Giada Maria and Severini, Giovanni Maria and Terreno, Enzo and Comes Franchini, Mauro} } @article {10553, title = {Towards measles elimination in Italy: Virological surveillance and genotypes trend (2013-2015).}, journal = {Virus Res}, volume = {236}, year = {2017}, month = {2017 05 15}, pages = {24-29}, abstract = {

In accordance with the goal of the World Health Organization Regional Office for Europe, the Italian National Measles and Rubella Elimination Plan aimed to interrupt indigenous measles transmission in Italy by the end of 2015. However, from 2013 to 2015, Italy experienced high measles burden with 4902 measles cases (49.3\% laboratory-confirmed) reported to the enhanced measles surveillance system (cumulative incidence in the triennium reference period: 2.4/100,000 population). The measles elimination goal was not reached. Laboratory surveillance of measles circulating genotypes is performed by the Measles and Rubella National Reference Laboratory (NRL) at the Italian National Institute of Health (Istituto Superiore di Sanit{\`a} - ISS), in Rome. Samples received from 1 January 2013-31 December 2015 were analysed. Those positive for measles genome by molecular tests were sequenced and phylogenetically analysed. Phylogenetic analysis performed by NRL identified that genotypes D4 and D8 were endemic and co-circulated in 2011-2013: study results show that genotype D4 disappeared during 2013. Sporadic cases were associated to genotype B3 during 2011-2013, which became endemic in Italy during 2014 and co-circulated with D8 until 2015. Sporadic cases were found belonging to genotypes D9 and H1 all over the period in exam. Similar trend has been observed in European WHO Region.

}, keywords = {Adolescent, Adult, Aged, Child, Child, Preschool, Disease Outbreaks, Female, Genotype, Humans, Infant, Italy, Male, Measles, Measles virus, Middle Aged, Molecular Epidemiology, Phylogeny, RNA, Viral, Sentinel Surveillance, Young Adult}, issn = {1872-7492}, doi = {10.1016/j.virusres.2017.05.009}, author = {Magurano, Fabio and Baggieri, Melissa and Filia, Antonietta and Del Manso, Martina and Lazzarotto, Tiziana and Amendola, Antonella and D{\textquoteright}Agaro, Pierlanfranco and Chironna, Maria and Ansaldi, Filippo and Iannazzo, Stefania and Bucci, Paola and Marchi, Antonella and Nicoletti, Loredana} } @article {10557, title = {Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jun 01}, pages = {865-884}, abstract = {

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71\% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

}, keywords = {Anthropometry, Body Height, Cohort Studies, Databases, Genetic, DNA Methylation, Female, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Lipodystrophy, Male, Meta-Analysis as Topic, Obesity, Physical Chromosome Mapping, Quantitative Trait Loci, Sequence Analysis, DNA, Sex Characteristics, Syndrome, United Kingdom}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.04.014}, author = {Tachmazidou, Ioanna and S{\"u}veges, D{\'a}niel and Min, Josine L and Ritchie, Graham R S and Steinberg, Julia and Walter, Klaudia and Iotchkova, Valentina and Schwartzentruber, Jeremy and Huang, Jie and Memari, Yasin and McCarthy, Shane and Crawford, Andrew A and Bombieri, Cristina and Cocca, Massimiliano and Farmaki, Aliki-Eleni and Gaunt, Tom R and Jousilahti, Pekka and Kooijman, Marjolein N and Lehne, Benjamin and Malerba, Giovanni and M{\"a}nnist{\"o}, Satu and Matchan, Angela and Medina-Gomez, Carolina and Metrustry, Sarah J and Nag, Abhishek and Ntalla, Ioanna and Paternoster, Lavinia and Rayner, Nigel W and Sala, Cinzia and Scott, William R and Shihab, Hashem A and Southam, Lorraine and St Pourcain, Beate and Traglia, Michela and Trajanoska, Katerina and Zaza, Gialuigi and Zhang, Weihua and Artigas, Mar{\'\i}a S and Bansal, Narinder and Benn, Marianne and Chen, Zhongsheng and Danecek, Petr and Lin, Wei-Yu and Locke, Adam and Luan, Jian{\textquoteright}an and Manning, Alisa K and Mulas, Antonella and Sidore, Carlo and Tybjaerg-Hansen, Anne and Varbo, Anette and Zoledziewska, Magdalena and Finan, Chris and Hatzikotoulas, Konstantinos and Hendricks, Audrey E and Kemp, John P and Moayyeri, Alireza and Panoutsopoulou, Kalliope and Szpak, Michal and Wilson, Scott G and Boehnke, Michael and Cucca, Francesco and Di Angelantonio, Emanuele and Langenberg, Claudia and Lindgren, Cecilia and McCarthy, Mark I and Morris, Andrew P and Nordestgaard, B{\o}rge G and Scott, Robert A and Tobin, Martin D and Wareham, Nicholas J and Burton, Paul and Chambers, John C and Smith, George Davey and Dedoussis, George and Felix, Janine F and Franco, Oscar H and Gambaro, Giovanni and Gasparini, Paolo and Hammond, Christopher J and Hofman, Albert and Jaddoe, Vincent W V and Kleber, Marcus and Kooner, Jaspal S and Perola, Markus and Relton, Caroline and Ring, Susan M and Rivadeneira, Fernando and Salomaa, Veikko and Spector, Timothy D and Stegle, Oliver and Toniolo, Daniela and Uitterlinden, Andr{\'e} G and Barroso, In{\^e}s and Greenwood, Celia M T and Perry, John R B and Walker, Brian R and Butterworth, Adam S and Xue, Yali and Durbin, Richard and Small, Kerrin S and Soranzo, Nicole and Timpson, Nicholas J and Zeggini, Eleftheria} } @article {10490, title = {Withdrawal Assessment Tool-1 Monitoring in PICU: A Multicenter Study on Iatrogenic Withdrawal Syndrome.}, journal = {Pediatr Crit Care Med}, volume = {18}, year = {2017}, month = {2017 02}, pages = {e86-e91}, abstract = {

OBJECTIVES: Withdrawal syndrome is an adverse reaction of analgesic and sedative therapy, with a reported occurrence rate between 17\% and 57\% in critically ill children. Although some factors related to the development of withdrawal syndrome have been identified, there is weak evidence for the effectiveness of preventive and therapeutic strategies. The main aim of this study was to evaluate the frequency of withdrawal syndrome in Italian PICUs, using a validated instrument. We also analyzed differences in patient characteristics, analgesic and sedative treatment, and patients{\textquoteright} outcome between patients with and without withdrawal syndrome.

DESIGN: Observational multicenter prospective study.

SETTING: Eight Italian PICUs belonging to the national PICU network Italian PICU network.

PATIENTS: One hundred thirteen patients, less than 18 years old, mechanically ventilated and treated with analgesic and sedative therapy for five or more days. They were admitted in PICU from November 2012 to May 2014.

INTERVENTIONS: Symptoms of withdrawal syndrome were monitored with Withdrawal Assessment Tool-1 scale.

MEASUREMENTS AND MAIN RESULTS: The occurrence rate of withdrawal syndrome was 64.6\%. The following variables were significantly different between the patients who developed withdrawal syndrome and those who did not: type, duration, and cumulative dose of analgesic therapy; duration and cumulative dose of sedative therapy; clinical team judgment about analgesia and sedation{\textquoteright}s difficulty; and duration of analgesic weaning, mechanical ventilation, and PICU stay. Multivariate logistic regression analysis revealed that patients receiving morphine as their primary analgesic were 83\% less likely to develop withdrawal syndrome than those receiving fentanyl or remifentanil.

CONCLUSIONS: Withdrawal syndrome was frequent in PICU patients, and patients with withdrawal syndrome had prolonged hospital treatment. We suggest adopting the lowest effective dose of analgesic and sedative drugs and frequent reevaluation of the need for continued use. Further studies are necessary to define common preventive and therapeutic strategies.

}, keywords = {Adolescent, Analgesics, Child, Child, Preschool, Critical Care, Female, Humans, Hypnotics and Sedatives, Iatrogenic Disease, Infant, Infant, Newborn, Intensive Care Units, Pediatric, Italy, Logistic Models, Male, Prospective Studies, Respiration, Artificial, Substance Withdrawal Syndrome}, issn = {1529-7535}, doi = {10.1097/PCC.0000000000001054}, author = {Amigoni, Angela and Mondardini, Maria Cristina and Vittadello, Ilaria and Zaglia, Federico and Rossetti, Emanuele and Vitale, Francesca and Ferrario, Stefania and Savron, Fabio and Coffaro, Giancarlo and Brugnaro, Luca and Amato, Roberta and Wolfler, Andrea and Franck, Linda S} } @article {8337, title = {Achieving early functional auditory access in paediatric cochlear implantation.}, journal = {Acta Otorhinolaryngol Ital}, volume = {36}, year = {2016}, month = {2016 Feb}, pages = {45-50}, abstract = {

Cochlear implantation (CI) is a viable option for providing access to auditory stimulation in severe-to-profound hearing loss/impairment of cochlear origin. It has been demonstrated that CI is safe and effective for deaf children. Younger age at activation after CI is linked with better outcomes. It is important to study variables and issues that can interfere with an early fitting and access to sound after CI. They range from patient characteristics, family compliance and support, to technical, medical or organisational problems. A SWOT analysis and a subsequent TOWS matrix was conducted to discuss issues and propose recommendations to be considered when operating an early switch on of the CI.

}, issn = {1827-675X}, doi = {10.14639/0392-100X-1075}, author = {Orzan, E and Muzzi, E and Marchi, R and Falzone, C and Battelino, S and Ciciriello, E} } @article {8493, title = {Anti-ApoA-1 IgG serum levels predict worse poststroke outcomes.}, journal = {Eur J Clin Invest}, volume = {46}, year = {2016}, month = {2016 Sep}, pages = {805-17}, abstract = {

BACKGROUND: Autoantibodies to apolipoprotein A-1 (anti-ApoA-1 IgG) were shown to predict major adverse cardiovascular events and promote atherogenesis. However, their potential relationship with clinical disability and ischaemic lesion volume after acute ischaemic stroke (AIS) remains unexplored.

MATERIALS AND METHODS: We included n = 76 patients admitted for AIS and we investigated whether baseline serum anti-ApoA-1 IgG levels could predict (i) AIS-induced clinical disability [assessed by the modified Rankin Scale (mRS)], and (ii) AIS-related ischaemic lesion volume [assessed by Computed Tomography (CT)]. We also evaluated the possible pro-apoptotic and pro-necrotic effects of anti-ApoA-1 IgG on human astrocytoma cell line (U251) using flow cytometry.

RESULTS: High levels of anti-ApoA-1 IgG were retrieved in 15{\textperiodcentered}8\% (12/76) of patients. Increased baseline levels of anti-ApoA-1 IgG were independently correlated with worse mRS [β = 0{\textperiodcentered}364; P = 0{\textperiodcentered}002; adjusted odds ratio (OR): 1{\textperiodcentered}05 (95\% CI 1{\textperiodcentered}01-1{\textperiodcentered}09); P = 0{\textperiodcentered}017] and CT-assessed ischaemic lesion volume [β = 0{\textperiodcentered}333; P < 0{\textperiodcentered}001; adjusted OR: 1{\textperiodcentered}06 (95\% CI 1{\textperiodcentered}01-1{\textperiodcentered}12); P = 0{\textperiodcentered}048] at 3 months. No difference in baseline clinical, biochemical and radiological characteristics was observed between patients with high vs. low levels of anti-ApoA-1 IgG. Incubating human astrocytoma cells with anti-ApoA-1 IgG dose dependently induced necrosis and apoptosis of U251 cells in vitro.

CONCLUSION: Anti-ApoA-1 IgG serum levels at AIS onset are associated with poorer clinical recovery and worse brain lesion volume 3 months after AIS. These observations could be partly explained by the deleterious effect of anti-ApoA-1 IgG on human brain cell survival in vitro and may have clinical implication in the prediction of poor outcome in AIS.

}, issn = {1365-2362}, doi = {10.1111/eci.12664}, author = {Carbone, Federico and Satta, Nathalie and Montecucco, Fabrizio and Virzi, Julien and Burger, Fabienne and Roth, Aline and Roversi, Gloria and Tamborino, Carmine and Casetta, Ilaria and Seraceni, Silva and Trentini, Alessandro and Padroni, Marina and Dallegri, Franco and Lalive, Patrice H and Mach, Fran{\c c}ois and Fainardi, Enrico and Vuilleumier, Nicolas} } @article {8482, title = {A Case of Prenatal Neurocytoma Associated With ATR-16 Syndrome.}, journal = {J Ultrasound Med}, volume = {35}, year = {2016}, month = {2016 Jun}, pages = {1359-61}, issn = {1550-9613}, doi = {10.7863/ultra.15.07045}, author = {Quadrifoglio, Mariachiara and Faletra, Flavio and Bussani, Rossana and Pecile, Vanna and Zennaro, Floriana and Grasso, Alessandra and Zandon{\`a}, Lorenzo and Alberico, Salvatore and Stampalija, Tamara} } @article {8332, title = {Chronic nonbacterial osteomyelitis may be associated with renal disease and bisphosphonates are a good option for the majority of patients.}, journal = {Acta Paediatr}, volume = {105}, year = {2016}, month = {2016 Jul}, pages = {e328-33}, abstract = {

AIM: The aim of this Italian study was to describe the clinical features, treatment options and outcomes of a cohort of patients with chronic nonbacterial osteomyelitis (CNO).

METHODS: This was a retrospective cohort study. Laboratory data, diagnostic imaging, histological features and clinical course are reported.

RESULTS: We enrolled 47 patients diagnosed with CNO. Bone pain was the leading symptom, and multifocal disease was present in 87\% of the patients. The majority of the bone lesions were located in the appendicular skeleton (58\%). Extraosseous manifestations were present in 34\% of the patients, and renal involvement was detected in four patients. Inflammatory indices were increased in 80\%, and bone x-rays were negative in 15\% of the patients. Nonsteroidal anti-inflammatory drugs (NSAIDs) were the first therapy for all patients, achieving clinical remission in 27\%. A good response to NSAIDs was significantly associated with a better prognosis. Bisphosphonates were used in 26 patients, with remission in 73\%. Only six patients (13\%), all with spine involvement, developed sequelae.

CONCLUSION: We found a possible association between CNO and renal disease. Bisphosphonates were more likely to lead to clinical remission when NSAIDs and corticosteroids had failed. Vertebral localisation was the only risk factor for potential sequelae.

}, issn = {1651-2227}, doi = {10.1111/apa.13420}, author = {Pastore, Serena and Ferrara, Giovanna and Monasta, Lorenzo and Meini, Antonella and Cattalini, Marco and Martino, Silvana and Alessio, Maria and La Torre, Francesco and Teruzzi, Barbara and Gerloni, Valeria and Breda, Luciana and Taddio, Andrea and Lepore, Loredana} } @article {8342, title = {Circulating levels of TNF-related apoptosis inducing-ligand are decreased in patients with large adult-type granulosa cell tumors-implications for therapeutic potential.}, journal = {Tumour Biol}, year = {2016}, month = {2016 Apr 11}, abstract = {

Targeted treatments are needed for advanced adult-type granulosa cell tumors (AGCTs). We set out to assess tumor tissue and circulating levels of TNF-related apoptosis-inducing ligand (TRAIL), a promising anti-cancer cytokine, in patients affected by AGCT. We analyzed tissue expression of TRAIL in 127 AGCTs using immunohistochemistry or RT-PCR. Soluble TRAIL was measured by means of ELISA from 141 AGCT patient serum samples, as well as the conditioned media of 15 AGCT patient-derived primary cell cultures, and the KGN cell line. Tissue and serum TRAIL levels were analyzed in relationship with clinical parameters, and serum estradiol, FSH, and LH levels. We found that AGCT samples expressed TRAIL mRNA and protein at levels comparable to normal granulosa cells. AGCT cells did not release soluble TRAIL. TRAIL protein levels were decreased in tumors over 10~cm in diameter (p = 0.04). Consistently, circulating TRAIL levels correlated negatively to tumor dimension (p = 0.01). Circulating TRAIL levels negatively associated with serum estradiol levels. In multiple regression analysis, tumor size was an independent factor contributing to the decreased levels of soluble TRAIL in AGCT patients. AGCTs associate with significantly decreased tumor tissue and serum TRAIL levels in patients with a large tumor mass. These findings encourage further study of agonistic TRAIL treatments in patients with advanced or recurrent AGCT.

}, issn = {1423-0380}, doi = {10.1007/s13277-016-5042-x}, author = {F{\"a}rkkil{\"a}, Anniina and Zauli, Giorgio and Haltia, Ulla-Maija and Pihlajoki, Marjut and Unkila-Kallio, Leila and Secchiero, Paola and Heikinheimo, Markku} } @article {8503, title = {Clinical and pathogenetic features of ETV6 related thrombocytopenia with predisposition to acute lymphoblastic leukemia.}, journal = {Haematologica}, year = {2016}, month = {2016 Jun 30}, abstract = {

ETV6-related thrombocytopenia (ETV6-RT) is an autosomal dominant thrombocytopenia that has been recently identified in a few families and has been suspected to predispose to hematological malignancies. To gain further information on this disorder, we searched for ETV6 mutations in the 130 families with inherited thrombocytopenia of unknown origin from our cohort of 274 consecutive pedigrees with familial thrombocytopenia. We identified 20 ETV6-RT patients from 7 pedigrees. They have 5 different ETV6 variants, including three novel mutations affecting the highly conserved E26 transformation-specific domain. The relative frequency of ETV6-RT resulted 2.6\% in the whole case series and 4.6\% among the families with known forms of inherited thrombocytopenia. The degree of thrombocytopenia and bleeding tendency of ETV6-RT patients were mild, but 4 subjects developed B-cell acute lymphoblastic leukemia during childhood, resulting in a significantly increased incidence compared to the general population. Clinical and laboratory findings did not identify any peculiar defects that can be used to suspect this disorder by routine diagnostic workup. However, at variance with most inherited thrombocytopenias, platelet size was not enlarged. In vitro studies revealed that patients megakaryocytes have defective maturation and impaired proplatelet formation. Moreover, ETV6-RT platelets have reduced ability to spread on fibrinogen. Since also the dominant thrombocytopenias due to mutations in RUNX1 and ANKRD26 are characterized by normal platelet size and predispose to hematological malignancies, we suggest that mutation screening of ETV6, RUNX1 and ANKRD26 should be performed in all the subjects with autosomal dominant thrombocytopenia and normal platelet size.

}, issn = {1592-8721}, doi = {10.3324/haematol.2016.147496}, author = {Melazzini, Federica and Palombo, Flavia and Balduini, Alessandra and De Rocco, Daniela and Marconi, Caterina and Noris, Patrizia and Gnan, Chiara and Pippucci, Tommaso and Bozzi, Valeria and Faleschini, Michela and Barozzi, Serena and Doubek, Michael and Di Buduo, Christian A and Stano Kozubik, Katerina and Radova, Lenka and Loffredo, Giuseppe and Pospisilova, Sarka and Alfano, Caterina and Seri, Marco and Balduini, Carlo L and Pecci, Alessandro and Savoia, Anna} } @article {8348, title = {Clinical Spectrum of PRKAG2 Syndrome.}, journal = {Circ Arrhythm Electrophysiol}, volume = {9}, year = {2016}, month = {2016 Jan}, pages = {e003121}, keywords = {AMP-Activated Protein Kinases, DNA, Heart Conduction System, Humans, Mutation, Wolff-Parkinson-White Syndrome}, issn = {1941-3084}, doi = {10.1161/CIRCEP.115.003121}, author = {Porto, Andrea Giuseppe and Brun, Francesca and Severini, Giovanni Maria and Losurdo, Pasquale and Fabris, Enrico and Taylor, Matthew R G and Mestroni, Luisa and Sinagra, Gianfranco} } @article {8352, title = {CNV analysis in 169 patients with bladder exstrophy-epispadias complex.}, journal = {BMC Med Genet}, volume = {17}, year = {2016}, month = {2016}, pages = {35}, abstract = {

BACKGROUND: The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the congenital uro-rectal malformation spectrum. Initial studies have implicated rare copy number variations (CNVs), including recurrent duplications of chromosomal region 22q11.21, in BEEC etiology.

METHODS: To detect further CNVs, array analysis was performed in 169 BEEC patients. Prior to inclusion, 22q11.21 duplications were excluded using multiplex ligation-dependent probe amplification.

RESULTS: Following the application of stringent filter criteria, seven rare CNVs were identified: n = 4, not present in 1307 in-house controls; n = 3, frequency of <0.002 in controls. These CNVs ranged from 1 to 6.08~Mb in size. To identify smaller CNVs, relaxed filter criteria used in the detection of previously reported BEEC associated chromosomal regions were applied. This resulted in the identification of six additional rare CNVs: n = 4, not present in 1307 in-house controls; n = 2, frequency <0.0008 in controls. These CNVs ranged from 0.03-0.08~Mb in size. For 10 of these 13 CNVs, confirmation and segregation analyses were performed (5 of maternal origin; 5 of paternal origin). Interestingly, one female with classic bladder extrophy carried a 1.18~Mb duplication of 22q11.1, a chromosomal region that is associated with cat eye syndrome.

CONCLUSIONS: A number of rare CNVs were identified in BEEC patients, and these represent candidates for further evaluation. Rare inherited CNVs may constitute modifiers of, or contributors to, multifactorial BEEC phenotypes.

}, issn = {1471-2350}, doi = {10.1186/s12881-016-0299-x}, author = {von Lowtzow, Catharina and Hofmann, Andrea and Zhang, Rong and Marsch, Florian and Ebert, Anne-Karoline and R{\"o}sch, Wolfgang and Stein, Raimund and Boemers, Thomas M and Hirsch, Karin and Marcelis, Carlo and Feitz, Wouter F J and Brusco, Alfredo and Migone, Nicola and Di Grazia, Massimo and Moebus, Susanne and N{\"o}then, Markus M and Reutter, Heiko and Ludwig, Michael and Draaken, Markus} } @article {8318, title = {Consensus Conference on Clinical Management of pediatric Atopic Dermatitis.}, journal = {Ital J Pediatr}, volume = {42}, year = {2016}, month = {2016}, pages = {26}, abstract = {

The Italian Consensus Conference on clinical management of atopic dermatitis in children reflects the best and most recent scientific evidence, with the aim to provide specialists with a useful tool for managing this common, but complex clinical condition. Thanks to the contribution of experts in the field and members of the Italian Society of Pediatric Allergology and Immunology (SIAIP) and the Italian Society of Pediatric Dermatology (SIDerP), this Consensus statement integrates the basic principles of the most recent guidelines for the management of atopic dermatitis to facilitate a practical approach to the disease. The therapeutical approach should be adapted to the clinical severity and requires a tailored strategy to ensure good compliance by children and their parents. In this Consensus, levels and models of intervention are also enriched by the Italian experience to facilitate a practical approach to the disease.

}, issn = {1824-7288}, doi = {10.1186/s13052-016-0229-8}, author = {Galli, Elena and Neri, Iria and Ricci, Giampaolo and Baldo, Ermanno and Barone, Maurizio and Belloni Fortina, Anna and Bernardini, Roberto and Berti, Irene and Caffarelli, Carlo and Calamelli, Elisabetta and Capra, Lucetta and Carello, Rossella and Cipriani, Francesca and Comberiati, Pasquale and Diociaiuti, Andrea and El Hachem, Maya and Fontana, Elena and Gruber, Michaela and Haddock, Ellen and Maiello, Nunzia and Meglio, Paolo and Patrizi, Annalisa and Peroni, Diego and Scarponi, Dorella and Wielander, Ingrid and Eichenfield, Lawrence F} } @article {8508, title = {Efficacy of ketamine in refractory convulsive status epilepticus in children: a protocol for a sequential design, multicentre, randomised, controlled, open-label, non-profit trial (KETASER01).}, journal = {BMJ Open}, volume = {6}, year = {2016}, month = {2016}, pages = {e011565}, abstract = {

INTRODUCTION: Status epilepticus (SE) is a life-threatening neurological emergency. SE lasting longer than 120 min and not responding to first-line and second-line antiepileptic drugs is defined as {\textquoteright}refractory{\textquoteright} (RCSE) and requires intensive care unit treatment. There is currently neither evidence nor consensus to guide either the optimal choice of therapy or treatment goals for RCSE, which is generally treated with coma induction using conventional anaesthetics (high dose midazolam, thiopental and/or propofol). Increasing evidence indicates that ketamine (KE), a strong N-methyl-d-aspartate glutamate receptor antagonist, may be effective in treating RCSE. We hypothesised that intravenous KE is more efficacious and safer than conventional anaesthetics in treating RCSE.

METHODS AND ANALYSIS: A multicentre, randomised, controlled, open-label, non-profit, sequentially designed study will be conducted to assess the efficacy of KE compared with conventional anaesthetics in the treatment of RCSE in children. 10 Italian centres/hospitals are involved in enrolling 57 patients aged 1 month to 18 years with RCSE. Primary outcome is the resolution of SE up to 24 hours after withdrawal of therapy and is updated for each patient treated according to the sequential method.

ETHICS AND DISSEMINATION: The study received ethical approval from the Tuscan Paediatric Ethics Committee (12/2015). The results of this study will be published in peer-reviewed journals and presented at international conferences.

TRIAL REGISTRATION NUMBER: NCT02431663; Pre-results.

}, issn = {2044-6055}, doi = {10.1136/bmjopen-2016-011565}, author = {Rosati, Anna and Ilvento, Lucrezia and L{\textquoteright}Erario, Manuela and De Masi, Salvatore and Biggeri, Annibale and Fabbro, Giancarlo and Bianchi, Roberto and Stoppa, Francesca and Fusco, Lucia and Pulitan{\`o}, Silvia and Battaglia, Domenica and Pettenazzo, Andrea and Sartori, Stefano and Biban, Paolo and Fontana, Elena and Cesaroni, Elisabetta and Mora, Donatella and Costa, Paola and Meleleo, Rosanna and Vittorini, Roberta and Conio, Alessandra and Wolfler, Andrea and Mastrangelo, Massimo and Mondardini, Maria Cristina and Franzoni, Emilio and McGreevy, Kathleen S and Di Simone, Lorena and Pugi, Alessandra and Mirabile, Lorenzo and Vigevano, Federico and Guerrini, Renzo} } @article {8339, title = {Empowering the family during the first months after identification of permanent hearing impairment in children.}, journal = {Acta Otorhinolaryngol Ital}, volume = {36}, year = {2016}, month = {2016 Feb}, pages = {64-70}, abstract = {

The latest international guidelines highlight the importance of involving the family in the diagnostic and rehabilitation process of children affected by permanent hearing impairment. This emphasises how meaningful this approach is for the development of the deaf child. So far, there is very little evidence about this approach in Italy, and there are still some barriers to its practical management. The aim of this paper is to report the results of a strategic analysis, which identifies the strengths, weaknesses, opportunities and threats of the family empowerment process during early auditory diagnosis and rehabilitation. The audiology programme should have the goal to offer information and support to families in order to achieve a conscious decision about the use and type of auditory prosthesis and rehabilitation choice within three months after audiologic diagnosis. Within the framework of the Ministry of Health project CCM 2013 "Preventing Communication Disorders: a Regional Program for Early Identification, Intervention and Care of Hearing Impaired Children", a group of professionals identified three main recommendations that can be useful to foster the natural communicative development of the child by strengthening the therapeutic alliance and empowerment of the family. The recommendations obtained with this analysis can help to develop new Italian guidelines with the aim to foster natural communicative development of the child by strengthening the therapeutic alliance and empowerment of the family.

}, issn = {1827-675X}, doi = {10.14639/0392-100X-1071}, author = {Ciciriello, E and Bolzonello, P and Marchi, R and Falzone, C and Muzzi, E and Orzan, E} } @article {8313, title = {EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.}, journal = {Brain}, volume = {139}, year = {2016}, month = {2016 Mar}, pages = {765-81}, abstract = {

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97\%, and a sensitivity of 89\% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95\% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.

}, keywords = {Agenesis of Corpus Callosum, Animals, Autophagy, Cataract, Child, Preschool, Cross-Sectional Studies, Drosophila melanogaster, Female, Hippocampus, Humans, Male, Mutation, Neurodevelopmental Disorders, Proteins, Retrospective Studies}, issn = {1460-2156}, doi = {10.1093/brain/awv393}, author = {Byrne, Susan and Jansen, Lara and U-King-Im, Jean-Marie and Siddiqui, Ata and Lidov, Hart G W and Bodi, Istvan and Smith, Luke and Mein, Rachael and Cullup, Thomas and Dionisi-Vici, Carlo and Al-Gazali, Lihadh and Al-Owain, Mohammed and Bruwer, Zandre and Al Thihli, Khalid and El-Garhy, Rana and Flanigan, Kevin M and Manickam, Kandamurugu and Zmuda, Erik and Banks, Wesley and Gershoni-Baruch, Ruth and Mandel, Hanna and Dagan, Efrat and Raas-Rothschild, Annick and Barash, Hila and Filloux, Francis and Creel, Donnell and Harris, Michael and Hamosh, Ada and K{\"o}lker, Stefan and Ebrahimi-Fakhari, Darius and Hoffmann, Georg F and Manchester, David and Boyer, Philip J and Manzur, Adnan Y and Lourenco, Charles Marques and Pilz, Daniela T and Kamath, Arveen and Prabhakar, Prab and Rao, Vamshi K and Rogers, R Curtis and Ryan, Monique M and Brown, Natasha J and McLean, Catriona A and Said, Edith and Schara, Ulrike and Stein, Anja and Sewry, Caroline and Travan, Laura and Wijburg, Frits A and Zenker, Martin and Mohammed, Shehla and Fanto, Manolis and Gautel, Mathias and Jungbluth, Heinz} } @article {8350, title = {Evaluation of energy metabolism and calcium homeostasis in cells affected by Shwachman-Diamond syndrome.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016}, pages = {25441}, abstract = {

Isomorphic mutation of the SBDS gene causes Shwachman-Diamond syndrome (SDS). SDS is a rare genetic bone marrow failure and cancer predisposition syndrome. SDS cells have ribosome biogenesis and their protein synthesis altered, which are two high-energy consuming cellular processes. The reported changes in reactive oxygen species production, endoplasmic reticulum stress response and reduced mitochondrial functionality suggest an energy production defect in SDS cells. In our work, we have demonstrated that SDS cells display a Complex IV activity impairment, which causes an oxidative phosphorylation metabolism defect, with a consequent decrease in ATP production. These data were confirmed by an increased glycolytic rate, which compensated for the energetic stress. Moreover, the signalling pathways involved in glycolysis activation also appeared more activated; i.e. we reported AMP-activated protein kinase hyper-phosphorylation. Notably, we also observed an increase in a mammalian target of rapamycin phosphorylation and high intracellular calcium concentration levels ([Ca(2+)]i), which probably represent new biochemical equilibrium modulation in SDS cells. Finally, the SDS cell response to leucine (Leu) was investigated, suggesting its possible use as a therapeutic adjuvant to be tested in clinical trials.

}, issn = {2045-2322}, doi = {10.1038/srep25441}, author = {Ravera, Silvia and Dufour, Carlo and Cesaro, Simone and Bottega, Roberta and Faleschini, Michela and Cuccarolo, Paola and Corsolini, Fabio and Usai, Cesare and Columbaro, Marta and Cipolli, Marco and Savoia, Anna and Degan, Paolo and Cappelli, Enrico} } @article {8481, title = {Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index.}, journal = {Mol Psychiatry}, year = {2016}, month = {2016 May 17}, abstract = {

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 {\texttimes} 10(-5), Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 {\texttimes} 10(-06)/Pfemales: 3.45 {\texttimes} 10(-07)/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.Molecular Psychiatry advance online publication, 17 May 2016; doi:10.1038/mp.2016.71.

}, issn = {1476-5578}, doi = {10.1038/mp.2016.71}, author = {Hinney, A and Kesselmeier, M and Jall, S and Volckmar, A-L and F{\"o}cker, M and Antel, J and Heid, I M and Winkler, T W and Grant, S F A and Guo, Y and Bergen, A W and Kaye, W and Berrettini, W and Hakonarson, H and Herpertz-Dahlmann, B and de Zwaan, M and Herzog, W and Ehrlich, S and Zipfel, S and Egberts, K M and Adan, R and Brandys, M and van Elburg, A and Boraska Perica, V and Franklin, C S and Tsch{\"o}p, M H and Zeggini, E and Bulik, C M and Collier, D and Scherag, A and M{\"u}ller, T D and Hebebrand, J} } @article {8304, title = {Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016}, pages = {10023}, abstract = {

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

}, keywords = {Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic}, issn = {2041-1723}, doi = {10.1038/ncomms10023}, author = {Pattaro, Cristian and Teumer, Alexander and Gorski, Mathias and Chu, Audrey Y and Li, Man and Mijatovic, Vladan and Garnaas, Maija and Tin, Adrienne and Sorice, Rossella and Li, Yong and Taliun, Daniel and Olden, Matthias and Foster, Meredith and Yang, Qiong and Chen, Ming-Huei and Pers, Tune H and Johnson, Andrew D and Ko, Yi-An and Fuchsberger, Christian and Tayo, Bamidele and Nalls, Michael and Feitosa, Mary F and Isaacs, Aaron and Dehghan, Abbas and d{\textquoteright}Adamo, Pio and Adeyemo, Adebowale and Dieffenbach, Aida Karina and Zonderman, Alan B and Nolte, Ilja M and van der Most, Peter J and Wright, Alan F and Shuldiner, Alan R and Morrison, Alanna C and Hofman, Albert and Smith, Albert V and Dreisbach, Albert W and Franke, Andre and Uitterlinden, Andr{\'e} G and Metspalu, Andres and T{\"o}njes, Anke and Lupo, Antonio and Robino, Antonietta and Johansson, {\r A}sa and Demirkan, Ayse and Kollerits, Barbara and Freedman, Barry I and Ponte, Belen and Oostra, Ben A and Paulweber, Bernhard and Kr{\"a}mer, Bernhard K and Mitchell, Braxton D and Buckley, Brendan M and Peralta, Carmen A and Hayward, Caroline and Helmer, Catherine and Rotimi, Charles N and Shaffer, Christian M and M{\"u}ller, Christian and Sala, Cinzia and van Duijn, Cornelia M and Saint-Pierre, Aude and Ackermann, Daniel and Shriner, Daniel and Ruggiero, Daniela and Toniolo, Daniela and Lu, Yingchang and Cusi, Daniele and Czamara, Darina and Ellinghaus, David and Siscovick, David S and Ruderfer, Douglas and Gieger, Christian and Grallert, Harald and Rochtchina, Elena and Atkinson, Elizabeth J and Holliday, Elizabeth G and Boerwinkle, Eric and Salvi, Erika and Bottinger, Erwin P and Murgia, Federico and Rivadeneira, Fernando and Ernst, Florian and Kronenberg, Florian and Hu, Frank B and Navis, Gerjan J and Curhan, Gary C and Ehret, George B and Homuth, Georg and Coassin, Stefan and Thun, Gian-Andri and Pistis, Giorgio and Gambaro, Giovanni and Malerba, Giovanni and Montgomery, Grant W and Eiriksdottir, Gudny and Jacobs, Gunnar and Li, Guo and Wichmann, H-Erich and Campbell, Harry and Schmidt, Helena and Wallaschofski, Henri and V{\"o}lzke, Henry and Brenner, Hermann and Kroemer, Heyo K and Kramer, Holly and Lin, Honghuang and Leach, I Mateo and Ford, Ian and Guessous, Idris and Rudan, Igor and Prokopenko, Inga and Borecki, Ingrid and Heid, Iris M and Kolcic, Ivana and Persico, Ivana and Jukema, J Wouter and Wilson, James F and Felix, Janine F and Divers, Jasmin and Lambert, Jean-Charles and Stafford, Jeanette M and Gaspoz, Jean-Michel and Smith, Jennifer A and Faul, Jessica D and Wang, Jie Jin and Ding, Jingzhong and Hirschhorn, Joel N and Attia, John and Whitfield, John B and Chalmers, John and Viikari, Jorma and Coresh, Josef and Denny, Joshua C and Karjalainen, Juha and Fernandes, Jyotika K and Endlich, Karlhans and Butterbach, Katja and Keene, Keith L and Lohman, Kurt and Portas, Laura and Launer, Lenore J and Lyytik{\"a}inen, Leo-Pekka and Yengo, Loic and Franke, Lude and Ferrucci, Luigi and Rose, Lynda M and Kedenko, Lyudmyla and Rao, Madhumathi and Struchalin, Maksim and Kleber, Marcus E and Cavalieri, Margherita and Haun, Margot and Cornelis, Marilyn C and Ciullo, Marina and Pirastu, Mario and de Andrade, Mariza and McEvoy, Mark A and Woodward, Mark and Adam, Martin and Cocca, Massimiliano and Nauck, Matthias and Imboden, Medea and Waldenberger, Melanie and Pruijm, Menno and Metzger, Marie and Stumvoll, Michael and Evans, Michele K and Sale, Michele M and K{\"a}h{\"o}nen, Mika and Boban, Mladen and Bochud, Murielle and Rheinberger, Myriam and Verweij, Niek and Bouatia-Naji, Nabila and Martin, Nicholas G and Hastie, Nick and Probst-Hensch, Nicole and Soranzo, Nicole and Devuyst, Olivier and Raitakari, Olli and Gottesman, Omri and Franco, Oscar H and Polasek, Ozren and Gasparini, Paolo and Munroe, Patricia B and Ridker, Paul M and Mitchell, Paul and Muntner, Paul and Meisinger, Christa and Smit, Johannes H and Kovacs, Peter and Wild, Philipp S and Froguel, Philippe and Rettig, Rainer and M{\"a}gi, Reedik and Biffar, Reiner and Schmidt, Reinhold and Middelberg, Rita P S and Carroll, Robert J and Penninx, Brenda W and Scott, Rodney J and Katz, Ronit and Sedaghat, Sanaz and Wild, Sarah H and Kardia, Sharon L R and Ulivi, Sheila and Hwang, Shih-Jen and Enroth, Stefan and Kloiber, Stefan and Trompet, Stella and Stengel, B{\'e}n{\'e}dicte and Hancock, Stephen J and Turner, Stephen T and Rosas, Sylvia E and Stracke, Sylvia and Harris, Tamara B and Zeller, Tanja and Zemunik, Tatijana and Lehtim{\"a}ki, Terho and Illig, Thomas and Aspelund, Thor and Nikopensius, Tiit and Esko, T{\~o}nu and Tanaka, Toshiko and Gyllensten, Ulf and V{\"o}lker, Uwe and Emilsson, Valur and Vitart, Veronique and Aalto, Ville and Gudnason, Vilmundur and Chouraki, Vincent and Chen, Wei-Min and Igl, Wilmar and M{\"a}rz, Winfried and Koenig, Wolfgang and Lieb, Wolfgang and Loos, Ruth J F and Liu, Yongmei and Snieder, Harold and Pramstaller, Peter P and Parsa, Afshin and O{\textquoteright}Connell, Jeffrey R and Susztak, Katalin and Hamet, Pavel and Tremblay, Johanne and de Boer, Ian H and B{\"o}ger, Carsten A and Goessling, Wolfram and Chasman, Daniel I and K{\"o}ttgen, Anna and Kao, W H Linda and Fox, Caroline S} } @article {8484, title = {Genome-wide association study identifies 74 loci associated with educational attainment.}, journal = {Nature}, volume = {533}, year = {2016}, month = {2016 May 26}, pages = {539-42}, abstract = {

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20\% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

}, keywords = {Alzheimer Disease, Bipolar Disorder, Brain, Cognition, Computational Biology, Educational Status, Fetus, Gene Expression Regulation, Gene-Environment Interaction, Genome-Wide Association Study, Great Britain, Humans, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Schizophrenia}, issn = {1476-4687}, doi = {10.1038/nature17671}, author = {Okbay, Aysu and Beauchamp, Jonathan P and Fontana, Mark Alan and Lee, James J and Pers, Tune H and Rietveld, Cornelius A and Turley, Patrick and Chen, Guo-Bo and Emilsson, Valur and Meddens, S Fleur W and Oskarsson, Sven and Pickrell, Joseph K and Thom, Kevin and Timshel, Pascal and de Vlaming, Ronald and Abdellaoui, Abdel and Ahluwalia, Tarunveer S and Bacelis, Jonas and Baumbach, Clemens and Bjornsdottir, Gyda and Brandsma, Johannes H and Pina Concas, Maria and Derringer, Jaime and Furlotte, Nicholas A and Galesloot, Tessel E and Girotto, Giorgia and Gupta, Richa and Hall, Leanne M and Harris, Sarah E and Hofer, Edith and Horikoshi, Momoko and Huffman, Jennifer E and Kaasik, Kadri and Kalafati, Ioanna P and Karlsson, Robert and Kong, Augustine and Lahti, Jari and van der Lee, Sven J and deLeeuw, Christiaan and Lind, Penelope A and Lindgren, Karl-Oskar and Liu, Tian and Mangino, Massimo and Marten, Jonathan and Mihailov, Evelin and Miller, Michael B and van der Most, Peter J and Oldmeadow, Christopher and Payton, Antony and Pervjakova, Natalia and Peyrot, Wouter J and Qian, Yong and Raitakari, Olli and Rueedi, Rico and Salvi, Erika and Schmidt, B{\"o}rge and Schraut, Katharina E and Shi, Jianxin and Smith, Albert V and Poot, Raymond A and St Pourcain, Beate and Teumer, Alexander and Thorleifsson, Gudmar and Verweij, Niek and Vuckovic, Dragana and Wellmann, Juergen and Westra, Harm-Jan and Yang, Jingyun and Zhao, Wei and Zhu, Zhihong and Alizadeh, Behrooz Z and Amin, Najaf and Bakshi, Andrew and Baumeister, Sebastian E and Biino, Ginevra and B{\o}nnelykke, Klaus and Boyle, Patricia A and Campbell, Harry and Cappuccio, Francesco P and Davies, Gail and De Neve, Jan-Emmanuel and Deloukas, Panos and Demuth, Ilja and Ding, Jun and Eibich, Peter and Eisele, Lewin and Eklund, Niina and Evans, David M and Faul, Jessica D and Feitosa, Mary F and Forstner, Andreas J and Gandin, Ilaria and Gunnarsson, Bjarni and Halld{\'o}rsson, Bjarni V and Harris, Tamara B and Heath, Andrew C and Hocking, Lynne J and Holliday, Elizabeth G and Homuth, Georg and Horan, Michael A and Hottenga, Jouke-Jan and de Jager, Philip L and Joshi, Peter K and Jugessur, Astanand and Kaakinen, Marika A and K{\"a}h{\"o}nen, Mika and Kanoni, Stavroula and Keltigangas-J{\"a}rvinen, Liisa and Kiemeney, Lambertus A L M and Kolcic, Ivana and Koskinen, Seppo and Kraja, Aldi T and Kroh, Martin and Kutalik, Zolt{\'a}n and Latvala, Antti and Launer, Lenore J and Lebreton, Ma{\"e}l P and Levinson, Douglas F and Lichtenstein, Paul and Lichtner, Peter and Liewald, David C M and Loukola, Anu and Madden, Pamela A and M{\"a}gi, Reedik and M{\"a}ki-Opas, Tomi and Marioni, Riccardo E and Marques-Vidal, Pedro and Meddens, Gerardus A and McMahon, George and Meisinger, Christa and Meitinger, Thomas and Milaneschi, Yusplitri and Milani, Lili and Montgomery, Grant W and Myhre, Ronny and Nelson, Christopher P and Nyholt, Dale R and Ollier, William E R and Palotie, Aarno and Paternoster, Lavinia and Pedersen, Nancy L and Petrovic, Katja E and Porteous, David J and R{\"a}ikk{\"o}nen, Katri and Ring, Susan M and Robino, Antonietta and Rostapshova, Olga and Rudan, Igor and Rustichini, Aldo and Salomaa, Veikko and Sanders, Alan R and Sarin, Antti-Pekka and Schmidt, Helena and Scott, Rodney J and Smith, Blair H and Smith, Jennifer A and Staessen, Jan A and Steinhagen-Thiessen, Elisabeth and Strauch, Konstantin and Terracciano, Antonio and Tobin, Martin D and Ulivi, Sheila and Vaccargiu, Simona and Quaye, Lydia and van Rooij, Frank J A and Venturini, Cristina and Vinkhuyzen, Anna A E and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Vonk, Judith M and Vozzi, Diego and Waage, Johannes and Ware, Erin B and Willemsen, Gonneke and Attia, John R and Bennett, David A and Berger, Klaus and Bertram, Lars and Bisgaard, Hans and Boomsma, Dorret I and Borecki, Ingrid B and B{\"u}ltmann, Ute and Chabris, Christopher F and Cucca, Francesco and Cusi, Daniele and Deary, Ian J and Dedoussis, George V and van Duijn, Cornelia M and Eriksson, Johan G and Franke, Barbara and Franke, Lude and Gasparini, Paolo and Gejman, Pablo V and Gieger, Christian and Grabe, Hans-J{\"o}rgen and Gratten, Jacob and Groenen, Patrick J F and Gudnason, Vilmundur and van der Harst, Pim and Hayward, Caroline and Hinds, David A and Hoffmann, Wolfgang and Hypp{\"o}nen, Elina and Iacono, William G and Jacobsson, Bo and J{\"a}rvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Kaprio, Jaakko and Kardia, Sharon L R and Lehtim{\"a}ki, Terho and Lehrer, Steven F and Magnusson, Patrik K E and Martin, Nicholas G and McGue, Matt and Metspalu, Andres and Pendleton, Neil and Penninx, Brenda W J H and Perola, Markus and Pirastu, Nicola and Pirastu, Mario and Polasek, Ozren and Posthuma, Danielle and Power, Christine and Province, Michael A and Samani, Nilesh J and Schlessinger, David and Schmidt, Reinhold and S{\o}rensen, Thorkild I A and Spector, Tim D and Stefansson, Kari and Thorsteinsdottir, Unnur and Thurik, A Roy and Timpson, Nicholas J and Tiemeier, Henning and Tung, Joyce Y and Uitterlinden, Andr{\'e} G and Vitart, Veronique and Vollenweider, Peter and Weir, David R and Wilson, James F and Wright, Alan F and Conley, Dalton C and Krueger, Robert F and Davey Smith, George and Hofman, Albert and Laibson, David I and Medland, Sarah E and Meyer, Michelle N and Yang, Jian and Johannesson, Magnus and Visscher, Peter M and Esko, T{\~o}nu and Koellinger, Philipp D and Cesarini, David and Benjamin, Daniel J} } @article {8522, title = {Heterologous Expression Systems for Plant Defensin Expression: Examples of Success and Pitfalls.}, journal = {Curr Protein Pept Sci}, year = {2016}, month = {2016 Jun 24}, abstract = {

Defensins are a superfamily of antimicrobial peptides, present in vertebrates, invertebrates, fungi and plants, suggesting that they appeared prior to the divergence in eukaryotes. The destitution of toxicity to mammalian cells of plant defensins has led to a new research ground, i.e., their potential medical use against human infectious diseases. Isolating defensins from natural sources, like plant tissues, can be time-consuming, labor intensive and usually present low yields. Strategies for large-scale production of purified active defensins have been employed using heterologous expression systems (HES) for defensin production, usually based in E. coli system. Like any other technology, HES present limitations and drawbacks demanding a careful experimental design prior the system selection. This review is proposed to discuss some of the major concerns when choosing to heterologously express plant defensins, with special attention on bacterial expression system.

}, issn = {1875-5550}, author = {Gazzaneo, Luis Rs and Pandolfi, Valesca and Jesus, Andr{\'e} Ls and Crovella, Sergio and Benko-Iseppon, Ana M and Freitas, Antonio Carlos} } @article {8328, title = {In vitro sensitivity to methyl-prednisolone is associated with clinical response in pediatric idiopathic nephrotic syndrome.}, journal = {Clin Pharmacol Ther}, volume = {100}, year = {2016}, month = {2016 Sep}, pages = {268-74}, abstract = {

The aim of this study was to evaluate the in vitro steroid sensitivity as a predictor of clinical response to glucocorticoids in childhood idiopathic nephrotic syndrome (INS). Seventy-four patients (median age 4.33, interquartile range [IQR] 2.82-7.23; 63.5\% male) were enrolled in a prospective multicenter study: in vitro steroid inhibition of patients{\textquoteright} peripheral blood mononuclear cell proliferation was evaluated by [methyl-(3) H] thymidine incorporation assay at disease onset (T0) and after 4 weeks (T4) of treatment. Steroid dependence was associated with increased in vitro sensitivity at T4 assessed both as drug concentration inducing 50\% of inhibition (IC50 ; odds ratio [OR] = 0.48, 95\% confidence interval [CI] = 0.24-0.85; P = 0.0094) and maximum inhibition at the highest drug concentration (Imax ; OR = 1.13, 95\% CI = 1.02-1.31; P = 0.017). IC50 > 4.4 nM and Imax < 92\% at T4 were good predictors for optimal clinical response. These results suggest that this test may be useful for predicting the response to glucocorticoid therapy in pediatric INS.

}, issn = {1532-6535}, doi = {10.1002/cpt.372}, author = {Cuzzoni, E and De Iudicibus, S and Stocco, G and Favretto, D and Pelin, M and Messina, G and Ghio, L and Monti, E and Pasini, A and Montini, G and Decorti, G} } @article {8330, title = {The incidence rate and prevalence of pediatric type 1 diabetes mellitus (age 0-18) in the Italian region Friuli Venezia Giulia: population-based estimates through the analysis of health administrative databases.}, journal = {Acta Diabetol}, volume = {53}, year = {2016}, month = {2016 Aug}, pages = {629-35}, abstract = {

AIMS: The main objective of this study was to estimate the incidence rate and prevalence of pediatric type 1 diabetes mellitus (T1DM; population 0-18~years of age) in the northeastern Italian region Friuli Venezia Giulia and to characterize the subjects affected by the disease.

METHODS: This was a retrospective population-based study conducted through the individual-level linkage of several health administrative databases of the Friuli Venezia Giulia region. The incidence rate and prevalence were calculated in the population 0-18~years of age. Using the Mid-p exact method, 95~\% confidence intervals for rates were calculated.

RESULTS: The incidence rate of pediatric T1DM in the years 2010-2013 was 15.8 new cases/100,000 person-years, peaking in the age class 10-14~years. The rate has increased substantially as compared with the previous regional estimate that dated back to 1993. We observed a seasonal pattern both in the date of birth of the incident cases and in the date of onset of the disease. In the region in 2013, there were 294 prevalent cases (15.1/10,000 inhabitants). Most of them had at least one glycated hemoglobin test in the year. More than 15~\% had co-existing autoimmune comorbidities.

CONCLUSIONS: The incidence rate of pediatric T1DM in Friuli Venezia Giulia has increased in the last years, and the disease is a relevant public health issue in the region.

}, issn = {1432-5233}, doi = {10.1007/s00592-016-0854-0}, author = {Valent, Francesca and Candido, Riccardo and Faleschini, Elena and Tonutti, Laura and Tortul, Carla and Zanatta, Manuela and Zanette, Giorgio and Zanier, Loris} } @article {8346, title = {Innate and adaptive immunity in self-reported nonceliac gluten sensitivity versus celiac disease.}, journal = {Dig Liver Dis}, volume = {48}, year = {2016}, month = {2016 Jul}, pages = {745-52}, abstract = {

BACKGROUND: Immune mechanisms have been implicated in nonceliac gluten sensitivity (NCGS), a condition characterized by intestinal and/or extraintestinal symptoms caused by the ingestion of gluten in non-celiac/non-wheat allergic individuals.

AIMS: We investigated innate and adaptive immunity in self-reported NCGS versus celiac disease (CD).

METHODS: In the supernatants of ex vivo-cultured duodenal biopsies from 14 self-reported NCGS patients, 9 untreated and 10 treated CD patients, and 12 controls we detected innate cytokines - interleukin (IL)-15, tumor necrosis factor-α, IL-1β, IL-6, IL-12p70, IL-23, IL-27, IL-32α, thymic stromal lymphopoietin (TSLP), IFN-α-, adaptive cytokines - interferon (IFN)-γ, IL-17A, IL-4, IL-5, IL-10, IL-13-, chemokines - IL-8, CCL1, CCL2, CCL3, CCL4, CCL5, CXCL1, CXCL10-, granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF).

RESULTS: Mucosal innate and adaptive cytokines, chemokines and growth factors did not differ between self-reported NCGS, treated CD and controls. On the contrary, IL-6, IL-15, IL-27, IFN-α, IFN-γ, IL-17A, IL-23, G-CSF, GM-CSF, IL-8, CCL1 and CCL4 were significantly higher in untreated CD than in self-reported NCGS, treated CD and controls, while TSLP was significantly lower in untreated CD than in self-reported NCGS, treated CD and controls.

CONCLUSION: In our hands, patients with self-reported NCGS showed no abnormalities of the mucosal immune response.

}, issn = {1878-3562}, doi = {10.1016/j.dld.2016.03.024}, author = {Di Sabatino, Antonio and Giuffrida, Paolo and Fornasa, Giulia and Salvatore, Chiara and Vanoli, Alessandro and Naviglio, Samuele and De Leo, Luigina and Pasini, Alessandra and De Amici, Mara and Alvisi, Costanza and Not, Tarcisio and Rescigno, Maria and Corazza, Gino Roberto} } @article {8293, title = {The Klinefelter syndrome is associated with high recurrence of copy number variations on the X chromosome with a potential role in the clinical phenotype.}, journal = {Andrology}, volume = {4}, year = {2016}, month = {2016 Mar}, pages = {328-34}, abstract = {

The Klinefelter syndrome (KS) is the most frequent sex chromosomal disorder in males, characterized by at least one supernumerary X chromosome (most frequent karyotype 47,XXY). This syndrome presents with a broad range of phenotypes. The common characteristics include small testes and infertility, but KS subjects are at increased risk of hypogonadism, cognitive dysfunction, obesity, diabetes, metabolic syndrome, osteoporosis, and autoimmune disorders, which are present in variable proportion. Although part of the clinical variability might be linked to a different degree of testicular function observed in KS patients, genetic mechanisms of the supernumerary X chromosome might contribute. Gene-dosage effects and parental origin of the supernumerary X chromosome have been suggested to this regard. No study has been performed analyzing the genetic constitution of the X chromosome in terms of copy number variations (CNVs) and their possible involvement in phenotype of KS. To this aim, we performed a SNP arrays analysis on 94 KS and 85 controls. We found that KS subjects have more frequently than controls X-linked CNVs (39/94, [41.5\%] with respect to 12/42, [28.6\%] of females, and 8/43, [18.6\%] of males, p < 0.01). The number of X-linked CNVs in KS patients was 4.58 {\textpm} 1.92 CNVs/subject, significantly higher with respect to that found in control females (1.50 {\textpm} 1.29 CNVs/subject) and males (1.14 {\textpm} 0.37 CNVs/subject). Importantly, 94.4\% X-linked CNVs in KS subjects were duplications, higher with respect to control males (50.0\%, p < 0.001) and females (83.3\%, p = 0.1). Half of the X-linked CNVs fell within regions encompassing genes and most of them (90\%) included genes escaping X-inactivation in the regions of X-Y homology, particularly in the pseudoautosomal region 1 (PAR1) and Xq21.31. This study described for the first time the genetic properties of the X chromosome in KS and suggests that X-linked CNVs (especially duplications) might contribute to the clinical phenotype.

}, issn = {2047-2927}, doi = {10.1111/andr.12146}, author = {Rocca, M S and Pecile, V and Cleva, L and Speltra, E and Selice, R and Di Mambro, A and Foresta, C and Ferlin, A} } @article {8316, title = {A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver-Russell and Beckwith-Wiedemann syndromes.}, journal = {Clin Epigenetics}, volume = {8}, year = {2016}, month = {2016}, pages = {23}, abstract = {

BACKGROUND: Multiple (epi)genetic defects affecting the expression of the imprinted genes within the 11p15.5 chromosomal region underlie Silver-Russell (SRS) and Beckwith-Wiedemann (BWS) syndromes. The molecular diagnosis of these opposite growth disorders requires a multi-approach flowchart to disclose known primary and secondary (epi)genetic alterations; however, up to 20 and 30~\% of clinically diagnosed BWS and SRS cases remain without molecular diagnosis. The complex structure of the 11p15 region with variable CpG methylation and low-rate mosaicism may account for missed diagnoses. Here, we demonstrate the relevance of complementary techniques for the assessment of different CpGs and the importance of testing multiple tissues to increase the SRS and BWS detection rate.

RESULTS: Molecular testing of 147 and 450 clinically diagnosed SRS and BWS cases provided diagnosis in 34 SRS and 185 BWS patients, with 9 SRS and 21 BWS cases remaining undiagnosed and herein referred to as "borderline." A flowchart including complementary techniques and, when applicable, the analysis of buccal swabs, allowed confirmation of the molecular diagnosis in all borderline cases. Comparison of methylation levels by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in borderline and control cases defined an interval of H19/IGF2:IG-DMR loss of methylation that was distinct between "easy to diagnose" and "borderline" cases, which were characterized by values <=mean -3 standard deviations (SDs) compared to controls. Values >=mean +1 SD at H19/IGF2: IG-DMR were assigned to borderline hypermethylated BWS cases and those <=mean -2 SD at KCNQ1OT1: TSS-DMR to hypomethylated BWS cases; these were supported by quantitative pyrosequencing or Southern blot analysis. Six BWS cases suspected to carry mosaic paternal uniparental disomy of chromosome 11 were confirmed by SNP array, which detected mosaicism till 10~\%. Regarding the clinical presentation, borderline SRS were representative of the syndromic phenotype, with exception of one patient, whereas BWS cases showed low frequency of the most common features except hemihyperplasia.

CONCLUSIONS: A conclusive molecular diagnosis was reached in borderline methylation cases, increasing the detection rate by 6~\% for SRS and 5~\% for BWS cases. The introduction of complementary techniques and additional tissue analyses into routine diagnostic work-up should facilitate the identification of cases undiagnosed because of mosaicism, a distinctive feature of epigenetic disorders.

}, keywords = {Beckwith-Wiedemann Syndrome, Blotting, Southern, Child, Child, Preschool, Chromosomes, Human, Pair 11, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Humans, Infant, Male, Mosaicism, Multiplex Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Silver-Russell Syndrome}, issn = {1868-7075}, doi = {10.1186/s13148-016-0183-8}, author = {Russo, Silvia and Calzari, Luciano and Mussa, Alessandro and Mainini, Ester and Cassina, Matteo and Di Candia, Stefania and Clementi, Maurizio and Guzzetti, Sara and Tabano, Silvia and Miozzo, Monica and Sirchia, Silvia and Finelli, Palma and Prontera, Paolo and Maitz, Silvia and Sorge, Giovanni and Calcagno, Annalisa and Maghnie, Mohamad and Divizia, Maria Teresa and Melis, Daniela and Manfredini, Emanuela and Ferrero, Giovanni Battista and Pecile, Vanna and Larizza, Lidia} } @article {7718, title = {Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease.}, journal = {Ear Hear}, volume = {37}, year = {2016}, month = {2016 Jan-Feb}, pages = {112-20}, abstract = {

OBJECTIVES: MYH9-related disease (MYH9-RD) is an autosomal- dominant disorder deriving from mutations in MYH9, the gene for the nonmuscle myosin heavy chain (NMMHC)-IIA. MYH9-RD has a complex phenotype including congenital features, such as thrombocytopenia, and noncongenital manifestations, namely sensorineural hearing loss (SNHL), nephropathy, cataract, and liver abnormalities. The disease is caused by a limited number of mutations affecting different regions of the NMMHC-IIA protein. SNHL is the most frequent noncongenital manifestation of MYH9-RD. However, only scarce and anecdotal information is currently available about the clinical and audiometric features of SNHL of MYH9-RD subjects. The objective of this study was to investigate the severity and propensity for progression of SNHL in a large series of MYH9-RD patients in relation to the causative NMMHC-IIA mutations.

DESIGN: This study included the consecutive patients diagnosed with MYH9-RD between July 2007 and March 2012 at four participating institutions. A total of 115 audiograms were analyzed from 63 patients belonging to 45 unrelated families with different NMMHC-IIA mutations. Cross-sectional analyses of audiograms were performed. Regression analysis was performed, and age-related typical audiograms (ARTAs) were derived to characterize the type of SNHL associated with different mutations.

RESULTS: Severity of SNHL appeared to depend on the specific NMMHC-IIA mutation. Patients carrying substitutions at the residue R702 located in the short functional SH1 helix had the most severe degree of SNHL, whereas patients with the p.E1841K substitution in the coiled-coil region or mutations at the nonhelical tailpiece presented a mild degree of SNHL even at advanced age. The authors also disclosed the effects of different amino acid changes at the same residue: for instance, individuals with the p.R702C mutation had more severe SNHL than those with the p.R702H mutation, and the p.R1165L substitution was associated with a higher degree of hearing loss than the p.R1165C. In general, mild SNHL was associated with a fairly flat audiogram configuration, whereas severe SNHL correlated with downsloping configurations. ARTA plots showed that the most progressive type of SNHL was associated with the p.R702C, the p.R702H, and the p.R1165L substitutions, whereas the p.R1165C mutation correlated with a milder, nonprogressive type of SNHL than the p.R1165L. ARTA for the p.E1841K mutation demonstrated a mild degree of SNHL with only mild progression, whereas the ARTA for the mutations at the nonhelical tailpiece did not show any substantial progression.

CONCLUSIONS: These data provide useful tools to predict the progression and the expected degree of severity of SNHL in individual MYH9-RD patients, which is especially relevant in young patients. Consequences in clinical practice are important not only for appropriate patient counseling but also for development of customized, genotype-driven clinical management. The authors recently reported that cochlear implantation has a good outcome in MYH9-RD patients; thus, stricter follow-up and earlier intervention are recommended for patients with unfavorable genotypes.

}, issn = {1538-4667}, doi = {10.1097/AUD.0000000000000198}, author = {Verver, Eva J J and Topsakal, Vedat and Kunst, Henricus P M and Huygen, Patrick L M and Heller, Paula G and Pujol-Moix, N{\'u}ria and Savoia, Anna and Benazzo, Marco and Fierro, Tiziana and Grolman, Wilko and Gresele, Paolo and Pecci, Alessandro} } @article {8072, title = {The one-step synthesis and surface functionalization of dumbbell-like gold-iron oxide nanoparticles: a chitosan-based nanotheranostic system.}, journal = {Chem Commun (Camb)}, volume = {52}, year = {2016}, month = {2016 Jan 7}, pages = {378-81}, abstract = {

The first one-step synthesis of dumbbell-like gold-iron oxide nanoparticles has been reported here. Surface functionalization with a biocompatible chitosan matrix allowed us to obtain a novel targetable diagnostic and therapeutic tool.

}, issn = {1364-548X}, doi = {10.1039/c5cc08275g}, author = {Kostevsek, Nina and Locatelli, Erica and Garrovo, Chiara and Arena, Francesca and Monaco, Ilaria and Nikolov, Ivaylo Petrov and Sturm, Saso and Zuzek Rozman, Kristina and Lorusso, Vito and Giustetto, Pierangela and Bardini, Paola and Biffi, Stefania and Comes Franchini, Mauro} } @article {8286, title = {The prognostic value of biological markers in paediatric Hodgkin lymphoma.}, journal = {Eur J Cancer}, volume = {52}, year = {2016}, month = {2016 Jan}, pages = {33-40}, abstract = {

BACKGROUND: Many biological and inflammatory markers have been proposed as having a prognostic value at diagnosis of Hodgkin lymphoma (HL), but very few have been validated in paediatric patients. We explored the significance of these markers in a large population of 769 affected children.

PATIENTS AND METHODS: By using the database of patients enrolled in A.I.E.O.P. (Associazione Italiana di Emato-Oncologia Pediatrica) trial LH2004 for paediatric HL, we identified 769 consecutive patients treated with curative intent from 1st June 2004 to 1st April 2014 with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or hybrid COPP/ABV (cyclophosphamide, vincristine, prednisone, procarbazine, doxorubicin, bleomycin and vinblastine) regimens.

RESULTS: On multivariate analysis with categorical forms, the 5-year freedom from progression survival was significantly lower in patients with stage IV or elevated value of platelets, eosinophils and ferritin at diagnosis. Furthermore, stage IV and eosinophils seem to maintain their predictive value independently of interim (after IV cycles of chemotherapy) positron emission tomography.

CONCLUSION: Using the combination of four simple markers such as stage IV and elevated levels of platelets, ferritin and eosinophils, it is possible to classify the patients into subgroups with very different outcomes.

}, keywords = {Adolescent, Age Factors, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Blood Platelets, Child, Child, Preschool, Databases, Factual, Disease Progression, Disease-Free Survival, Eosinophils, Female, Ferritins, Hodgkin Disease, Humans, Infant, Infant, Newborn, Italy, Kaplan-Meier Estimate, Leukocyte Count, Male, Multivariate Analysis, Neoplasm Staging, Platelet Count, Predictive Value of Tests, Proportional Hazards Models, Retrospective Studies, Risk Factors, Time Factors, Treatment Outcome}, issn = {1879-0852}, doi = {10.1016/j.ejca.2015.09.003}, author = {Farruggia, Piero and Puccio, Giuseppe and Sala, Alessandra and Todesco, Alessandra and Buffardi, Salvatore and Garaventa, Alberto and Bottigliero, Gaetano and Bianchi, Maurizio and Zecca, Marco and Locatelli, Franco and Pession, Andrea and Pillon, Marta and Favre, Claudio and D{\textquoteright}Amico, Salvatore and Provenzi, Massimo and Trizzino, Angela and Zanazzo, Giulio Andrea and Sau, Antonella and Santoro, Nicola and Murgia, Giulio and Casini, Tommaso and Mascarin, Maurizio and Burnelli, Roberta} } @article {8341, title = {A Proteomic Approach for the Identification of Up-Regulated Proteins Involved in the Metabolic Process of the Leiomyoma.}, journal = {Int J Mol Sci}, volume = {17}, year = {2016}, month = {2016}, pages = {540}, abstract = {

Uterine leiomyoma is the most common benign smooth muscle cell tumor of the uterus. Proteomics is a powerful tool for the analysis of complex mixtures of proteins. In our study, we focused on proteins that were upregulated in the leiomyoma compared to the myometrium. Paired samples of eight leiomyomas and adjacent myometrium were obtained and submitted to two-dimensional gel electrophoresis (2-DE) and mass spectrometry for protein identification and to Western blotting for 2-DE data validation. The comparison between the patterns revealed 24 significantly upregulated (p < 0.05) protein spots, 12 of which were found to be associated with the metabolic processes of the leiomyoma and not with the normal myometrium. The overexpression of seven proteins involved in the metabolic processes of the leiomyoma was further validated by Western blotting and 2D Western blotting. Four of these proteins have never been associated with the leiomyoma before. The 2-DE approach coupled with mass spectrometry, which is among the methods of choice for comparative proteomic studies, identified a number of proteins overexpressed in the leiomyoma and involved in several biological processes, including metabolic processes. A better understanding of the mechanism underlying the overexpression of these proteins may be important for therapeutic purposes.

}, issn = {1422-0067}, doi = {10.3390/ijms17040540}, author = {Ura, Blendi and Scrimin, Federica and Arrigoni, Giorgio and Franchin, Cinzia and Monasta, Lorenzo and Ricci, Giuseppe} } @article {8290, title = {A quasi randomized-controlled trial to evaluate the effectiveness of clowntherapy on children{\textquoteright}s anxiety and pain levels in emergency department.}, journal = {Eur J Pediatr}, volume = {175}, year = {2016}, month = {2016 May}, pages = {645-50}, abstract = {

UNLABELLED: The aim of the study is to investigate if the presence of medical clowns during painful procedures in the emergency department (ED) affects children{\textquoteright}s anxiety and pain. Forty children (4-11 years) admitted to the ED with the need of painful procedures were prospectively enrolled. They were randomly assigned to the clown group, where children interacted with clowns or to the control group in which they were entertained by parents and ED nurses. The children{\textquoteright}s anxiety was assessed by the Children{\textquoteright}s Anxiety and Pain Scales; pain was evaluated with the Numerical Rating Scale and Wong-Backer Scale, according to the children{\textquoteright}s age. Staff and clown{\textquoteright}s opinions were evaluated by means of dedicated questionnaires. Children{\textquoteright}s anxiety levels in the clown group were significantly lower than those compared with the control group, while children{\textquoteright}s pain levels did not change between the two groups.

CONCLUSION: The presence of clowns in the ED before and during painful procedures was effective in reducing children{\textquoteright}s anxiety.

WHAT IS KNOWN: {\textbullet} Anxiety and fear caused by medical procedures exacerbate children{\textquoteright}s pain and may interfere with the procedure. {\textbullet} To reduce anxiety, fear, and pain and to facilitate patient{\textquoteright}s evaluation, different non-pharmacological approaches have been proposed and positive effects of laughter and humor have been reported. What is New: {\textbullet} The presence of clowns in the waiting room and in the ED during medical evaluation and painful procedures helps to reduce children{\textquoteright}s anxiety.

}, issn = {1432-1076}, doi = {10.1007/s00431-015-2688-0}, author = {Felluga, Margherita and Rabach, Ingrid and Minute, Marta and Montico, Marcella and Giorgi, Rita and Lonciari, Isabella and Taddio, Andrea and Barbi, Egidio} } @article {8526, title = {A reference panel of 64,976 haplotypes for genotype imputation.}, journal = {Nat Genet}, year = {2016}, month = {2016 Aug 22}, abstract = {

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1\% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.

}, issn = {1546-1718}, doi = {10.1038/ng.3643}, author = {McCarthy, Shane and Das, Sayantan and Kretzschmar, Warren and Delaneau, Olivier and Wood, Andrew R and Teumer, Alexander and Kang, Hyun Min and Fuchsberger, Christian and Danecek, Petr and Sharp, Kevin and Luo, Yang and Sidore, Carlo and Kwong, Alan and Timpson, Nicholas and Koskinen, Seppo and Vrieze, Scott and Scott, Laura J and Zhang, He and Mahajan, Anubha and Veldink, Jan and Peters, Ulrike and Pato, Carlos and van Duijn, Cornelia M and Gillies, Christopher E and Gandin, Ilaria and Mezzavilla, Massimo and Gilly, Arthur and Cocca, Massimiliano and Traglia, Michela and Angius, Andrea and Barrett, Jeffrey C and Boomsma, Dorrett and Branham, Kari and Breen, Gerome and Brummett, Chad M and Busonero, Fabio and Campbell, Harry and Chan, Andrew and Chen, Sai and Chew, Emily and Collins, Francis S and Corbin, Laura J and Smith, George Davey and Dedoussis, George and D{\"o}rr, Marcus and Farmaki, Aliki-Eleni and Ferrucci, Luigi and Forer, Lukas and Fraser, Ross M and Gabriel, Stacey and Levy, Shawn and Groop, Leif and Harrison, Tabitha and Hattersley, Andrew and Holmen, Oddgeir L and Hveem, Kristian and Kretzler, Matthias and Lee, James C and McGue, Matt and Meitinger, Thomas and Melzer, David and Min, Josine L and Mohlke, Karen L and Vincent, John B and Nauck, Matthias and Nickerson, Deborah and Palotie, Aarno and Pato, Michele and Pirastu, Nicola and McInnis, Melvin and Richards, J Brent and Sala, Cinzia and Salomaa, Veikko and Schlessinger, David and Schoenherr, Sebastian and Slagboom, P Eline and Small, Kerrin and Spector, Timothy and Stambolian, Dwight and Tuke, Marcus and Tuomilehto, Jaakko and Van den Berg, Leonard H and van Rheenen, Wouter and V{\"o}lker, Uwe and Wijmenga, Cisca and Toniolo, Daniela and Zeggini, Eleftheria and Gasparini, Paolo and Sampson, Matthew G and Wilson, James F and Frayling, Timothy and de Bakker, Paul I W and Swertz, Morris A and McCarroll, Steven and Kooperberg, Charles and Dekker, Annelot and Altshuler, David and Willer, Cristen and Iacono, William and Ripatti, Samuli and Soranzo, Nicole and Walter, Klaudia and Swaroop, Anand and Cucca, Francesco and Anderson, Carl A and Myers, Richard M and Boehnke, Michael and McCarthy, Mark I and Durbin, Richard} } @article {8327, title = {Somatic, hematologic phenotype, long-term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Associ}, journal = {Am J Hematol}, volume = {91}, year = {2016}, month = {2016 Jul}, pages = {666-71}, abstract = {

We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy-two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow-up, 33\% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6\% with median follow-up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666-671, 2016. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, issn = {1096-8652}, doi = {10.1002/ajh.24373}, author = {Svahn, Johanna and Bagnasco, Francesca and Cappelli, Enrico and Onofrillo, Daniela and Caruso, Silvia and Corsolini, Fabio and De Rocco, Daniela and Savoia, Anna and Longoni, Daniela and Pillon, Marta and Marra, Nicoletta and Ramenghi, Ugo and Farruggia, Piero and Locasciulli, Anna and Addari, Carmen and Cerri, Carla and Mastrodicasa, Elena and Casazza, Gabriella and Verzegnassi, Federico and Riccardi, Francesca and Haupt, Riccardo and Barone, Angelica and Cesaro, Simone and Cugno, Chiara and Dufour, Carlo} } @article {8333, title = {Toward SERS-based point-of-care approaches for therapeutic drug monitoring: the case of methotrexate.}, journal = {Faraday Discuss}, volume = {187}, year = {2016}, month = {2016 Jun 23}, pages = {485-99}, abstract = {

To date, in spite of their toxicity, the plasmatic concentration of most chemotherapeutic drugs is difficult to monitor in oncological patients, because their quantitative determination is expensive and time consuming. This contribution reports a first attempt for the direct quantitative determination of a chemotherapeutic drug in human serum samples by means of Surface Enhanced Raman Spectroscopy (SERS). In this study, SERS substrates constituted by Au nanoparticles deposited on paper by a simple dipping method have been used for rapid (few minutes) analysis of diluted human serum spiked with different concentrations of methotrexate, MTX. The drug concentrations were chosen in a range designed to cover typical therapeutic plasmatic values (from nanomolar to millimolar) in oncological patients, and the pertinent calibration was obtained by Partial Least-Squares Regression (PLSR). Stability selection was employed to evaluate the capability of the PLSR model to accurately predict and extract spectral variations correlated to MTX concentration. Such a quantitative determination is crucial for frequent, and hence adherent, therapeutic drug monitoring, TDM, of chemiotherapic drugs, given their heavy side effects. Its low cost, rapid response and the possibility of obtaining spectra with simple and compact instruments, make SERS particularly apt for implementing effective TDM. The promising results obtained in the analytical validation indicate which steps are to be taken on the way toward a clinical validation with real samples from oncological patients, for MTX as well as for other chemotherapeutic drugs.

}, issn = {1359-6640}, doi = {10.1039/c5fd00173k}, author = {Fornasaro, Stefano and Marta, Silvia Dalla and Rabusin, Marco and Bonifacio, Alois and Sergo, Valter} } @article {8303, title = {Tracking of the origin of recurrent mutations of the BRCA1 and BRCA2 genes in the North-East of Italy and improved mutation analysis strategy.}, journal = {BMC Med Genet}, volume = {17}, year = {2016}, month = {2016}, pages = {11}, abstract = {

BACKGROUND: About 20 \% of hereditary breast cancers are caused by mutations in BRCA1 and BRCA2 genes. Since BRCA1 and BRCA2 mutations may be spread throughout the gene, genetic testing is usually performed by direct sequencing of entire coding regions. In some populations, especially if relatively isolated, a few number of recurrent mutations is reported, sometimes caused by founder effect.

METHODS: BRCA1 and BRCA2 screening for mutations was carried out on 1114 breast and/or ovarian cancer patients complying with the eligibility criteria for BRCA testing. Haplotype analysis was performed on the probands carrying recurrent mutations and their relatives, using two sets of microsatellite markers covering the BRCA1 (D17S588, D17S806, D17S902, D17S1325, D17S855, D17S1328, D17S800, and D17S250) and BRCA2 (D13S220, D13S267, D13S171, D13S1701, D13S1698, D13S260, D13S290, D13S1246) loci. The DMLE + 2.2 software was used to estimate the age of BRCA1 c.676delT and BRCA2 c.7806-2A > G. A multiplex PCR and two different primer extension assays were optimized and used for genotyping the recurrent mutations of the two genes.

RESULTS: In the time frame of almost 20 years of genetic testing, we have found that five BRCA1 and three BRCA2 mutations are recurrent in a substantial subset of carriers from North-East Italy and neighboring Istria, where they represent more than 50 \% of all mutations. Microsatellite analyses identified a common haplotype of different length for each mutation. Age estimation of BRCA1 c.676delT and BRCA2 c.7806-2A > G mutations revealed that they arose in the Friuli Venezia Giulia area about 86 and 94 generations ago, respectively. Suggestion of an association between BRCA2 c.7806-2A > G and risk of breast cancer in males has emerged. Finally, we developed a simple and efficient pre-screening test, performing an in-house primer extension SNaPshot{\textregistered} assay for the rapid identification of the eight recurrent mutations.

CONCLUSIONS: Proofs of common ancestry has been obtained for the eight recurrent mutations. The observed genotype-phenotype correlation and the proposed rapid mutation detection strategy could improve the clinical management of breast and ovarian patients in North-East of Italy and neighboring geographic areas.

}, keywords = {Adult, Aged, Alleles, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Case-Control Studies, DNA Mutational Analysis, Female, Founder Effect, Genetic Testing, Genome-Wide Association Study, Genotyping Techniques, Haplotypes, Humans, Italy, Male, Microsatellite Repeats, Middle Aged, Mutation, Ovarian Neoplasms, Young Adult}, issn = {1471-2350}, doi = {10.1186/s12881-016-0274-6}, author = {Cini, Giulia and Mezzavilla, Massimo and Della Puppa, Lara and Cupelli, Elisa and Fornasin, Alessio and D{\textquoteright}Elia, Angela Valentina and Dolcetti, Riccardo and Damante, Giuseppe and Bertok, Sara and Miolo, Gianmaria and Maestro, Roberta and de Paoli, Paolo and Amoroso, Antonio and Viel, Alessandra} } @article {3592, title = {5-Aminoimidazole-4-carboxamide ribonucleotide-transformylase and inosine-triphosphate-pyrophosphatase genes variants predict remission rate during methotrexate therapy in patients with juvenile idiopathic arthritis.}, journal = {Rheumatol Int}, volume = {35}, year = {2015}, month = {2015 Apr}, pages = {619-27}, abstract = {

For children with juvenile idiopathic arthritis (JIA) who fail to respond to methotrexate, the delay in identifying the optimal treatment at an early stage of disease can lead to long-term joint damage. Recent studies indicate that relevant variants to predict methotrexate response in JIA are those in 5-aminoimidazole-4-carboxamide ribonucleotide-transformylase (ATIC), inosine-triphosphate-pyrophosphatase (ITPA) and solute-liquid-carrier-19A1 genes. The purpose of the study was, therefore, to explore the role of these candidate genetic factors on methotrexate response in an Italian cohort of children with JIA. Clinical response to methotrexate was evaluated as clinical remission stable for a 6-month period, as ACRPed score and as change in Juvenile Arthritis Disease score. The most relevant SNPs for each gene considered were assayed on patients{\textquoteright} DNA. ITPA activity was measured in patients{\textquoteright} erythrocytes. Sixty-nine patients with JIA were analyzed: 52.2 \% responded to therapy (ACRPed70 score), while 37.7 \% reached clinical remission stable for 6 months. ATIC rs2372536 GG genotype was associated with improved clinical remission (adjusted p value = 0.0090). For ITPA, rs1127354 A variant was associated with reduced clinical remission: (adjusted p value = 0.028); this association was present even for patients with wild-type ITPA and low ITPA activity. These preliminary results indicate that genotyping of ATIC rs2372536 and ITPA rs1127354 variants or measuring ITPA activity could be useful to predict methotrexate response in children with JIA after validation by further prospective studies on a larger patient cohort.

}, issn = {1437-160X}, doi = {10.1007/s00296-014-3131-y}, author = {Pastore, Serena and Stocco, Gabriele and Moressa, Valentina and Zandon{\`a}, Luigi and Favretto, Diego and Malus{\`a}, Noelia and Decorti, Giuliana and Lepore, Loredana and Ventura, Alessandro} } @article {3633, title = {ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization.}, journal = {Blood}, volume = {125}, year = {2015}, month = {2015 Jan 29}, pages = {869-72}, abstract = {

Inherited thrombocytopenias (ITs) are a heterogeneous group of syndromic and nonsyndromic diseases caused by mutations affecting different genes. Alterations of ACTN1, the gene encoding for α-actinin 1, have recently been identified in a few families as being responsible for a mild form of IT (ACTN1-related thrombocytopenia; ACTN1-RT). To better characterize this disease, we screened ACTN1 in 128 probands and found 10 (8 novel) missense heterozygous variants in 11 families. Combining bioinformatics, segregation, and functional studies, we demonstrated that all but 1 amino acid substitution had deleterious effects. The clinical and laboratory findings of 31 affected individuals confirmed that ACTN1-RT is a mild macrothrombocytopenia with low risk for bleeding. Low reticulated platelet counts and only slightly increased serum thrombopoietin levels indicated that the latest phases of megakaryopoiesis were affected. Given its relatively high frequency in our cohort (4.2\%), ACTN1-RT has to be taken into consideration in the differential diagnosis of ITs.

}, keywords = {Actinin, Adolescent, Adult, Aged, Aged, 80 and over, Blood Platelets, Case-Control Studies, Child, Child, Preschool, Female, Gene Expression, Genotype, Heterozygote, Humans, Male, Middle Aged, Mutation, Missense, Pedigree, Phenotype, Platelet Count, Severity of Illness Index, Thrombocytopenia, Thrombopoiesis, Thrombopoietin}, issn = {1528-0020}, doi = {10.1182/blood-2014-08-594531}, author = {Bottega, Roberta and Marconi, Caterina and Faleschini, Michela and Baj, Gabriele and Cagioni, Claudia and Pecci, Alessandro and Pippucci, Tommaso and Ramenghi, Ugo and Pardini, Simonetta and Ngu, Loretta and Baronci, Carlo and Kunishima, Shinji and Balduini, Carlo L and Seri, Marco and Savoia, Anna and Noris, Patrizia} } @article {8093, title = {Acute myeloid leukemia in a 3 years old child with cleidocranial dysplasia.}, journal = {Leuk Lymphoma}, year = {2015}, month = {2015 Dec 24}, pages = {1-3}, issn = {1029-2403}, doi = {10.3109/10428194.2015.1115030}, author = {Callea, Michele and Bellacchio, Emanuele and Fattori, Fabiana and Bertini, Enrico and Callea, Francesco and Cammarata-Scalisi, Francisco} } @article {3640, title = {Advertisements of follow-on formula and their perception by pregnant women and mothers in Italy.}, journal = {Arch Dis Child}, volume = {100}, year = {2015}, month = {2015 Apr}, pages = {323-8}, abstract = {

OBJECTIVE: To assess how follow-on formula milks for infants aged 6-12 months are presented to and understood by mothers.

DESIGN: A quantitative and qualitative cross-sectional study including (1) an analysis of advertisements in three magazines for parents; (2) in-depth semistructured qualitative interviews to pregnant women on their perception of two advertisements for follow-on formula and (3) self-administered questionnaires for mothers to explore their exposure to and perception of formula advertisements.

PARTICIPANTS: Eighty pregnant women 32-36 weeks of gestation with no previous children and 562 mothers of children <3 years old.

SETTING: Maternal and child health centres in eight cities of Italy.

RESULTS: Advertisements of formula (n=89) represented about 7\% of all advertisements in the three magazines, the majority (58\%) being for follow-on formula. Advertisements were parent-oriented, aimed at helping parents solve health problems of their babies or at eliciting good feelings, or both. The qualitative interviews to pregnant women showed inability to define the advertised products at first glance due to the ambiguity of the numeral 2 and the presumed age of the portrayed baby; this inability did not disappear after carefully viewing the advertisements and reading the text. When asked in the self-administered questionnaires whether they had ever come across advertisements of infant formula, 81\% of mothers reported that they had, despite the legal inexistence of such advertisements, and 65\% thought that it was for a product to be used from birth.

CONCLUSIONS: Advertisements of follow-on formula are perceived by pregnant women and mothers as promoting infant formula.

}, keywords = {Adult, Advertising as Topic, Attitude to Health, Cross-Sectional Studies, Female, Humans, Infant, Infant Formula, Italy, Mothers, Perception, Periodicals as Topic, Pregnancy, Pregnant Women, Reading, Surveys and Questionnaires, Young Adult}, issn = {1468-2044}, doi = {10.1136/archdischild-2014-306996}, author = {Cattaneo, Adriano and Pani, Paola and Carletti, Claudia and Guidetti, Margherita and Mutti, Valentina and Guidetti, Cecilia and Knowles, Alessandra} } @article {7722, title = {Advising Mothers on the Use of Medications during Breastfeeding: A Need for a Positive Attitude.}, journal = {J Hum Lact}, year = {2015}, month = {2015 Jul 14}, abstract = {

The use of medications by the nursing mother is a common reason for interrupting breastfeeding. Few drugs have been demonstrated to be absolutely contraindicated during breastfeeding. Excessive caution may lead health professionals to unnecessarily advise to interrupt breastfeeding, without assessing the latest evidence or considering the risk-benefit ratio of taking a medication versus terminating breastfeeding. To foster an appropriate approach toward the use of medications in breastfeeding women, the Italian Society of Perinatal Medicine created the following policy statement.

}, issn = {1552-5732}, doi = {10.1177/0890334415595513}, author = {Davanzo, Riccardo and Bua, Jenny and De Cunto, Angela and Farina, Maria Luisa and De Ponti, Fabrizio and Clavenna, Antonio and Mandrella, Stefania and Sagone, Antonella and Clementi, Maurizio} } @article {7787, title = {Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype.}, journal = {Clin Immunol}, volume = {159}, year = {2015}, month = {2015 Jul}, pages = {33-6}, keywords = {B-Lymphocytes, Child, Preschool, Female, Germinal Center, Humans, Hyper-IgM Immunodeficiency Syndrome, Infant, Male, Mutation, Phenotype, Phosphatidylinositol 3-Kinases, RNA Splice Sites, Sequence Analysis, DNA}, issn = {1521-7035}, doi = {10.1016/j.clim.2015.04.014}, author = {Lougaris, Vassilios and Faletra, Flavio and Lanzi, Gaetana and Vozzi, Diego and Marcuzzi, Annalisa and Valencic, Erica and Piscianz, Elisa and Bianco, AnnaMonica and Girardelli, Martina and Baronio, Manuela and Loganes, Claudia and Fasth, Anders and Salvini, Filippo and Trizzino, Antonino and Moratto, Daniele and Facchetti, Fabio and Giliani, Silvia and Plebani, Alessandro and Tommasini, Alberto} } @article {7760, title = {Are all cases of paediatric essential thrombocythaemia really myeloproliferative neoplasms? Analysis of a large cohort.}, journal = {Br J Haematol}, volume = {169}, year = {2015}, month = {2015 May}, pages = {584-9}, abstract = {

Sporadic essential thrombocythaemia (ET) is rare in paediatrics, and the diagnostic and clinical approach to paediatric cases cannot be simply copied from experience with adults. Here, we assessed 89 children with a clinical diagnosis of ET and found that 23 patients (25{\textperiodcentered}8\%) had a clonal disease. The JAK2 V617F mutation was identified in 14 children, 1 child had the MPL W515L mutation, and 6 had CALR mutations. The monoclonal X-chromosome inactivation pattern was seen in six patients (two with JAK2 V617F and two with CALR mutations). The other 66 patients (74{\textperiodcentered}2\%) had persistent thrombocytosis with no clonality. There were no clinical or haematological differences between the clonal and non-clonal patients. The relative proportion of ET-specific mutations in the clonal children was much the same as in adults. The higher prevalence of non-clonal cases suggests that some patients may not have myeloproliferative neoplasms, with significant implications for their treatment.

}, keywords = {Adolescent, Adult, Amino Acid Substitution, Child, Child, Preschool, Cohort Studies, Female, Hematologic Neoplasms, Humans, Infant, Janus Kinase 2, Male, Mutation, Missense, Neoplasm Proteins, Thrombocythemia, Essential}, issn = {1365-2141}, doi = {10.1111/bjh.13329}, author = {Randi, Maria L and Geranio, Giulia and Bertozzi, Irene and Micalizzi, Concetta and Ramenghi, Ugo and Tucci, Fabio and Notarangelo, Lucia D and Ladogana, Saverio and Menna, Giuseppe and Giordano, Paola and Consarino, Caterina and Farruggia, Piero and Zanazzo, Giulio A and Fiori, Giovanni M and Burnelli, Roberta and Russo, Giovanna and Jankovich, Momcilo and Peroni, Edoardo and Duner, Elena and Basso, Giuseppe and Fabris, Fabrizio and Putti, Maria C} } @article {8034, title = {Bedside diagnosis of two major clinical phenotypes of hypertensive disorders of pregnancy.}, journal = {Ultrasound Obstet Gynecol}, year = {2015}, month = {2015 Sep 9}, abstract = {

OBJECTIVE: We hypothesized that fetal abdominal circumference (AC) and Uterine Doppler Pulsatility Index (UtA-PI) could select two homogenous subgroups of women affected by hypertensive disorders of pregnancy (HDP), characterized by the coexistence of maternal hypertension with and without IUGR.

METHODS: This is a multicentre study that studied cases affected by HDP in whom fetal AC and UtA-PI had been measured at admission to feto Maternal Medicine Units. Maternal characteristics, pregnancy complications and outcome were recorded. These data allowed us to model the characteristics of fetal growth in cases affected by HDP, and to design a composite index for risk factors of maternal metabolic syndrome (rfMMS) and composite index of severity for maternal organ and/or function damage (OFD).

RESULTS: Measurements of fetal AC and UtA-PI allowed us to define a group of HDP with AGA fetuses (HDP-AGAf) diagnosed by normal fetal AC and a UtA-PI ($\#$205), and a group of HDP with IUGR fetuses (HDP-IUGR) diagnosed by fetal AC <5(th) centile and UtA-PI >95(th) centile ($\#$124). Curves fitted to birth-weight of the two groups were significantly different, and gestational age at admission for HDP, <34 or >=34, had no effect on their models. When birth-weight was expressed as standard deviation score (SDS) of local reference charts, the average SDS ({\textpm}standard error) corresponded to the 6(th) and 48(th) centile respectively. The risk of developing HDP-AGAf was significantly associated with risk factors for maternal metabolic syndrome (OR= 2.79;CI 1.57-4.97), independently of gestational age. The same risk factors yielded a non significant ORs of developing late onset HDP. Women with HDP-IUGR proved to be associated with the worst clinical outcomes.

CONCLUSIONS: This study adds genuine new data based on simple prenatal bedside examinations, that might help to differentiate HDP with IUGR, from HDP with AGA fetuses, associated with different fetal growth patterns and different risk factors, not affected by gestational age at onset of the disease.

}, issn = {1469-0705}, doi = {10.1002/uog.15741}, author = {Ferrazzi, E and Zullino, S and Stampalija, T and Vener, C and Cavoretto, P and Gervasi, M T and Vergani, P and Mecacci, F and Marozio, L and Ogg{\`e}, G and Algeri, P and Ruffatti, A and Milani, S and Todros, T} } @article {3621, title = {"Blaschkoid dyspigmentation" in a child: don{\textquoteright}t forget fibroblast chromosomal analysis.}, journal = {J Pediatr}, volume = {166}, year = {2015}, month = {2015 Feb}, pages = {490-90.e1}, keywords = {Abnormalities, Multiple, Child, Preschool, Chromosomes, DNA, Female, Fibroblasts, Humans, Phenotype, Pigmentation Disorders}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2014.10.028}, author = {Gortani, Giulia and Faletra, Flavio and Bruno, Irene and Berti, Irene and Ventura, Alessandro} } @article {8024, title = {A brain and heart connection: X-linked periventricular heterotopia.}, journal = {J Pediatr}, volume = {166}, year = {2015}, month = {2015 Mar}, pages = {776}, keywords = {Adolescent, Brain, Diagnosis, Differential, DNA Mutational Analysis, Epilepsy, Female, Filamins, Humans, Magnetic Resonance Imaging, Mutation, Periventricular Nodular Heterotopia}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2014.11.037}, author = {Naviglio, Samuele and Bruno, Irene and Zanus, Caterina and Faletra, Flavio and Ventura, Alessandro} } @article {8046, title = {Brain sparing effect in growth-restricted fetuses is associated with decreased cardiac acceleration and deceleration capacities: a case-control study.}, journal = {BJOG}, year = {2015}, month = {2015 Sep 23}, abstract = {

OBJECTIVE: Phase rectified signal averaging (PRSA) is a new method of fetal heart rate variability (fHRV) analysis that quantifies the average acceleration (AC) and deceleration capacity (DC) of the heart. The aim of this study was to evaluate AC and DC of fHR [recorded by trans-abdominal fetal electrocardiogram (ta-fECG)] in relation to Doppler velocimetry characteristics of intrauterine growth restriction (IUGR).

DESIGN: Prospective case-control study.

SETTING: Single third referral centre.

POPULATION: IUGR (n = 66) between 25 and 40 gestational weeks and uncomplicated pregnancies (n = 79).

METHODS: In IUGR the nearest ta-fECG monitoring to delivery was used for PRSA analysis and Doppler velocimetry parameters obtained within 48 hours. AC and DC were computed at s = T = 9. The relation was evaluated between either AC or DC and Doppler velocimetry parameters adjusting for gestational age at monitoring, as well as the association between either AC or DC and IUGR with or without brain sparing.

RESULTS: In IUGRs there was a significant association between either AC and DC and middle cerebral artery pulsatility index (PI; P = 0.01; P = 0.005), but the same was not true for uterine or umbilical artery PI (P > 0.05). Both IUGR fetuses with and without brain sparing had lower AC and DC than controls, but this association was stronger for IUGRs with brain sparing.

CONCLUSIONS: Our study observed for the first time that AC and DC at PRSA analysis are associated with middle cerebral artery PI, but not with uterine or umbilical artery PI, and that there is a significant decrease of AC and DC in association with brain sparing in IUGR fetuses from 25 weeks of gestation to term.

TWEETABLE ABSTRACT: Brain sparing in IUGR fetuses is associated with decreased acceleration and deceleration capacities of the heart.

}, issn = {1471-0528}, doi = {10.1111/1471-0528.13607}, author = {Stampalija, T and Casati, D and Monasta, L and Sassi, R and Rivolta, M W and Muggiasca, M L and Bauer, A and Ferrazzi, E} } @article {8070, title = {Brain-derived neurotrophic factor serum levels in genetically isolated populations: gender-specific association with anxiety disorder subtypes but not with anxiety levels or Val66Met polymorphism.}, journal = {PeerJ}, volume = {3}, year = {2015}, month = {2015}, pages = {e1252}, abstract = {

Anxiety disorders (ADs) are disabling chronic disorders with exaggerated behavioral response to threats. This study was aimed at testing the hypothesis that ADs may be associated with reduced neurotrophic activity, particularly of Brain-derived neurotrophic factor (BDNF), and determining possible effects of genetics on serum BDNF concentrations. In 672 adult subjects from six isolated villages in North-Eastern Italy with high inbreeding, we determined serum BDNF levels and identified subjects with different ADs subtypes such as Social and Specific Phobias (PHSOC, PHSP), Generalized Anxiety Disorder (GAD), and Panic Disorder (PAD). Analysis of the population as a whole or individual village showed no significant correlation between serum BDNF levels and Val66Met polymorphism and no association with anxiety levels. Stratification of subjects highlighted a significant decrease in serum BDNF in females with GAD and males with PHSP. This study indicates low heritability and absence of any impact of the Val66Met polymorphism on circulating concentrations of BDNF. Our results show that BDNF is not a general biomarker of anxiety but serum BDNF levels correlate in a gender-specific manner with ADs subtypes.

}, issn = {2167-8359}, doi = {10.7717/peerj.1252}, author = {Carlino, Davide and Francavilla, Ruggiero and Baj, Gabriele and Kulak, Karolina and d{\textquoteright}Adamo, Pio and Ulivi, Sheila and Cappellani, Stefania and Gasparini, Paolo and Tongiorgi, Enrico} } @article {8078, title = {[Breastfeeding in the first months of life: data from the "Piccolipi{\`u}" cohorts].}, journal = {Epidemiol Prev}, volume = {39}, year = {2015}, month = {2015 Sep-Dec}, pages = {392}, issn = {1120-9763}, author = {Farchi, Sara and Ronfani, Luca} } @article {7757, title = {A case of Rubinstein-Taybi syndrome associated with growth hormone deficiency in childhood.}, journal = {Clin Endocrinol (Oxf)}, volume = {83}, year = {2015}, month = {2015 Sep}, pages = {437-9}, issn = {1365-2265}, doi = {10.1111/cen.12748}, author = {Tornese, Gianluca and Marzuillo, Pierluigi and Pellegrin, Maria Chiara and Germani, Claudio and Faleschini, Elena and Zennaro, Floriana and Grandone, Anna and Miraglia Del Giudice, Emanuele and Perrone, Laura and Ventura, Alessandro} } @article {7783, title = {Characterization of 14 novel deletions underlying Rubinstein-Taybi syndrome: an update of the CREBBP deletion repertoire.}, journal = {Hum Genet}, volume = {134}, year = {2015}, month = {2015 Jun}, pages = {613-26}, abstract = {

Rubinstein-Taybi syndrome (RSTS) is a rare, clinically heterogeneous disorder characterized by cognitive impairment and several multiple congenital anomalies. The syndrome is caused by almost private point mutations in the CREBBP (~55\% of cases) and EP300 (~8\%) genes. The CREBBP mutational spectrum is variegated and characterized by point mutations (30-50 \%) and deletions (~10\%). The latter are diverse in size and genomic position and remove either the whole CREBBP gene and its flanking regions or only an intragenic portion. Here, we report 14 novel CREBBP deletions ranging from single exons to the whole gene and flanking regions which were identified by applying complementary cytomolecular techniques: fluorescence in situ hybridization, multiplex ligation-dependent probe amplification and array comparative genome hybridization, to a large cohort of RSTS patients. Deletions involving CREBBP account for 23\% of our detected CREBBP mutations, making an important contribution to the mutational spectrum. Genotype-phenotype correlations revealed that patients with CREBBP deletions extending beyond this gene did not always have a more severe phenotype than patients harboring CREBBP point mutations, suggesting that neighboring genes play only a limited role in the etiopathogenesis of CREBBP-centerd contiguous gene syndrome. Accordingly, the extent of the deletion is not predictive of the severity of the clinical phenotype.

}, keywords = {Adolescent, Adult, Base Sequence, Child, Child, Preschool, Cohort Studies, CREB-Binding Protein, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Point Mutation, Rubinstein-Taybi Syndrome, Sequence Deletion}, issn = {1432-1203}, doi = {10.1007/s00439-015-1542-9}, author = {Rusconi, Daniela and Negri, Gloria and Colapietro, Patrizia and Picinelli, Chiara and Milani, Donatella and Spena, Silvia and Magnani, Cinzia and Silengo, Margherita Cirillo and Sorasio, Lorena and Curtisova, Vaclava and Cavaliere, Maria Luigia and Prontera, Paolo and Stangoni, Gabriela and Ferrero, Giovanni Battista and Biamino, Elisa and Fischetto, Rita and Piccione, Maria and Gasparini, Paolo and Salviati, Leonardo and Selicorni, Angelo and Finelli, Palma and Larizza, Lidia and Gervasini, Cristina} } @article {7698, title = {Clinical aspects of Fanconi anemia individuals with the same mutation of FANCF identified by next generation sequencing.}, journal = {Birth Defects Res A Clin Mol Teratol}, volume = {103}, year = {2015}, month = {2015 Dec}, pages = {1003-1010}, abstract = {

BACKGROUND: Fanconi anemia (FA) is a rare genetic disease characterized by congenital malformations, aplastic anemia and increased risk of developing malignancies. FA is genetically heterogeneous as it is caused by at least 17 different genes. Among these, FANCA, FANCC, and FANCG account for approximately 85\% of the patients whereas the remaining genes are mutated in only a small percentage of cases. For this reason, the molecular diagnostic process is complex and not always extended to all the FA genes, preventing the characterization of individuals belonging to rare groups.

METHODS: The FA genes were analyzed using a next generation sequencing approach in two unrelated families.

RESULTS: The analysis identified the same, c.484_485del, homozygous mutation of FANCF in both families. A careful examination of three electively aborted fetuses in one family and one affected girl in the other indicated an association of the FANCF loss-of-function mutation with a severe phenotype characterized by multiple malformations.

CONCLUSION: The systematic use of next generation sequencing will allow the recognition of individuals from rare complementation groups, a better definition of their clinical phenotypes, and consequently, an appropriate genetic counseling. Birth Defects Research (Part A) 103:1003-1010, 2015. {\textcopyright} 2015 Wiley Periodicals, Inc.

}, issn = {1542-0760}, doi = {10.1002/bdra.23388}, author = {Nicchia, Elena and Benedicenti, Francesco and Rocco, Daniela De and Greco, Chiara and Bottega, Roberta and Inzana, Francesca and Faleschini, Michela and Bonin, Serena and Cappelli, Enrico and Mogni, Massimo and Stanzial, Franco and Svahn, Johanna and Dufour, Carlo and Savoia, Anna} } @article {7753, title = {Comprehensive analysis of polymorphisms in the HLA-G 5{\textquoteright} upstream regulatory and 3{\textquoteright} untranslated regions in Brazilian patients with systemic lupus erythematosus.}, journal = {Tissue Antigens}, volume = {85}, year = {2015}, month = {2015 Jun}, pages = {458-65}, abstract = {

This study aims to comprehensively analyze human leucocyte antigen (HLA)-G polymorphisms association with susceptibility to systemic lupus erythematosus (SLE) development and clinical manifestations. The HLA-G 5{\textquoteright} upstream regulatory region (URR), 3{\textquoteright} untranslated region (UTR) and a cytosine deletion at exon 3 (ΔC, HLA-G*0105N allele) were analyzed in 114 SLE patients and 128 healthy controls from North East Brazil. The +3003T>C (rs1707) C allele and the HG010101c extended HLA-G allele were significantly more frequent in SLE patients than healthy controls (+3003C allele frequency: 12\% in SLE patients vs 6\% in controls; odds ratio (OR), 2.10, 95\% confidence interval (CI), 1.06-4.28, P = 0.026; HG010101c frequency: 11.8\% in SLE patients and 6.3\% in controls; OR, 2.14, 95\% CI, 1.01-4.51, P = 0.046) and were associated with susceptibility for disease development. Other polymorphisms were associated with different clinical manifestations. Although HLA-G role in SLE disease is far from being elucidated yet, our association study results along with a systematic review and meta-analysis suggest that HLA-G might be able to slightly modulate the complex SLE phenotype (pooled OR, 1.14, 95\% CI, 1.02-1.27, P = 0.021).

}, issn = {1399-0039}, doi = {10.1111/tan.12545}, author = {Catamo, E and Addobbati, C and Segat, L and Sotero Fragoso, T and Tavares Dantas, A and de Ata{\'\i}de Mariz, H and Ferreira da Rocha Junior, L and Branco PintoDuarte, A L and Coelho, A V C and de Moura, R R and Polesello, V and Crovella, S and Sandrin Garcia, P} } @article {3584, title = {Connexin 26 variant carriers have a better gastrointestinal health: is this the heterozygote advantage?}, journal = {Eur J Hum Genet}, volume = {23}, year = {2015}, month = {2015 May}, pages = {563-4}, issn = {1476-5438}, doi = {10.1038/ejhg.2014.151}, author = {Vuckovic, Dragana and Dallapiccola, Bruno and Franz{\`e}, Annamaria and Mauri, Lucia and Perrone, Maria Dolores and Gasparini, Paolo} } @article {8097, title = {Design, Synthesis, and Biological Characterization of Novel Mitochondria Targeted Dichloroacetate-Loaded Compounds with Antileukemic Activity.}, journal = {J Med Chem}, year = {2015}, month = {2015 Dec 23}, abstract = {

The mitochondrial kinase inhibitor dichloroacetate (DCA) has recently received attention in oncology due to its ability to target glycolysis. However, DCA molecule exhibits poor bioavailability and cellular uptake with limited ability to reach its target mitochondria. To overcome these biases, we have synthesized novel DCA-loaded compounds. The selection of the most promising therapeutic molecule was evaluated by combining in vitro assays, to test the antitumoral potential on leukemic cells, and a preliminary characterization of the molecule stability in vivo, in mice. Among the newly synthesized compounds, we have selected the multiple DCA-loaded compound 10, characterized by a tertiary amine scaffold, because it exhibited enhanced (>30-fold) in vitro antitumor activity with respect to DCA and increased in vivo stability. On the basis of these results, we believe that compound 10 should be considered for further preclinical evaluations for the treatment of cancers and/or other diseases characterized by altered metabolic origin.

}, issn = {1520-4804}, doi = {10.1021/acs.jmedchem.5b01165}, author = {Trapella, Claudio and Voltan, Rebecca and Melloni, Elisabetta and Tisato, Veronica and Celeghini, Claudio and Bianco, Sara and Fantinati, Anna and Salvadori, Severo and Guerrini, Remo and Secchiero, Paola and Zauli, Giorgio} } @article {7696, title = {Directional dominance on stature and cognition in~diverse human populations.}, journal = {Nature}, volume = {523}, year = {2015}, month = {2015 Jul 23}, pages = {459-62}, abstract = {

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs~of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 {\texttimes} 10(-300), 2.1 {\texttimes} 10(-6), 2.5 {\texttimes} 10(-10) and 1.8 {\texttimes} 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months{\textquoteright} less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

}, keywords = {Biological Evolution, Blood Pressure, Body Height, Cholesterol, LDL, Cognition, Cohort Studies, Educational Status, Female, Forced Expiratory Volume, Genome, Human, Homozygote, Humans, Lung Volume Measurements, Male, Phenotype}, issn = {1476-4687}, doi = {10.1038/nature14618}, author = {Joshi, Peter K and Esko, T{\~o}nu and Mattsson, Hannele and Eklund, Niina and Gandin, Ilaria and Nutile, Teresa and Jackson, Anne U and Schurmann, Claudia and Smith, Albert V and Zhang, Weihua and Okada, Yukinori and Stan{\v c}{\'a}kov{\'a}, Alena and Faul, Jessica D and Zhao, Wei and Bartz, Traci M and Concas, Maria Pina and Franceschini, Nora and Enroth, Stefan and Vitart, Veronique and Trompet, Stella and Guo, Xiuqing and Chasman, Daniel I and O{\textquoteright}Connel, Jeffrey R and Corre, Tanguy and Nongmaithem, Suraj S and Chen, Yuning and Mangino, Massimo and Ruggiero, Daniela and Traglia, Michela and Farmaki, Aliki-Eleni and Kacprowski, Tim and Bjonnes, Andrew and van der Spek, Ashley and Wu, Ying and Giri, Anil K and Yanek, Lisa R and Wang, Lihua and Hofer, Edith and Rietveld, Cornelius A and McLeod, Olga and Cornelis, Marilyn C and Pattaro, Cristian and Verweij, Niek and Baumbach, Clemens and Abdellaoui, Abdel and Warren, Helen R and Vuckovic, Dragana and Mei, Hao and Bouchard, Claude and Perry, John R B and Cappellani, Stefania and Mirza, Saira S and Benton, Miles C and Broeckel, Ulrich and Medland, Sarah E and Lind, Penelope A and Malerba, Giovanni and Drong, Alexander and Yengo, Loic and Bielak, Lawrence F and Zhi, Degui and van der Most, Peter J and Shriner, Daniel and M{\"a}gi, Reedik and Hemani, Gibran and Karaderi, Tugce and Wang, Zhaoming and Liu, Tian and Demuth, Ilja and Zhao, Jing Hua and Meng, Weihua and Lataniotis, Lazaros and van der Laan, Sander W and Bradfield, Jonathan P and Wood, Andrew R and Bonnefond, Amelie and Ahluwalia, Tarunveer S and Hall, Leanne M and Salvi, Erika and Yazar, Seyhan and Carstensen, Lisbeth and de Haan, Hugoline G and Abney, Mark and Afzal, Uzma and Allison, Matthew A and Amin, Najaf and Asselbergs, Folkert W and Bakker, Stephan J L and Barr, R Graham and Baumeister, Sebastian E and Benjamin, Daniel J and Bergmann, Sven and Boerwinkle, Eric and Bottinger, Erwin P and Campbell, Archie and Chakravarti, Aravinda and Chan, Yingleong and Chanock, Stephen J and Chen, Constance and Chen, Y-D Ida and Collins, Francis S and Connell, John and Correa, Adolfo and Cupples, L Adrienne and Smith, George Davey and Davies, Gail and D{\"o}rr, Marcus and Ehret, Georg and Ellis, Stephen B and Feenstra, Bjarke and Feitosa, Mary F and Ford, Ian and Fox, Caroline S and Frayling, Timothy M and Friedrich, Nele and Geller, Frank and Scotland, Generation and Gillham-Nasenya, Irina and Gottesman, Omri and Graff, Misa and Grodstein, Francine and Gu, Charles and Haley, Chris and Hammond, Christopher J and Harris, Sarah E and Harris, Tamara B and Hastie, Nicholas D and Heard-Costa, Nancy L and Heikkil{\"a}, Kauko and Hocking, Lynne J and Homuth, Georg and Hottenga, Jouke-Jan and Huang, Jinyan and Huffman, Jennifer E and Hysi, Pirro G and Ikram, M Arfan and Ingelsson, Erik and Joensuu, Anni and Johansson, {\r A}sa and Jousilahti, Pekka and Jukema, J Wouter and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanoni, Stavroula and Kerr, Shona M and Khan, Nazir M and Koellinger, Philipp and Koistinen, Heikki A and Kooner, Manraj K and Kubo, Michiaki and Kuusisto, Johanna and Lahti, Jari and Launer, Lenore J and Lea, Rodney A and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liewald, David C M and Lind, Lars and Loh, Marie and Lokki, Marja-Liisa and London, Stephanie J and Loomis, Stephanie J and Loukola, Anu and Lu, Yingchang and Lumley, Thomas and Lundqvist, Annamari and M{\"a}nnist{\"o}, Satu and Marques-Vidal, Pedro and Masciullo, Corrado and Matchan, Angela and Mathias, Rasika A and Matsuda, Koichi and Meigs, James B and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Mentch, Frank D and Mihailov, Evelin and Milani, Lili and Montasser, May E and Montgomery, Grant W and Morrison, Alanna and Myers, Richard H and Nadukuru, Rajiv and Navarro, Pau and Nelis, Mari and Nieminen, Markku S and Nolte, Ilja M and O{\textquoteright}Connor, George T and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmas, Walter R and Pankow, James S and Patarcic, Inga and Pavani, Francesca and Peyser, Patricia A and Pietilainen, Kirsi and Poulter, Neil and Prokopenko, Inga and Ralhan, Sarju and Redmond, Paul and Rich, Stephen S and Rissanen, Harri and Robino, Antonietta and Rose, Lynda M and Rose, Richard and Sala, Cinzia and Salako, Babatunde and Salomaa, Veikko and Sarin, Antti-Pekka and Saxena, Richa and Schmidt, Helena and Scott, Laura J and Scott, William R and Sennblad, Bengt and Seshadri, Sudha and Sever, Peter and Shrestha, Smeeta and Smith, Blair H and Smith, Jennifer A and Soranzo, Nicole and Sotoodehnia, Nona and Southam, Lorraine and Stanton, Alice V and Stathopoulou, Maria G and Strauch, Konstantin and Strawbridge, Rona J and Suderman, Matthew J and Tandon, Nikhil and Tang, Sian-Tsun and Taylor, Kent D and Tayo, Bamidele O and T{\"o}glhofer, Anna Maria and Tomaszewski, Maciej and T{\v s}ernikova, Natalia and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and van Hylckama Vlieg, Astrid and van Setten, Jessica and Vasankari, Tuula and Vedantam, Sailaja and Vlachopoulou, Efthymia and Vozzi, Diego and Vuoksimaa, Eero and Waldenberger, Melanie and Ware, Erin B and Wentworth-Shields, William and Whitfield, John B and Wild, Sarah and Willemsen, Gonneke and Yajnik, Chittaranjan S and Yao, Jie and Zaza, Gianluigi and Zhu, Xiaofeng and Salem, Rany M and Melbye, Mads and Bisgaard, Hans and Samani, Nilesh J and Cusi, Daniele and Mackey, David A and Cooper, Richard S and Froguel, Philippe and Pasterkamp, Gerard and Grant, Struan F A and Hakonarson, Hakon and Ferrucci, Luigi and Scott, Robert A and Morris, Andrew D and Palmer, Colin N A and Dedoussis, George and Deloukas, Panos and Bertram, Lars and Lindenberger, Ulman and Berndt, Sonja I and Lindgren, Cecilia M and Timpson, Nicholas J and T{\"o}njes, Anke and Munroe, Patricia B and S{\o}rensen, Thorkild I A and Rotimi, Charles N and Arnett, Donna K and Oldehinkel, Albertine J and Kardia, Sharon L R and Balkau, Beverley and Gambaro, Giovanni and Morris, Andrew P and Eriksson, Johan G and Wright, Margie J and Martin, Nicholas G and Hunt, Steven C and Starr, John M and Deary, Ian J and Griffiths, Lyn R and Tiemeier, Henning and Pirastu, Nicola and Kaprio, Jaakko and Wareham, Nicholas J and P{\'e}russe, Louis and Wilson, James G and Girotto, Giorgia and Caulfield, Mark J and Raitakari, Olli and Boomsma, Dorret I and Gieger, Christian and van der Harst, Pim and Hicks, Andrew A and Kraft, Peter and Sinisalo, Juha and Knekt, Paul and Johannesson, Magnus and Magnusson, Patrik K E and Hamsten, Anders and Schmidt, Reinhold and Borecki, Ingrid B and Vartiainen, Erkki and Becker, Diane M and Bharadwaj, Dwaipayan and Mohlke, Karen L and Boehnke, Michael and van Duijn, Cornelia M and Sanghera, Dharambir K and Teumer, Alexander and Zeggini, Eleftheria and Metspalu, Andres and Gasparini, Paolo and Ulivi, Sheila and Ober, Carole and Toniolo, Daniela and Rudan, Igor and Porteous, David J and Ciullo, Marina and Spector, Tim D and Hayward, Caroline and Dupuis, Jos{\'e}e and Loos, Ruth J F and Wright, Alan F and Chandak, Giriraj R and Vollenweider, Peter and Shuldiner, Alan R and Ridker, Paul M and Rotter, Jerome I and Sattar, Naveed and Gyllensten, Ulf and North, Kari E and Pirastu, Mario and Psaty, Bruce M and Weir, David R and Laakso, Markku and Gudnason, Vilmundur and Takahashi, Atsushi and Chambers, John C and Kooner, Jaspal S and Strachan, David P and Campbell, Harry and Hirschhorn, Joel N and Perola, Markus and Polasek, Ozren and Wilson, James F} } @article {3599, title = {Does Teno Torque Virus Induce Autoimmunity After Hematopoietic Stem Cell Transplantation? A Case Report.}, journal = {J Pediatr Hematol Oncol}, volume = {37}, year = {2015}, month = {2015 Apr}, pages = {e194-7}, abstract = {

Teno Torque virus, member of the family of Anelloviridae, has been associated with many autoimmune diseases such as idiopathic hepatitis, systemic lupus erythematosus, and multiple sclerosis. Its viral load tends to be higher in the bone marrow and in tissues with high turnover rate. We report here a case of an 11-month-old infant affected by acute myeloid leukemia who underwent hematopoietic stem cell transplantation, and after 6 months had autoimmune hepatitis and atopic dermatitis. Extremely high-cytokine IP-10 and eotaxin levels were found in her sera, and serological tests and RT-PCR for viruses showed positive results exclusively for Teno Torque virus.

}, keywords = {Autoimmune Diseases, Autoimmunity, Dermatitis, Atopic, DNA Virus Infections, DNA, Viral, Female, Hematopoietic Stem Cell Transplantation, Hepatitis, Humans, Infant, Leukemia, Myeloid, Acute, Prognosis, Torque teno virus, Viral Load}, issn = {1536-3678}, doi = {10.1097/MPH.0000000000000194}, author = {Maximova, Natalia and Pizzol, Antonio and Ferrara, Giovanna and Maestro, Alessandra and Tamaro, Paolo} } @article {7708, title = {Effect of Thalidomide on Clinical Remission in Children and Adolescents with Ulcerative Colitis Refractory to Other Immunosuppressives: Pilot Randomized Clinical Trial.}, journal = {Inflamm Bowel Dis}, volume = {21}, year = {2015}, month = {2015 Aug}, pages = {1739-49}, abstract = {

BACKGROUND: In a randomized controlled trial, thalidomide has shown to be effective in refractory Crohn{\textquoteright}s disease in children. This pilot study aimed at evaluating thalidomide in refractory pediatric ulcerative colitis (UC).

METHODS: Double-blind, placebo-controlled randomized clinical trial on thalidomide 1.5 to 2.5 mg/kg/day in children with active UC despite multiple immunosuppressive treatments. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks; all responders were followed up for a minimum of 52 weeks.

RESULTS: Twenty-six children with refractory UC were randomized to thalidomide or placebo. Clinical remission at week 8 was achieved by significantly more children treated with thalidomide {10/12 (83.3\%) versus 2/11 (18.8\%); risk ratio, 4.5 (95\% confidence interval [CI], 1.2-16.4); P = 0.005; number needed to treat, 1.5}. Of the nonresponders to placebo who were switched to thalidomide, 8 of 11 (72.7\%) subsequently reached remission at week 8 (risk ratio, 4.0 [95\% CI, 1.1-14.7]; number needed to treat, 2.45; P = 0.01). Clinical remission in the thalidomide group was 135.0 weeks (95\% CI, 32-238), compared with 8.0 weeks (95\% CI, 2.4-13.6) in the placebo group (P < 0.0001). Cumulative incidence of severe adverse events was 3.1 per 1000 patient-weeks. Peripheral neuropathy and amenorrhea were the most frequent adverse events.

CONCLUSIONS: In this pilot randomized controlled trial on cases of UC refractory to immunosuppressive therapy, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and in longer term maintenance of remission. These findings require replication in larger clinical studies evaluating both thalidomide efficacy and safety.

}, issn = {1536-4844}, doi = {10.1097/MIB.0000000000000437}, author = {Lazzerini, Marzia and Martelossi, Stefano and Magazz{\`u}, Giuseppe and Pellegrino, Salvatore and Lucanto, Maria Cristina and Barabino, Arrigo and Calvi, Angela and Arrigo, Serena and Lionetti, Paolo and Lorusso, Monica and Mangiantini, Francesca and Fontana, Massimo and Zuin, Giovanna and Palla, Gabriella and Maggiore, Giuseppe and Bramuzzo, Matteo and Pellegrin, Maria Chiara and Maschio, Massimo and Villanacci, Vincenzo and Manenti, Stefania and Decorti, Giuliana and De Iudicibus, Sara and Paparazzo, Rossella and Montico, Marcella and Ventura, Alessandro} } @article {8092, title = {Genetic analysis of Italian patients with congenital tufting enteropathy.}, journal = {World J Pediatr}, year = {2015}, month = {2015 Dec 18}, abstract = {

BACKGROUND: Congenital tufting enteropathy (CTE), an inherited autosomal recessive rare disease, is a severe diarrhea of infancy which is clinically characterized by absence of inflammation and presence of intestinal villous atrophy. Mutations in the EpCAM gene were identified to cause CTE. Recent cases of syndromic tufting enteropathy harboring the SPINT2 (19q13.2) mutation were described.

METHODS: Four CTE Italian patients were clinically and immunohistochemically characterized. Direct DNA sequencing of EpCAM and SPINT2 genes was performed.

RESULTS: All patients were of Italian origin. Three different mutations were detected (p.Asp219Metfs*15, Tyr186Phefs*6 and p.Ile146Asn) in the EpCAM gene; one of them is novel (p.Ile146Asn). Two patients (P1 and P2) showed compound heterozygosity revealing two mutations in separate alleles. A third patient (P3) was heterozygous for only one novel EpCAM missense mutation (p.Ile146Asn). In a syndromic patient (P4), no deleterious EpCAM mutation was found. Additional SPINT2 mutational analysis was performed. P4 showed a homozygous SPINT2 mutation (p.Y163C). No SPINT2 mutation was found in P3. CLDN7 was also evaluated as a candidate gene by mutational screening in P3 but no mutation was identified.

CONCLUSIONS: This study presented a molecular characterization of CTE Italian patients, and identified three mutations in the EpCAM gene and one in the SPINT2 gene. One of EpCAM mutations was novel, therefore increasing the mutational spectrum of allelic variants of the EpCAM gene. Molecular analysis of the SPINT2 gene also allowed us to identify a SPINT2 substitution mutation (c.488A>G) recently found to be associated with syndromic CTE subjects.

}, issn = {1867-0687}, doi = {10.1007/s12519-015-0070-y}, author = {d{\textquoteright}Apolito, Maria and Pisanelli, Daniela and Faletra, Flavio and Giardino, Ida and Gigante, Maddalena and Pettoello-Mantovani, Massimo and Goulet, Olivier and Gasparini, Paolo and Campanozzi, Angelo} } @article {7762, title = {Genetic determinants for methotrexate response in juvenile idiopathic arthritis.}, journal = {Front Pharmacol}, volume = {6}, year = {2015}, month = {2015}, pages = {52}, abstract = {

Juvenile idiopathic arthritis (JIAs) is the most common chronic rheumatic disease of childhood and is an important cause of disability. The folic acid analog methotrexate is the first choice disease-modifying anti-rheumatic drug in this disease, however, 35-45\% of patients fail to respond. Molecular elements, such as variants in genes of pharmacological relevance, influencing response to methotrexate in JIA, would be important to individualize treatment strategies. Several studies have evaluated the effects of candidate genetic variants in the complex pathway of genes involved in methotrexate pharmacodynamics and pharmacokinetics, however, results are still contrasting and no definitive genetic marker of methotrexate response useful for the clinician to tailor therapy of children with JIA has been identified. Recently, genome-wide approaches have been applied, identifying new potential biological processes involved in methotrexate response in JIA such as TGF-beta signaling and calcium channels. If these genomic results are properly validated and integrated with innovative analyses comprising deep sequencing, epigenetics, and pharmacokinetics, they will greatly contribute to personalize therapy with methotrexate in children with JIA.

}, issn = {1663-9812}, doi = {10.3389/fphar.2015.00052}, author = {Pastore, Serena and Stocco, Gabriele and Favretto, Diego and De Iudicibus, Sara and Taddio, Andrea and d{\textquoteright}Adamo, Pio and Malus{\`a}, Noelia and Addobbati, Riccardo and Decorti, Giuliana and Lepore, Loredana and Ventura, Alessandro} } @article {7691, title = {Genetic studies of body mass index yield new insights for obesity biology.}, journal = {Nature}, volume = {518}, year = {2015}, month = {2015 Feb 12}, pages = {197-206}, abstract = {

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P~<~5~{\texttimes}~10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for \~{}2.7\% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20\% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

}, keywords = {Adipogenesis, Adiposity, Age Factors, Body Mass Index, Continental Population Groups, Energy Metabolism, Europe, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glutamic Acid, Humans, Insulin, Male, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Synapses}, issn = {1476-4687}, doi = {10.1038/nature14177}, author = {Locke, Adam E and Kahali, Bratati and Berndt, Sonja I and Justice, Anne E and Pers, Tune H and Day, Felix R and Powell, Corey and Vedantam, Sailaja and Buchkovich, Martin L and Yang, Jian and Croteau-Chonka, Damien C and Esko, T{\~o}nu and Fall, Tove and Ferreira, Teresa and Gustafsson, Stefan and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Randall, Joshua C and Winkler, Thomas W and Wood, Andrew R and Workalemahu, Tsegaselassie and Faul, Jessica D and Smith, Jennifer A and Hua Zhao, Jing and Zhao, Wei and Chen, Jin and Fehrmann, Rudolf and Hedman, {\r A}sa K and Karjalainen, Juha and Schmidt, Ellen M and Absher, Devin and Amin, Najaf and Anderson, Denise and Beekman, Marian and Bolton, Jennifer L and Bragg-Gresham, Jennifer L and Buyske, Steven and Demirkan, Ayse and Deng, Guohong and Ehret, Georg B and Feenstra, Bjarke and Feitosa, Mary F and Fischer, Krista and Goel, Anuj and Gong, Jian and Jackson, Anne U and Kanoni, Stavroula and Kleber, Marcus E and Kristiansson, Kati and Lim, Unhee and Lotay, Vaneet and Mangino, Massimo and Mateo Leach, Irene and Medina-Gomez, Carolina and Medland, Sarah E and Nalls, Michael A and Palmer, Cameron D and Pasko, Dorota and Pechlivanis, Sonali and Peters, Marjolein J and Prokopenko, Inga and Shungin, Dmitry and Stan{\v c}{\'a}kov{\'a}, Alena and Strawbridge, Rona J and Ju Sung, Yun and Tanaka, Toshiko and Teumer, Alexander and Trompet, Stella and van der Laan, Sander W and van Setten, Jessica and Van Vliet-Ostaptchouk, Jana V and Wang, Zhaoming and Yengo, Loic and Zhang, Weihua and Isaacs, Aaron and Albrecht, Eva and Arnl{\"o}v, Johan and Arscott, Gillian M and Attwood, Antony P and Bandinelli, Stefania and Barrett, Amy and Bas, Isabelita N and Bellis, Claire and Bennett, Amanda J and Berne, Christian and Blagieva, Roza and Bl{\"u}her, Matthias and B{\"o}hringer, Stefan and Bonnycastle, Lori L and B{\"o}ttcher, Yvonne and Boyd, Heather A and Bruinenberg, Marcel and Caspersen, Ida H and Ida Chen, Yii-Der and Clarke, Robert and Daw, E Warwick and de Craen, Anton J M and Delgado, Graciela and Dimitriou, Maria and Doney, Alex S F and Eklund, Niina and Estrada, Karol and Eury, Elodie and Folkersen, Lasse and Fraser, Ross M and Garcia, Melissa E and Geller, Frank and Giedraitis, Vilmantas and Gigante, Bruna and Go, Alan S and Golay, Alain and Goodall, Alison H and Gordon, Scott D and Gorski, Mathias and Grabe, Hans-J{\"o}rgen and Grallert, Harald and Grammer, Tanja B and Gr{\"a}{\ss}ler, J{\"u}rgen and Gr{\"o}nberg, Henrik and Groves, Christopher J and Gusto, Ga{\"e}lle and Haessler, Jeffrey and Hall, Per and Haller, Toomas and Hallmans, Goran and Hartman, Catharina A and Hassinen, Maija and Hayward, Caroline and Heard-Costa, Nancy L and Helmer, Quinta and Hengstenberg, Christian and Holmen, Oddgeir and Hottenga, Jouke-Jan and James, Alan L and Jeff, Janina M and Johansson, {\r A}sa and Jolley, Jennifer and Juliusdottir, Thorhildur and Kinnunen, Leena and Koenig, Wolfgang and Koskenvuo, Markku and Kratzer, Wolfgang and Laitinen, Jaana and Lamina, Claudia and Leander, Karin and Lee, Nanette R and Lichtner, Peter and Lind, Lars and Lindstr{\"o}m, Jaana and Sin Lo, Ken and Lobbens, St{\'e}phane and Lorbeer, Roberto and Lu, Yingchang and Mach, Fran{\c c}ois and Magnusson, Patrik K E and Mahajan, Anubha and McArdle, Wendy L and McLachlan, Stela and Menni, Cristina and Merger, Sigrun and Mihailov, Evelin and Milani, Lili and Moayyeri, Alireza and Monda, Keri L and Morken, Mario A and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Musk, Arthur W and Nagaraja, Ramaiah and N{\"o}then, Markus M and Nolte, Ilja M and Pilz, Stefan and Rayner, Nigel W and Renstrom, Frida and Rettig, Rainer and Ried, Janina S and Ripke, Stephan and Robertson, Neil R and Rose, Lynda M and Sanna, Serena and Scharnagl, Hubert and Scholtens, Salome and Schumacher, Fredrick R and Scott, William R and Seufferlein, Thomas and Shi, Jianxin and Vernon Smith, Albert and Smolonska, Joanna and Stanton, Alice V and Steinthorsdottir, Valgerdur and Stirrups, Kathleen and Stringham, Heather M and Sundstr{\"o}m, Johan and Swertz, Morris A and Swift, Amy J and Syv{\"a}nen, Ann-Christine and Tan, Sian-Tsung and Tayo, Bamidele O and Thorand, Barbara and Thorleifsson, Gudmar and Tyrer, Jonathan P and Uh, Hae-Won and Vandenput, Liesbeth and Verhulst, Frank C and Vermeulen, Sita H and Verweij, Niek and Vonk, Judith M and Waite, Lindsay L and Warren, Helen R and Waterworth, Dawn and Weedon, Michael N and Wilkens, Lynne R and Willenborg, Christina and Wilsgaard, Tom and Wojczynski, Mary K and Wong, Andrew and Wright, Alan F and Zhang, Qunyuan and Brennan, Eoin P and Choi, Murim and Dastani, Zari and Drong, Alexander W and Eriksson, Per and Franco-Cereceda, Anders and G{\r a}din, Jesper R and Gharavi, Ali G and Goddard, Michael E and Handsaker, Robert E and Huang, Jinyan and Karpe, Fredrik and Kathiresan, Sekar and Keildson, Sarah and Kiryluk, Krzysztof and Kubo, Michiaki and Lee, Jong-Young and Liang, Liming and Lifton, Richard P and Ma, Baoshan and McCarroll, Steven A and McKnight, Amy J and Min, Josine L and Moffatt, Miriam F and Montgomery, Grant W and Murabito, Joanne M and Nicholson, George and Nyholt, Dale R and Okada, Yukinori and Perry, John R B and Dorajoo, Rajkumar and Reinmaa, Eva and Salem, Rany M and Sandholm, Niina and Scott, Robert A and Stolk, Lisette and Takahashi, Atsushi and Tanaka, Toshihiro and Van{\textquoteright}t Hooft, Ferdinand M and Vinkhuyzen, Anna A E and Westra, Harm-Jan and Zheng, Wei and Zondervan, Krina T and Heath, Andrew C and Arveiler, Dominique and Bakker, Stephan J L and Beilby, John and Bergman, Richard N and Blangero, John and Bovet, Pascal and Campbell, Harry and Caulfield, Mark J and Cesana, Giancarlo and Chakravarti, Aravinda and Chasman, Daniel I and Chines, Peter S and Collins, Francis S and Crawford, Dana C and Cupples, L Adrienne and Cusi, Daniele and Danesh, John and de Faire, Ulf and den Ruijter, Hester M and Dominiczak, Anna F and Erbel, Raimund and Erdmann, Jeanette and Eriksson, Johan G and Farrall, Martin and Felix, Stephan B and Ferrannini, Ele and Ferri{\`e}res, Jean and Ford, Ian and Forouhi, Nita G and Forrester, Terrence and Franco, Oscar H and Gansevoort, Ron T and Gejman, Pablo V and Gieger, Christian and Gottesman, Omri and Gudnason, Vilmundur and Gyllensten, Ulf and Hall, Alistair S and Harris, Tamara B and Hattersley, Andrew T and Hicks, Andrew A and Hindorff, Lucia A and Hingorani, Aroon D and Hofman, Albert and Homuth, Georg and Hovingh, G Kees and Humphries, Steve E and Hunt, Steven C and Hypp{\"o}nen, Elina and Illig, Thomas and Jacobs, Kevin B and J{\"a}rvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Johansen, Berit and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti M and Kaprio, Jaakko and Kastelein, John J P and Keinanen-Kiukaanniemi, Sirkka M and Kiemeney, Lambertus A and Knekt, Paul and Kooner, Jaspal S and Kooperberg, Charles and Kovacs, Peter and Kraja, Aldi T and Kumari, Meena and Kuusisto, Johanna and Lakka, Timo A and Langenberg, Claudia and Le Marchand, Loic and Lehtim{\"a}ki, Terho and Lyssenko, Valeriya and M{\"a}nnist{\"o}, Satu and Marette, Andr{\'e} and Matise, Tara C and McKenzie, Colin A and McKnight, Barbara and Moll, Frans L and Morris, Andrew D and Morris, Andrew P and Murray, Jeffrey C and Nelis, Mari and Ohlsson, Claes and Oldehinkel, Albertine J and Ong, Ken K and Madden, Pamela A F and Pasterkamp, Gerard and Peden, John F and Peters, Annette and Postma, Dirkje S and Pramstaller, Peter P and Price, Jackie F and Qi, Lu and Raitakari, Olli T and Rankinen, Tuomo and Rao, D C and Rice, Treva K and Ridker, Paul M and Rioux, John D and Ritchie, Marylyn D and Rudan, Igor and Salomaa, Veikko and Samani, Nilesh J and Saramies, Jouko and Sarzynski, Mark A and Schunkert, Heribert and Schwarz, Peter E H and Sever, Peter and Shuldiner, Alan R and Sinisalo, Juha and Stolk, Ronald P and Strauch, Konstantin and T{\"o}njes, Anke and Tr{\'e}gou{\"e}t, David-Alexandre and Tremblay, Angelo and Tremoli, Elena and Virtamo, Jarmo and Vohl, Marie-Claude and V{\"o}lker, Uwe and Waeber, Gerard and Willemsen, Gonneke and Witteman, Jacqueline C and Zillikens, M Carola and Adair, Linda S and Amouyel, Philippe and Asselbergs, Folkert W and Assimes, Themistocles L and Bochud, Murielle and Boehm, Bernhard O and Boerwinkle, Eric and Bornstein, Stefan R and Bottinger, Erwin P and Bouchard, Claude and Cauchi, St{\'e}phane and Chambers, John C and Chanock, Stephen J and Cooper, Richard S and de Bakker, Paul I W and Dedoussis, George and Ferrucci, Luigi and Franks, Paul W and Froguel, Philippe and Groop, Leif C and Haiman, Christopher A and Hamsten, Anders and Hui, Jennie and Hunter, David J and Hveem, Kristian and Kaplan, Robert C and Kivimaki, Mika and Kuh, Diana and Laakso, Markku and Liu, Yongmei and Martin, Nicholas G and M{\"a}rz, Winfried and Melbye, Mads and Metspalu, Andres and Moebus, Susanne and Munroe, Patricia B and Nj{\o}lstad, Inger and Oostra, Ben A and Palmer, Colin N A and Pedersen, Nancy L and Perola, Markus and P{\'e}russe, Louis and Peters, Ulrike and Power, Chris and Quertermous, Thomas and Rauramaa, Rainer and Rivadeneira, Fernando and Saaristo, Timo E and Saleheen, Danish and Sattar, Naveed and Schadt, Eric E and Schlessinger, David and Slagboom, P Eline and Snieder, Harold and Spector, Tim D and Thorsteinsdottir, Unnur and Stumvoll, Michael and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and van der Harst, Pim and Walker, Mark and Wallaschofski, Henri and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wichmann, H-Erich and Wilson, James F and Zanen, Pieter and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Heid, Iris M and O{\textquoteright}Connell, Jeffrey R and Strachan, David P and Stefansson, Kari and van Duijn, Cornelia M and Abecasis, Goncalo R and Franke, Lude and Frayling, Timothy M and McCarthy, Mark I and Visscher, Peter M and Scherag, Andr{\'e} and Willer, Cristen J and Boehnke, Michael and Mohlke, Karen L and Lindgren, Cecilia M and Beckmann, Jacques S and Barroso, In{\^e}s and North, Kari E and Ingelsson, Erik and Hirschhorn, Joel N and Loos, Ruth J F and Speliotes, Elizabeth K} } @article {8038, title = {Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Nov}, pages = {1272-81}, abstract = {

We report \~{}17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22\% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, \~{}76,000 variants common in our sample (frequency >5\%) are rare elsewhere (<0.5\% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population.

}, issn = {1546-1718}, doi = {10.1038/ng.3368}, author = {Sidore, Carlo and Busonero, Fabio and Maschio, Andrea and Porcu, Eleonora and Naitza, Silvia and Zoledziewska, Magdalena and Mulas, Antonella and Pistis, Giorgio and Steri, Maristella and Danjou, Fabrice and Kwong, Alan and Ortega Del Vecchyo, Vicente Diego and Chiang, Charleston W K and Bragg-Gresham, Jennifer and Pitzalis, Maristella and Nagaraja, Ramaiah and Tarrier, Brendan and Brennan, Christine and Uzzau, Sergio and Fuchsberger, Christian and Atzeni, Rossano and Reinier, Frederic and Berutti, Riccardo and Huang, Jie and Timpson, Nicholas J and Toniolo, Daniela and Gasparini, Paolo and Malerba, Giovanni and Dedoussis, George and Zeggini, Eleftheria and Soranzo, Nicole and Jones, Chris and Lyons, Robert and Angius, Andrea and Kang, Hyun M and Novembre, John and Sanna, Serena and Schlessinger, David and Cucca, Francesco and Abecasis, Goncalo R} } @article {7723, title = {The Global Burden of Cancer 2013.}, journal = {JAMA Oncol}, volume = {1}, year = {2015}, month = {2015 Jul}, pages = {505-27}, abstract = {

IMPORTANCE: Cancer is among the leading causes of death worldwide. Current estimates of cancer burden in individual countries and regions are necessary to inform local cancer control strategies.

OBJECTIVE: To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 28 cancers in 188 countries by sex from 1990 to 2013.

EVIDENCE REVIEW: The general methodology of the Global Burden of Disease (GBD) 2013 study was used. Cancer registries were the source for cancer incidence data as well as mortality incidence (MI) ratios. Sources for cause of death data include vital registration system data, verbal autopsy studies, and other sources. The MI ratios were used to transform incidence data to mortality estimates and cause of death estimates to incidence estimates. Cancer prevalence was estimated using MI ratios as surrogates for survival data; YLDs were calculated by multiplying prevalence estimates with disability weights, which were derived from population-based surveys; YLLs were computed by multiplying the number of estimated cancer deaths at each age with a reference life expectancy; and DALYs were calculated as the sum of YLDs and YLLs.

FINDINGS: In 2013 there were 14.9 million incident cancer cases, 8.2 million deaths, and 196.3 million DALYs. Prostate cancer was the leading cause for cancer incidence (1.4 million) for men and breast cancer for women (1.8 million). Tracheal, bronchus, and lung (TBL) cancer was the leading cause for cancer death in men and women, with 1.6 million deaths. For men, TBL cancer was the leading cause of DALYs (24.9 million). For women, breast cancer was the leading cause of DALYs (13.1 million). Age-standardized incidence rates (ASIRs) per 100 000 and age-standardized death rates (ASDRs) per 100 000 for both sexes in 2013 were higher in developing vs developed countries for stomach cancer (ASIR, 17 vs 14; ASDR, 15 vs 11), liver cancer (ASIR, 15 vs 7; ASDR, 16 vs 7), esophageal cancer (ASIR, 9 vs 4; ASDR, 9 vs 4), cervical cancer (ASIR, 8 vs 5; ASDR, 4 vs 2), lip and oral cavity cancer (ASIR, 7 vs 6; ASDR, 2 vs 2), and nasopharyngeal cancer (ASIR, 1.5 vs 0.4; ASDR, 1.2 vs 0.3). Between 1990 and 2013, ASIRs for all cancers combined (except nonmelanoma skin cancer and Kaposi sarcoma) increased by more than 10\% in 113 countries and decreased by more than 10\% in 12 of 188 countries.

CONCLUSIONS AND RELEVANCE: Cancer poses a major threat to public health worldwide, and incidence rates have increased in most countries since 1990. The trend is a particular threat to developing nations with health systems that are ill-equipped to deal with complex and expensive cancer treatments. The annual update on the Global Burden of Cancer will provide all stakeholders with timely estimates to guide policy efforts in cancer prevention, screening, treatment, and palliation.

}, issn = {2374-2445}, doi = {10.1001/jamaoncol.2015.0735}, author = {Fitzmaurice, Christina and Dicker, Daniel and Pain, Amanda and Hamavid, Hannah and Moradi-Lakeh, Maziar and MacIntyre, Michael F and Allen, Christine and Hansen, Gillian and Woodbrook, Rachel and Wolfe, Charles and Hamadeh, Randah R and Moore, Ami and Werdecker, Andrea and Gessner, Bradford D and Te Ao, Braden and McMahon, Brian and Karimkhani, Chante and Yu, Chuanhua and Cooke, Graham S and Schwebel, David C and Carpenter, David O and Pereira, David M and Nash, Denis and Kazi, Dhruv S and De Leo, Diego and Plass, Dietrich and Ukwaja, Kingsley N and Thurston, George D and Yun Jin, Kim and Simard, Edgar P and Mills, Edward and Park, Eun-Kee and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and deVeber, Gabrielle and Gotay, Carolyn and Khan, Gulfaraz and Hosgood, H Dean and Santos, Itamar S and Leasher, Janet L and Singh, Jasvinder and Leigh, James and Jonas, Jost and Sanabria, Juan and Beardsley, Justin and Jacobsen, Kathryn H and Takahashi, Ken and Franklin, Richard C and Ronfani, Luca and Montico, Marcella and Naldi, Luigi and Tonelli, Marcello and Geleijnse, Johanna and Petzold, Max and Shrime, Mark G and Younis, Mustafa and Yonemoto, Naohiro and Breitborde, Nicholas and Yip, Paul and Pourmalek, Farshad and Lotufo, Paulo A and Esteghamati, Alireza and Hankey, Graeme J and Ali, Raghib and Lunevicius, Raimundas and Malekzadeh, Reza and Dellavalle, Robert and Weintraub, Robert and Lucas, Robyn and Hay, Roderick and Rojas-Rueda, David and Westerman, Ronny and Sepanlou, Sadaf G and Nolte, Sandra and Patten, Scott and Weichenthal, Scott and Abera, Semaw Ferede and Fereshtehnejad, Seyed-Mohammad and Shiue, Ivy and Driscoll, Tim and Vasankari, Tommi and Alsharif, Ubai and Rahimi-Movaghar, Vafa and Vlassov, Vasiliy V and Marcenes, W S and Mekonnen, Wubegzier and Melaku, Yohannes Adama and Yano, Yuichiro and Artaman, Al and Campos, Ismael and MacLachlan, Jennifer and Mueller, Ulrich and Kim, Daniel and Trillini, Matias and Eshrati, Babak and Williams, Hywel C and Shibuya, Kenji and Dandona, Rakhi and Murthy, Kinnari and Cowie, Benjamin and Amare, Azmeraw T and Antonio, Carl Abelardo and Casta{\~n}eda-Orjuela, Carlos and van Gool, Coen H and Violante, Francesco and Oh, In-Hwan and Deribe, Kedede and Soreide, Kjetil and Knibbs, Luke and Kereselidze, Maia and Green, Mark and C{\'a}rdenas, Rosario and Roy, Nobhojit and Tillman, Taavi and Li, Yongmei and Krueger, Hans and Monasta, Lorenzo and Dey, Subhojit and Sheikhbahaei, Sara and Hafezi-Nejad, Nima and Kumar, G Anil and Sreeramareddy, Chandrashekhar T and Dandona, Lalit and Wang, Haidong and Vollset, Stein Emil and Mokdad, Ali and Salomon, Joshua A and Lozano, Rafael and Vos, Theo and Forouzanfar, Mohammad and Lopez, Alan and Murray, Christopher and Naghavi, Mohsen} } @article {8043, title = {Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.}, journal = {Lancet}, volume = {386}, year = {2015}, month = {2015 Dec 5}, pages = {2287-323}, abstract = {

BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.

METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol.

FINDINGS: All risks combined account for 57{\textperiodcentered}2\% (95\% uncertainty interval [UI] 55{\textperiodcentered}8-58{\textperiodcentered}5) of deaths and 41{\textperiodcentered}6\% (40{\textperiodcentered}1-43{\textperiodcentered}0) of DALYs. Risks quantified account for 87{\textperiodcentered}9\% (86{\textperiodcentered}5-89{\textperiodcentered}3) of cardiovascular disease DALYs, ranging to a low of 0\% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5\% of DALYs: dietary risks accounting for 11{\textperiodcentered}3 million deaths and 241{\textperiodcentered}4 million DALYs, high systolic blood pressure for 10{\textperiodcentered}4 million deaths and 208{\textperiodcentered}1 million DALYs, child and maternal malnutrition for 1{\textperiodcentered}7 million deaths and 176{\textperiodcentered}9 million DALYs, tobacco smoke for 6{\textperiodcentered}1 million deaths and 143{\textperiodcentered}5 million DALYs, air pollution for 5{\textperiodcentered}5 million deaths and 141{\textperiodcentered}5 million DALYs, and high BMI for 4{\textperiodcentered}4 million deaths and 134{\textperiodcentered}0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa.

INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.

FUNDING: Bill \& Melinda Gates Foundation.

}, issn = {1474-547X}, doi = {10.1016/S0140-6736(15)00128-2}, author = {Forouzanfar, Mohammad H and Alexander, Lily and Anderson, H Ross and Bachman, Victoria F and Biryukov, Stan and Brauer, Michael and Burnett, Richard and Casey, Daniel and Coates, Matthew M and Cohen, Aaron and Delwiche, Kristen and Estep, Kara and Frostad, Joseph J and Astha, K C and Kyu, Hmwe H and Moradi-Lakeh, Maziar and Ng, Marie and Slepak, Erica Leigh and Thomas, Bernadette A and Wagner, Joseph and Aasvang, Gunn Marit and Abbafati, Cristiana and Abbasoglu Ozgoren, Ayse and Abd-Allah, Foad and Abera, Semaw F and Aboyans, Victor and Abraham, Biju and Abraham, Jerry Puthenpurakal and Abubakar, Ibrahim and Abu-Rmeileh, Niveen M E and Aburto, Tania C and Achoki, Tom and Adelekan, Ademola and Adofo, Koranteng and Adou, Ars{\`e}ne K and Adsuar, Jos{\'e} C and Afshin, Ashkan and Agardh, Emilie E and Al Khabouri, Mazin J and Al Lami, Faris H and Alam, Sayed Saidul and Alasfoor, Deena and Albittar, Mohammed I and Alegretti, Miguel A and Aleman, Alicia V and Alemu, Zewdie A and Alfonso-Cristancho, Rafael and Alhabib, Samia and Ali, Raghib and Ali, Mohammed K and Alla, Fran{\c c}ois and Allebeck, Peter and Allen, Peter J and Alsharif, Ubai and Alvarez, Elena and Alvis-Guzm{\'a}n, Nelson and Amankwaa, Adansi A and Amare, Azmeraw T and Ameh, Emmanuel A and Ameli, Omid and Amini, Heresh and Ammar, Walid and Anderson, Benjamin O and Antonio, Carl Abelardo T and Anwari, Palwasha and Argeseanu Cunningham, Solveig and Arnl{\"o}v, Johan and Arsenijevic, Valentina S Arsic and Artaman, Al and Asghar, Rana J and Assadi, Reza and Atkins, Lydia S and Atkinson, Charles and Avila, Marco A and Awuah, Baffour and Badawi, Alaa and Bahit, Maria C and Bakfalouni, Talal and Balakrishnan, Kalpana and Balalla, Shivanthi and Balu, Ravi Kumar and Banerjee, Amitava and Barber, Ryan M and Barker-Collo, Suzanne L and Barquera, Simon and Barregard, Lars and Barrero, Lope H and Barrientos-Gutierrez, Tonatiuh and Basto-Abreu, Ana C and Basu, Arindam and Basu, Sanjay and Basulaiman, Mohammed O and Batis Ruvalcaba, Carolina and Beardsley, Justin and Bedi, Neeraj and Bekele, Tolesa and Bell, Michelle L and Benjet, Corina and Bennett, Derrick A and Benzian, Habib and Bernabe, Eduardo and Beyene, Tariku J and Bhala, Neeraj and Bhalla, Ashish and Bhutta, Zulfiqar A and Bikbov, Boris and Bin Abdulhak, Aref A and Blore, Jed D and Blyth, Fiona M and Bohensky, Megan A and Bora Ba{\c s}ara, Berrak and Borges, Guilherme and Bornstein, Natan M and Bose, Dipan and Boufous, Soufiane and Bourne, Rupert R and Brainin, Michael and Brazinova, Alexandra and Breitborde, Nicholas J and Brenner, Hermann and Briggs, Adam D M and Broday, David M and Brooks, Peter M and Bruce, Nigel G and Brugha, Traolach S and Brunekreef, Bert and Buchbinder, Rachelle and Bui, Linh N and Bukhman, Gene and Bulloch, Andrew G and Burch, Michael and Burney, Peter G J and Campos-Nonato, Ismael R and Campuzano, Julio C and Cantoral, Alejandra J and Caravanos, Jack and C{\'a}rdenas, Rosario and Cardis, Elisabeth and Carpenter, David O and Caso, Valeria and Casta{\~n}eda-Orjuela, Carlos A and Castro, Ruben E and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and Cavalleri, Fiorella and Cavlin, Alanur and Chadha, Vineet K and Chang, Jung-Chen and Charlson, Fiona J and Chen, Honglei and Chen, Wanqing and Chen, Zhengming and Chiang, Peggy P and Chimed-Ochir, Odgerel and Chowdhury, Rajiv and Christophi, Costas A and Chuang, Ting-Wu and Chugh, Sumeet S and Cirillo, Massimo and Cla{\ss}en, Thomas K D and Colistro, Valentina and Colomar, Mercedes and Colquhoun, Samantha M and Contreras, Alejandra G and Cooper, Cyrus and Cooperrider, Kimberly and Cooper, Leslie T and Coresh, Josef and Courville, Karen J and Criqui, Michael H and Cuevas-Nasu, Lucia and Damsere-Derry, James and Danawi, Hadi and Dandona, Lalit and Dandona, Rakhi and Dargan, Paul I and Davis, Adrian and Davitoiu, Dragos V and Dayama, Anand and de Castro, E Filipa and De la Cruz-G{\'o}ngora, Vanessa and De Leo, Diego and de Lima, Gra{\c c}a and Degenhardt, Louisa and del Pozo-Cruz, Borja and Dellavalle, Robert P and Deribe, Kebede and Derrett, Sarah and Des Jarlais, Don C and Dessalegn, Muluken and deVeber, Gabrielle A and Devries, Karen M and Dharmaratne, Samath D and Dherani, Mukesh K and Dicker, Daniel and Ding, Eric L and Dokova, Klara and Dorsey, E Ray and Driscoll, Tim R and Duan, Leilei and Durrani, Adnan M and Ebel, Beth E and Ellenbogen, Richard G and Elshrek, Yousef M and Endres, Matthias and Ermakov, Sergey P and Erskine, Holly E and Eshrati, Babak and Esteghamati, Alireza and Fahimi, Saman and Faraon, Emerito Jose A and Farzadfar, Farshad and Fay, Derek F J and Feigin, Valery L and Feigl, Andrea B and Fereshtehnejad, Seyed-Mohammad and Ferrari, Alize J and Ferri, Cleusa P and Flaxman, Abraham D and Fleming, Thomas D and Foigt, Nataliya and Foreman, Kyle J and Paleo, Urbano Fra and Franklin, Richard C and Gabbe, Belinda and Gaffikin, Lynne and Gakidou, Emmanuela and Gamkrelidze, Amiran and Gankp{\'e}, Fortun{\'e} G and Gansevoort, Ron T and Garc{\'\i}a-Guerra, Francisco A and Gasana, Evariste and Geleijnse, Johanna M and Gessner, Bradford D and Gething, Pete and Gibney, Katherine B and Gillum, Richard F and Ginawi, Ibrahim A M and Giroud, Maurice and Giussani, Giorgia and Goenka, Shifalika and Goginashvili, Ketevan and Gomez Dantes, Hector and Gona, Philimon and Gonzalez de Cosio, Teresita and Gonz{\'a}lez-Castell, Dinorah and Gotay, Carolyn C and Goto, Atsushi and Gouda, Hebe N and Guerrant, Richard L and Gugnani, Harish C and Guillemin, Francis and Gunnell, David and Gupta, Rahul and Gupta, Rajeev and Guti{\'e}rrez, Reyna A and Hafezi-Nejad, Nima and Hagan, Holly and Hagstromer, Maria and Halasa, Yara A and Hamadeh, Randah R and Hammami, Mouhanad and Hankey, Graeme J and Hao, Yuantao and Harb, Hilda L and Haregu, Tilahun Nigatu and Haro, Josep Maria and Havmoeller, Rasmus and Hay, Simon I and Hedayati, Mohammad T and Heredia-Pi, Ileana B and Hernandez, Lucia and Heuton, Kyle R and Heydarpour, Pouria and Hijar, Martha and Hoek, Hans W and Hoffman, Howard J and Hornberger, John C and Hosgood, H Dean and Hoy, Damian G and Hsairi, Mohamed and Hu, Guoqing and Hu, Howard and Huang, Cheng and Huang, John J and Hubbell, Bryan J and Huiart, Laetitia and Husseini, Abdullatif and Iannarone, Marissa L and Iburg, Kim M and Idrisov, Bulat T and Ikeda, Nayu and Innos, Kaire and Inoue, Manami and Islami, Farhad and Ismayilova, Samaya and Jacobsen, Kathryn H and Jansen, Henrica A and Jarvis, Deborah L and Jassal, Simerjot K and Jauregui, Alejandra and Jayaraman, Sudha and Jeemon, Panniyammakal and Jensen, Paul N and Jha, Vivekanand and Jiang, Fan and Jiang, Guohong and Jiang, Ying and Jonas, Jost B and Juel, Knud and Kan, Haidong and Kany Roseline, Sidibe S and Karam, Nadim E and Karch, Andr{\'e} and Karema, Corine K and Karthikeyan, Ganesan and Kaul, Anil and Kawakami, Norito and Kazi, Dhruv S and Kemp, Andrew H and Kengne, Andre P and Keren, Andre and Khader, Yousef S and Khalifa, Shams Eldin Ali Hassan and Khan, Ejaz A and Khang, Young-Ho and Khatibzadeh, Shahab and Khonelidze, Irma and Kieling, Christian and Kim, Daniel and Kim, Sungroul and Kim, Yunjin and Kimokoti, Ruth W and Kinfu, Yohannes and Kinge, Jonas M and Kissela, Brett M and Kivipelto, Miia and Knibbs, Luke D and Knudsen, Ann Kristin and Kokubo, Yoshihiro and Kose, M Rifat and Kosen, Soewarta and Kraemer, Alexander and Kravchenko, Michael and Krishnaswami, Sanjay and Kromhout, Hans and Ku, Tiffany and Kuate Defo, Barthelemy and Kucuk Bicer, Burcu and Kuipers, Ernst J and Kulkarni, Chanda and Kulkarni, Veena S and Kumar, G Anil and Kwan, Gene F and Lai, Taavi and Lakshmana Balaji, Arjun and Lalloo, Ratilal and Lallukka, Tea and Lam, Hilton and Lan, Qing and Lansingh, Van C and Larson, Heidi J and Larsson, Anders and Laryea, Dennis O and Lavados, Pablo M and Lawrynowicz, Alicia E and Leasher, Janet L and Lee, Jong-Tae and Leigh, James and Leung, Ricky and Levi, Miriam and Li, Yichong and Li, Yongmei and Liang, Juan and Liang, Xiaofeng and Lim, Stephen S and Lindsay, M Patrice and Lipshultz, Steven E and Liu, Shiwei and Liu, Yang and Lloyd, Belinda K and Logroscino, Giancarlo and London, Stephanie J and Lopez, Nancy and Lortet-Tieulent, Joannie and Lotufo, Paulo A and Lozano, Rafael and Lunevicius, Raimundas and Ma, Jixiang and Ma, Stefan and Machado, Vasco M P and MacIntyre, Michael F and Magis-Rodriguez, Carlos and Mahdi, Abbas A and Majdan, Marek and Malekzadeh, Reza and Mangalam, Srikanth and Mapoma, Christopher C and Marape, Marape and Marcenes, Wagner and Margolis, David J and Margono, Christopher and Marks, Guy B and Martin, Randall V and Marzan, Melvin B and Mashal, Mohammad T and Masiye, Felix and Mason-Jones, Amanda J and Matsushita, Kunihiro and Matzopoulos, Richard and Mayosi, Bongani M and Mazorodze, Tasara T and McKay, Abigail C and McKee, Martin and McLain, Abigail and Meaney, Peter A and Medina, Catalina and Mehndiratta, Man Mohan and Mejia-Rodriguez, Fabiola and Mekonnen, Wubegzier and Melaku, Yohannes A and Meltzer, Michele and Memish, Ziad A and Mendoza, Walter and Mensah, George A and Meretoja, Atte and Mhimbira, Francis Apolinary and Micha, Renata and Miller, Ted R and Mills, Edward J and Misganaw, Awoke and Mishra, Santosh and Mohamed Ibrahim, Norlinah and Mohammad, Karzan A and Mokdad, Ali H and Mola, Glen L and Monasta, Lorenzo and Monta{\~n}ez Hernandez, Julio C and Montico, Marcella and Moore, Ami R and Morawska, Lidia and Mori, Rintaro and Moschandreas, Joanna and Moturi, Wilkister N and Mozaffarian, Dariush and Mueller, Ulrich O and Mukaigawara, Mitsuru and Mullany, Erin C and Murthy, Kinnari S and Naghavi, Mohsen and Nahas, Ziad and Naheed, Aliya and Naidoo, Kovin S and Naldi, Luigi and Nand, Devina and Nangia, Vinay and Narayan, K M Venkat and Nash, Denis and Neal, Bruce and Nejjari, Chakib and Neupane, Sudan P and Newton, Charles R and Ngalesoni, Frida N and Ngirabega, Jean de Dieu and Nguyen, Grant and Nguyen, Nhung T and Nieuwenhuijsen, Mark J and Nisar, Muhammad I and Nogueira, Jos{\'e} R and Nolla, Joan M and Nolte, Sandra and Norheim, Ole F and Norman, Rosana E and Norrving, Bo and Nyakarahuka, Luke and Oh, In-Hwan and Ohkubo, Takayoshi and Olusanya, Bolajoko O and Omer, Saad B and Opio, John Nelson and Orozco, Ricardo and Pagcatipunan, Rodolfo S and Pain, Amanda W and Pandian, Jeyaraj D and Panelo, Carlo Irwin A and Papachristou, Christina and Park, Eun-Kee and Parry, Charles D and Paternina Caicedo, Angel J and Patten, Scott B and Paul, Vinod K and Pavlin, Boris I and Pearce, Neil and Pedraza, Lilia S and Pedroza, Andrea and Pejin Stokic, Ljiljana and Pekericli, Ayfer and Pereira, David M and Perez-Padilla, Rogelio and Perez-Ruiz, Fernando and Perico, Norberto and Perry, Samuel A L and Pervaiz, Aslam and Pesudovs, Konrad and Peterson, Carrie B and Petzold, Max and Phillips, Michael R and Phua, Hwee Pin and Plass, Dietrich and Poenaru, Dan and Polanczyk, Guilherme V and Polinder, Suzanne and Pond, Constance D and Pope, C Arden and Pope, Daniel and Popova, Svetlana and Pourmalek, Farshad and Powles, John and Prabhakaran, Dorairaj and Prasad, Noela M and Qato, Dima M and Quezada, Amado D and Quistberg, D Alex A and Racap{\'e}, Lionel and Rafay, Anwar and Rahimi, Kazem and Rahimi-Movaghar, Vafa and Rahman, Sajjad Ur and Raju, Murugesan and Rakovac, Ivo and Rana, Saleem M and Rao, Mayuree and Razavi, Homie and Reddy, K Srinath and Refaat, Amany H and Rehm, J{\"u}rgen and Remuzzi, Giuseppe and Ribeiro, Antonio L and Riccio, Patricia M and Richardson, Lee and Riederer, Anne and Robinson, Margaret and Roca, Anna and Rodriguez, Alina and Rojas-Rueda, David and Romieu, Isabelle and Ronfani, Luca and Room, Robin and Roy, Nobhojit and Ruhago, George M and Rushton, Lesley and Sabin, Nsanzimana and Sacco, Ralph L and Saha, Sukanta and Sahathevan, Ramesh and Sahraian, Mohammad Ali and Salomon, Joshua A and Salvo, Deborah and Sampson, Uchechukwu K and Sanabria, Juan R and Sanchez, Luz Maria and S{\'a}nchez-Pimienta, Tania G and Sanchez-Riera, Lidia and Sandar, Logan and Santos, Itamar S and Sapkota, Amir and Satpathy, Maheswar and Saunders, James E and Sawhney, Monika and Saylan, Mete I and Scarborough, Peter and Schmidt, J{\"u}rgen C and Schneider, Ione J C and Sch{\"o}ttker, Ben and Schwebel, David C and Scott, James G and Seedat, Soraya and Sepanlou, Sadaf G and Serdar, Berrin and Servan-Mori, Edson E and Shaddick, Gavin and Shahraz, Saeid and Levy, Teresa Shamah and Shangguan, Siyi and She, Jun and Sheikhbahaei, Sara and Shibuya, Kenji and Shin, Hwashin H and Shinohara, Yukito and Shiri, Rahman and Shishani, Kawkab and Shiue, Ivy and Sigfusdottir, Inga D and Silberberg, Donald H and Simard, Edgar P and Sindi, Shireen and Singh, Abhishek and Singh, Gitanjali M and Singh, Jasvinder A and Skirbekk, Vegard and Sliwa, Karen and Soljak, Michael and Soneji, Samir and S{\o}reide, Kjetil and Soshnikov, Sergey and Sposato, Luciano A and Sreeramareddy, Chandrashekhar T and Stapelberg, Nicolas J C and Stathopoulou, Vasiliki and Steckling, Nadine and Stein, Dan J and Stein, Murray B and Stephens, Natalie and St{\"o}ckl, Heidi and Straif, Kurt and Stroumpoulis, Konstantinos and Sturua, Lela and Sunguya, Bruno F and Swaminathan, Soumya and Swaroop, Mamta and Sykes, Bryan L and Tabb, Karen M and Takahashi, Ken and Talongwa, Roberto T and Tandon, Nikhil and Tanne, David and Tanner, Marcel and Tavakkoli, Mohammad and Te Ao, Braden J and Teixeira, Carolina M and T{\'e}llez Rojo, Martha M and Terkawi, Abdullah S and Texcalac-Sangrador, Jos{\'e} Luis and Thackway, Sarah V and Thomson, Blake and Thorne-Lyman, Andrew L and Thrift, Amanda G and Thurston, George D and Tillmann, Taavi and Tobollik, Myriam and Tonelli, Marcello and Topouzis, Fotis and Towbin, Jeffrey A and Toyoshima, Hideaki and Traebert, Jefferson and Tran, Bach X and Trasande, Leonardo and Trillini, Matias and Trujillo, Ulises and Dimbuene, Zacharie Tsala and Tsilimbaris, Miltiadis and Tuzcu, Emin Murat and Uchendu, Uche S and Ukwaja, Kingsley N and Uzun, Selen B and van de Vijver, Steven and Van Dingenen, Rita and van Gool, Coen H and van Os, Jim and Varakin, Yuri Y and Vasankari, Tommi J and Vasconcelos, Ana Maria N and Vavilala, Monica S and Veerman, Lennert J and Velasquez-Melendez, Gustavo and Venketasubramanian, N and Vijayakumar, Lakshmi and Villalpando, Salvador and Violante, Francesco S and Vlassov, Vasiliy Victorovich and Vollset, Stein Emil and Wagner, Gregory R and Waller, Stephen G and Wallin, Mitchell T and Wan, Xia and Wang, Haidong and Wang, JianLi and Wang, Linhong and Wang, Wenzhi and Wang, Yanping and Warouw, Tati S and Watts, Charlotte H and Weichenthal, Scott and Weiderpass, Elisabete and Weintraub, Robert G and Werdecker, Andrea and Wessells, K Ryan and Westerman, Ronny and Whiteford, Harvey A and Wilkinson, James D and Williams, Hywel C and Williams, Thomas N and Woldeyohannes, Solomon M and Wolfe, Charles D A and Wong, John Q and Woolf, Anthony D and Wright, Jonathan L and Wurtz, Brittany and Xu, Gelin and Yan, Lijing L and Yang, Gonghuan and Yano, Yuichiro and Ye, Pengpeng and Yenesew, Muluken and Yent{\"u}r, G{\"o}kalp K and Yip, Paul and Yonemoto, Naohiro and Yoon, Seok-Jun and Younis, Mustafa Z and Younoussi, Zourkaleini and Yu, Chuanhua and Zaki, Maysaa E and Zhao, Yong and Zheng, Yingfeng and Zhou, Maigeng and Zhu, Jun and Zhu, Shankuan and Zou, Xiaonong and Zunt, Joseph R and Lopez, Alan D and Vos, Theo and Murray, Christopher J} } @article {8044, title = {Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition.}, journal = {Lancet}, volume = {386}, year = {2015}, month = {2015 Nov 28}, pages = {2145-91}, abstract = {

BACKGROUND: The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age-sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development.

METHODS: We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95\% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95\% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time.

FINDINGS: Worldwide, from 1990 to 2013, life expectancy at birth rose by 6{\textperiodcentered}2 years (95\% UI 5{\textperiodcentered}6-6{\textperiodcentered}6), from 65{\textperiodcentered}3 years (65{\textperiodcentered}0-65{\textperiodcentered}6) in 1990 to 71{\textperiodcentered}5 years (71{\textperiodcentered}0-71{\textperiodcentered}9) in 2013, HALE at birth rose by 5{\textperiodcentered}4 years (4{\textperiodcentered}9-5{\textperiodcentered}8), from 56{\textperiodcentered}9 years (54{\textperiodcentered}5-59{\textperiodcentered}1) to 62{\textperiodcentered}3 years (59{\textperiodcentered}7-64{\textperiodcentered}8), total DALYs fell by 3{\textperiodcentered}6\% (0{\textperiodcentered}3-7{\textperiodcentered}4), and age-standardised DALY rates per 100 000 people fell by 26{\textperiodcentered}7\% (24{\textperiodcentered}6-29{\textperiodcentered}1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non-communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50\% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10\% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries.

INTERPRETATION: Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition--in which increasing sociodemographic status brings structured change in disease burden--is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Aged, Chronic Disease, Communicable Diseases, Female, Global Health, Health Transition, Humans, Life Expectancy, Male, Middle Aged, Mortality, Premature, Quality-Adjusted Life Years, Socioeconomic Factors, Wounds and Injuries}, issn = {1474-547X}, doi = {10.1016/S0140-6736(15)61340-X}, author = {Murray, Christopher J L and Barber, Ryan M and Foreman, Kyle J and Abbasoglu Ozgoren, Ayse and Abd-Allah, Foad and Abera, Semaw F and Aboyans, Victor and Abraham, Jerry P and Abubakar, Ibrahim and Abu-Raddad, Laith J and Abu-Rmeileh, Niveen M and Achoki, Tom and Ackerman, Ilana N and Ademi, Zanfina and Adou, Ars{\`e}ne K and Adsuar, Jos{\'e} C and Afshin, Ashkan and Agardh, Emilie E and Alam, Sayed Saidul and Alasfoor, Deena and Albittar, Mohammed I and Alegretti, Miguel A and Alemu, Zewdie A and Alfonso-Cristancho, Rafael and Alhabib, Samia and Ali, Raghib and Alla, Fran{\c c}ois and Allebeck, Peter and AlMazroa, Mohammad A and Alsharif, Ubai and Alvarez, Elena and Alvis-Guzm{\'a}n, Nelson and Amare, Azmeraw T and Ameh, Emmanuel A and Amini, Heresh and Ammar, Walid and Anderson, H Ross and Anderson, Benjamin O and Antonio, Carl Abelardo T and Anwari, Palwasha and Arnl{\"o}v, Johan and Arsic Arsenijevic, Valentina S and Artaman, Al and Asghar, Rana J and Assadi, Reza and Atkins, Lydia S and Avila, Marco A and Awuah, Baffour and Bachman, Victoria F and Badawi, Alaa and Bahit, Maria C and Balakrishnan, Kalpana and Banerjee, Amitava and Barker-Collo, Suzanne L and Barquera, Simon and Barregard, Lars and Barrero, Lope H and Basu, Arindam and Basu, Sanjay and Basulaiman, Mohammed O and Beardsley, Justin and Bedi, Neeraj and Beghi, Ettore and Bekele, Tolesa and Bell, Michelle L and Benjet, Corina and Bennett, Derrick A and Bensenor, Isabela M and Benzian, Habib and Bernabe, Eduardo and Bertozzi-Villa, Amelia and Beyene, Tariku J and Bhala, Neeraj and Bhalla, Ashish and Bhutta, Zulfiqar A and Bienhoff, Kelly and Bikbov, Boris and Biryukov, Stan and Blore, Jed D and Blosser, Christopher D and Blyth, Fiona M and Bohensky, Megan A and Bolliger, Ian W and Bora Ba{\c s}ara, Berrak and Bornstein, Natan M and Bose, Dipan and Boufous, Soufiane and Bourne, Rupert R A and Boyers, Lindsay N and Brainin, Michael and Brayne, Carol E and Brazinova, Alexandra and Breitborde, Nicholas J K and Brenner, Hermann and Briggs, Adam D and Brooks, Peter M and Brown, Jonathan C and Brugha, Traolach S and Buchbinder, Rachelle and Buckle, Geoffrey C and Budke, Christine M and Bulchis, Anne and Bulloch, Andrew G and Campos-Nonato, Ismael R and Carabin, H{\'e}l{\`e}ne and Carapetis, Jonathan R and C{\'a}rdenas, Rosario and Carpenter, David O and Caso, Valeria and Casta{\~n}eda-Orjuela, Carlos A and Castro, Ruben E and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and Cavalleri, Fiorella and Cavlin, Alanur and Chadha, Vineet K and Chang, Jung-Chen and Charlson, Fiona J and Chen, Honglei and Chen, Wanqing and Chiang, Peggy P and Chimed-Ochir, Odgerel and Chowdhury, Rajiv and Christensen, Hanne and Christophi, Costas A and Cirillo, Massimo and Coates, Matthew M and Coffeng, Luc E and Coggeshall, Megan S and Colistro, Valentina and Colquhoun, Samantha M and Cooke, Graham S and Cooper, Cyrus and Cooper, Leslie T and Coppola, Luis M and Cortinovis, Monica and Criqui, Michael H and Crump, John A and Cuevas-Nasu, Lucia and Danawi, Hadi and Dandona, Lalit and Dandona, Rakhi and Dansereau, Emily and Dargan, Paul I and Davey, Gail and Davis, Adrian and Davitoiu, Dragos V and Dayama, Anand and De Leo, Diego and Degenhardt, Louisa and del Pozo-Cruz, Borja and Dellavalle, Robert P and Deribe, Kebede and Derrett, Sarah and Des Jarlais, Don C and Dessalegn, Muluken and Dharmaratne, Samath D and Dherani, Mukesh K and Diaz-Torn{\'e}, Cesar and Dicker, Daniel and Ding, Eric L and Dokova, Klara and Dorsey, E Ray and Driscoll, Tim R and Duan, Leilei and Duber, Herbert C and Ebel, Beth E and Edmond, Karen M and Elshrek, Yousef M and Endres, Matthias and Ermakov, Sergey P and Erskine, Holly E and Eshrati, Babak and Esteghamati, Alireza and Estep, Kara and Faraon, Emerito Jose A and Farzadfar, Farshad and Fay, Derek F and Feigin, Valery L and Felson, David T and Fereshtehnejad, Seyed-Mohammad and Fernandes, Jefferson G and Ferrari, Alize J and Fitzmaurice, Christina and Flaxman, Abraham D and Fleming, Thomas D and Foigt, Nataliya and Forouzanfar, Mohammad H and Fowkes, F Gerry R and Paleo, Urbano Fra and Franklin, Richard C and F{\"u}rst, Thomas and Gabbe, Belinda and Gaffikin, Lynne and Gankp{\'e}, Fortun{\'e} G and Geleijnse, Johanna M and Gessner, Bradford D and Gething, Peter and Gibney, Katherine B and Giroud, Maurice and Giussani, Giorgia and Gomez Dantes, Hector and Gona, Philimon and Gonzalez-Medina, Diego and Gosselin, Richard A and Gotay, Carolyn C and Goto, Atsushi and Gouda, Hebe N and Graetz, Nicholas and Gugnani, Harish C and Gupta, Rahul and Gupta, Rajeev and Guti{\'e}rrez, Reyna A and Haagsma, Juanita and Hafezi-Nejad, Nima and Hagan, Holly and Halasa, Yara A and Hamadeh, Randah R and Hamavid, Hannah and Hammami, Mouhanad and Hancock, Jamie and Hankey, Graeme J and Hansen, Gillian M and Hao, Yuantao and Harb, Hilda L and Haro, Josep Maria and Havmoeller, Rasmus and Hay, Simon I and Hay, Roderick J and Heredia-Pi, Ileana B and Heuton, Kyle R and Heydarpour, Pouria and Higashi, Hideki and Hijar, Martha and Hoek, Hans W and Hoffman, Howard J and Hosgood, H Dean and Hossain, Mazeda and Hotez, Peter J and Hoy, Damian G and Hsairi, Mohamed and Hu, Guoqing and Huang, Cheng and Huang, John J and Husseini, Abdullatif and Huynh, Chantal and Iannarone, Marissa L and Iburg, Kim M and Innos, Kaire and Inoue, Manami and Islami, Farhad and Jacobsen, Kathryn H and Jarvis, Deborah L and Jassal, Simerjot K and Jee, Sun Ha and Jeemon, Panniyammakal and Jensen, Paul N and Jha, Vivekanand and Jiang, Guohong and Jiang, Ying and Jonas, Jost B and Juel, Knud and Kan, Haidong and Karch, Andr{\'e} and Karema, Corine K and Karimkhani, Chante and Karthikeyan, Ganesan and Kassebaum, Nicholas J and Kaul, Anil and Kawakami, Norito and Kazanjan, Konstantin and Kemp, Andrew H and Kengne, Andre P and Keren, Andre and Khader, Yousef S and Khalifa, Shams Eldin A and Khan, Ejaz A and Khan, Gulfaraz and Khang, Young-Ho and Kieling, Christian and Kim, Daniel and Kim, Sungroul and Kim, Yunjin and Kinfu, Yohannes and Kinge, Jonas M and Kivipelto, Miia and Knibbs, Luke D and Knudsen, Ann Kristin and Kokubo, Yoshihiro and Kosen, Soewarta and Krishnaswami, Sanjay and Kuate Defo, Barthelemy and Kucuk Bicer, Burcu and Kuipers, Ernst J and Kulkarni, Chanda and Kulkarni, Veena S and Kumar, G Anil and Kyu, Hmwe H and Lai, Taavi and Lalloo, Ratilal and Lallukka, Tea and Lam, Hilton and Lan, Qing and Lansingh, Van C and Larsson, Anders and Lawrynowicz, Alicia E B and Leasher, Janet L and Leigh, James and Leung, Ricky and Levitz, Carly E and Li, Bin and Li, Yichong and Li, Yongmei and Lim, Stephen S and Lind, Maggie and Lipshultz, Steven E and Liu, Shiwei and Liu, Yang and Lloyd, Belinda K and Lofgren, Katherine T and Logroscino, Giancarlo and Looker, Katharine J and Lortet-Tieulent, Joannie and Lotufo, Paulo A and Lozano, Rafael and Lucas, Robyn M and Lunevicius, Raimundas and Lyons, Ronan A and Ma, Stefan and MacIntyre, Michael F and Mackay, Mark T and Majdan, Marek and Malekzadeh, Reza and Marcenes, Wagner and Margolis, David J and Margono, Christopher and Marzan, Melvin B and Masci, Joseph R and Mashal, Mohammad T and Matzopoulos, Richard and Mayosi, Bongani M and Mazorodze, Tasara T and Mcgill, Neil W and McGrath, John J and McKee, Martin and McLain, Abigail and Meaney, Peter A and Medina, Catalina and Mehndiratta, Man Mohan and Mekonnen, Wubegzier and Melaku, Yohannes A and Meltzer, Michele and Memish, Ziad A and Mensah, George A and Meretoja, Atte and Mhimbira, Francis A and Micha, Renata and Miller, Ted R and Mills, Edward J and Mitchell, Philip B and Mock, Charles N and Mohamed Ibrahim, Norlinah and Mohammad, Karzan A and Mokdad, Ali H and Mola, Glen L D and Monasta, Lorenzo and Monta{\~n}ez Hernandez, Julio C and Montico, Marcella and Montine, Thomas J and Mooney, Meghan D and Moore, Ami R and Moradi-Lakeh, Maziar and Moran, Andrew E and Mori, Rintaro and Moschandreas, Joanna and Moturi, Wilkister N and Moyer, Madeline L and Mozaffarian, Dariush and Msemburi, William T and Mueller, Ulrich O and Mukaigawara, Mitsuru and Mullany, Erin C and Murdoch, Michele E and Murray, Joseph and Murthy, Kinnari S and Naghavi, Mohsen and Naheed, Aliya and Naidoo, Kovin S and Naldi, Luigi and Nand, Devina and Nangia, Vinay and Narayan, K M Venkat and Nejjari, Chakib and Neupane, Sudan P and Newton, Charles R and Ng, Marie and Ngalesoni, Frida N and Nguyen, Grant and Nisar, Muhammad I and Nolte, Sandra and Norheim, Ole F and Norman, Rosana E and Norrving, Bo and Nyakarahuka, Luke and Oh, In-Hwan and Ohkubo, Takayoshi and Ohno, Summer L and Olusanya, Bolajoko O and Opio, John Nelson and Ortblad, Katrina and Ortiz, Alberto and Pain, Amanda W and Pandian, Jeyaraj D and Panelo, Carlo Irwin A and Papachristou, Christina and Park, Eun-Kee and Park, Jae-Hyun and Patten, Scott B and Patton, George C and Paul, Vinod K and Pavlin, Boris I and Pearce, Neil and Pereira, David M and Perez-Padilla, Rogelio and Perez-Ruiz, Fernando and Perico, Norberto and Pervaiz, Aslam and Pesudovs, Konrad and Peterson, Carrie B and Petzold, Max and Phillips, Michael R and Phillips, Bryan K and Phillips, David E and Piel, Fr{\'e}d{\'e}ric B and Plass, Dietrich and Poenaru, Dan and Polinder, Suzanne and Pope, Daniel and Popova, Svetlana and Poulton, Richie G and Pourmalek, Farshad and Prabhakaran, Dorairaj and Prasad, Noela M and Pullan, Rachel L and Qato, Dima M and Quistberg, D Alex and Rafay, Anwar and Rahimi, Kazem and Rahman, Sajjad U and Raju, Murugesan and Rana, Saleem M and Razavi, Homie and Reddy, K Srinath and Refaat, Amany and Remuzzi, Giuseppe and Resnikoff, Serge and Ribeiro, Antonio L and Richardson, Lee and Richardus, Jan Hendrik and Roberts, D Allen and Rojas-Rueda, David and Ronfani, Luca and Roth, Gregory A and Rothenbacher, Dietrich and Rothstein, David H and Rowley, Jane T and Roy, Nobhojit and Ruhago, George M and Saeedi, Mohammad Y and Saha, Sukanta and Sahraian, Mohammad Ali and Sampson, Uchechukwu K A and Sanabria, Juan R and Sandar, Logan and Santos, Itamar S and Satpathy, Maheswar and Sawhney, Monika and Scarborough, Peter and Schneider, Ione J and Sch{\"o}ttker, Ben and Schumacher, Austin E and Schwebel, David C and Scott, James G and Seedat, Soraya and Sepanlou, Sadaf G and Serina, Peter T and Servan-Mori, Edson E and Shackelford, Katya A and Shaheen, Amira and Shahraz, Saeid and Shamah Levy, Teresa and Shangguan, Siyi and She, Jun and Sheikhbahaei, Sara and Shi, Peilin and Shibuya, Kenji and Shinohara, Yukito and Shiri, Rahman and Shishani, Kawkab and Shiue, Ivy and Shrime, Mark G and Sigfusdottir, Inga D and Silberberg, Donald H and Simard, Edgar P and Sindi, Shireen and Singh, Abhishek and Singh, Jasvinder A and Singh, Lavanya and Skirbekk, Vegard and Slepak, Erica Leigh and Sliwa, Karen and Soneji, Samir and S{\o}reide, Kjetil and Soshnikov, Sergey and Sposato, Luciano A and Sreeramareddy, Chandrashekhar T and Stanaway, Jeffrey D and Stathopoulou, Vasiliki and Stein, Dan J and Stein, Murray B and Steiner, Caitlyn and Steiner, Timothy J and Stevens, Antony and Stewart, Andrea and Stovner, Lars J and Stroumpoulis, Konstantinos and Sunguya, Bruno F and Swaminathan, Soumya and Swaroop, Mamta and Sykes, Bryan L and Tabb, Karen M and Takahashi, Ken and Tandon, Nikhil and Tanne, David and Tanner, Marcel and Tavakkoli, Mohammad and Taylor, Hugh R and Te Ao, Braden J and Tediosi, Fabrizio and Temesgen, Awoke M and Templin, Tara and Ten Have, Margreet and Tenkorang, Eric Y and Terkawi, Abdullah S and Thomson, Blake and Thorne-Lyman, Andrew L and Thrift, Amanda G and Thurston, George D and Tillmann, Taavi and Tonelli, Marcello and Topouzis, Fotis and Toyoshima, Hideaki and Traebert, Jefferson and Tran, Bach X and Trillini, Matias and Truelsen, Thomas and Tsilimbaris, Miltiadis and Tuzcu, Emin M and Uchendu, Uche S and Ukwaja, Kingsley N and Undurraga, Eduardo A and Uzun, Selen B and Van Brakel, Wim H and van de Vijver, Steven and van Gool, Coen H and van Os, Jim and Vasankari, Tommi J and Venketasubramanian, N and Violante, Francesco S and Vlassov, Vasiliy V and Vollset, Stein Emil and Wagner, Gregory R and Wagner, Joseph and Waller, Stephen G and Wan, Xia and Wang, Haidong and Wang, JianLi and Wang, Linhong and Warouw, Tati S and Weichenthal, Scott and Weiderpass, Elisabete and Weintraub, Robert G and Wenzhi, Wang and Werdecker, Andrea and Westerman, Ronny and Whiteford, Harvey A and Wilkinson, James D and Williams, Thomas N and Wolfe, Charles D and Wolock, Timothy M and Woolf, Anthony D and Wulf, Sarah and Wurtz, Brittany and Xu, Gelin and Yan, Lijing L and Yano, Yuichiro and Ye, Pengpeng and Yent{\"u}r, G{\"o}kalp K and Yip, Paul and Yonemoto, Naohiro and Yoon, Seok-Jun and Younis, Mustafa Z and Yu, Chuanhua and Zaki, Maysaa E and Zhao, Yong and Zheng, Yingfeng and Zonies, David and Zou, Xiaonong and Salomon, Joshua A and Lopez, Alan D and Vos, Theo} } @article {8065, title = {Glucocorticoid pharmacogenetics in pediatric idiopathic nephrotic syndrome.}, journal = {Pharmacogenomics}, volume = {16}, year = {2015}, month = {2015 Sep}, pages = {1631-48}, abstract = {

Idiopathic nephrotic syndrome represents the most common type of primary glomerular disease in children: glucocorticoids (GCs) are the first-line therapy, even if considerable interindividual differences in thepir efficacy and side effects have been reported. Immunosuppressive and anti-inflammatory effects of these drugs are mainly due to the GC-mediated transcription regulation of pro- and anti-inflammatory genes. This mechanism of action is the result of a complex multistep pathway that involves the glucocorticoid receptor and several other proteins, encoded by polymorphic genes. Aim of this review is to highlight the current knowledge on genetic variants that could affect GC response, particularly focusing on children with idiopathic nephrotic syndrome.

}, issn = {1744-8042}, doi = {10.2217/pgs.15.101}, author = {Cuzzoni, Eva and De Iudicibus, Sara and Franca, Raffaella and Stocco, Gabriele and Lucaf{\`o}, Marianna and Pelin, Marco and Favretto, Diego and Pasini, Andrea and Montini, Giovanni and Decorti, Giuliana} } @article {7772, title = {Immunologic evidence of a strong association between non-Hodgkin lymphoma and simian virus 40.}, journal = {Cancer}, volume = {121}, year = {2015}, month = {2015 Aug 1}, pages = {2618-26}, abstract = {

BACKGROUND: Non-Hodgkin lymphoma (NHL), the most common cancer of the lymphatic system, is of unknown etiology. The identification of etiologic factors in the onset of NHL is a key event that could facilitate the prevention and cure of this malignancy. Simian virus 40 (SV40) has been considered an oncogenic agent in the onset/progression of NHL.

METHODS: In this study, an indirect enzyme-linked immunosorbent assay with 2 synthetic peptides that mimic SV40 antigens of viral capsid proteins 1 to 3 was employed to detect specific antibodies against SV40. Serum samples were taken from 2 distinct cohorts of NHL-affected patients (NHL1 [n = 89] and NHL2 [n = 61]) along with controls represented by oncologic patients affected by breast cancer (BC; n = 78) and undifferentiated nasopharyngeal carcinoma (UNPC; n = 64) and 3 different cohorts of healthy subjects (HSs; HS1 [n = 130], HS2 [n = 83], and HS3 [n = 87]).

RESULTS: Immunologic data indicated that in serum samples from NHL patients, antibodies against SV40 mimotopes were detectable with a prevalence of 40\% in NHL1 patients and with a prevalence of 43\% in NHL2 patients. In HSs of the same median age as NHL patients, the prevalence was 16\% for the HS1 group (57 years) and 14\% for the HS2 group (65 years). The difference was statistically significant (P < .0001 and P < .001). Interestingly, the difference between NHL1/NHL2 patients and BC patients (40\%/43\% vs 15\%, P < .001) and between NHL1/NHL2 patients and UNPC patients (40\%/43\% vs 25\%, P < .05) was significant.

CONCLUSIONS: Our data indicate a strong association between NHL and SV40 and thus a need for innovative therapeutic approaches for this hematologic malignancy.

}, keywords = {Adult, Aged, Antibodies, Viral, Capsid Proteins, Enzyme-Linked Immunosorbent Assay, Female, Humans, Lymphoma, Non-Hodgkin, Male, Middle Aged, Polyomavirus Infections, Seroepidemiologic Studies, Simian virus 40, Tumor Virus Infections}, issn = {1097-0142}, doi = {10.1002/cncr.29404}, author = {Tognon, Mauro and Luppi, Mario and Corallini, Alfredo and Taronna, Angelo and Barozzi, Patrizia and Rotondo, John Charles and Comar, Manola and Casali, Maria Vittoria and Bovenzi, Massimo and D{\textquoteright}Agostino, Antonio and Vinante, Fabrizio and Rigo, Antonella and Ferrarini, Isacco and Barbanti-Brodano, Giuseppe and Martini, Fernanda and Mazzoni, Elisa} } @article {8089, title = {Impaired immune response to Candida albicans in cells from Fanconi anemia patients.}, journal = {Cytokine}, volume = {73}, year = {2015}, month = {2015 May}, pages = {203-7}, abstract = {

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure and cancer predisposition. Several studies show alterations of the immunological status of FA patients including defects in peripheral blood lymphocyte subsets, serum immunoglobulin levels, and inflammatory cytokines. However scanty information is available on the response of FA cells to specific infectious antigens. In this work we examined the response of FA cells to different immunological stimuli and found a defective response of IL-1β, TNF-α and IL-17 to Candida albicans stimulation thus pointing to a potentially impaired response to fungal infections of FA patients.

}, keywords = {Adolescent, Candida albicans, CD8-Positive T-Lymphocytes, Cell Proliferation, Cells, Cultured, Child, Child, Preschool, Cytokines, Fanconi Anemia, Humans, Immunity, Infant, Young Adult}, issn = {1096-0023}, doi = {10.1016/j.cyto.2015.02.016}, author = {Parodi, Alessia and Kalli, Francesca and Svahn, Johanna and Stroppiana, Giorgia and De Rocco, Daniela and Terranova, Paola and Dufour, Carlo and Fenoglio, Daniela and Cappelli, Enrico} } @article {8077, title = {Insights from Cardiac Mechanics after Three Decades from Successfully Repaired Aortic Coarctation.}, journal = {Congenit Heart Dis}, year = {2015}, month = {2015 Nov 11}, abstract = {

BACKGROUND AND AIMS: Patients who underwent a successful repair of the aortic coarctation show chronic hyperdynamic state and normal left ventricular (LV) geometry; however, there are few data regarding the LV systolic function in the long term. Accordingly, we assessed LV systolic mechanics and factors associated with LV systolic dysfunction (LVSD) in patients with repaired CoA.

METHODS: Clinical and echocardiographic data from 19 repaired CoA were analyzed 28 {\textpm} 13 years after surgery. Stress-corrected midwall shortening (sc-MS) and mitral annular peak systolic velocity (S{\textquoteright}) were analyzed as indexes of LV circumferential and longitudinal systolic function, respectively. Echocardiographic data of CoA patients were compared with 19 patients matched for age and hypertension and 38 healthy controls. Sc-MS was considered impaired if <89\%, S{\textquoteright} if <8.5 cm/s (10th percentiles of healthy controls, respectively).

RESULTS: There were no statistical differences between study groups in LV volumes, mass and geometry. LV ejection fraction and Sc-MS were similar in all groups, however, CoA group had a significantly lower peak S{\textquoteright} in comparison with matched and healthy controls (7.1 {\textpm} 1.3, 10.3 {\textpm} 1.9, and 11.1 {\textpm} 1.5, respectively; all P < 0.001). Prevalence of longitudinal LVSD defined as low S{\textquoteright} was 84\% in CoA, 13\% in matched, and 5\% in healthy control group (all P<0.05). Multivariate logistic regression analysis revealed that low peak S{\textquoteright} was independently related to higher E/E{\textquoteright} ratio and the presence of CoA.

CONCLUSIONS: Patients who underwent a successful repair of CoA commonly show asymptomatic longitudinal LVSD associated with worse LV diastolic function in the long-term follow-up.

}, issn = {1747-0803}, doi = {10.1111/chd.12310}, author = {Faganello, Giorgio and Fisicaro, Maurizio and Russo, Giulia and Iorio, Anita and Mazzone, Carmine and Grande, Eliana and Humar, Franco and Cherubini, Antonella and Pandullo, Claudio and Barbati, Giulia and Tarantini, Luigi and Benettoni, Alessandra and Pozzi, Marco and Di Lenarda, Andrea and Cioffi, Giovanni} } @article {8066, title = {Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Nov}, pages = {1294-303}, abstract = {

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in \~{}70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (\~{}6\% increase in risk per year; P = 3 {\texttimes} 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

}, issn = {1546-1718}, doi = {10.1038/ng.3412}, author = {Day, Felix R and Ruth, Katherine S and Thompson, Deborah J and Lunetta, Kathryn L and Pervjakova, Natalia and Chasman, Daniel I and Stolk, Lisette and Finucane, Hilary K and Sulem, Patrick and Bulik-Sullivan, Brendan and Esko, T{\~o}nu and Johnson, Andrew D and Elks, Cathy E and Franceschini, Nora and He, Chunyan and Altmaier, Elisabeth and Brody, Jennifer A and Franke, Lude L and Huffman, Jennifer E and Keller, Margaux F and McArdle, Patrick F and Nutile, Teresa and Porcu, Eleonora and Robino, Antonietta and Rose, Lynda M and Schick, Ursula M and Smith, Jennifer A and Teumer, Alexander and Traglia, Michela and Vuckovic, Dragana and Yao, Jie and Zhao, Wei and Albrecht, Eva and Amin, Najaf and Corre, Tanguy and Hottenga, Jouke-Jan and Mangino, Massimo and Smith, Albert V and Tanaka, Toshiko and Abecasis, Goncalo R and Andrulis, Irene L and Anton-Culver, Hoda and Antoniou, Antonis C and Arndt, Volker and Arnold, Alice M and Barbieri, Caterina and Beckmann, Matthias W and Beeghly-Fadiel, Alicia and Benitez, Javier and Bernstein, Leslie and Bielinski, Suzette J and Blomqvist, Carl and Boerwinkle, Eric and Bogdanova, Natalia V and Bojesen, Stig E and Bolla, Manjeet K and Borresen-Dale, Anne-Lise and Boutin, Thibaud S and Brauch, Hiltrud and Brenner, Hermann and Br{\"u}ning, Thomas and Burwinkel, Barbara and Campbell, Archie and Campbell, Harry and Chanock, Stephen J and Chapman, J Ross and Chen, Yii-Der Ida and Chenevix-Trench, Georgia and Couch, Fergus J and Coviello, Andrea D and Cox, Angela and Czene, Kamila and Darabi, Hatef and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Devilee, Peter and D{\"o}rk, Thilo and Dos-Santos-Silva, Isabel and Dunning, Alison M and Eicher, John D and Fasching, Peter A and Faul, Jessica D and Figueroa, Jonine and Flesch-Janys, Dieter and Gandin, Ilaria and Garcia, Melissa E and Garc{\'\i}a-Closas, Montserrat and Giles, Graham G and Girotto, Giorgia G and Goldberg, Mark S and Gonz{\'a}lez-Neira, Anna and Goodarzi, Mark O and Grove, Megan L and Gudbjartsson, Daniel F and Guenel, Pascal and Guo, Xiuqing and Haiman, Christopher A and Hall, Per and Hamann, Ute and Henderson, Brian E and Hocking, Lynne J and Hofman, Albert and Homuth, Georg and Hooning, Maartje J and Hopper, John L and Hu, Frank B and Huang, Jinyan and Humphreys, Keith and Hunter, David J and Jakubowska, Anna and Jones, Samuel E and Kabisch, Maria and Karasik, David and Knight, Julia A and Kolcic, Ivana and Kooperberg, Charles and Kosma, Veli-Matti and Kriebel, Jennifer and Kristensen, Vessela and Lambrechts, Diether and Langenberg, Claudia and Li, Jingmei and Li, Xin and Lindstr{\"o}m, Sara and Liu, Yongmei and Luan, Jian{\textquoteright}an and Lubinski, Jan and M{\"a}gi, Reedik and Mannermaa, Arto and Manz, Judith and Margolin, Sara and Marten, Jonathan and Martin, Nicholas G and Masciullo, Corrado and Meindl, Alfons and Michailidou, Kyriaki and Mihailov, Evelin and Milani, Lili and Milne, Roger L and M{\"u}ller-Nurasyid, Martina and Nalls, Michael and Neale, Benjamin M and Nevanlinna, Heli and Neven, Patrick and Newman, Anne B and Nordestgaard, B{\o}rge G and Olson, Janet E and Padmanabhan, Sandosh and Peterlongo, Paolo and Peters, Ulrike and Petersmann, Astrid and Peto, Julian and Pharoah, Paul D P and Pirastu, Nicola N and Pirie, Ailith and Pistis, Giorgio and Polasek, Ozren and Porteous, David and Psaty, Bruce M and Pylk{\"a}s, Katri and Radice, Paolo and Raffel, Leslie J and Rivadeneira, Fernando and Rudan, Igor and Rudolph, Anja and Ruggiero, Daniela and Sala, Cinzia F and Sanna, Serena and Sawyer, Elinor J and Schlessinger, David and Schmidt, Marjanka K and Schmidt, Frank and Schmutzler, Rita K and Schoemaker, Minouk J and Scott, Robert A and Seynaeve, Caroline M and Simard, Jacques and Sorice, Rossella and Southey, Melissa C and St{\"o}ckl, Doris and Strauch, Konstantin and Swerdlow, Anthony and Taylor, Kent D and Thorsteinsdottir, Unnur and Toland, Amanda E and Tomlinson, Ian and Truong, Therese and Tryggvadottir, Laufey and Turner, Stephen T and Vozzi, Diego and Wang, Qin and Wellons, Melissa and Willemsen, Gonneke and Wilson, James F and Winqvist, Robert and Wolffenbuttel, Bruce B H R and Wright, Alan F and Yannoukakos, Drakoulis and Zemunik, Tatijana and Zheng, Wei and Zygmunt, Marek and Bergmann, Sven and Boomsma, Dorret I and Buring, Julie E and Ferrucci, Luigi and Montgomery, Grant W and Gudnason, Vilmundur and Spector, Tim D and van Duijn, Cornelia M and Alizadeh, Behrooz Z and Ciullo, Marina and Crisponi, Laura and Easton, Douglas F and Gasparini, Paolo P and Gieger, Christian and Harris, Tamara B and Hayward, Caroline and Kardia, Sharon L R and Kraft, Peter and McKnight, Barbara and Metspalu, Andres and Morrison, Alanna C and Reiner, Alex P and Ridker, Paul M and Rotter, Jerome I and Toniolo, Daniela and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and V{\"o}lzke, Henry and Wareham, Nicholas J and Weir, David R and Yerges-Armstrong, Laura M and Price, Alkes L and Stefansson, Kari and Visser, Jenny A and Ong, Ken K and Chang-Claude, Jenny and Murabito, Joanne M and Perry, John R B and Murray, Anna} } @article {8040, title = {Leptin/adiponectin ratio predicts poststroke neurological outcome.}, journal = {Eur J Clin Invest}, volume = {45}, year = {2015}, month = {2015 Nov}, pages = {1184-91}, abstract = {

BACKGROUND AND AIMS: Different adipokines have been associated with atherosclerotic plaque rupture and cardiovascular events, such as acute ischaemic stroke (AIS). However, the potential role of these molecules in postischaemic brain injury remains largely unknown.

METHODS AND METHODS: We performed a substudy analysis on nonobese patients with first atherothrombotic stroke (n = 35) from a recently published prospective cohort. Primary endpoint was to investigate the predictive value of serum leptin/adiponectin ratio on neurological recovery at 90 days after AIS. The secondary endpoint was the predictive value of serum adipokine levels of clinical and radiological outcomes at a shorter follow-up (at days 1 and 7 after AIS). The radiological evaluation included ischaemic lesion volume and haemorrhagic transformation (HT). The clinical examination was based on National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS).

RESULTS: At day 1 after AIS, serum leptin and leptin/adiponectin ratio were increased and inversely correlated with both radiological and clinical parameters at all follow-up time points. Once identified the best cut-off points by receiver operating characteristic (ROC) analysis, risk analysis showed that higher circulating leptin improved neurological recovery at day 90. In addition, leptin/adiponectin ratio maintained statistical significance after adjustment for age, gender and thrombolysis, also predicting the occurrence of HT in the first 7 days after AIS (adjusted OR 0{\textperiodcentered}15 [95\% CI 0{\textperiodcentered}03-0{\textperiodcentered}83); P = 0{\textperiodcentered}030]).

CONCLUSIONS: Higher leptin/adiponectin ratio at day 1 predicted better neurological outcomes in patients with atherothrombotic AIS and might be potentially useful as a prognostic biomarker of the disease.

}, issn = {1365-2362}, doi = {10.1111/eci.12538}, author = {Carbone, Federico and Burger, Fabienne and Roversi, Gloria and Tamborino, Carmine and Casetta, Ilaria and Seraceni, Silva and Trentini, Alessandro and Padroni, Marina and Bertolotto, Maria and Dallegri, Franco and Mach, Fran{\c c}ois and Fainardi, Enrico and Montecucco, Fabrizio} } @article {7758, title = {MBL2 polymorphisms in women with atypical squamous cells of undetermined significance.}, journal = {J Med Virol}, volume = {87}, year = {2015}, month = {2015 May}, pages = {851-9}, abstract = {

Infection with high risk Human papillomavirus (HPV) is the main known cause of cervical cancer. HPV induces different grades of lesions: among them, Atypical squamous cells of undetermined significance are abnormal lesions that could evolve in pre-cancer lesions or spontaneously regress. The mannose binding lectin (MBL) is an innate immunity serum protein also found in cervico-vaginal mucosa, whose expression is known to be affected by polymorphisms in exon 1 and promoter of the MBL2 gene. In the present study the possible association between MBL2 functional polymorphisms and susceptibility to develop atypical squamous cells of undetermined significance was investigated in a group of women from North-East of Italy, stratified for HPV infection status. The MBL2 D and O alleles and the deficient producer combined genotypes, responsible for low MBL production, were more represented among atypical squamous cells of undetermined significance positive women than healthy controls and the results were confirmed when only HPV negative samples were considered. These results suggest a possible involvement of MBL2 functional polymorphisms in atypical squamous cells of undetermined significance susceptibility.

}, keywords = {Adolescent, Adult, Atypical Squamous Cells of the Cervix, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Italy, Mannose-Binding Lectin, Polymorphism, Single Nucleotide, Young Adult}, issn = {1096-9071}, doi = {10.1002/jmv.24080}, author = {Zupin, Luisa and Polesello, Vania and Casalicchio, Giorgia and Freato, Nadia and Maestri, Iva and Comar, Manola and Crovella, Sergio and Segat, Ludovica} } @article {7712, title = {The mediating role of interpersonal conflict at work in the relationship between negative affectivity and biomarkers of stress.}, journal = {J Behav Med}, volume = {38}, year = {2015}, month = {2015 Dec}, pages = {922-31}, abstract = {

This study examined the association between interpersonal conflict at work (ICW) and serum levels of three possible biomarkers of stress, namely the pro-inflammatory cytokines Interleukin 1 beta (IL-1β), Interleukin 12 (IL-12), and Interleukin 17 (IL-17). Additionally, this study investigated the role of negative affectivity (NA) in the relationship between ICW and the pro-inflammatory cytokines. Data from 121 employees in an Italian healthcare organization were analyzed using structural equation modeling. Results showed that ICW was positively associated with IL-1β, IL-12, and IL-17, after controlling for the effect of gender. Moreover, ICW completely mediated the relationship between NA and the pro-inflammatory cytokines IL-1β, IL-12, and IL-17. This mediating effect was significant after controlling for the effect of gender. Overall, this study suggests that work-related stress may be associated with biomarkers of inflammation, and that negative affectivity may influence the stress process affecting the exposure to psychosocial stressors.

}, issn = {1573-3521}, doi = {10.1007/s10865-015-9658-x}, author = {Girardi, Damiano and Falco, Alessandra and De Carlo, Alessandro and Benevene, Paula and Comar, Manola and Tongiorgi, Enrico and Bartolucci, Giovanni Battista} } @article {7784, title = {Modulation of genetic associations with serum urate levels by body-mass-index in humans.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0119752}, abstract = {

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95\% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0119752}, author = {Huffman, Jennifer E and Albrecht, Eva and Teumer, Alexander and Mangino, Massimo and Kapur, Karen and Johnson, Toby and Kutalik, Zolt{\'a}n and Pirastu, Nicola and Pistis, Giorgio and Lopez, Lorna M and Haller, Toomas and Salo, Perttu and Goel, Anuj and Li, Man and Tanaka, Toshiko and Dehghan, Abbas and Ruggiero, Daniela and Malerba, Giovanni and Smith, Albert V and Nolte, Ilja M and Portas, Laura and Phipps-Green, Amanda and Boteva, Lora and Navarro, Pau and Johansson, {\r A}sa and Hicks, Andrew A and Polasek, Ozren and Esko, T{\~o}nu and Peden, John F and Harris, Sarah E and Murgia, Federico and Wild, Sarah H and Tenesa, Albert and Tin, Adrienne and Mihailov, Evelin and Grotevendt, Anne and Gislason, Gauti K and Coresh, Josef and d{\textquoteright}Adamo, Pio and Ulivi, Sheila and Vollenweider, Peter and Waeber, Gerard and Campbell, Susan and Kolcic, Ivana and Fisher, Krista and Viigimaa, Margus and Metter, Jeffrey E and Masciullo, Corrado and Trabetti, Elisabetta and Bombieri, Cristina and Sorice, Rossella and D{\"o}ring, Angela and Reischl, Eva and Strauch, Konstantin and Hofman, Albert and Uitterlinden, Andr{\'e} G and Waldenberger, Melanie and Wichmann, H-Erich and Davies, Gail and Gow, Alan J and Dalbeth, Nicola and Stamp, Lisa and Smit, Johannes H and Kirin, Mirna and Nagaraja, Ramaiah and Nauck, Matthias and Schurmann, Claudia and Budde, Kathrin and Farrington, Susan M and Theodoratou, Evropi and Jula, Antti and Salomaa, Veikko and Sala, Cinzia and Hengstenberg, Christian and Burnier, Michel and M{\"a}gi, Reedik and Klopp, Norman and Kloiber, Stefan and Schipf, Sabine and Ripatti, Samuli and Cabras, Stefano and Soranzo, Nicole and Homuth, Georg and Nutile, Teresa and Munroe, Patricia B and Hastie, Nicholas and Campbell, Harry and Rudan, Igor and Cabrera, Claudia and Haley, Chris and Franco, Oscar H and Merriman, Tony R and Gudnason, Vilmundur and Pirastu, Mario and Penninx, Brenda W and Snieder, Harold and Metspalu, Andres and Ciullo, Marina and Pramstaller, Peter P and van Duijn, Cornelia M and Ferrucci, Luigi and Gambaro, Giovanni and Deary, Ian J and Dunlop, Malcolm G and Wilson, James F and Gasparini, Paolo and Gyllensten, Ulf and Spector, Tim D and Wright, Alan F and Hayward, Caroline and Watkins, Hugh and Perola, Markus and Bochud, Murielle and Kao, W H Linda and Caulfield, Mark and Toniolo, Daniela and V{\"o}lzke, Henry and Gieger, Christian and K{\"o}ttgen, Anna and Vitart, Veronique} } @article {7716, title = {More than (Double) Bubble.}, journal = {J Pediatr}, volume = {167}, year = {2015}, month = {2015 Oct}, pages = {942-942.e1}, keywords = {Amniotic Fluid, Duodenum, Female, Humans, Infant, Infant, Newborn, Polyhydramnios, Pregnancy, Pregnancy Trimester, Third, Prenatal Diagnosis, Ultrasonography, Prenatal}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2015.06.066}, author = {Ferrara, Giovanna and Stampalija, Tamara and Codrich, Daniela and Simionato, Cristina and Taddio, Andrea and Travan, Laura} } @article {8047, title = {Music Training Increases Phonological Awareness and Reading Skills in Developmental Dyslexia: A Randomized Control Trial.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0138715}, abstract = {

There is some evidence for a role of music training in boosting phonological awareness, word segmentation, working memory, as well as reading abilities in children with typical development. Poor performance in tasks requiring temporal processing, rhythm perception and sensorimotor synchronization seems to be a crucial factor underlying dyslexia in children. Interestingly, children with dyslexia show deficits in temporal processing, both in language and in music. Within this framework, we test the hypothesis that music training, by improving temporal processing and rhythm abilities, improves phonological awareness and reading skills in children with dyslexia. The study is a prospective, multicenter, open randomized controlled trial, consisting of test, rehabilitation and re-test (ID NCT02316873). After rehabilitation, the music group (N = 24) performed better than the control group (N = 22) in tasks assessing rhythmic abilities, phonological awareness and reading skills. This is the first randomized control trial testing the effect of music training in enhancing phonological and reading abilities in children with dyslexia. The findings show that music training can modify reading and phonological abilities even when these skills are severely impaired. Through the enhancement of temporal processing and rhythmic skills, music might become an important tool in both remediation and early intervention programs.Trial Registration: ClinicalTrials.gov NCT02316873

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0138715}, author = {Flaugnacco, Elena and Lopez, Luisa and Terribili, Chiara and Montico, Marcella and Zoia, Stefania and Sch{\"o}n, Daniele} } @article {3612, title = {A nationwide survey of PMM2-CDG in Italy: high frequency of a mild neurological variant associated with the L32R mutation.}, journal = {J Neurol}, volume = {262}, year = {2015}, month = {2015 Jan}, pages = {154-64}, abstract = {

PMM2-CDG (PMM2 gene mutations) is the most common congenital disorder of N-glycosylation. We conducted a nationwide survey to characterize the frequency, clinical features, glycosylation and genetic correlates in Italian patients with PMM2-CDG. Clinical information was obtained through a questionnaire filled in by the referral physicians including demographics, neurological and systemic features, neuroimaging data and genotype. Glycosylation analyses of serum transferrin were complemented by MALDI-Mass Spectrometry (MALDI-MS). Between 1996 and 2012, data on 37 Italian patients with PMM2-CDG were collected. All the patients with a severe phenotype were unable to walk unaided, 84 \% had severe intellectual disability and 81 \% microcephaly. Conversely, among 17 mildly affected patients 82 \% had independent ambulation, 64 \% had borderline to mild intellectual disability and 35 \% microcephaly. Epilepsy and stroke-like events did not occur among patients with the mild phenotype. The rate and extent of systemic involvement were more pronounced in severely affected patients. The L32R misfolding mutation of the PMM2 gene occurred in 70 \% of the patients with the mild phenotype and was associated with a less severe underglycosylation of serum Tf at MALDI-MS analyses. Despite their different disease severity, all patients had progressive (olivo)ponto-cerebellar atrophy that was the hallmark clinical feature for the diagnosis. A mild neurological phenotype of PMM2-CDG marked by preserved ambulatory ability and autonomy and associated with L32R mutation is particularly frequent in Italy. PMM2-CDG should be considered in patients with even mild developmental disability and/or unexplained progressive cerebellar atrophy.

}, issn = {1432-1459}, doi = {10.1007/s00415-014-7549-7}, author = {Barone, Rita and Carrozzi, M and Parini, R and Battini, R and Martinelli, D and Elia, M and Spada, M and Lilliu, F and Ciana, G and Burlina, A and Leuzzi, V and Leoni, M and Sturiale, L and Matthijs, G and Jaeken, J and Di Rocco, M and Garozzo, D and Fiumara, A} } @article {7692, title = {New genetic loci link adipose and insulin biology to body fat distribution.}, journal = {Nature}, volume = {518}, year = {2015}, month = {2015 Feb 12}, pages = {187-96}, abstract = {

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P~<~5~{\texttimes}~10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

}, keywords = {Adipocytes, Adipogenesis, Adipose Tissue, Age Factors, Body Fat Distribution, Body Mass Index, Continental Population Groups, Epigenesis, Genetic, Europe, Female, Genome, Human, Genome-Wide Association Study, Humans, Insulin, Insulin Resistance, Male, Models, Biological, Neovascularization, Physiologic, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Sex Characteristics, Transcription, Genetic, Waist-Hip Ratio}, issn = {1476-4687}, doi = {10.1038/nature14132}, author = {Shungin, Dmitry and Winkler, Thomas W and Croteau-Chonka, Damien C and Ferreira, Teresa and Locke, Adam E and M{\"a}gi, Reedik and Strawbridge, Rona J and Pers, Tune H and Fischer, Krista and Justice, Anne E and Workalemahu, Tsegaselassie and Wu, Joseph M W and Buchkovich, Martin L and Heard-Costa, Nancy L and Roman, Tamara S and Drong, Alexander W and Song, Ci and Gustafsson, Stefan and Day, Felix R and Esko, T{\~o}nu and Fall, Tove and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Randall, Joshua C and Scherag, Andr{\'e} and Vedantam, Sailaja and Wood, Andrew R and Chen, Jin and Fehrmann, Rudolf and Karjalainen, Juha and Kahali, Bratati and Liu, Ching-Ti and Schmidt, Ellen M and Absher, Devin and Amin, Najaf and Anderson, Denise and Beekman, Marian and Bragg-Gresham, Jennifer L and Buyske, Steven and Demirkan, Ayse and Ehret, Georg B and Feitosa, Mary F and Goel, Anuj and Jackson, Anne U and Johnson, Toby and Kleber, Marcus E and Kristiansson, Kati and Mangino, Massimo and Mateo Leach, Irene and Medina-Gomez, Carolina and Palmer, Cameron D and Pasko, Dorota and Pechlivanis, Sonali and Peters, Marjolein J and Prokopenko, Inga and Stan{\v c}{\'a}kov{\'a}, Alena and Ju Sung, Yun and Tanaka, Toshiko and Teumer, Alexander and Van Vliet-Ostaptchouk, Jana V and Yengo, Loic and Zhang, Weihua and Albrecht, Eva and Arnl{\"o}v, Johan and Arscott, Gillian M and Bandinelli, Stefania and Barrett, Amy and Bellis, Claire and Bennett, Amanda J and Berne, Christian and Bl{\"u}her, Matthias and B{\"o}hringer, Stefan and Bonnet, Fabrice and B{\"o}ttcher, Yvonne and Bruinenberg, Marcel and Carba, Delia B and Caspersen, Ida H and Clarke, Robert and Daw, E Warwick and Deelen, Joris and Deelman, Ewa and Delgado, Graciela and Doney, Alex S F and Eklund, Niina and Erdos, Michael R and Estrada, Karol and Eury, Elodie and Friedrich, Nele and Garcia, Melissa E and Giedraitis, Vilmantas and Gigante, Bruna and Go, Alan S and Golay, Alain and Grallert, Harald and Grammer, Tanja B and Gr{\"a}{\ss}ler, J{\"u}rgen and Grewal, Jagvir and Groves, Christopher J and Haller, Toomas and Hallmans, Goran and Hartman, Catharina A and Hassinen, Maija and Hayward, Caroline and Heikkil{\"a}, Kauko and Herzig, Karl-Heinz and Helmer, Quinta and Hillege, Hans L and Holmen, Oddgeir and Hunt, Steven C and Isaacs, Aaron and Ittermann, Till and James, Alan L and Johansson, Ingegerd and Juliusdottir, Thorhildur and Kalafati, Ioanna-Panagiota and Kinnunen, Leena and Koenig, Wolfgang and Kooner, Ishminder K and Kratzer, Wolfgang and Lamina, Claudia and Leander, Karin and Lee, Nanette R and Lichtner, Peter and Lind, Lars and Lindstr{\"o}m, Jaana and Lobbens, St{\'e}phane and Lorentzon, Mattias and Mach, Fran{\c c}ois and Magnusson, Patrik K E and Mahajan, Anubha and McArdle, Wendy L and Menni, Cristina and Merger, Sigrun and Mihailov, Evelin and Milani, Lili and Mills, Rebecca and Moayyeri, Alireza and Monda, Keri L and Mooijaart, Simon P and M{\"u}hleisen, Thomas W and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Nagaraja, Ramaiah and Nalls, Michael A and Narisu, Narisu and Glorioso, Nicola and Nolte, Ilja M and Olden, Matthias and Rayner, Nigel W and Renstrom, Frida and Ried, Janina S and Robertson, Neil R and Rose, Lynda M and Sanna, Serena and Scharnagl, Hubert and Scholtens, Salome and Sennblad, Bengt and Seufferlein, Thomas and Sitlani, Colleen M and Vernon Smith, Albert and Stirrups, Kathleen and Stringham, Heather M and Sundstr{\"o}m, Johan and Swertz, Morris A and Swift, Amy J and Syv{\"a}nen, Ann-Christine and Tayo, Bamidele O and Thorand, Barbara and Thorleifsson, Gudmar and Tomaschitz, Andreas and Troffa, Chiara and van Oort, Floor V A and Verweij, Niek and Vonk, Judith M and Waite, Lindsay L and Wennauer, Roman and Wilsgaard, Tom and Wojczynski, Mary K and Wong, Andrew and Zhang, Qunyuan and Hua Zhao, Jing and Brennan, Eoin P and Choi, Murim and Eriksson, Per and Folkersen, Lasse and Franco-Cereceda, Anders and Gharavi, Ali G and Hedman, {\r A}sa K and Hivert, Marie-France and Huang, Jinyan and Kanoni, Stavroula and Karpe, Fredrik and Keildson, Sarah and Kiryluk, Krzysztof and Liang, Liming and Lifton, Richard P and Ma, Baoshan and McKnight, Amy J and McPherson, Ruth and Metspalu, Andres and Min, Josine L and Moffatt, Miriam F and Montgomery, Grant W and Murabito, Joanne M and Nicholson, George and Nyholt, Dale R and Olsson, Christian and Perry, John R B and Reinmaa, Eva and Salem, Rany M and Sandholm, Niina and Schadt, Eric E and Scott, Robert A and Stolk, Lisette and Vallejo, Edgar E and Westra, Harm-Jan and Zondervan, Krina T and Amouyel, Philippe and Arveiler, Dominique and Bakker, Stephan J L and Beilby, John and Bergman, Richard N and Blangero, John and Brown, Morris J and Burnier, Michel and Campbell, Harry and Chakravarti, Aravinda and Chines, Peter S and Claudi-Boehm, Simone and Collins, Francis S and Crawford, Dana C and Danesh, John and de Faire, Ulf and de Geus, Eco J C and D{\"o}rr, Marcus and Erbel, Raimund and Eriksson, Johan G and Farrall, Martin and Ferrannini, Ele and Ferri{\`e}res, Jean and Forouhi, Nita G and Forrester, Terrence and Franco, Oscar H and Gansevoort, Ron T and Gieger, Christian and Gudnason, Vilmundur and Haiman, Christopher A and Harris, Tamara B and Hattersley, Andrew T and Heli{\"o}vaara, Markku and Hicks, Andrew A and Hingorani, Aroon D and Hoffmann, Wolfgang and Hofman, Albert and Homuth, Georg and Humphries, Steve E and Hypp{\"o}nen, Elina and Illig, Thomas and J{\"a}rvelin, Marjo-Riitta and Johansen, Berit and Jousilahti, Pekka and Jula, Antti M and Kaprio, Jaakko and Kee, Frank and Keinanen-Kiukaanniemi, Sirkka M and Kooner, Jaspal S and Kooperberg, Charles and Kovacs, Peter and Kraja, Aldi T and Kumari, Meena and Kuulasmaa, Kari and Kuusisto, Johanna and Lakka, Timo A and Langenberg, Claudia and Le Marchand, Loic and Lehtim{\"a}ki, Terho and Lyssenko, Valeriya and M{\"a}nnist{\"o}, Satu and Marette, Andr{\'e} and Matise, Tara C and McKenzie, Colin A and McKnight, Barbara and Musk, Arthur W and M{\"o}hlenkamp, Stefan and Morris, Andrew D and Nelis, Mari and Ohlsson, Claes and Oldehinkel, Albertine J and Ong, Ken K and Palmer, Lyle J and Penninx, Brenda W and Peters, Annette and Pramstaller, Peter P and Raitakari, Olli T and Rankinen, Tuomo and Rao, D C and Rice, Treva K and Ridker, Paul M and Ritchie, Marylyn D and Rudan, Igor and Salomaa, Veikko and Samani, Nilesh J and Saramies, Jouko and Sarzynski, Mark A and Schwarz, Peter E H and Shuldiner, Alan R and Staessen, Jan A and Steinthorsdottir, Valgerdur and Stolk, Ronald P and Strauch, Konstantin and T{\"o}njes, Anke and Tremblay, Angelo and Tremoli, Elena and Vohl, Marie-Claude and V{\"o}lker, Uwe and Vollenweider, Peter and Wilson, James F and Witteman, Jacqueline C and Adair, Linda S and Bochud, Murielle and Boehm, Bernhard O and Bornstein, Stefan R and Bouchard, Claude and Cauchi, St{\'e}phane and Caulfield, Mark J and Chambers, John C and Chasman, Daniel I and Cooper, Richard S and Dedoussis, George and Ferrucci, Luigi and Froguel, Philippe and Grabe, Hans-J{\"o}rgen and Hamsten, Anders and Hui, Jennie and Hveem, Kristian and J{\"o}ckel, Karl-Heinz and Kivimaki, Mika and Kuh, Diana and Laakso, Markku and Liu, Yongmei and M{\"a}rz, Winfried and Munroe, Patricia B and Nj{\o}lstad, Inger and Oostra, Ben A and Palmer, Colin N A and Pedersen, Nancy L and Perola, Markus and P{\'e}russe, Louis and Peters, Ulrike and Power, Chris and Quertermous, Thomas and Rauramaa, Rainer and Rivadeneira, Fernando and Saaristo, Timo E and Saleheen, Danish and Sinisalo, Juha and Slagboom, P Eline and Snieder, Harold and Spector, Tim D and Thorsteinsdottir, Unnur and Stumvoll, Michael and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and van der Harst, Pim and Veronesi, Giovanni and Walker, Mark and Wareham, Nicholas J and Watkins, Hugh and Wichmann, H-Erich and Abecasis, Goncalo R and Assimes, Themistocles L and Berndt, Sonja I and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and Franke, Lude and Frayling, Timothy M and Groop, Leif C and Hunter, David J and Kaplan, Robert C and O{\textquoteright}Connell, Jeffrey R and Qi, Lu and Schlessinger, David and Strachan, David P and Stefansson, Kari and van Duijn, Cornelia M and Willer, Cristen J and Visscher, Peter M and Yang, Jian and Hirschhorn, Joel N and Zillikens, M Carola and McCarthy, Mark I and Speliotes, Elizabeth K and North, Kari E and Fox, Caroline S and Barroso, In{\^e}s and Franks, Paul W and Ingelsson, Erik and Heid, Iris M and Loos, Ruth J F and Cupples, L Adrienne and Morris, Andrew P and Lindgren, Cecilia M and Mohlke, Karen L} } @article {8081, title = {New lenses to look at preeclampsia.}, journal = {Gynecol Endocrinol}, year = {2015}, month = {2015 Nov 25}, pages = {1-4}, issn = {1473-0766}, doi = {10.3109/09513590.2015.1115833}, author = {Zullino, Sara and Di Martino, Daniela and Stampalija, Tamara and Ferrazzi, Enrico} } @article {8036, title = {Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases.}, journal = {Ann Rheum Dis}, year = {2015}, month = {2015 Sep 17}, abstract = {

OBJECTIVES: Systemic auto-inflammatory disorders (SAIDs) are a heterogeneous group of monogenic diseases sharing a primary dysfunction of the innate immune system. More than 50\% of patients with SAID does not show any mutation at gene(s) tested because of lack of precise clinical classification criteria and/or incomplete gene screening. To improve the molecular diagnosis and genotype interpretation of SAIDs, we undertook the development of a next-generation sequencing (NGS)-based protocol designed to simultaneous screening of 10 genes.

METHODS: Fifty patients with SAID, already genotyped for the respective causative gene(s), were massively sequenced for the coding portions of MEFV, MVK, TNFRSF1A, NLRP3, NLRP12, NOD2, PSTPIP1, IL1RN, LPIN2 and PSMB8. Three different bioinformatic pipelines (Ion Reporter, CLC Bio Genomics Workbench, GATK-based in-house workflow) were compared.

RESULTS: Once resulting variants were compared with the expected mutation list, no workflow turned out to be able to detect all the 79 variants known in the 50 DNAs. Additional variants were also detected, validated by Sanger sequencing and compared to assess true and false positive detection rates of the three workflows. Finally, the overall clinical picture of 34 patients was re-evaluated in the light of the new mutations found.

CONCLUSIONS: The present gene panel has resulted suitable for molecular diagnosis of SAIDs. Moreover, genotype-phenotype correlation has confirmed that the interpretation of NGS data in patients with an undefined inflammatory phenotype is remarkably difficult, thus supporting the need of evidence-based and validated clinical criteria to be used concurrently with the genetic analysis for the final diagnosis and classification of patients with SAIDs.

}, issn = {1468-2060}, doi = {10.1136/annrheumdis-2015-207701}, author = {Rusmini, Marta and Federici, Silvia and Caroli, Francesco and Grossi, Alice and Baldi, Maurizia and Obici, Laura and Insalaco, Antonella and Tommasini, Alberto and Caorsi, Roberta and Gallo, Eleonora and Olivieri, Alma Nunzia and Marzano, AngeloValerio and Coviello, Domenico and Ravazzolo, Roberto and Martini, Alberto and Gattorno, Marco and Ceccherini, Isabella} } @article {3594, title = {Is "option B+" also being adopted in pregnant women in high-income countries? Temporal trends from a national study in Italy.}, journal = {Clin Infect Dis}, volume = {60}, year = {2015}, month = {2015 Jan 1}, pages = {159-61}, keywords = {Anti-Retroviral Agents, Antiretroviral Therapy, Highly Active, Developed Countries, Female, HIV Infections, Humans, Infant, Newborn, Italy, Patient Acceptance of Health Care, Pregnancy, Pregnancy Complications, Infectious}, issn = {1537-6591}, doi = {10.1093/cid/ciu736}, author = {Floridia, Marco and Guaraldi, Giovanni and Ravizza, Marina and Tibaldi, Cecilia and Pinnetti, Carmela and Maccabruni, Anna and Molinari, Atim and Liuzzi, Giuseppina and Alberico, Salvatore and Meloni, Alessandra and Rizzi, Laura and Dalzero, Serena and Tamburrini, Enrica} } @article {7745, title = {Orofacial granulomatosis in children: think about Crohn{\textquoteright}s disease.}, journal = {Dig Liver Dis}, volume = {47}, year = {2015}, month = {2015 Apr}, pages = {338-41}, abstract = {

BACKGROUND: The term orofacial granulomatosis is conventionally used to describe patients with granulomatous lesions affecting the orofacial tissues, in absence of intestinal lesions. Lip swelling and facial swelling are the most common clinical signs. Despite the fact that histologically it is not distinguishable from Crohn{\textquoteright}s disease, and that both diseases have a chronic/recurrent course, the relationship between orofacial granulomatosis and Crohn{\textquoteright}s disease is still debated.

METHODS: Herein we present five cases of orofacial granulomatosis.

RESULTS: All patients presented concomitant Crohn{\textquoteright}s disease, supporting the hypothesis that orofacial granulomatosis and Crohn{\textquoteright}s disease may be one single disease. Thalidomide was effective in inducing remission of oral and intestinal symptoms in all five cases and could be considered a valid treatment opportunity for these patients.

CONCLUSIONS: Orofacial granulomatosis and Crohn{\textquoteright}s disease may be part of the same disease; both may respond to thalidomide.

}, keywords = {Adolescent, Biopsy, Child, Colonoscopy, Crohn Disease, Diagnosis, Differential, Female, Granulomatosis, Orofacial, Humans, Immunosuppressive Agents, Male, Thalidomide}, issn = {1878-3562}, doi = {10.1016/j.dld.2014.12.012}, author = {Lazzerini, Marzia and Martelossi, Stefano and Cont, Gabriele and Bersanini, Chiara and Ventura, Giovanna and Fontana, Massimo and Zuin, Giovanna and Ventura, Alessandro and Taddio, Andrea} } @article {7769, title = {Phenotypic and genetic characterization of a family carrying two Xq21.1-21.3 interstitial deletions associated with syndromic hearing loss.}, journal = {Mol Cytogenet}, volume = {8}, year = {2015}, month = {2015}, pages = {18}, abstract = {

BACKGROUND: Sensorineural hearing impairment is a common pathological manifestation in patients affected by X-linked intellectual disability. A few cases of interstitial deletions at Xq21 with several different phenotypic characteristics have been described, but to date, a complete molecular characterization of the deletions harboring disease-causing genes is still missing. Thus, the aim of this study is to realize a detailed clinical and molecular analysis of a family affected by syndromic X-linked hearing loss with intellectual disability.

RESULTS: Clinical analyses revealed a very complex phenotype that included inner ear malformations, vestibular problems, choroideremia and hypotonia with a peculiar pattern of phenotypic variability. Genomic analysis revealed, for the first time, the presence of two close interstitial deletions in the Xq21.1-21.3, harboring 11 protein coding, 9 non-coding genes and 19 pseudogenes. Among these, 3 protein coding genes have already been associated with X-linked hearing loss, intellectual disability and choroideremia.

CONCLUSIONS: In this study we highlighted the presence of peculiar genotypic and phenotypic details in a family affected by syndromic X-linked hearing loss with intellectual disability. We identified two, previously unreported, Xq21.1-21.3 interstitial deletions. The two rearrangements, containing several genes, segregate with the clinical features, suggesting their role in the pathogenicity. However, not all the observed phenotypic features can be clearly associated with the known genes thus, further study is necessary to determine regions involved.

}, issn = {1755-8166}, doi = {10.1186/s13039-015-0120-0}, author = {Iossa, Sandra and Costa, Valerio and Corvino, Virginia and Auletta, Gennaro and Barruffo, Luigi and Cappellani, Stefania and Ceglia, Carlo and Cennamo, Giovanni and d{\textquoteright}Adamo, Adamo Pio and D{\textquoteright}Amico, Alessandra and Di Paolo, Nilde and Forte, Raimondo and Gasparini, Paolo and Laria, Carla and Lombardo, Barbara and Malesci, Rita and Vitale, Andrea and Marciano, Elio and Franz{\`e}, Annamaria} } @article {8039, title = {Population genetic differentiation of height and body mass index across Europe.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Nov}, pages = {1357-62}, abstract = {

Across-nation differences in the mean values for complex traits are common, but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24\% (95\% credible interval (CI) = 9\%, 41\%) and 8\% (95\% CI = 4\%, 16\%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 {\texttimes} 10(-8); BMI, P < 5.95 {\texttimes} 10(-4)), and we find an among-population genetic correlation for tall and slender individuals (r = -0.80, 95\% CI = -0.95, -0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58).

}, issn = {1546-1718}, doi = {10.1038/ng.3401}, author = {Robinson, Matthew R and Hemani, Gibran and Medina-Gomez, Carolina and Mezzavilla, Massimo and Esko, T{\~o}nu and Shakhbazov, Konstantin and Powell, Joseph E and Vinkhuyzen, Anna and Berndt, Sonja I and Gustafsson, Stefan and Justice, Anne E and Kahali, Bratati and Locke, Adam E and Pers, Tune H and Vedantam, Sailaja and Wood, Andrew R and van Rheenen, Wouter and Andreassen, Ole A and Gasparini, Paolo and Metspalu, Andres and Berg, Leonard H van den and Veldink, Jan H and Rivadeneira, Fernando and Werge, Thomas M and Abecasis, Goncalo R and Boomsma, Dorret I and Chasman, Daniel I and de Geus, Eco J C and Frayling, Timothy M and Hirschhorn, Joel N and Hottenga, Jouke Jan and Ingelsson, Erik and Loos, Ruth J F and Magnusson, Patrik K E and Martin, Nicholas G and Montgomery, Grant W and North, Kari E and Pedersen, Nancy L and Spector, Timothy D and Speliotes, Elizabeth K and Goddard, Michael E and Yang, Jian and Visscher, Peter M} } @article {8050, title = {Positron emission tomography-laparoscopy based method in the prediction of complete cytoreduction in platinum-sensitive recurrent ovarian cancer.}, journal = {Ann Surg Oncol}, volume = {22}, year = {2015}, month = {2015 Feb}, pages = {649-54}, abstract = {

BACKGROUND: This study was designed to evaluate the positron emission tomography-laparoscopy-based method in the prediction of complete/optimal cytoreduction in platinum sensitive recurrent epithelial ovarian cancer patients.

METHODS: We analysed 223 consecutive recurrent epithelial ovarian cancer patients. Inclusion criteria were absence of extra-abdominal disease and Eastern Cooperative Oncology Group Performance Status <=2. Complete and optimal secondary cytoreduction are defined as macroscopic absence or less than 1~cm of residual tumor at the end of surgery.

RESULTS: Laparoscopy was feasible in 210 of 223 patients (94.2~\%). Laparoscopy stated 127 (60.5~\%) possible cytoreductions and 83 (39.5~\%) systemic chemotherapies. In the same population, AGO score evaluation avowed 150 possible cytoreduction (71.5~\%) and 60 unresectable women (28.5~\%). Overall, 115 of 210 patients (54.7~\%) underwent successful secondary cytoreduction: complete and optimal cytoreduction was obtained in 103 (89.5~\%) and 12 (10.5~\%) patients, respectively. Laparoscopy obtained a positive predictive value of 91.3~\%. Laparoscopy recovered to secondary cytoreduction 13 of 60 patients (21.7~\%) deemed as not resectable according to AGO score. Forty-eight of 150 AGO score positive patients (32~\%) were judged nonresectable by laparoscopy.

CONCLUSIONS: This study confirmed that laparoscopy could be effective for the selection of platinum-sensitive recurrent epithelial ovarian cancer patients suitable for complete cytoreduction.

}, keywords = {Adult, Aged, Algorithms, Cytoreduction Surgical Procedures, Female, Humans, Laparoscopy, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Positron-Emission Tomography, Tomography, X-Ray Computed}, issn = {1534-4681}, doi = {10.1245/s10434-014-4011-0}, author = {Fanfani, Francesco and Monterossi, Giorgia and Fagotti, Anna and Gallotta, Valerio and Costantini, Barbara and Vizzielli, Giuseppe and Petrillo, Marco and Carbone, Maria Vittoria and Scambia, Giovanni} } @article {7736, title = {Rare coding variants and X-linked loci associated with age at menarche.}, journal = {Nat Commun}, volume = {6}, year = {2015}, month = {2015}, pages = {7756}, abstract = {

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only \~{}3\% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6\%; effect sizes 0.08-1.25 years per allele; P<5 {\texttimes} 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 {\texttimes} 10(-13)) and FAAH2 (rs5914101, P=4.9 {\texttimes} 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 {\texttimes} 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain \~{}0.5\% variance, indicating that these overlooked sources of variation do not substantially explain the {\textquoteright}missing heritability{\textquoteright} of this complex trait.

}, issn = {2041-1723}, doi = {10.1038/ncomms8756}, author = {Lunetta, Kathryn L and Day, Felix R and Sulem, Patrick and Ruth, Katherine S and Tung, Joyce Y and Hinds, David A and Esko, T{\~o}nu and Elks, Cathy E and Altmaier, Elisabeth and He, Chunyan and Huffman, Jennifer E and Mihailov, Evelin and Porcu, Eleonora and Robino, Antonietta and Rose, Lynda M and Schick, Ursula M and Stolk, Lisette and Teumer, Alexander and Thompson, Deborah J and Traglia, Michela and Wang, Carol A and Yerges-Armstrong, Laura M and Antoniou, Antonis C and Barbieri, Caterina and Coviello, Andrea D and Cucca, Francesco and Demerath, Ellen W and Dunning, Alison M and Gandin, Ilaria and Grove, Megan L and Gudbjartsson, Daniel F and Hocking, Lynne J and Hofman, Albert and Huang, Jinyan and Jackson, Rebecca D and Karasik, David and Kriebel, Jennifer and Lange, Ethan M and Lange, Leslie A and Langenberg, Claudia and Li, Xin and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Morrison, Alanna C and Padmanabhan, Sandosh and Pirie, Ailith and Polasek, Ozren and Porteous, David and Reiner, Alex P and Rivadeneira, Fernando and Rudan, Igor and Sala, Cinzia F and Schlessinger, David and Scott, Robert A and St{\"o}ckl, Doris and Visser, Jenny A and V{\"o}lker, Uwe and Vozzi, Diego and Wilson, James G and Zygmunt, Marek and Boerwinkle, Eric and Buring, Julie E and Crisponi, Laura and Easton, Douglas F and Hayward, Caroline and Hu, Frank B and Liu, Simin and Metspalu, Andres and Pennell, Craig E and Ridker, Paul M and Strauch, Konstantin and Streeten, Elizabeth A and Toniolo, Daniela and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and V{\"o}lzke, Henry and Wareham, Nicholas J and Wellons, Melissa and Franceschini, Nora and Chasman, Daniel I and Thorsteinsdottir, Unnur and Murray, Anna and Stefansson, Kari and Murabito, Joanne M and Ong, Ken K and Perry, John R B} } @article {7766, title = {Relapse and metastasis of atypical teratoid/rhabdoid tumor in a boy with neurofibromatosis type 1 treated with recombinant human growth hormone.}, journal = {Neuropediatrics}, volume = {46}, year = {2015}, month = {2015 Apr}, pages = {126-9}, abstract = {

Even though no increased recurrence rate seems to be reported in patients with brain tumors receiving recombinant human growth hormone (rhGH) replacement, in some patients multiple risk factors could put at higher risk for recurrence. In such cases, the decision to start rhGH therapy should be very cautious. A boy with neurofibromatosis type 1 developed an atypical teratoid/rhabdoid tumor (AT/RT) of right cerebellum, treated with surgery, radiotherapy, and chemotherapy. After 3 years of remission, he started rhGH for growth hormone deficiency, having a negative magnetic resonance imaging (MRI) scan. Ten weeks after starting therapy, the boy became symptomatic and MRI showed relapse of AT/RT in the right cerebellum and a new lesion in the brainstem. The boy died of progressive disease. In this case, the connection between AT/RT recurrence and the beginning of rhGH therapy, with a negative pretreatment MRI, cannot be excluded. Additional caution should be used for rhGH in patients with multiple risk factors.

}, keywords = {Brain Stem Neoplasms, Cerebellar Neoplasms, Child, Human Growth Hormone, Humans, Magnetic Resonance Imaging, Male, Neurofibromatosis 1, Recombinant Proteins, Recurrence, Rhabdoid Tumor, Risk Factors, Teratoma}, issn = {1439-1899}, doi = {10.1055/s-0034-1393706}, author = {Tornese, Gianluca and Faleschini, Elena and Matarazzo, Lorenza and Bibalo, Cristina and Zanazzo, Giulio Andrea and Rabusin, Marco and Tonini, Giorgio and Zennaro, Floriana and Ventura, Alessandro} } @article {7779, title = {Role of oxidative stress mediated by glutathione-s-transferase in thiopurines{\textquoteright} toxic effects.}, journal = {Chem Res Toxicol}, volume = {28}, year = {2015}, month = {2015 Jun 15}, pages = {1186-95}, abstract = {

Azathioprine (AZA), 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG) are antimetabolite drugs, widely used as immunosuppressants and anticancer agents. Despite their proven efficacy, a high incidence of toxic effects in patients during standard-dose therapy is recorded. The aim of this study is to explain, from a mechanistic point of view, the clinical evidence showing a significant role of glutathione-S-transferase (GST)-M1 genotype on AZA toxicity in inflammatory bowel disease patients. To this aim, the human nontumor IHH and HCEC cell lines were chosen as predictive models of the hepatic and intestinal tissues, respectively. AZA, but not 6-MP and 6-TG, induced a concentration-dependent superoxide anion production that seemed dependent on GSH depletion. N-Acetylcysteine reduced the AZA antiproliferative effect in both cell lines, and GST-M1 overexpression increased both superoxide anion production and cytotoxicity, especially in transfected HCEC cells. In this study, an in vitro model to study thiopurines{\textquoteright} metabolism has been set up and helped us to demonstrate, for the first time, a clear role of GST-M1 in modulating AZA cytotoxicity, with a close dependency on superoxide anion production. These results provide the molecular basis to shed light on the clinical evidence suggesting a role of GST-M1 genotype in influencing the toxic effects of AZA treatment.

}, issn = {1520-5010}, doi = {10.1021/acs.chemrestox.5b00019}, author = {Pelin, Marco and De Iudicibus, Sara and Fusco, Laura and Taboga, Eleonora and Pellizzari, Giulia and Lagatolla, Cristina and Martelossi, Stefano and Ventura, Alessandro and Decorti, Giuliana and Stocco, Gabriele} } @article {7737, title = {Role of Pharmacogenetics in Hematopoietic Stem Cell Transplantation Outcome in Children.}, journal = {Int J Mol Sci}, volume = {16}, year = {2015}, month = {2015}, pages = {18601-27}, abstract = {

Hematopoietic stem cell transplantation (HSCT) is an established therapeutic procedure for several congenital and acquired disorders, both malignant and nonmalignant. Despite the great improvements in HSCT clinical practices over the last few decades, complications, such as graft vs. host disease (GVHD) and sinusoidal obstructive syndrome (SOS), are still largely unpredictable and remain the major causes of morbidity and mortality. Both donor and patient genetic background might influence the success of bone marrow transplantation and could at least partially explain the inter-individual variability in HSCT outcome. This review summarizes some of the recent studies on candidate gene polymorphisms in HSCT, with particular reference to pediatric cohorts. The interest is especially focused on pharmacogenetic variants affecting myeloablative and immunosuppressive drugs, although genetic traits involved in SOS susceptibility and transplant-related mortality are also reviewed.

}, issn = {1422-0067}, doi = {10.3390/ijms160818601}, author = {Franca, Raffaella and Stocco, Gabriele and Favretto, Diego and Giurici, Nagua and Decorti, Giuliana and Rabusin, Marco} } @article {8059, title = {Sirolimus Therapy in Congenital Hyperinsulinism: A Successful Experience Beyond Infancy.}, journal = {Pediatrics}, volume = {136}, year = {2015}, month = {2015 Nov}, pages = {e1373-6}, abstract = {

Congenital hyperinsulinism (CHI) due to diffuse involvement of the pancreas is a challenging and severe illness in children. Its treatment is based on chronic therapy with diazoxide and/or octreotide, followed by partial pancreatectomy, which is often not resolutive. Sirolimus, a mammalian target of rapamycin inhibitor, was reported to be effective in treating CHI in infants. We report here the case of an 8-year-old boy affected by a severe form of CHI due to a biallelic heterozygous ABCC8 mutation who responded to sirolimus with a dramatic improvement in his glucose blood level regulation and quality of life, with no serious adverse events after 6 months of follow-up. To the best of our knowledge, this is the first report of a successful intervention in an older child. It provides a promising basis for further studies comparing sirolimus with other treatments, particularly in older children.

}, issn = {1098-4275}, doi = {10.1542/peds.2015-1132}, author = {Minute, Marta and Patti, Giuseppa and Tornese, Gianluca and Faleschini, Elena and Zuiani, Chiara and Ventura, Alessandro} } @article {8067, title = {Target sequencing approach intended to discover new mutations in non-syndromic intellectual disability.}, journal = {Mutat Res}, volume = {781}, year = {2015}, month = {2015 Nov}, pages = {32-6}, abstract = {

The technological improvements over the last years made considerable progresses in the knowledge of the etiology of intellectual Disability (ID). However, at present very little is known about the genetic heterogeneity underlying the non-syndromic form of ID (NS-ID). To investigate the genetic basis of NS-ID we analyzed 43 trios and 22 isolated NS-ID patients using a targeted sequencing (TS) approach. 71 NS-ID genes have been selected and sequenced in all subjects. We found putative pathogenic mutations in 7 out of 65 patients. The pathogenic role of mutations was evaluated through sequence comparison and structural analysis was performed to predict the effect of alterations in a 3D computational model through molecular dynamics simulations. Additionally, a deep patient clinical re-evaluation has been performed after the molecular results. This approach allowed us to find novel pathogenic mutations with a detection rate close to 11\% in our cohort of patients. This result supports the hypothesis that many NS-ID related genes still remain to be discovered and that NS-ID is a more complex phenotype compared to syndromic form, likely caused by a complex and broad interaction between genes alterations and environment factors.

}, issn = {1873-135X}, doi = {10.1016/j.mrfmmm.2015.09.002}, author = {Morgan, Anna and Gandin, Ilaria and Belcaro, Chiara and Palumbo, Pietro and Palumbo, Orazio and Biamino, Elisa and Dal Col, Valentina and Laurini, Erik and Pricl, Sabrina and Bosco, Paolo and Carella, Massimo and Ferrero, Giovanni Battista and Romano, Corrado and d{\textquoteright}Adamo, Adamo Pio and Faletra, Flavio and Vozzi, Diego} } @article {7730, title = {TRAIL modulates the immune system and protects against the development of diabetes.}, journal = {J Immunol Res}, volume = {2015}, year = {2015}, month = {2015}, pages = {680749}, abstract = {

TRAIL or tumor necrosis factor (TNF) related apoptosis-inducing ligand is a member of the TNF superfamily of proteins, whose best characterized function is the induction of apoptosis in tumor, infected, or transformed cells through activation of specific receptors. In nontransformed cells, however, the actions of TRAIL are less well characterized. Recent studies suggest that TRAIL may be implicated in the development and progression of diabetes. Here we review TRAIL biological actions, its effects on the immune system, and how and to what extent it has been shown to protect against diabetes.

}, keywords = {Animals, Diabetes Mellitus, Humans, Immune System, Receptors, TNF-Related Apoptosis-Inducing Ligand, Signal Transduction}, issn = {2314-7156}, doi = {10.1155/2015/680749}, author = {Bossi, Fleur and Bernardi, Stella and Zauli, Giorgio and Secchiero, Paola and Fabris, Bruno} } @article {8028, title = {Two-gene mutation in a single patient: Biochemical and functional analysis for a correct interpretation of exome results.}, journal = {Mol Med Rep}, volume = {12}, year = {2015}, month = {2015 Oct}, pages = {6128-32}, abstract = {

Next-generation sequencing (NGS) has generated a large amount of sequence data with the requirement of frequent critical revisions of reported mutations. This innovative tool has proved to be effective in detecting pathogenic mutations; however, it requires a certain degree of experience to identify incidental findings. In the present study, whole exome sequencing analysis was performed for the molecular diagnosis and correct genotype/phenotype correlation between parents and a patient presenting with an atypical phenotype. In addition, mevalonic acid quantification and frequency analysis of detected variants in public databases and X-chromosome inactivation (XCI) studies on the patient{\textquoteright}s mother were performed. V377I as well as the S135L mutations were identified on the mevalonate kinase deficiency gene and the levels of mevalonic acid in the patient were 5,496 {\textmu}g/ml. A D59G variation, reported in ESP6500 in two healthy individuals, was found on the Martin Probst syndrome gene (RAB40AL). Based on XCI studies on the patient{\textquoteright}s mother, it is likely that RAB40AL escapes XCI, while still remaining balanced. In conclusion, the results of the present study indicated that the Martin Probst syndrome is an X-linked condition, which is probably not caused by RAB40AL mutations. Although NGS is a powerful tool to identify pathogenic mutations, the analysis of genetic data requires expert critical revision of all detected variants.

}, issn = {1791-3004}, doi = {10.3892/mmr.2015.4215}, author = {Bianco, Anna Monica and Faletra, Flavio and Vozzi, Diego and Girardelli, Martina and Knowles, Alessandra and Tommasini, Alberto and Zauli, Giorgio and Marcuzzi, Annalisa} } @article {8095, title = {Vitamin D receptor polymorphisms and expression profile in rheumatoid arthritis brazilian patients.}, journal = {Mol Biol Rep}, year = {2015}, month = {2015 Dec 19}, abstract = {

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and important joint commitment, being the most common systemic autoimmune disease worldwide. RA displays important genetic background with a variety of genes contributing to the immune balance breakdown. Recent studies have demonstrated that vitamin D, through its receptor (VDR), is able to regulate the immune balance and suppress the autoimmunity process, being a potential target in autoimmune diseases. In the present genetic association study, we assessed 5 Tag single nucleotide polymorphisms (SNPs) (rs11168268, rs2248098, rs1540339, rs4760648 and rs3890733), which cover most of the VDR gene, in three different Brazilian populations (from Northeast, Southeast and South Brazil). We also evaluated the VDR expression profile in whole blood and monocytes from RA patients. For genotyping study, 428 RA patients and 616 healthy controls were genotyped with fluorogenic allele specific probes on an ABI7500 platform. For gene expression study, VDR mRNA levels of 15 RA patients and 26 healthy individuals were assessed by RT-PCR. Our results showed that SNPs rs4760648 and rs3890733 are associated to RA susceptibility (p value~=~0.0026, OR 1.31 and p value~=~0.0091, OR 1.28 with statistical power~=~0.999 and 0.993, respectively). Regarding RA clinical features, the studied SNPs did not show significant associations. The gene expression assays showed that VDR mRNA levels were down regulated in both whole blood (-3.3 fold) and monocytes (-3.2 fold) of RA patients when compared to healthy controls. Our results, the first reported for distinct Brazilian populations, support a role of the VDR gene in the susceptibility to RA.

}, issn = {1573-4978}, doi = {10.1007/s11033-015-3937-z}, author = {Cavalcanti, Catarina Addobbati Jord{\~a}o and De Azev{\^e}do Silva, Jaqueline and de Barros Pita, Will and Veit, Tiago Degani and Monticielo, Odirlei Andre and Xavier, Ricardo Machado and Brenol, Jo{\~a}o Carlos Tavares and Brenol, Cleiton Viegas and Fragoso, Thiago Sotero and Barbosa, Alexandre Domingues and Duarte, {\^A}ngela Luiza Branco Pinto and Oliveira, Ren{\^e} Donizeti Ribeiro and Louzada-J{\'u}nior, Paulo and Donadi, Eduardo Ant{\^o}nio and Crovella, Sergio and Chies, Jos{\'e} Artur Bogo and Sandrin-Garcia, Paula} } @article {7751, title = {Wharton{\textquoteright}s jelly derived mesenchymal stromal cells: Biological properties, induction of neuronal phenotype and current applications in neurodegeneration research.}, journal = {Acta Histochem}, volume = {117}, year = {2015}, month = {2015 May-Jun}, pages = {329-38}, abstract = {

Multipotent mesenchymal stromal cells, also known as mesenchymal stem cells (MSC), can be isolated from bone marrow or other tissues, including fat, muscle and umbilical cord. It has been shown that MSC behave in vitro as stem cells: they self-renew and are able to differentiate into mature cells typical of several mesenchymal tissues. Moreover, the differentiation toward non-mesenchymal cell lineages (e.g. neurons) has been reported as well. The clinical relevance of these cells is mainly related to their ability to spontaneously migrate to the site of inflammation/damage, to their safety profile thanks to their low immunogenicity and to their immunomodulation capacities. To date, MSCs isolated from the post-natal bone marrow have represented the most extensively studied population of adult MSCs, in view of their possible use in various therapeutical applications. However, the bone marrow-derived MSCs exhibit a series of limitations, mainly related to their problematic isolation, culturing and use. In recent years, umbilical cord (UC) matrix (i.e. Wharton{\textquoteright}s jelly, WJ) stromal cells have therefore emerged as a more suitable alternative source of MSCs, thanks to their primitive nature and the easy isolation without relevant ethical concerns. This review seeks to provide an overview of the main biological properties of WJ-derived MSCs. Moreover, the potential application of these cells for the treatment of some known dysfunctions in the central and peripheral nervous system will also be discussed.

}, issn = {1618-0372}, doi = {10.1016/j.acthis.2015.02.005}, author = {Frausin, Stefano and Viventi, Serena and Verga Falzacappa, Lucia and Quattromani, Miriana Jlenia and Leanza, Giampiero and Tommasini, Alberto and Valencic, Erica} } @article {3515, title = {Acquired long QT syndrome: a focus for the general pediatrician.}, journal = {Pediatr Emerg Care}, volume = {30}, year = {2014}, month = {2014 Apr}, pages = {257-61}, abstract = {

Acquired long QT syndrome (LQTS) is a disorder of cardiac repolarization most often due to specific drugs, hypokalemia, or hypomagnesemia that may precipitate torsade de pointes and cause sudden cardiac death. Common presentations of the LQTS are palpitations, presyncope, syncope, cardiac arrest, and seizures. An abnormal 12-lead electrocardiogram obtained while the patient is at rest is the key to diagnosis. The occurrence of drug-induced LQTS is unpredictable in any given individual, but a common observation is that most patients have at least 1 identifiable risk factor in addition to drug exposure. The cornerstone of the management of acquired LQTS includes the identification and discontinuation of any precipitating drug and the correction of metabolic abnormalities, such as hypokalemia or hypomagnesemia. Most of the episodes of torsade de pointes are short-lived and terminate spontaneously. We propose a management protocol that could be useful for the daily practice in the emergency pediatric department to reduce the risk of acquired QT prolongation.

}, keywords = {Adolescent, Death, Sudden, Cardiac, Electrocardiography, Female, General Practitioners, Humans, Long QT Syndrome, Ondansetron, Risk Factors, Serotonin Antagonists}, issn = {1535-1815}, doi = {10.1097/PEC.0000000000000108}, author = {Marzuillo, Pierluigi and Benettoni, Alessandra and Germani, Claudio and Ferrara, Giovanna and D{\textquoteright}Agata, Biancamaria and Barbi, Egidio} } @article {3554, title = {Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia.}, journal = {Haematologica}, volume = {99}, year = {2014}, month = {2014 Aug}, pages = {1387-94}, abstract = {

Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8\% to 14.2\% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 {\texttimes} 10(9)/L.

}, keywords = {Adult, Female, Humans, Infant, Newborn, Pregnancy, Pregnancy Complications, Hematologic, Retrospective Studies, Thrombocytopenia, Young Adult}, issn = {1592-8721}, doi = {10.3324/haematol.2014.105924}, author = {Noris, Patrizia and Schlegel, Nicole and Klersy, Catherine and Heller, Paula G and Civaschi, Elisa and Pujol-Moix, N{\'u}ria and Fabris, Fabrizio and Favier, R{\'e}mi and Gresele, Paolo and Latger-Cannard, V{\'e}ronique and Cuker, Adam and Nurden, Paquita and Greinacher, Andreas and Cattaneo, Marco and De Candia, Erica and Pecci, Alessandro and Hurtaud-Roux, Marie-Fran{\c c}oise and Glembotsky, Ana C and Mu{\~n}iz-Diaz, Eduardo and Randi, Maria Luigia and Trillot, Nathalie and Bury, Loredana and Lecompte, Thomas and Marconi, Caterina and Savoia, Anna and Balduini, Carlo L and Bayart, Sophie and Bauters, Anne and Benabdallah-Guedira, Sch{\'e}h{\'e}razade and Boehlen, Fran{\c c}oise and Borg, Jeanne-Yvonne and Bottega, Roberta and Bussel, James and De Rocco, Daniela and de Maistre, Emmanuel and Faleschini, Michela and Falcinelli, Emanuela and Ferrari, Silvia and Ferster, Alina and Fierro, Tiziana and Fleury, Dominique and Fontana, Pierre and James, Chlo{\'e} and Lanza, Francois and Le Cam Duchez, V{\'e}ronique and Loffredo, Giuseppe and Magini, Pamela and Martin-Coignard, Dominique and Menard, Fanny and Mercier, Sandra and Mezzasoma, Annamaria and Minuz, Pietro and Nichele, Ilaria and Notarangelo, Lucia D and Pippucci, Tommaso and Podda, Gian Marco and Pouymayou, Catherine and Rigouzzo, Agnes and Royer, Bruno and Sie, Pierre and Siguret, Virginie and Trichet, Catherine and Tucci, Alessandra and Saposnik, B{\'e}atrice and Veneri, Dino} } @article {3545, title = {Assessment of coupling between trans-abdominally acquired fetal ECG and uterine activity by bivariate phase-rectified signal averaging analysis.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e94557}, abstract = {

UNLABELLED: Couplings between uterine contractions (UC) and fetal heart rate (fHR) provide important information on fetal condition during labor. At present, couplings between UC and fHR are assessed by visual analysis and interpretation of cardiotocography. The application of computerized approaches is restricted due to the non-stationarity of the signal, missing data and noise, typical for fHR. Herein, we propose a novel approach to assess couplings between UC and fHR, based on a signal-processing algorithm termed bivariate phase-rectified signal averaging (BPRSA).

METHODS: Electrohysterogram (EHG) and fetal electrocardiogram (fECG) were recorded non-invasively by a trans-abdominal device in 73 women at term with uneventful singleton pregnancy during the first stage of labor. Coupling between UC and fHR was analyzed by BPRSA and by conventional cross power spectral density analysis (CPSD). For both methods, degree of coupling was assessed by the maximum coefficient of coherence (CPRSA and CRAW, respectively) in the UC frequency domain. Coherence values greater than 0.50 were consider significant. CPRSA and CRAW were compared by Wilcoxon test.

RESULTS: At visual inspection BPRSA analysis identified coupled periodicities in 86.3\% (63/73) of the cases. 11/73 (15\%) cases were excluded from further analysis because no 30 minutes of fECG recording without signal loss was available for spectral analysis. Significant coupling was found in 90.3\% (56/62) of the cases analyzed by BPRSA, and in 24.2\% (15/62) of the cases analyzed by CPSD, respectively. The difference between median value of CPRSA and CRAW was highly significant (0.79 [IQR 0.69-0.90] and 0.29 [IQR 0.17-0.47], respectively; p<0.0001).

CONCLUSION: BPRSA is a novel computer-based approach that can be reliably applied to trans-abdominally acquired EHG-fECG. It allows the assessment of correlations between UC and fHR patterns in the majority of labors, overcoming the limitations of non-stationarity and artifacts. Compared to standard techniques of cross-correlations, such as CPSD, BPRSA is significantly superior.

}, keywords = {Electrocardiography, Female, Heart Rate, Fetal, Humans, Labor, Obstetric, Pregnancy, Uterine Contraction}, issn = {1932-6203}, doi = {10.1371/journal.pone.0094557}, author = {Casati, Daniela and Stampalija, Tamara and Rizas, Konstantinos and Ferrazzi, Enrico and Mastroianni, Cristina and Rosti, Eleonora and Quadrifoglio, Mariachiara and Bauer, Axel} } @article {3636, title = {Autoimmune hematological diseases after allogeneic hematopoietic stem cell transplantation in children: an Italian multicenter experience.}, journal = {Biol Blood Marrow Transplant}, volume = {20}, year = {2014}, month = {2014 Feb}, pages = {272-8}, abstract = {

Autoimmune hematological diseases (AHDs) may occur after allogeneic hematopoietic stem cell transplantation (HSCT), but reports on these complications in large cohorts of pediatric patients are lacking. Between 1998 and 2011, 1574 consecutive children underwent allogeneic HSCT in 9 Italian centers. Thirty-three children (2.1\%) developed AHDs: 15 autoimmune hemolytic anemia (45\%), 10 immune thrombocytopenia (30\%), 5 Evans{\textquoteright} syndrome (15\%), 2 pure red cell aplasia (6\%), and 1 immune neutropenia (3\%). The 10-year cumulative incidence of AHDs was 2.5\% (95\% confidence interval, 1.7 to 3.6). In a multivariate analysis, the use of alternative donor and nonmalignant disease was statistically associated with AHDs. Most patients with AHDs (64\%) did not respond to steroids. Sustained complete remission was achieved in 87\% of cases with the anti-CD20 monoclonal antibody (rituximab). Four patients (9\%) (1 autoimmune hemolytic anemia, 1 Evans{\textquoteright} syndrome, 2 immune thrombocytopenia) died at a median of 87~days after AHD diagnosis as a direct or indirect consequence of their disorder. Our data suggest that AHDs are a relatively rare complication occurring after HSCT that usually respond to treatment with rituximab.

}, keywords = {Child, Child, Preschool, Female, Hematologic Diseases, Hematopoietic Stem Cell Transplantation, Humans, Italy, Male, Remission Induction, Risk Factors, Transplantation Conditioning}, issn = {1523-6536}, doi = {10.1016/j.bbmt.2013.11.014}, author = {Faraci, Maura and Zecca, Marco and Pillon, Marta and Rovelli, Attilio and Menconi, Maria Cristina and Ripaldi, Mimmo and Fagioli, Franca and Rabusin, Marco and Ziino, Ottavio and Lanino, Edoardo and Locatelli, Franco and Daikeler, Thomas and Prete, Arcangelo} } @article {3478, title = {Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Jan}, pages = {42-7}, abstract = {

Stickler syndrome (STL) is a clinically variable and genetically heterogeneous syndrome characterized by ophthalmic, articular, orofacial, and auditory manifestations. STL has been described with both autosomal dominant and recessive inheritance. The dominant form is caused by mutations of COL2A1 (STL 1, OMIM 108300), COL11A1 (STL 2, OMIM 604841), and COL11A2 (STL 3, OMIM 184840) genes, while recessive forms have been associated with mutations of COL9A1 (OMIM 120210) and COL9A2 (OMIM 120260) genes. Type IX collagen is a heterotrimeric molecule formed by three genetically distinct chains: α1, α2, and α3 encoded by the COL9A1, COL9A2, and COL9A3 genes. Up to this time, only heterozygous mutations of COL9A3 gene have been reported in human and related to: (1) multiple epiphyseal dysplasia type 3, (2) susceptibility to an intervertebral disc disease, and (3) hearing loss. Here, we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene. These findings extend further the role of collagen genes family in the disease pathogenesis.

}, keywords = {Adolescent, Arthritis, Bone and Bones, Child, Child, Preschool, Collagen Diseases, Collagen Type IX, Connective Tissue Diseases, DNA Mutational Analysis, Facies, Female, Genes, Recessive, Hearing Loss, Hearing Loss, Sensorineural, Homozygote, Humans, Male, Mutation, Pedigree, Retinal Detachment}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36165}, author = {Faletra, Flavio and d{\textquoteright}Adamo, Adamo P and Bruno, Irene and Athanasakis, Emmanouil and Biskup, Saskia and Esposito, Laura and Gasparini, Paolo} } @article {3490, title = {Beta defensin-1 gene polymorphisms and susceptibility to atypical squamous cells of undetermined significance lesions in Italian gynecological patients.}, journal = {J Med Virol}, volume = {86}, year = {2014}, month = {2014 Dec}, pages = {1999-2004}, abstract = {

The role of the human beta-defensin 1 (hBD-1) in the susceptibility to the onset of the Atypical Squamous Cells of Undetermined Significance (ASCUS) lesion, in the presence or not of HPV infection, is still unknown. In the current study, the three functional single nucleotide polymorphisms (SNPs) -52G > A, -44C > G, and -20G > A at the 5{\textquoteright} un-translated region (UTR) of DEFB1 gene, encoding hBD-1, were analyzed in ASCUS lesion gynecological patients and healthy women from the north-east of Italy (Trieste). Cervical samples from 249 European-Caucasian women were collected, screened for HPV and cytologically evaluated; DEFB1 genotyping has been performed by direct sequencing. No significant differences were found for -52G > A, -44C > G, and -20G > A SNPs allele and genotype frequencies between women with and without ASCUS lesions. DEFB1 minor haplotypes were significantly more frequent in ASCUS lesion positive than negative women, associating with an increased risk of this type of lesion. When women were stratified according to HPV infection status, significant differences in the distribution of -52G > A SNP genotype frequencies were found: the presence of the A allele in the homozygous genotype A/A associated with a lower risk of developing ASCUS lesions in HPV negative women. DEFB1 minor haplotypes were also associated with an increased risk of developing ASCUS lesions, being significantly more frequent in HPV negative women with lesions, than without lesions. Although these results highlight the possible involvement of DEFB1, further studies are needed to support the role of DEFB1 in the modulation of the susceptibility to ASCUS lesions.

}, keywords = {5{\textquoteright} Untranslated Regions, Adolescent, Adult, Atypical Squamous Cells of the Cervix, beta-Defensins, Female, Genotype, Humans, Italy, Papillomavirus Infections, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Uterine Cervical Neoplasms, Young Adult}, issn = {1096-9071}, doi = {10.1002/jmv.23878}, author = {Casalicchio, Giorgia and Freato, Nadia and Maestri, Iva and Comar, Manola and Crovella, Sergio and Segat, Ludovica} } @article {3590, title = {Breastfeeding and migraine drugs.}, journal = {Eur J Clin Pharmacol}, volume = {70}, year = {2014}, month = {2014 Nov}, pages = {1313-24}, abstract = {

PURPOSE: Breastfeeding women may suffer from migraine. While we have many drugs for its treatment and prophylaxis, the majority are poorly studied in breastfeeding women. We conducted a review of the most common anti-migraine drugs (AMDs) and we determined their lactation risk.

METHODS: For each AMD, we collected all retrievable data from Hale{\textquoteright}s Medications and Mother Milk (2012), from the LactMed database (2014) of the National Library of Medicine, and from a MedLine Search of relevant studies published in the last 10 years.

RESULTS: According to our review, AMDs safe during breastfeeding are as follows: low-dose acetylsalicylic acid (ASA), ibuprofen, sumatriptan, metoprolol, propranolol, verapamil, amitriptyline, escitalopram, paroxetine, sertraline, acetaminophen, caffeine, and metoclopramide. AMDs compatible with breastfeeding but warranting caution are as follows: diclofenac, ketoprofen, naproxen, most new triptans, topiramate, valproate, venlafaxine, and cyproheptadine. Finally, high-dose ASA, atenolol, nadolol, cinnarizine, flunarizine, ergotamine, methysergide, and pizotifen are contraindicated.

CONCLUSIONS: According to our review, the majority of the revised AMDs were assessed to be compatible with breastfeeding.

}, keywords = {Adrenergic beta-Antagonists, Analgesics, Non-Narcotic, Animals, Anti-Inflammatory Agents, Non-Steroidal, Anticonvulsants, Antidepressive Agents, Breast Feeding, Calcium Channel Blockers, Female, Humans, Migraine Disorders, Tryptamines}, issn = {1432-1041}, doi = {10.1007/s00228-014-1748-0}, author = {Davanzo, Riccardo and Bua, Jenny and Paloni, Giulia and Facchina, Giulia} } @article {3602, title = {Clinical features and follow-up in patients with 22q11.2 deletion syndrome.}, journal = {J Pediatr}, volume = {164}, year = {2014}, month = {2014 Jun}, pages = {1475-80.e2}, abstract = {

OBJECTIVE: To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease.

STUDY DESIGN: A retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis.

RESULTS: The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71\% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations (P = .015) and speech disorders (P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis.

CONCLUSIONS: Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.

}, keywords = {Abnormalities, Multiple, Adolescent, Adult, Age Factors, Child, Child, Preschool, Chromosomes, Human, Pair 22, Delayed Diagnosis, Developmental Disabilities, DiGeorge Syndrome, Disease Progression, Early Diagnosis, Female, Follow-Up Studies, Genetic Testing, Humans, Infant, Infant, Newborn, Male, Monitoring, Physiologic, Prospective Studies, Retrospective Studies, Risk Assessment, Severity of Illness Index, Sex Factors, Time Factors, Young Adult}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2014.01.056}, author = {Cancrini, Caterina and Puliafito, Pamela and Digilio, Maria Cristina and Soresina, Annarosa and Martino, Silvana and Rondelli, Roberto and Consolini, Rita and Ruga, Ezia Maria and Cardinale, Fabio and Finocchi, Andrea and Romiti, Maria Luisa and Martire, Baldassarre and Bacchetta, Rosa and Albano, Veronica and Carotti, Adriano and Specchia, Fernando and Montin, Davide and Cirillo, Emilia and Cocchi, Guido and Trizzino, Antonino and Bossi, Grazia and Milanesi, Ornella and Azzari, Chiara and Corsello, Giovanni and Pignata, Claudio and Aiuti, Alessandro and Pietrogrande, Maria Cristina and Marino, Bruno and Ugazio, Alberto Giovanni and Plebani, Alessandro and Rossi, Paolo} } @article {3506, title = {Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis.}, journal = {J Am Soc Nephrol}, volume = {25}, year = {2014}, month = {2014 Aug}, pages = {1869-82}, abstract = {

Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 μg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.

}, keywords = {Creatinine, European Continental Ancestry Group, Genetic Variation, Humans, Polymorphism, Single Nucleotide, Uromodulin}, issn = {1533-3450}, doi = {10.1681/ASN.2013070781}, author = {Olden, Matthias and Corre, Tanguy and Hayward, Caroline and Toniolo, Daniela and Ulivi, Sheila and Gasparini, Paolo and Pistis, Giorgio and Hwang, Shih-Jen and Bergmann, Sven and Campbell, Harry and Cocca, Massimiliano and Gandin, Ilaria and Girotto, Giorgia and Glaudemans, Bob and Hastie, Nicholas D and Loffing, Johannes and Polasek, Ozren and Rampoldi, Luca and Rudan, Igor and Sala, Cinzia and Traglia, Michela and Vollenweider, Peter and Vuckovic, Dragana and Youhanna, Sonia and Weber, Julien and Wright, Alan F and Kutalik, Zolt{\'a}n and Bochud, Murielle and Fox, Caroline S and Devuyst, Olivier} } @article {3572, title = {A comparison of three scales for measuring pain in children with cognitive impairment.}, journal = {Acta Paediatr}, volume = {103}, year = {2014}, month = {2014 Nov}, pages = {e495-500}, abstract = {

AIM: Pain is a neglected problem in children with cognitive impairments, and few studies compare the clinical use of specific pain scales. We compared the Non-Communicating Children{\textquoteright}s Pain Checklist Postoperative Version (NCCPC-PV), the Echelle Douleur Enfant San Salvador (DESS) and the Children{\textquoteright}s Hospital of Eastern Ontario Pain Scale (CHEOPS). The first two were developed for children with cognitive impairment, and the third is a more general pain scale.

METHODS: Two external observers and the child{\textquoteright}s caregiver assessed 40 children with cognitive impairment for pain levels. We assessed inter-rater agreement, correlation, dependence on knowledge of the child{\textquoteright}s behaviour, simplicity and adequacy in pain rating according to the caregiver for all three scales.

RESULTS: The correlation between the NCCPC-PV and the DESS was strong (Spearman correlation coefficient = 0.76) and better than between each scale and the CHEOPS. Although the DESS showed better inter-rater agreement, it was more dependent on familiarity with the child and was judged more difficult to use by all observers. The NCCPC-PV was the easiest use and the most appropriate for rating the child{\textquoteright}s pain.

CONCLUSION: The NCCPC-PV was the easiest to use for pain assessment in cognitively impaired children and should be adopted in clinical settings.

}, issn = {1651-2227}, doi = {10.1111/apa.12748}, author = {Massaro, Marta and Ronfani, Luca and Ferrara, Giovanna and Badina, Laura and Giorgi, Rita and D{\textquoteright}Osualdo, Flavio and Taddio, Andrea and Barbi, Egidio} } @article {3528, title = {Development of an enzyme-linked immunosorbent assay for Bartonella henselae infection detection.}, journal = {Lett Appl Microbiol}, volume = {59}, year = {2014}, month = {2014 Sep}, pages = {253-62}, abstract = {

UNLABELLED: Several serological diagnostics rely on enzyme-linked immunosorbent assay (ELISA) to detect bacterial infections. However, for some pathogens, including Bartonella henselae, diagnosis still depends on manually intensive, time-consuming assays including micro-immunofluorescence, Western blotting or indirect immunofluorescence. For such pathogens, there is obviously still a need to identify antigens to establish a reliable, fast and high-throughput assay (Dupon et~al. ). We evaluated two B.~henselae proteins to develop a novel serological ELISA: a well-known antigen, the 17-kDa protein, and GroEL, identified during this study by a proteomic approach. When serum IgG were tested, the specificity and sensitivity were 76 and 65{\textperiodcentered}7\% for 17-kDa, respectively, and 82 and 42{\textperiodcentered}9\% for GroEL, respectively. IgM were found to be more sensitive and specific for both proteins: 17-kDa protein, specificity 86{\textperiodcentered}2\% and sensitivity 75\%; GroEL, specificity 97{\textperiodcentered}7\% and sensitivity 45{\textperiodcentered}3\%. IgM antibodies were also measured in lymphoma patients and patients with Mycobacterium tuberculosis infection to assess the usefulness of our ELISA to distinguish them from B.~henselae infected patients. The resulting specificities were 89{\textperiodcentered}1 and 93{\textperiodcentered}5\% for 17-kDa protein and GroEL, respectively. Combining the results from the two tests, we obtained a sensitivity of 82{\textperiodcentered}8\% and a specificity of 83{\textperiodcentered}9\%. Our work described and validated a proteomic approach suitable to identify immunogenic proteins useful for developing a serological test of B.~henselae infection.

SIGNIFICANCE AND IMPACT OF THE STUDY: A reliable serological assay for the diagnosis of Cat Scratch Disease (CSD) - a pathological condition caused by Bartonella henselae infection - has not yet been developed. Such an assay would be extremely useful to discriminate between CSD and other pathologies with similar symptoms but different aetiologies, for example lymphoma or tuberculosis. We investigate the use of two B.~henselae proteins - GroEL and 17-kDa - to develop a serological-based ELISA, showing promising results with the potential for further development as an effective tool for the differential diagnosing of B.~henselae infection.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Antibodies, Bacterial, Antigens, Bacterial, Bacterial Proteins, Bartonella henselae, Case-Control Studies, Cat-Scratch Disease, Chaperonin 60, Child, Child, Preschool, Diagnosis, Differential, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunoglobulin M, Lymphoma, Male, Molecular Sequence Data, ROC Curve, Tuberculosis, Pulmonary, Young Adult}, issn = {1472-765X}, doi = {10.1111/lam.12286}, author = {Ferrara, F and Di Niro, R and D{\textquoteright}Angelo, S and Busetti, M and Marzari, R and Not, T and Sblattero, D} } @article {3480, title = {DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 May 1}, pages = {2490-7}, abstract = {

The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to \~{}50\% of the variation in both age at menarche and menopause, but to date the known genes explain <15\% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 {\texttimes} 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.

}, keywords = {Age Factors, DNA-Binding Proteins, Female, Genome-Wide Association Study, Humans, Menopause, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/ddt620}, author = {Perry, John R B and Hsu, Yi-Hsiang and Chasman, Daniel I and Johnson, Andrew D and Elks, Cathy and Albrecht, Eva and Andrulis, Irene L and Beesley, Jonathan and Berenson, Gerald S and Bergmann, Sven and Bojesen, Stig E and Bolla, Manjeet K and Brown, Judith and Buring, Julie E and Campbell, Harry and Chang-Claude, Jenny and Chenevix-Trench, Georgia and Corre, Tanguy and Couch, Fergus J and Cox, Angela and Czene, Kamila and d{\textquoteright}Adamo, Adamo Pio and Davies, Gail and Deary, Ian J and Dennis, Joe and Easton, Douglas F and Engelhardt, Ellen G and Eriksson, Johan G and Esko, T{\~o}nu and Fasching, Peter A and Figueroa, Jonine D and Flyger, Henrik and Fraser, Abigail and Garcia-Closas, Montse and Gasparini, Paolo and Gieger, Christian and Giles, Graham and Guenel, Pascal and H{\"a}gg, Sara and Hall, Per and Hayward, Caroline and Hopper, John and Ingelsson, Erik and Kardia, Sharon L R and Kasiman, Katherine and Knight, Julia A and Lahti, Jari and Lawlor, Debbie A and Magnusson, Patrik K E and Margolin, Sara and Marsh, Julie A and Metspalu, Andres and Olson, Janet E and Pennell, Craig E and Polasek, Ozren and Rahman, Iffat and Ridker, Paul M and Robino, Antonietta and Rudan, Igor and Rudolph, Anja and Salumets, Andres and Schmidt, Marjanka K and Schoemaker, Minouk J and Smith, Erin N and Smith, Jennifer A and Southey, Melissa and St{\"o}ckl, Doris and Swerdlow, Anthony J and Thompson, Deborah J and Truong, Therese and Ulivi, Sheila and Waldenberger, Melanie and Wang, Qin and Wild, Sarah and Wilson, James F and Wright, Alan F and Zgaga, Lina and Ong, Ken K and Murabito, Joanne M and Karasik, David and Murray, Anna} } @article {3600, title = {Experience from a single paediatric transplant centre with identification of some protective and risk factors concerning the development of hepatic veno-occlusive disease in children after allogeneic hematopoietic stem cell transplant.}, journal = {Int J Hematol}, volume = {99}, year = {2014}, month = {2014 Jun}, pages = {766-72}, abstract = {

Hepatic veno-occlusive disease (VOD) is a frequent and severe complication of hematopoietic stem cell transplantation (HSCT) affecting 9.6-17.3 \% of cases. 200 HSCT, performed between January 1995 and March 2013 in our Paediatric HSCT Centre in Trieste, were retrospectively analysed to evaluate the frequency of VOD and to identify the associated risk factors. The frequency of VOD according to the Seattle criteria was 17 \%, within the range reported in literature. The mortality rate was 37.5 \% (75 out of 200 transplantations) in the general population and 73.5 \% (25 out of 34) in VOD patients (p < 0.05). Veno-occlusive disease significantly decreased from 38 \% (1995-2000) to 8 \% (2007-2013) p < 0.05. Univariate and multivariate analyses identified sepsis and pre-transplant ferritin levels above 1000 ng/ml as two significant risk factors for VOD, while the use of tacrolimus appeared to be associated with a lower VOD risk. Veno-occlusive disease still remains an important cause of transplant-related mortality even if it appears to have decreased over the last few years.

}, keywords = {Adolescent, Child, Child, Preschool, Female, Hematopoietic Stem Cell Transplantation, Hepatic Veno-Occlusive Disease, Humans, Infant, Infant, Newborn, Male, Mortality, Retrospective Studies, Risk Factors, Transplantation, Homologous, Young Adult}, issn = {1865-3774}, doi = {10.1007/s12185-014-1578-y}, author = {Maximova, N and Ferrara, G and Minute, M and Pizzol, A and Kiren, V and Montico, M and Gregori, M and Tamaro, P} } @article {3520, title = {A general approach for haplotype phasing across the full spectrum of relatedness.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Apr}, pages = {e1004234}, abstract = {

Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally {\textquoteright}unrelated{\textquoteright} individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.

}, keywords = {Chromosome Mapping, Cohort Effect, Family, Genotype, Haplotypes, Humans, Models, Genetic, Pedigree, Phenotype, Recombination, Genetic}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004234}, author = {O{\textquoteright}Connell, Jared and Gurdasani, Deepti and Delaneau, Olivier and Pirastu, Nicola and Ulivi, Sheila and Cocca, Massimiliano and Traglia, Michela and Huang, Jie and Huffman, Jennifer E and Rudan, Igor and McQuillan, Ruth and Fraser, Ross M and Campbell, Harry and Polasek, Ozren and Asiki, Gershim and Ekoru, Kenneth and Hayward, Caroline and Wright, Alan F and Vitart, Veronique and Navarro, Pau and Zagury, Jean-Francois and Wilson, James F and Toniolo, Daniela and Gasparini, Paolo and Soranzo, Nicole and Sandhu, Manjinder S and Marchini, Jonathan} } @article {3568, title = {Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Aug}, pages = {826-36}, abstract = {

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain \~{}8-10\% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

}, keywords = {Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.3014}, author = {Arking, Dan E and Pulit, Sara L and Crotti, Lia and van der Harst, Pim and Munroe, Patricia B and Koopmann, Tamara T and Sotoodehnia, Nona and Rossin, Elizabeth J and Morley, Michael and Wang, Xinchen and Johnson, Andrew D and Lundby, Alicia and Gudbjartsson, Daniel F and Noseworthy, Peter A and Eijgelsheim, Mark and Bradford, Yuki and Tarasov, Kirill V and D{\"o}rr, Marcus and M{\"u}ller-Nurasyid, Martina and Lahtinen, Annukka M and Nolte, Ilja M and Smith, Albert Vernon and Bis, Joshua C and Isaacs, Aaron and Newhouse, Stephen J and Evans, Daniel S and Post, Wendy S and Waggott, Daryl and Lyytik{\"a}inen, Leo-Pekka and Hicks, Andrew A and Eisele, Lewin and Ellinghaus, David and Hayward, Caroline and Navarro, Pau and Ulivi, Sheila and Tanaka, Toshiko and Tester, David J and Chatel, St{\'e}phanie and Gustafsson, Stefan and Kumari, Meena and Morris, Richard W and Naluai, {\r A}sa T and Padmanabhan, Sandosh and Kluttig, Alexander and Strohmer, Bernhard and Panayiotou, Andrie G and Torres, Maria and Knoflach, Michael and Hubacek, Jaroslav A and Slowikowski, Kamil and Raychaudhuri, Soumya and Kumar, Runjun D and Harris, Tamara B and Launer, Lenore J and Shuldiner, Alan R and Alonso, Alvaro and Bader, Joel S and Ehret, Georg and Huang, Hailiang and Kao, W H Linda and Strait, James B and Macfarlane, Peter W and Brown, Morris and Caulfield, Mark J and Samani, Nilesh J and Kronenberg, Florian and Willeit, Johann and Smith, J Gustav and Greiser, Karin H and Meyer Zu Schwabedissen, Henriette and Werdan, Karl and Carella, Massimo and Zelante, Leopoldo and Heckbert, Susan R and Psaty, Bruce M and Rotter, Jerome I and Kolcic, Ivana and Polasek, Ozren and Wright, Alan F and Griffin, Maura and Daly, Mark J and Arnar, David O and Holm, Hilma and Thorsteinsdottir, Unnur and Denny, Joshua C and Roden, Dan M and Zuvich, Rebecca L and Emilsson, Valur and Plump, Andrew S and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Yin, Xiaoyan and Bobbo, Marco and d{\textquoteright}Adamo, Adamo P and Iorio, Annamaria and Sinagra, Gianfranco and Carracedo, Angel and Cummings, Steven R and Nalls, Michael A and Jula, Antti and Kontula, Kimmo K and Marjamaa, Annukka and Oikarinen, Lasse and Perola, Markus and Porthan, Kimmo and Erbel, Raimund and Hoffmann, Per and J{\"o}ckel, Karl-Heinz and K{\"a}lsch, Hagen and N{\"o}then, Markus M and den Hoed, Marcel and Loos, Ruth J F and Thelle, Dag S and Gieger, Christian and Meitinger, Thomas and Perz, Siegfried and Peters, Annette and Prucha, Hanna and Sinner, Moritz F and Waldenberger, Melanie and de Boer, Rudolf A and Franke, Lude and van der Vleuten, Pieter A and Beckmann, Britt Maria and Martens, Eimo and Bardai, Abdennasser and Hofman, Nynke and Wilde, Arthur A M and Behr, Elijah R and Dalageorgou, Chrysoula and Giudicessi, John R and Medeiros-Domingo, Argelia and Barc, Julien and Kyndt, Florence and Probst, Vincent and Ghidoni, Alice and Insolia, Roberto and Hamilton, Robert M and Scherer, Stephen W and Brandimarto, Jeffrey and Margulies, Kenneth and Moravec, Christine E and del Greco M, Fabiola and Fuchsberger, Christian and O{\textquoteright}Connell, Jeffrey R and Lee, Wai K and Watt, Graham C M and Campbell, Harry and Wild, Sarah H and El Mokhtari, Nour E and Frey, Norbert and Asselbergs, Folkert W and Mateo Leach, Irene and Navis, Gerjan and van den Berg, Maarten P and van Veldhuisen, Dirk J and Kellis, Manolis and Krijthe, Bouwe P and Franco, Oscar H and Hofman, Albert and Kors, Jan A and Uitterlinden, Andr{\'e} G and Witteman, Jacqueline C M and Kedenko, Lyudmyla and Lamina, Claudia and Oostra, Ben A and Abecasis, Goncalo R and Lakatta, Edward G and Mulas, Antonella and Orru, Marco and Schlessinger, David and Uda, Manuela and Markus, Marcello R P and V{\"o}lker, Uwe and Snieder, Harold and Spector, Timothy D and Arnl{\"o}v, Johan and Lind, Lars and Sundstr{\"o}m, Johan and Syv{\"a}nen, Ann-Christine and Kivimaki, Mika and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Raitakari, Olli T and Viikari, Jorma S and Adamkova, Vera and Kiechl, Stefan and Brion, Maria and Nicolaides, Andrew N and Paulweber, Bernhard and Haerting, Johannes and Dominiczak, Anna F and Nyberg, Fredrik and Whincup, Peter H and Hingorani, Aroon D and Schott, Jean-Jacques and Bezzina, Connie R and Ingelsson, Erik and Ferrucci, Luigi and Gasparini, Paolo and Wilson, James F and Rudan, Igor and Franke, Andre and M{\"u}hleisen, Thomas W and Pramstaller, Peter P and Lehtim{\"a}ki, Terho J and Paterson, Andrew D and Parsa, Afshin and Liu, Yongmei and van Duijn, Cornelia M and Siscovick, David S and Gudnason, Vilmundur and Jamshidi, Yalda and Salomaa, Veikko and Felix, Stephan B and Sanna, Serena and Ritchie, Marylyn D and Stricker, Bruno H and Stefansson, Kari and Boyer, Laurie A and Cappola, Thomas P and Olsen, Jesper V and Lage, Kasper and Schwartz, Peter J and K{\"a}{\"a}b, Stefan and Chakravarti, Aravinda and Ackerman, Michael J and Pfeufer, Arne and de Bakker, Paul I W and Newton-Cheh, Christopher} } @article {3517, title = {A girl with photosensitivity and hepatic steatosis.}, journal = {J Pediatr}, volume = {165}, year = {2014}, month = {2014 Jul}, pages = {201-201.e1}, keywords = {Child, Diagnosis, Differential, Fatty Liver, Female, Humans, Photosensitivity Disorders, Protoporphyria, Erythropoietic}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2014.02.056}, author = {Pavan, Matteo and Gortani, Giulia and Rubinato, Elisa and Faletra, Flavio and Pastore, Serena and Ventura, Alessandro} } @article {3576, title = {Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.}, journal = {Lancet}, volume = {384}, year = {2014}, month = {2014 Sep 13}, pages = {1005-70}, abstract = {

BACKGROUND: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration.

METHODS: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets.

FINDINGS: Globally in 2013, there were 1{\textperiodcentered}8 million new HIV infections (95\% uncertainty interval 1{\textperiodcentered}7 million to 2{\textperiodcentered}1 million), 29{\textperiodcentered}2 million prevalent HIV cases (28{\textperiodcentered}1 to 31{\textperiodcentered}7), and 1{\textperiodcentered}3 million HIV deaths (1{\textperiodcentered}3 to 1{\textperiodcentered}5). At the peak of the epidemic in 2005, HIV caused 1{\textperiodcentered}7 million deaths (1{\textperiodcentered}6 million to 1{\textperiodcentered}9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19{\textperiodcentered}1 million life-years (16{\textperiodcentered}6 million to 21{\textperiodcentered}5 million) have been saved, 70{\textperiodcentered}3\% (65{\textperiodcentered}4 to 76{\textperiodcentered}1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7{\textperiodcentered}5 million (7{\textperiodcentered}4 million to 7{\textperiodcentered}7 million), prevalence was 11{\textperiodcentered}9 million (11{\textperiodcentered}6 million to 12{\textperiodcentered}2 million), and number of deaths was 1{\textperiodcentered}4 million (1{\textperiodcentered}3 million to 1{\textperiodcentered}5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7{\textperiodcentered}1 million (6{\textperiodcentered}9 million to 7{\textperiodcentered}3 million), prevalence was 11{\textperiodcentered}2 million (10{\textperiodcentered}8 million to 11{\textperiodcentered}6 million), and number of deaths was 1{\textperiodcentered}3 million (1{\textperiodcentered}2 million to 1{\textperiodcentered}4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64{\textperiodcentered}0\% of cases (63{\textperiodcentered}6 to 64{\textperiodcentered}3) and 64{\textperiodcentered}7\% of deaths (60{\textperiodcentered}8 to 70{\textperiodcentered}3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1{\textperiodcentered}2 million deaths (1{\textperiodcentered}1 million to 1{\textperiodcentered}4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31{\textperiodcentered}5\% (15{\textperiodcentered}7 to 44{\textperiodcentered}1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.

INTERPRETATION: Our estimates of the number of people living with HIV are 18{\textperiodcentered}7\% smaller than UNAIDS{\textquoteright}s estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Age Distribution, Epidemics, Female, Global Health, HIV Infections, Humans, Incidence, Malaria, Male, Mortality, Organizational Objectives, Sex Distribution, Tuberculosis}, issn = {1474-547X}, doi = {10.1016/S0140-6736(14)60844-8}, author = {Murray, Christopher J L and Ortblad, Katrina F and Guinovart, Caterina and Lim, Stephen S and Wolock, Timothy M and Roberts, D Allen and Dansereau, Emily A and Graetz, Nicholas and Barber, Ryan M and Brown, Jonathan C and Wang, Haidong and Duber, Herbert C and Naghavi, Mohsen and Dicker, Daniel and Dandona, Lalit and Salomon, Joshua A and Heuton, Kyle R and Foreman, Kyle and Phillips, David E and Fleming, Thomas D and Flaxman, Abraham D and Phillips, Bryan K and Johnson, Elizabeth K and Coggeshall, Megan S and Abd-Allah, Foad and Abera, Semaw Ferede and Abraham, Jerry P and Abubakar, Ibrahim and Abu-Raddad, Laith J and Abu-Rmeileh, Niveen Me and Achoki, Tom and Adeyemo, Austine Olufemi and Adou, Ars{\`e}ne Kouablan and Adsuar, Jos{\'e} C and Agardh, Emilie Elisabet and Akena, Dickens and Al Kahbouri, Mazin J and Alasfoor, Deena and Albittar, Mohammed I and Alcal{\'a}-Cerra, Gabriel and Alegretti, Miguel Angel and Alemu, Zewdie Aderaw and Alfonso-Cristancho, Rafael and Alhabib, Samia and Ali, Raghib and Alla, Fran{\c c}ois and Allen, Peter J and Alsharif, Ubai and Alvarez, Elena and Alvis-Guzm{\'a}n, Nelson and Amankwaa, Adansi A and Amare, Azmeraw T and Amini, Hassan and Ammar, Walid and Anderson, Benjamin O and Antonio, Carl Abelardo T and Anwari, Palwasha and Arnl{\"o}v, Johan and Arsenijevic, Valentina S Arsic and Artaman, Ali and Asghar, Rana J and Assadi, Reza and Atkins, Lydia S and Badawi, Alaa and Balakrishnan, Kalpana and Banerjee, Amitava and Basu, Sanjay and Beardsley, Justin and Bekele, Tolesa and Bell, Michelle L and Bernabe, Eduardo and Beyene, Tariku Jibat and Bhala, Neeraj and Bhalla, Ashish and Bhutta, Zulfiqar A and Abdulhak, Aref Bin and Binagwaho, Agnes and Blore, Jed D and Basara, Berrak Bora and Bose, Dipan and Brainin, Michael and Breitborde, Nicholas and Casta{\~n}eda-Orjuela, Carlos A and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and Chadha, Vineet K and Chang, Jung-Chen and Chiang, Peggy Pei-Chia and Chuang, Ting-Wu and Colomar, Mercedes and Cooper, Leslie Trumbull and Cooper, Cyrus and Courville, Karen J and Cowie, Benjamin C and Criqui, Michael H and Dandona, Rakhi and Dayama, Anand and De Leo, Diego and Degenhardt, Louisa and del Pozo-Cruz, Borja and Deribe, Kebede and Des Jarlais, Don C and Dessalegn, Muluken and Dharmaratne, Samath D and Dilmen, U{\u g}ur and Ding, Eric L and Driscoll, Tim R and Durrani, Adnan M and Ellenbogen, Richard G and Ermakov, Sergey Petrovich and Esteghamati, Alireza and Faraon, Emerito Jose A and Farzadfar, Farshad and Fereshtehnejad, Seyed-Mohammad and Fijabi, Daniel Obadare and Forouzanfar, Mohammad H and Fra Paleo, Urbano and Gaffikin, Lynne and Gamkrelidze, Amiran and Gankp{\'e}, Fortun{\'e} Gb{\`e}toho and Geleijnse, Johanna M and Gessner, Bradford D and Gibney, Katherine B and Ginawi, Ibrahim Abdelmageem Mohamed and Glaser, Elizabeth L and Gona, Philimon and Goto, Atsushi and Gouda, Hebe N and Gugnani, Harish Chander and Gupta, Rajeev and Gupta, Rahul and Hafezi-Nejad, Nima and Hamadeh, Randah Ribhi and Hammami, Mouhanad and Hankey, Graeme J and Harb, Hilda L and Haro, Josep Maria and Havmoeller, Rasmus and Hay, Simon I and Hedayati, Mohammad T and Pi, Ileana B Heredia and Hoek, Hans W and Hornberger, John C and Hosgood, H Dean and Hotez, Peter J and Hoy, Damian G and Huang, John J and Iburg, Kim M and Idrisov, Bulat T and Innos, Kaire and Jacobsen, Kathryn H and Jeemon, Panniyammakal and Jensen, Paul N and Jha, Vivekanand and Jiang, Guohong and Jonas, Jost B and Juel, Knud and Kan, Haidong and Kankindi, Ida and Karam, Nadim E and Karch, Andr{\'e} and Karema, Corine Kakizi and Kaul, Anil and Kawakami, Norito and Kazi, Dhruv S and Kemp, Andrew H and Kengne, Andre Pascal and Keren, Andre and Kereselidze, Maia and Khader, Yousef Saleh and Khalifa, Shams Eldin Ali Hassan and Khan, Ejaz Ahmed and Khang, Young-Ho and Khonelidze, Irma and Kinfu, Yohannes and Kinge, Jonas M and Knibbs, Luke and Kokubo, Yoshihiro and Kosen, S and Defo, Barthelemy Kuate and Kulkarni, Veena S and Kulkarni, Chanda and Kumar, Kaushalendra and Kumar, Ravi B and Kumar, G Anil and Kwan, Gene F and Lai, Taavi and Balaji, Arjun Lakshmana and Lam, Hilton and Lan, Qing and Lansingh, Van C and Larson, Heidi J and Larsson, Anders and Lee, Jong-Tae and Leigh, James and Leinsalu, Mall and Leung, Ricky and Li, Yichong and Li, Yongmei and de Lima, Gra{\c c}a Maria Ferreira and Lin, Hsien-Ho and Lipshultz, Steven E and Liu, Shiwei and Liu, Yang and Lloyd, Belinda K and Lotufo, Paulo A and Machado, Vasco Manuel Pedro and Maclachlan, Jennifer H and Magis-Rodriguez, Carlos and Majdan, Marek and Mapoma, Christopher Chabila and Marcenes, Wagner and Marzan, Melvin Barrientos and Masci, Joseph R and Mashal, Mohammad Taufiq and Mason-Jones, Amanda J and Mayosi, Bongani M and Mazorodze, Tasara T and Mckay, Abigail Cecilia and Meaney, Peter A and Mehndiratta, Man Mohan and Mejia-Rodriguez, Fabiola and Melaku, Yohannes Adama and Memish, Ziad A and Mendoza, Walter and Miller, Ted R and Mills, Edward J and Mohammad, Karzan Abdulmuhsin and Mokdad, Ali H and Mola, Glen Liddell and Monasta, Lorenzo and Montico, Marcella and Moore, Ami R and Mori, Rintaro and Moturi, Wilkister Nyaora and Mukaigawara, Mitsuru and Murthy, Kinnari S and Naheed, Aliya and Naidoo, Kovin S and Naldi, Luigi and Nangia, Vinay and Narayan, K M Venkat and Nash, Denis and Nejjari, Chakib and Nelson, Robert G and Neupane, Sudan Prasad and Newton, Charles R and Ng, Marie and Nisar, Muhammad Imran and Nolte, Sandra and Norheim, Ole F and Nowaseb, Vincent and Nyakarahuka, Luke and Oh, In-Hwan and Ohkubo, Takayoshi and Olusanya, Bolajoko O and Omer, Saad B and Opio, John Nelson and Orisakwe, Orish Ebere and Pandian, Jeyaraj D and Papachristou, Christina and Caicedo, Angel J Paternina and Patten, Scott B and Paul, Vinod K and Pavlin, Boris Igor and Pearce, Neil and Pereira, David M and Pervaiz, Aslam and Pesudovs, Konrad and Petzold, Max and Pourmalek, Farshad and Qato, Dima and Quezada, Amado D and Quistberg, D Alex and Rafay, Anwar and Rahimi, Kazem and Rahimi-Movaghar, Vafa and ur Rahman, Sajjad and Raju, Murugesan and Rana, Saleem M and Razavi, Homie and Reilly, Robert Quentin and Remuzzi, Giuseppe and Richardus, Jan Hendrik and Ronfani, Luca and Roy, Nobhojit and Sabin, Nsanzimana and Saeedi, Mohammad Yahya and Sahraian, Mohammad Ali and Samonte, Genesis May J and Sawhney, Monika and Schneider, Ione J C and Schwebel, David C and Seedat, Soraya and Sepanlou, Sadaf G and Servan-Mori, Edson E and Sheikhbahaei, Sara and Shibuya, Kenji and Shin, Hwashin Hyun and Shiue, Ivy and Shivakoti, Rupak and Sigfusdottir, Inga Dora and Silberberg, Donald H and Silva, Andrea P and Simard, Edgar P and Singh, Jasvinder A and Skirbekk, Vegard and Sliwa, Karen and Soneji, Samir and Soshnikov, Sergey S and Sreeramareddy, Chandrashekhar T and Stathopoulou, Vasiliki Kalliopi and Stroumpoulis, Konstantinos and Swaminathan, Soumya and Sykes, Bryan L and Tabb, Karen M and Talongwa, Roberto Tchio and Tenkorang, Eric Yeboah and Terkawi, Abdullah Sulieman and Thomson, Alan J and Thorne-Lyman, Andrew L and Towbin, Jeffrey A and Traebert, Jefferson and Tran, Bach X and Dimbuene, Zacharie Tsala and Tsilimbaris, Miltiadis and Uchendu, Uche S and Ukwaja, Kingsley N and Uzun, Selen Beg{\"u}m and Vallely, Andrew J and Vasankari, Tommi J and Venketasubramanian, N and Violante, Francesco S and Vlassov, Vasiliy Victorovich and Vollset, Stein Emil and Waller, Stephen and Wallin, Mitchell T and Wang, Linhong and Wang, XiaoRong and Wang, Yanping and Weichenthal, Scott and Weiderpass, Elisabete and Weintraub, Robert G and Westerman, Ronny and White, Richard A and Wilkinson, James D and Williams, Thomas Neil and Woldeyohannes, Solomon Meseret and Wong, John Q and Xu, Gelin and Yang, Yang C and Yano, Yuichiro and Yentur, Gokalp Kadri and Yip, Paul and Yonemoto, Naohiro and Yoon, Seok-Jun and Younis, Mustafa and Yu, Chuanhua and Jin, Kim Yun and El Sayed Zaki, Maysaa and Zhao, Yong and Zheng, Yingfeng and Zhou, Maigeng and Zhu, Jun and Zou, Xiao Nong and Lopez, Alan D and Vos, Theo} } @article {3531, title = {Global, regional, and national levels and causes of maternal mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.}, journal = {Lancet}, volume = {384}, year = {2014}, month = {2014 Sep 13}, pages = {980-1004}, abstract = {

BACKGROUND: The fifth Millennium Development Goal (MDG 5) established the goal of a 75\% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100,000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.

METHODS: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95\% uncertainty intervals (UIs) for all values.

FINDINGS: 292,982 (95\% UI 261,017-327,792) maternal deaths occurred in 2013, compared with 376,034 (343,483-407,574) in 1990. The global annual rate of change in the MMR was -0{\textperiodcentered}3\% (-1{\textperiodcentered}1 to 0{\textperiodcentered}6) from 1990 to 2003, and -2{\textperiodcentered}7\% (-3{\textperiodcentered}9 to -1{\textperiodcentered}5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0{\textperiodcentered}4\% (0{\textperiodcentered}2-0{\textperiodcentered}6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956{\textperiodcentered}8 (685{\textperiodcentered}1-1262{\textperiodcentered}8) in South Sudan to 2{\textperiodcentered}4 (1{\textperiodcentered}6-3{\textperiodcentered}6) in Iceland.

INTERPRETATION: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Age Distribution, Cause of Death, Female, Global Health, HIV Infections, Humans, Maternal Mortality, Models, Statistical, Organizational Objectives, Pregnancy, Pregnancy Complications, Infectious, Risk Factors, Socioeconomic Factors, Time Factors}, issn = {1474-547X}, doi = {10.1016/S0140-6736(14)60696-6}, author = {Kassebaum, Nicholas J and Bertozzi-Villa, Amelia and Coggeshall, Megan S and Shackelford, Katya A and Steiner, Caitlyn and Heuton, Kyle R and Gonzalez-Medina, Diego and Barber, Ryan and Huynh, Chantal and Dicker, Daniel and Templin, Tara and Wolock, Timothy M and Ozgoren, Ayse Abbasoglu and Abd-Allah, Foad and Abera, Semaw Ferede and Abubakar, Ibrahim and Achoki, Tom and Adelekan, Ademola and Ademi, Zanfina and Adou, Ars{\`e}ne Kouablan and Adsuar, Jos{\'e} C and Agardh, Emilie E and Akena, Dickens and Alasfoor, Deena and Alemu, Zewdie Aderaw and Alfonso-Cristancho, Rafael and Alhabib, Samia and Ali, Raghib and Al Kahbouri, Mazin J and Alla, Fran{\c c}ois and Allen, Peter J and AlMazroa, Mohammad A and Alsharif, Ubai and Alvarez, Elena and Alvis-Guzm{\'a}n, Nelson and Amankwaa, Adansi A and Amare, Azmeraw T and Amini, Hassan and Ammar, Walid and Antonio, Carl A T and Anwari, Palwasha and Arnl{\"o}v, Johan and Arsenijevic, Valentina S Arsic and Artaman, Ali and Asad, Majed Masoud and Asghar, Rana J and Assadi, Reza and Atkins, Lydia S and Badawi, Alaa and Balakrishnan, Kalpana and Basu, Arindam and Basu, Sanjay and Beardsley, Justin and Bedi, Neeraj and Bekele, Tolesa and Bell, Michelle L and Bernabe, Eduardo and Beyene, Tariku J and Bhutta, Zulfiqar and Bin Abdulhak, Aref and Blore, Jed D and Basara, Berrak Bora and Bose, Dipan and Breitborde, Nicholas and C{\'a}rdenas, Rosario and Casta{\~n}eda-Orjuela, Carlos A and Castro, Ruben Estanislao and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and Cavlin, Alanur and Chang, Jung-Chen and Che, Xuan and Christophi, Costas A and Chugh, Sumeet S and Cirillo, Massimo and Colquhoun, Samantha M and Cooper, Leslie Trumbull and Cooper, Cyrus and da Costa Leite, Iuri and Dandona, Lalit and Dandona, Rakhi and Davis, Adrian and Dayama, Anand and Degenhardt, Louisa and De Leo, Diego and del Pozo-Cruz, Borja and Deribe, Kebede and Dessalegn, Muluken and deVeber, Gabrielle A and Dharmaratne, Samath D and Dilmen, U{\u g}ur and Ding, Eric L and Dorrington, Rob E and Driscoll, Tim R and Ermakov, Sergei Petrovich and Esteghamati, Alireza and Faraon, Emerito Jose A and Farzadfar, Farshad and Felicio, Manuela Mendonca and Fereshtehnejad, Seyed-Mohammad and de Lima, Gra{\c c}a Maria Ferreira and Forouzanfar, Mohammad H and Fran{\c c}a, Elisabeth B and Gaffikin, Lynne and Gambashidze, Ketevan and Gankp{\'e}, Fortun{\'e} Gb{\`e}toho and Garcia, Ana C and Geleijnse, Johanna M and Gibney, Katherine B and Giroud, Maurice and Glaser, Elizabeth L and Goginashvili, Ketevan and Gona, Philimon and Gonz{\'a}lez-Castell, Dinorah and Goto, Atsushi and Gouda, Hebe N and Gugnani, Harish Chander and Gupta, Rahul and Gupta, Rajeev and Hafezi-Nejad, Nima and Hamadeh, Randah Ribhi and Hammami, Mouhanad and Hankey, Graeme J and Harb, Hilda L and Havmoeller, Rasmus and Hay, Simon I and Pi, Ileana B Heredia and Hoek, Hans W and Hosgood, H Dean and Hoy, Damian G and Husseini, Abdullatif and Idrisov, Bulat T and Innos, Kaire and Inoue, Manami and Jacobsen, Kathryn H and Jahangir, Eiman and Jee, Sun Ha and Jensen, Paul N and Jha, Vivekanand and Jiang, Guohong and Jonas, Jost B and Juel, Knud and Kabagambe, Edmond Kato and Kan, Haidong and Karam, Nadim E and Karch, Andr{\'e} and Karema, Corine Kakizi and Kaul, Anil and Kawakami, Norito and Kazanjan, Konstantin and Kazi, Dhruv S and Kemp, Andrew H and Kengne, Andre Pascal and Kereselidze, Maia and Khader, Yousef Saleh and Khalifa, Shams Eldin Ali Hassan and Khan, Ejaz Ahmed and Khang, Young-Ho and Knibbs, Luke and Kokubo, Yoshihiro and Kosen, Soewarta and Defo, Barthelemy Kuate and Kulkarni, Chanda and Kulkarni, Veena S and Kumar, G Anil and Kumar, Kaushalendra and Kumar, Ravi B and Kwan, Gene and Lai, Taavi and Lalloo, Ratilal and Lam, Hilton and Lansingh, Van C and Larsson, Anders and Lee, Jong-Tae and Leigh, James and Leinsalu, Mall and Leung, Ricky and Li, Xiaohong and Li, Yichong and Li, Yongmei and Liang, Juan and Liang, Xiaofeng and Lim, Stephen S and Lin, Hsien-Ho and Lipshultz, Steven E and Liu, Shiwei and Liu, Yang and Lloyd, Belinda K and London, Stephanie J and Lotufo, Paulo A and Ma, Jixiang and Ma, Stefan and Machado, Vasco Manuel Pedro and Mainoo, Nana Kwaku and Majdan, Marek and Mapoma, Christopher Chabila and Marcenes, Wagner and Marzan, Melvin Barrientos and Mason-Jones, Amanda J and Mehndiratta, Man Mohan and Mejia-Rodriguez, Fabiola and Memish, Ziad A and Mendoza, Walter and Miller, Ted R and Mills, Edward J and Mokdad, Ali H and Mola, Glen Liddell and Monasta, Lorenzo and de la Cruz Monis, Jonathan and Hernandez, Julio Cesar Monta{\~n}ez and Moore, Ami R and Moradi-Lakeh, Maziar and Mori, Rintaro and Mueller, Ulrich O and Mukaigawara, Mitsuru and Naheed, Aliya and Naidoo, Kovin S and Nand, Devina and Nangia, Vinay and Nash, Denis and Nejjari, Chakib and Nelson, Robert G and Neupane, Sudan Prasad and Newton, Charles R and Ng, Marie and Nieuwenhuijsen, Mark J and Nisar, Muhammad Imran and Nolte, Sandra and Norheim, Ole F and Nyakarahuka, Luke and Oh, In-Hwan and Ohkubo, Takayoshi and Olusanya, Bolajoko O and Omer, Saad B and Opio, John Nelson and Orisakwe, Orish Ebere and Pandian, Jeyaraj D and Papachristou, Christina and Park, Jae-Hyun and Caicedo, Angel J Paternina and Patten, Scott B and Paul, Vinod K and Pavlin, Boris Igor and Pearce, Neil and Pereira, David M and Pesudovs, Konrad and Petzold, Max and Poenaru, Dan and Polanczyk, Guilherme V and Polinder, Suzanne and Pope, Dan and Pourmalek, Farshad and Qato, Dima and Quistberg, D Alex and Rafay, Anwar and Rahimi, Kazem and Rahimi-Movaghar, Vafa and ur Rahman, Sajjad and Raju, Murugesan and Rana, Saleem M and Refaat, Amany and Ronfani, Luca and Roy, Nobhojit and Pimienta, Tania Georgina S{\'a}nchez and Sahraian, Mohammad Ali and Salomon, Joshua A and Sampson, Uchechukwu and Santos, Itamar S and Sawhney, Monika and Sayinzoga, Felix and Schneider, Ione J C and Schumacher, Austin and Schwebel, David C and Seedat, Soraya and Sepanlou, Sadaf G and Servan-Mori, Edson E and Shakh-Nazarova, Marina and Sheikhbahaei, Sara and Shibuya, Kenji and Shin, Hwashin Hyun and Shiue, Ivy and Sigfusdottir, Inga Dora and Silberberg, Donald H and Silva, Andrea P and Singh, Jasvinder A and Skirbekk, Vegard and Sliwa, Karen and Soshnikov, Sergey S and Sposato, Luciano A and Sreeramareddy, Chandrashekhar T and Stroumpoulis, Konstantinos and Sturua, Lela and Sykes, Bryan L and Tabb, Karen M and Talongwa, Roberto Tchio and Tan, Feng and Teixeira, Carolina Maria and Tenkorang, Eric Yeboah and Terkawi, Abdullah Sulieman and Thorne-Lyman, Andrew L and Tirschwell, David L and Towbin, Jeffrey A and Tran, Bach X and Tsilimbaris, Miltiadis and Uchendu, Uche S and Ukwaja, Kingsley N and Undurraga, Eduardo A and Uzun, Selen Beg{\"u}m and Vallely, Andrew J and van Gool, Coen H and Vasankari, Tommi J and Vavilala, Monica S and Venketasubramanian, N and Villalpando, Salvador and Violante, Francesco S and Vlassov, Vasiliy Victorovich and Vos, Theo and Waller, Stephen and Wang, Haidong and Wang, Linhong and Wang, XiaoRong and Wang, Yanping and Weichenthal, Scott and Weiderpass, Elisabete and Weintraub, Robert G and Westerman, Ronny and Wilkinson, James D and Woldeyohannes, Solomon Meseret and Wong, John Q and Wordofa, Muluemebet Abera and Xu, Gelin and Yang, Yang C and Yano, Yuichiro and Yentur, Gokalp Kadri and Yip, Paul and Yonemoto, Naohiro and Yoon, Seok-Jun and Younis, Mustafa Z and Yu, Chuanhua and Jin, Kim Yun and El Sayed Zaki, Maysaa and Zhao, Yong and Zheng, Yingfeng and Zhou, Maigeng and Zhu, Jun and Zou, Xiao Nong and Lopez, Alan D and Naghavi, Mohsen and Murray, Christopher J L and Lozano, Rafael} } @article {3532, title = {Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.}, journal = {Lancet}, volume = {384}, year = {2014}, month = {2014 Sep 13}, pages = {957-79}, abstract = {

BACKGROUND: Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success.

METHODS: We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29,000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.

FINDINGS: We estimated that 6{\textperiodcentered}3 million (95\% UI 6{\textperiodcentered}0-6{\textperiodcentered}6) children under-5 died in 2013, a 64\% reduction from 17{\textperiodcentered}6 million (17{\textperiodcentered}1-18{\textperiodcentered}1) in 1970. In 2013, child mortality rates ranged from 152{\textperiodcentered}5 per 1000 livebirths (130{\textperiodcentered}6-177{\textperiodcentered}4) in Guinea-Bissau to 2{\textperiodcentered}3 (1{\textperiodcentered}8-2{\textperiodcentered}9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6{\textperiodcentered}8\% to 0{\textperiodcentered}1\%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41{\textperiodcentered}6\% of under-5 deaths compared with 37{\textperiodcentered}4\% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1{\textperiodcentered}4 million more child deaths, and rising income per person and maternal education led to 0{\textperiodcentered}9 million and 2{\textperiodcentered}2 million fewer deaths, respectively. Changes in secular trends led to 4{\textperiodcentered}2 million fewer deaths. Unexplained factors accounted for only -1\% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.

INTERPRETATION: Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.

FUNDING: Bill \& Melinda Gates Foundation, US Agency for International Development.

}, keywords = {Child Mortality, Child, Preschool, Global Health, Humans, Infant, Infant Mortality, Infant, Newborn, Organizational Objectives, Risk Factors, Socioeconomic Factors}, issn = {1474-547X}, doi = {10.1016/S0140-6736(14)60497-9}, author = {Wang, Haidong and Liddell, Chelsea A and Coates, Matthew M and Mooney, Meghan D and Levitz, Carly E and Schumacher, Austin E and Apfel, Henry and Iannarone, Marissa and Phillips, Bryan and Lofgren, Katherine T and Sandar, Logan and Dorrington, Rob E and Rakovac, Ivo and Jacobs, Troy A and Liang, Xiaofeng and Zhou, Maigeng and Zhu, Jun and Yang, Gonghuan and Wang, Yanping and Liu, Shiwei and Li, Yichong and Ozgoren, Ayse Abbasoglu and Abera, Semaw Ferede and Abubakar, Ibrahim and Achoki, Tom and Adelekan, Ademola and Ademi, Zanfina and Alemu, Zewdie Aderaw and Allen, Peter J and AlMazroa, Mohammad AbdulAziz and Alvarez, Elena and Amankwaa, Adansi A and Amare, Azmeraw T and Ammar, Walid and Anwari, Palwasha and Cunningham, Solveig Argeseanu and Asad, Majed Masoud and Assadi, Reza and Banerjee, Amitava and Basu, Sanjay and Bedi, Neeraj and Bekele, Tolesa and Bell, Michelle L and Bhutta, Zulfiqar and Blore, Jed D and Basara, Berrak Bora and Boufous, Soufiane and Breitborde, Nicholas and Bruce, Nigel G and Bui, Linh Ngoc and Carapetis, Jonathan R and C{\'a}rdenas, Rosario and Carpenter, David O and Caso, Valeria and Castro, Ruben Estanislao and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and Cavlin, Alanur and Che, Xuan and Chiang, Peggy Pei-Chia and Chowdhury, Rajiv and Christophi, Costas A and Chuang, Ting-Wu and Cirillo, Massimo and da Costa Leite, Iuri and Courville, Karen J and Dandona, Lalit and Dandona, Rakhi and Davis, Adrian and Dayama, Anand and Deribe, Kebede and Dharmaratne, Samath D and Dherani, Mukesh K and Dilmen, U{\u g}ur and Ding, Eric L and Edmond, Karen M and Ermakov, Sergei Petrovich and Farzadfar, Farshad and Fereshtehnejad, Seyed-Mohammad and Fijabi, Daniel Obadare and Foigt, Nataliya and Forouzanfar, Mohammad H and Garcia, Ana C and Geleijnse, Johanna M and Gessner, Bradford D and Goginashvili, Ketevan and Gona, Philimon and Goto, Atsushi and Gouda, Hebe N and Green, Mark A and Greenwell, Karen Fern and Gugnani, Harish Chander and Gupta, Rahul and Hamadeh, Randah Ribhi and Hammami, Mouhanad and Harb, Hilda L and Hay, Simon and Hedayati, Mohammad T and Hosgood, H Dean and Hoy, Damian G and Idrisov, Bulat T and Islami, Farhad and Ismayilova, Samaya and Jha, Vivekanand and Jiang, Guohong and Jonas, Jost B and Juel, Knud and Kabagambe, Edmond Kato and Kazi, Dhruv S and Kengne, Andre Pascal and Kereselidze, Maia and Khader, Yousef Saleh and Khalifa, Shams Eldin Ali Hassan and Khang, Young-Ho and Kim, Daniel and Kinfu, Yohannes and Kinge, Jonas M and Kokubo, Yoshihiro and Kosen, Soewarta and Defo, Barthelemy Kuate and Kumar, G Anil and Kumar, Kaushalendra and Kumar, Ravi B and Lai, Taavi and Lan, Qing and Larsson, Anders and Lee, Jong-Tae and Leinsalu, Mall and Lim, Stephen S and Lipshultz, Steven E and Logroscino, Giancarlo and Lotufo, Paulo A and Lunevicius, Raimundas and Lyons, Ronan Anthony and Ma, Stefan and Mahdi, Abbas Ali and Marzan, Melvin Barrientos and Mashal, Mohammad Taufiq and Mazorodze, Tasara T and McGrath, John J and Memish, Ziad A and Mendoza, Walter and Mensah, George A and Meretoja, Atte and Miller, Ted R and Mills, Edward J and Mohammad, Karzan Abdulmuhsin and Mokdad, Ali H and Monasta, Lorenzo and Montico, Marcella and Moore, Ami R and Moschandreas, Joanna and Msemburi, William T and Mueller, Ulrich O and Muszynska, Magdalena M and Naghavi, Mohsen and Naidoo, Kovin S and Narayan, K M Venkat and Nejjari, Chakib and Ng, Marie and de Dieu Ngirabega, Jean and Nieuwenhuijsen, Mark J and Nyakarahuka, Luke and Ohkubo, Takayoshi and Omer, Saad B and Caicedo, Angel J Paternina and Pillay-van Wyk, Victoria and Pope, Dan and Pourmalek, Farshad and Prabhakaran, Dorairaj and Rahman, Sajjad U R and Rana, Saleem M and Reilly, Robert Quentin and Rojas-Rueda, David and Ronfani, Luca and Rushton, Lesley and Saeedi, Mohammad Yahya and Salomon, Joshua A and Sampson, Uchechukwu and Santos, Itamar S and Sawhney, Monika and Schmidt, J{\"u}rgen C and Shakh-Nazarova, Marina and She, Jun and Sheikhbahaei, Sara and Shibuya, Kenji and Shin, Hwashin Hyun and Shishani, Kawkab and Shiue, Ivy and Sigfusdottir, Inga Dora and Singh, Jasvinder A and Skirbekk, Vegard and Sliwa, Karen and Soshnikov, Sergey S and Sposato, Luciano A and Stathopoulou, Vasiliki Kalliopi and Stroumpoulis, Konstantinos and Tabb, Karen M and Talongwa, Roberto Tchio and Teixeira, Carolina Maria and Terkawi, Abdullah Sulieman and Thomson, Alan J and Thorne-Lyman, Andrew L and Toyoshima, Hideaki and Dimbuene, Zacharie Tsala and Uwaliraye, Parfait and Uzun, Selen Beg{\"u}m and Vasankari, Tommi J and Vasconcelos, Ana Maria Nogales and Vlassov, Vasiliy Victorovich and Vollset, Stein Emil and Waller, Stephen and Wan, Xia and Weichenthal, Scott and Weiderpass, Elisabete and Weintraub, Robert G and Westerman, Ronny and Wilkinson, James D and Williams, Hywel C and Yang, Yang C and Yentur, Gokalp Kadri and Yip, Paul and Yonemoto, Naohiro and Younis, Mustafa and Yu, Chuanhua and Jin, Kim Yun and El Sayed Zaki, Maysaa and Zhu, Shankuan and Vos, Theo and Lopez, Alan D and Murray, Christopher J L} } @article {3558, title = {Hematopoietic stem cell transplantation effects on spinal cord compression in Hurler.}, journal = {Pediatr Transplant}, volume = {18}, year = {2014}, month = {2014 May}, pages = {E96-9}, abstract = {

Hurler syndrome type 1 (MPS-1) is an autosomal recessive lysosomal disorder due to the deficiency of the enzyme alpha-L-iduronidase which is necessary for the degradation of dermatan and heparan sulfate. It is characterized by deposit of glycosaminoglycans in tissues, progressive multisystem dysfunction, and early death. HSCT for children with MPS-I is effective, resulting in increased life expectancy and improvement of clinical parameters. The spinal MRI performed on a female 10 yr old undergoing HSCT at the age of 18 months and receiving ERT revealed a considerable decrease in soft tissue around the tip of odontoid causing a significant reduction in spinal cord compression. In light of this result, we suppose that combined ERT and HSCT are successful in Hurler I disease.

}, keywords = {Bone Marrow Transplantation, Child, Enzyme Replacement Therapy, Female, Glycosaminoglycans, Hematopoietic Stem Cell Transplantation, Humans, Iduronidase, Magnetic Resonance Imaging, Mucopolysaccharidosis I, Odontoid Process, Spinal Cord Compression, Treatment Outcome}, issn = {1399-3046}, doi = {10.1111/petr.12231}, author = {Ferrara, Giovanna and Maximova, Natalia and Zennaro, Floriana and Gregori, Massimo and Tamaro, Paolo} } @article {3567, title = {HLA-G gene polymorphisms associated with susceptibility to rheumatoid arthritis disease and its severity in Brazilian patients.}, journal = {Tissue Antigens}, volume = {84}, year = {2014}, month = {2014 Sep}, pages = {308-15}, abstract = {

We analyzed the possible association between human leukocyte antigen-G (HLA-G) genetic variants, supposed to regulate HLA-G expression, and the susceptibility to develop rheumatoid arthritis (RA) as well as its clinical manifestations. The 5{\textquoteright}upstream regulatory region (5{\textquoteright}URR) and 3{\textquoteright}untranslated region (3{\textquoteright}UTR) regions of the HLA-G gene were screened in 127 RA patients and 128 controls: 10 5{\textquoteright}URR and 3 3{\textquoteright}UTR HLA-G polymorphisms as well as two haplotypes were associated with risk for RA development, while a polymorphism in the 5{\textquoteright}URR showed an association with the degree of disease activity. These findings, although the number of cases analyzed is limited and the P-values are modest, indicate a possible association between HLA-G gene polymorphisms and susceptibility to develop RA disease and its severity.

}, keywords = {3{\textquoteright} Untranslated Regions, 5{\textquoteright} Flanking Region, Aged, Arthritis, Rheumatoid, Brazil, Disease Progression, DNA Mutational Analysis, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, HLA-G Antigens, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk}, issn = {1399-0039}, doi = {10.1111/tan.12396}, author = {Catamo, E and Addobbati, C and Segat, L and Sotero Fragoso, T and Domingues Barbosa, A and Tavares Dantas, A and de Ata{\'\i}de Mariz, H and F da Rocha, L and Branco Pinto Duarte, A L and Monasta, L and Sandrin-Garcia, P and Crovella, S} } @article {3540, title = {In vitro endothelial cell proliferation assay reveals distinct levels of proangiogenic cytokines characterizing sera of healthy subjects and of patients with heart failure.}, journal = {Mediators Inflamm}, volume = {2014}, year = {2014}, month = {2014}, pages = {257081}, abstract = {

Although myocardial angiogenesis is thought to play an important role in heart failure (HF), the involvement of circulating proinflammatory and proangiogenic cytokines in the pathogenesis and/or prognosis of HF has not been deeply investigated. By using a highly standardized proliferation assay with human endothelial cells, we first demonstrated that sera from older (mean age 52 {\textpm} 7.6 years; n = 46) healthy donors promoted endothelial cell proliferation to a significantly higher extent compared to sera obtained from younger healthy donors (mean age 29 {\textpm} 8.6 years; n = 20). The promotion of endothelial cell proliferation was accompanied by high serum levels of several proangiogenic cytokines. When we assessed endothelial cell proliferation in response to HF patients{\textquoteright} sera, we observed that a subset of sera (n = 11) promoted cell proliferation to a significantly lesser extent compared to the majority of sera (n = 18). Also, in this case, the difference between the patient groups in the ability to induce endothelial cell proliferation correlated to significant (P < 0.05) differences in serum proangiogenic cytokine levels. Unexpectedly, HF patients associated to the highest endothelial proliferation index showed the worst prognosis as evaluated in terms of subsequent cardiovascular events in the follow-up, suggesting that high levels of circulating proangiogenic cytokines might be related to a worse prognosis.

}, keywords = {Adult, Cell Proliferation, Cells, Cultured, Chemokines, Cytokines, Heart Failure, Human Umbilical Vein Endothelial Cells, Humans, Middle Aged, Neovascularization, Pathologic, Prognosis}, issn = {1466-1861}, doi = {10.1155/2014/257081}, author = {Voltan, Rebecca and Zauli, Giorgio and Rizzo, Paola and Fucili, Alessandro and Pannella, Micaela and Marci, Roberto and Tisato, Veronica and Ferrari, Roberto and Secchiero, Paola} } @article {3503, title = {In vivo detection of polyomaviruses JCV and SV40 in mesenchymal stem cells from human umbilical cords.}, journal = {Pediatr Blood Cancer}, volume = {61}, year = {2014}, month = {2014 Aug}, pages = {1347-9}, abstract = {

BACKGROUND: Multipotent stromal cells are present in the Wharton{\textquoteright}s jelly matrix (WJSC) of the umbilical cord and can be used as an allogeneic source of cells to treat immunological disorders. Recently it was demonstrated that adult bone marrow (BM)-derived mesenchimal stromal cells (MSC) are susceptible to infection with viruses showing potential oncogenic properties, such as the polyomavirus JC (JCV). The aim of this study was to investigate the presence of human polyomaviruses (JCV, BK Virus-BKV, SV40, and Merkel cell polyomavirus-MCPyV) in WJSC, and explore the risk of infection.

PROCEDURE: MSC samples from 35 umbilical cords were investigated by quantitative Real Time PCRs for the presence of DNA sequences of JCV, BKV, SV40, and MCPyV.

RESULTS: JCV DNA was detected in 1/35 (2.8\%) of MSC samples, while SV40 DNA was found in 3/35 (8.6\%) of the examined samples. None of the samples showed sequences of BKV and MCPyV.

CONCLUSIONS: The present study demonstrates the in vivo ability of polyomaviruses to infect WJSC. Since the therapeutic approach with the WJSC has high potentiality and a more intensive use can be easily hypothesized, the need to develop consensus guidelines to detect rare viral infections in MSC is pressing.

}, keywords = {DNA, Viral, Female, Fetal Blood, Humans, JC Virus, Male, Mesenchymal Stromal Cells, Polyomavirus Infections, Simian virus 40, Tumor Virus Infections}, issn = {1545-5017}, doi = {10.1002/pbc.24943}, author = {Comar, Manola and Delbue, Serena and Zanotta, Nunzia and Valencic, Erica and Piscianz, Elisa and Del Savio, Rossella and Tesser, Alessandra and Tommasini, Alberto and Ferrante, Pasquale} } @article {3613, title = {Long-term follow-up in children with benign convulsions associated with gastroenteritis.}, journal = {Eur J Paediatr Neurol}, volume = {18}, year = {2014}, month = {2014 Sep}, pages = {572-7}, abstract = {

BACKGROUND: The outcome of benign convulsions associated with gastroenteritis (CwG) has generally been reported as being excellent. However, these data need to be confirmed in studies with longer follow-up evaluations.

AIM: To assess the long-term neurological outcome of a large sample of children presenting with CwG.

METHODS: We reviewed clinical features of 81 subjects presenting with CwG (1994-2010) from three different Italian centers with a follow-up period of at least 3 years.

RESULTS: Follow-up period ranged from 39 months to 15 years (mean 9.8 years). Neurological examination and cognitive level at the last evaluation were normal in all the patients. A mild attention deficit was detected in three cases (3.7\%). Fourteen children (17.3\%) received chronic anti-epileptic therapy. Interictal EEG abnormalities detected at onset in 20 patients (24.7\%) reverted to normal. Transient EEG epileptiform abnormalities were detected in other three cases (3.7\%), and a transient photosensitivity in one (1.2\%). No recurrence of CwG was observed. Three patients (3.7\%) presented with a febrile seizure and two (2.5\%) with an unprovoked seizure, but none developed epilepsy.

CONCLUSIONS: The long-term evaluation of children with CwG confirms the excellent prognosis of this condition, with normal psychomotor development and low risk of relapse and of subsequent epilepsy.

}, keywords = {Adolescent, Anticonvulsants, Attention Deficit Disorder with Hyperactivity, Child, Child, Preschool, Electroencephalography, Epilepsy, Female, Gastroenteritis, Humans, Longitudinal Studies, Male, Neurologic Examination, Retrospective Studies}, issn = {1532-2130}, doi = {10.1016/j.ejpn.2014.04.006}, author = {Verrotti, Alberto and Moavero, Romina and Vigevano, Federico and Cantonetti, Laura and Guerra, Azzurra and Spezia, Elisabetta and Tricarico, Antonella and Nanni, Giuliana and Agostinelli, Sergio and Chiarelli, Francesco and Parisi, Pasquale and Capovilla, Giuseppe and Beccaria, Francesca and Spalice, Alberto and Coppola, Giangennaro and Franzoni, Emilio and Gentile, Valentina and Casellato, Susanna and Veggiotti, Pierangelo and Malgesini, Sara and Crichiutti, Giovanni and Balestri, Paolo and Grosso, Salvatore and Zamponi, Nelia and Incorpora, Gemma and Savasta, Salvatore and Costa, Paola and Pruna, Dario and Cusmai, Raffaella} } @article {3549, title = {Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology.}, journal = {Haematologica}, volume = {99}, year = {2014}, month = {2014 Jun}, pages = {1022-31}, abstract = {

Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26\% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes.

}, keywords = {Amino Acid Substitution, Cell Line, Cohort Studies, Computational Biology, Databases, Nucleic Acid, Fanconi Anemia, Fanconi Anemia Complementation Group Proteins, Founder Effect, Genotype, Humans, Italy, Mosaicism, Mutation, Polymorphism, Single Nucleotide}, issn = {1592-8721}, doi = {10.3324/haematol.2014.104224}, author = {De Rocco, Daniela and Bottega, Roberta and Cappelli, Enrico and Cavani, Simona and Criscuolo, Maria and Nicchia, Elena and Corsolini, Fabio and Greco, Chiara and Borriello, Adriana and Svahn, Johanna and Pillon, Marta and Mecucci, Cristina and Casazza, Gabriella and Verzegnassi, Federico and Cugno, Chiara and Locasciulli, Anna and Farruggia, Piero and Longoni, Daniela and Ramenghi, Ugo and Barberi, Walter and Tucci, Fabio and Perrotta, Silverio and Grammatico, Paola and Hanenberg, Helmut and Della Ragione, Fulvio and Dufour, Carlo and Savoia, Anna} } @article {3635, title = {MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Feb}, pages = {236-47}, abstract = {

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD is characterized by a considerable variability in clinical evolution: patients present at birth with only thrombocytopenia, but some of them subsequently develop sensorineural deafness, cataract, and/or nephropathy often leading to end-stage renal disease (ESRD). We searched for genotype-phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far (255 cases from 121 families). Association of genotypes with noncongenital features was assessed by a generalized linear regression model. The analysis defined disease evolution associated to seven different MYH9 genotypes that are responsible for 85\% of MYH9-RD cases. Mutations hitting residue R702 demonstrated a complete penetrance for early-onset ESRD and deafness. The p.D1424H substitution associated with high risk of developing all the noncongenital manifestations of disease. Mutations hitting a distinct hydrophobic seam in the NMMHC-IIA head domain or substitutions at R1165 associated with high risk of deafness but low risk of nephropathy or cataract. Patients with p.E1841K, p.D1424N, and C-terminal deletions had low risk of noncongenital defects. These findings are essential to patients{\textquoteright} clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD.

}, keywords = {Adult, Age of Onset, Amino Acid Substitution, Cataract, Female, Genetic Association Studies, Genotype, Hearing Loss, Sensorineural, Humans, Italy, Linear Models, Male, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Phenotype, Risk Factors, Thrombocytopenia}, issn = {1098-1004}, doi = {10.1002/humu.22476}, author = {Pecci, Alessandro and Klersy, Catherine and Gresele, Paolo and Lee, Kieran J D and De Rocco, Daniela and Bozzi, Valeria and Russo, Giovanna and Heller, Paula G and Loffredo, Giuseppe and Ballmaier, Matthias and Fabris, Fabrizio and Beggiato, Eloise and Kahr, Walter H A and Pujol-Moix, N{\'u}ria and Platokouki, Helen and Van Geet, Christel and Noris, Patrizia and Yerram, Preethi and Hermans, Cedric and Gerber, Bernhard and Economou, Marina and De Groot, Marco and Zieger, Barbara and De Candia, Erica and Fraticelli, Vincenzo and Kersseboom, Rogier and Piccoli, Giorgina B and Zimmermann, Stefanie and Fierro, Tiziana and Glembotsky, Ana C and Vianello, Fabrizio and Zaninetti, Carlo and Nicchia, Elena and G{\"u}thner, Christiane and Baronci, Carlo and Seri, Marco and Knight, Peter J and Balduini, Carlo L and Savoia, Anna} } @article {3535, title = {A neonate with a {\textquoteright}milky{\textquoteright} blood. What can it be?}, journal = {Arch Dis Child Fetal Neonatal Ed}, volume = {99}, year = {2014}, month = {2014 Nov}, pages = {F514}, keywords = {Female, Humans, Hyperlipoproteinemia Type IV, Infant, Newborn, Lipoprotein Lipase, Milk Proteins, Mutation}, issn = {1468-2052}, doi = {10.1136/archdischild-2014-305940}, author = {Bordugo, Andrea and Carlin, Eva and Demarini, Sergio and Faletra, Flavio and Colonna, Franco} } @article {3499, title = {Next generation sequencing in nonsyndromic intellectual disability: from a negative molecular karyotype to a possible causative mutation detection.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Jan}, pages = {170-6}, abstract = {

The identification of causes underlying intellectual disability (ID) is one of the most demanding challenges for clinical Geneticists and Researchers. Despite molecular diagnostics improvements, the vast majority of patients still remain without genetic diagnosis. Here, we report the results obtained using Whole Exome and Target Sequencing on nine patients affected by isolated ID without pathological copy number variations, which were accurately selected from an initial cohort of 236 patients. Three patterns of inheritance were used to search for: (1) de novo, (2) X-linked, and (3) autosomal recessive variants. In three of the nine proband-parent trios analyzed, we identified and validated two de novo and one X-linked potentially causative mutations located in three ID-related genes. We proposed three genes as ID candidate, carrying one de novo and three X-linked mutations. Overall, this systematic proband-parent trio approach using next generation sequencing could explain a consistent percentage of patients with isolated ID, thus increasing our knowledge on the molecular bases of this disease and opening new perspectives for a better diagnosis, counseling, and treatment.

}, keywords = {Computational Biology, Exome, Female, Genes, Recessive, Genes, X-Linked, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, Intellectual Disability, Karyotype, Male, Mutation, Workflow}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36274}, author = {Athanasakis, Emmanouil and Licastro, Danilo and Faletra, Flavio and Fabretto, Antonella and Dipresa, Savina and Vozzi, Diego and Morgan, Anna and d{\textquoteright}Adamo, Adamo P and Pecile, Vanna and Biarn{\'e}s, Xevi and Gasparini, Paolo} } @article {3529, title = {A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta.}, journal = {Gene}, volume = {545}, year = {2014}, month = {2014 Jul 25}, pages = {290-2}, abstract = {

Osteogenesis imperfecta (OI) is a hereditary bone disease characterized by decreased bone density and multiple fractures, usually inherited in an autosomal dominant manner. Several gene encoding proteins related to collagen metabolism have been described in some cases of autosomal recessive OI (including CRTAP, LEPRE1, PPIB, FKBP65, SERPINF1, BMP1, WNT1, FKBP10). Recently, TMEM38B, a gene that encodes TRIC-B, a monovalent cation-specific channel involved in calcium flux from intracellular stores and in cell differentiation, has been associated with autosomal recessive OI. Here, we describe the second deletion-mutation involving the TMEM38B gene in an 11 year-old Albanian female with a clinical phenotype of OI, born to parents with suspected consanguinity. SNP array analysis revealed a homozygous region larger than 2 Mb that overlapped with the TMEM38B locus and was characterized by a 35 kb homozygous deletion involving exons 1 and 2 of TMEM38B gene.

}, keywords = {Child, Chromosomes, Human, Pair 19, DNA Mutational Analysis, Exons, Female, Genes, Recessive, Homozygote, Humans, Ion Channels, Osteogenesis Imperfecta, Sequence Deletion}, issn = {1879-0038}, doi = {10.1016/j.gene.2014.05.028}, author = {Rubinato, Elisa and Morgan, Anna and D{\textquoteright}Eustacchio, Angela and Pecile, Vanna and Gortani, Giulia and Gasparini, Paolo and Faletra, Flavio} } @article {3477, title = {A novel P2RX2 mutation in an Italian family affected by autosomal dominant nonsyndromic hearing loss.}, journal = {Gene}, volume = {534}, year = {2014}, month = {2014 Jan 25}, pages = {236-9}, abstract = {

Hereditary hearing loss (HHL) is a common disorder accounting for at least 60\% of prelingual deafness. It is characterized by a large genetic heterogeneity, and despite the presence of a major gene, still there is a need to search for new causative mutations/genes. Very recently, a mutation within ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) gene (P2RX2) at DNFA41 locus has been reported leading to a bilateral and symmetrical sensorineural non-syndromic autosomal dominant HHL in two Chinese families. We performed a linkage analysis in a large Italian family with a dominant pattern of inheritance showing a significant 3.31 LOD score in a 2Mb region overlapping with the DNFA41 locus. Molecular analyses of P2RX2 identified a novel missense mutation (p.Gly353Arg) affecting a residue highly conserved across species. Visual inspection of the protein structure as obtained from comparative modeling suggests that substitution of the small glycine residue with a charged bulky residue such as an arginine that is close to the {\textquoteright}neck{\textquoteright} of the region responsible for ion channel gating should have a high energetic cost and should lead to a severely destabilization of the fold. The identification of a second most likely causative mutation in P2RX2 gene further supports the possible role of this gene in causing autosomal dominant HHL.

}, keywords = {Amino Acid Sequence, Deafness, European Continental Ancestry Group, Female, Genotype, Hearing Loss, Sensorineural, Humans, Italy, Male, Molecular Sequence Data, Mutation, Missense, Pedigree, Receptors, Purinergic P2X2}, issn = {1879-0038}, doi = {10.1016/j.gene.2013.10.052}, author = {Faletra, Flavio and Girotto, Giorgia and d{\textquoteright}Adamo, Adamo Pio and Vozzi, Diego and Morgan, Anna and Gasparini, Paolo} } @article {3579, title = {Osteoprotegerin increases in metabolic syndrome and promotes adipose tissue proinflammatory changes.}, journal = {Mol Cell Endocrinol}, volume = {394}, year = {2014}, month = {2014 Aug 25}, pages = {13-20}, abstract = {

BACKGROUND: Inflammation is believed to link obesity to insulin resistance, as in the setting of metabolic syndrome (MetS). Osteoprotegerin (OPG) is a soluble protein that seems to exert proatherogenic and prodiabetogenic effects. This study aims at determining OPG levels in MetS and whether OPG might contribute to MetS development and progression.

METHODOLOGY/PRINCIPAL FINDINGS: Circulating OPG was measured in 46 patients with MetS and 63 controls, and was found significantly elevated in those with MetS. In addition, circulating and tissue OPG was significantly increased in high-fat diet (HFD) fed C57BL6 mice, which is one of the animal models for the study of MetS. To evaluate the consequences of OPG elevation, we delivered this protein to C57BL6 mice, finding that it promoted systemic and adipose tissue proinflammatory changes in association with metabolic abnormalities.

CONCLUSIONS/SIGNIFICANCE: These data suggest that OPG may trigger adipose tissue proinflammatory changes in MetS/HFD-induced obesity.

}, keywords = {Adipose Tissue, Adult, Animals, Blood Glucose, Body Mass Index, C-Reactive Protein, Case-Control Studies, Cholesterol, HDL, Cholesterol, LDL, Diet, High-Fat, Female, Humans, Inflammation, Insulin, Insulin Resistance, Male, Metabolic Syndrome X, Mice, Mice, Inbred C57BL, Middle Aged, Obesity, Osteoprotegerin, Triglycerides}, issn = {1872-8057}, doi = {10.1016/j.mce.2014.06.004}, author = {Bernardi, Stella and Fabris, Bruno and Thomas, Merlin and Toffoli, Barbara and Tikellis, Christos and Candido, Riccardo and Catena, Cristiana and Mulatero, Paolo and Barbone, Fabio and Radillo, Oriano and Zauli, Giorgio and Secchiero, Paola} } @article {3593, title = {Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.}, journal = {Nature}, volume = {514}, year = {2014}, month = {2014 Oct 2}, pages = {92-7}, abstract = {

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 {\texttimes} 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

}, keywords = {Adolescent, Age Factors, Alleles, Body Mass Index, Breast Neoplasms, Cardiovascular Diseases, Child, Diabetes Mellitus, Type 2, Europe, Female, Genetic Loci, Genome-Wide Association Study, Genomic Imprinting, Humans, Hypothalamo-Hypophyseal System, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Obesity, Ovary, Parents, Polymorphism, Single Nucleotide, Potassium Channels, Tandem Pore Domain, Proteins, Quantitative Trait Loci, Receptors, GABA-B, Receptors, Retinoic Acid, Ribonucleoproteins}, issn = {1476-4687}, doi = {10.1038/nature13545}, author = {Perry, John R B and Day, Felix and Elks, Cathy E and Sulem, Patrick and Thompson, Deborah J and Ferreira, Teresa and He, Chunyan and Chasman, Daniel I and Esko, T{\~o}nu and Thorleifsson, Gudmar and Albrecht, Eva and Ang, Wei Q and Corre, Tanguy and Cousminer, Diana L and Feenstra, Bjarke and Franceschini, Nora and Ganna, Andrea and Johnson, Andrew D and Kjellqvist, Sanela and Lunetta, Kathryn L and McMahon, George and Nolte, Ilja M and Paternoster, Lavinia and Porcu, Eleonora and Smith, Albert V and Stolk, Lisette and Teumer, Alexander and T{\v s}ernikova, Natalia and Tikkanen, Emmi and Ulivi, Sheila and Wagner, Erin K and Amin, Najaf and Bierut, Laura J and Byrne, Enda M and Hottenga, Jouke-Jan and Koller, Daniel L and Mangino, Massimo and Pers, Tune H and Yerges-Armstrong, Laura M and Hua Zhao, Jing and Andrulis, Irene L and Anton-Culver, Hoda and Atsma, Femke and Bandinelli, Stefania and Beckmann, Matthias W and Benitez, Javier and Blomqvist, Carl and Bojesen, Stig E and Bolla, Manjeet K and Bonanni, Bernardo and Brauch, Hiltrud and Brenner, Hermann and Buring, Julie E and Chang-Claude, Jenny and Chanock, Stephen and Chen, Jinhui and Chenevix-Trench, Georgia and Coll{\'e}e, J Margriet and Couch, Fergus J and Couper, David and Coviello, Andrea D and Cox, Angela and Czene, Kamila and d{\textquoteright}Adamo, Adamo Pio and Davey Smith, George and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Devilee, Peter and Dieffenbach, Aida K and Dunning, Alison M and Eiriksdottir, Gudny and Eriksson, Johan G and Fasching, Peter A and Ferrucci, Luigi and Flesch-Janys, Dieter and Flyger, Henrik and Foroud, Tatiana and Franke, Lude and Garcia, Melissa E and Garc{\'\i}a-Closas, Montserrat and Geller, Frank and de Geus, Eco E J and Giles, Graham G and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Guenel, Pascal and Guo, Suiqun and Hall, Per and Hamann, Ute and Haring, Robin and Hartman, Catharina A and Heath, Andrew C and Hofman, Albert and Hooning, Maartje J and Hopper, John L and Hu, Frank B and Hunter, David J and Karasik, David and Kiel, Douglas P and Knight, Julia A and Kosma, Veli-Matti and Kutalik, Zolt{\'a}n and Lai, Sandra and Lambrechts, Diether and Lindblom, Annika and M{\"a}gi, Reedik and Magnusson, Patrik K and Mannermaa, Arto and Martin, Nicholas G and Masson, Gisli and McArdle, Patrick F and McArdle, Wendy L and Melbye, Mads and Michailidou, Kyriaki and Mihailov, Evelin and Milani, Lili and Milne, Roger L and Nevanlinna, Heli and Neven, Patrick and Nohr, Ellen A and Oldehinkel, Albertine J and Oostra, Ben A and Palotie, Aarno and Peacock, Munro and Pedersen, Nancy L and Peterlongo, Paolo and Peto, Julian and Pharoah, Paul D P and Postma, Dirkje S and Pouta, Anneli and Pylk{\"a}s, Katri and Radice, Paolo and Ring, Susan and Rivadeneira, Fernando and Robino, Antonietta and Rose, Lynda M and Rudolph, Anja and Salomaa, Veikko and Sanna, Serena and Schlessinger, David and Schmidt, Marjanka K and Southey, Mellissa C and Sovio, Ulla and Stampfer, Meir J and St{\"o}ckl, Doris and Storniolo, Anna M and Timpson, Nicholas J and Tyrer, Jonathan and Visser, Jenny A and Vollenweider, Peter and V{\"o}lzke, Henry and Waeber, Gerard and Waldenberger, Melanie and Wallaschofski, Henri and Wang, Qin and Willemsen, Gonneke and Winqvist, Robert and Wolffenbuttel, Bruce H R and Wright, Margaret J and Boomsma, Dorret I and Econs, Michael J and Khaw, Kay-Tee and Loos, Ruth J F and McCarthy, Mark I and Montgomery, Grant W and Rice, John P and Streeten, Elizabeth A and Thorsteinsdottir, Unnur and van Duijn, Cornelia M and Alizadeh, Behrooz Z and Bergmann, Sven and Boerwinkle, Eric and Boyd, Heather A and Crisponi, Laura and Gasparini, Paolo and Gieger, Christian and Harris, Tamara B and Ingelsson, Erik and J{\"a}rvelin, Marjo-Riitta and Kraft, Peter and Lawlor, Debbie and Metspalu, Andres and Pennell, Craig E and Ridker, Paul M and Snieder, Harold and S{\o}rensen, Thorkild I A and Spector, Tim D and Strachan, David P and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Widen, Elisabeth and Zygmunt, Marek and Murray, Anna and Easton, Douglas F and Stefansson, Kari and Murabito, Joanne M and Ong, Ken K} } @article {3516, title = {Pharmacogenetics of azathioprine in inflammatory bowel disease: a role for glutathione-S-transferase?}, journal = {World J Gastroenterol}, volume = {20}, year = {2014}, month = {2014 Apr 7}, pages = {3534-41}, abstract = {

Azathioprine is a purine antimetabolite drug commonly used to treat inflammatory bowel disease (IBD). In vivo it is active after reaction with reduced glutathione (GSH) and conversion to mercaptopurine. Although this reaction may occur spontaneously, the presence of isoforms M and A of the enzyme glutathione-S-transferase (GST) may increase its speed. Indeed, in pediatric patients with IBD, deletion of GST-M1, which determines reduced enzymatic activity, was recently associated with reduced sensitivity to azathioprine and reduced production of azathioprine active metabolites. In addition to increase the activation of azathioprine to mercaptopurine, GSTs may contribute to azathioprine effects even by modulating GSH consumption, oxidative stress and apoptosis. Therefore, genetic polymorphisms in genes for GSTs may be useful to predict response to azathioprine even if more in vitro and clinical validation studies are needed.

}, keywords = {6-Mercaptopurine, Animals, Apoptosis, Azathioprine, Glutathione, Glutathione Transferase, Humans, Immunosuppressive Agents, Inflammatory Bowel Diseases, Oxidative Stress, Pharmacogenetics, Polymorphism, Genetic}, issn = {2219-2840}, doi = {10.3748/wjg.v20.i13.3534}, author = {Stocco, Gabriele and Pelin, Marco and Franca, Raffaella and De Iudicibus, Sara and Cuzzoni, Eva and Favretto, Diego and Martelossi, Stefano and Ventura, Alessandro and Decorti, Giuliana} } @article {3548, title = {Piccolipi{\`u}, a multicenter birth cohort in Italy: protocol of the study.}, journal = {BMC Pediatr}, volume = {14}, year = {2014}, month = {2014}, pages = {36}, abstract = {

BACKGROUND: The fetal and infant life are periods of rapid development, characterized by high susceptibility to exposures. Birth cohorts provide unique opportunities to study early-life exposures in association with child development and health, as well as, with longer follow-up, the early life origin of adult diseases. Piccolipi{\`u} is an Italian birth cohort recently set up to investigate the effects of environmental exposures, parental conditions and social factors acting during pre-natal and early post-natal life on infant and child health and development. We describe here its main characteristics.

METHODS/DESIGN: Piccolipi{\`u} is a prospective cohort of expected 3000 newborns, who will be recruiting in six maternity units of five Italian cities (Florence, Rome, Trieste, Turin and Viareggio) since October 2011. Mothers are contacted during pregnancy or at delivery and are offered to participate in the study. Upon acceptance, their newborns are recruited at birth and followed up until at least 18 years of age. At recruitment, the mothers donate a blood sample and complete a baseline questionnaire. Umbilical cord blood, pieces of umbilical cord and heel blood spots are also collected. Postnatal follow-up currently occurs at 6, 12, and 24 months of age using on-line or postal self administered questionnaire; further questionnaires and medical examinations are envisaged. Questionnaires collect information on several factors, including mother{\textquoteright}s and/or child{\textquoteright}s environmental exposures, anthropometric measures, reproductive factors, diet, supplements, medical history, cognitive development, mental health and socioeconomic factors. Health promotion materials are also offered to parents.

DISCUSSION: Piccolipi{\`u} will broaden our understanding of the contribution of early-life factors to infant and child health and development. Several hypotheses on the developmental origins of health can be tested or piloted using the data collected from the Piccolipi{\`u} cohort. By pooling these data with those collected by other existing birth cohorts it will be possible to validate previous findings and to study rare exposures and outcomes.

}, keywords = {Adolescent, Child, Child Development, Child Welfare, Child, Preschool, Cohort Studies, Environmental Exposure, Humans, Infant, Infant, Newborn, Italy, Prospective Studies, Socioeconomic Factors}, issn = {1471-2431}, doi = {10.1186/1471-2431-14-36}, author = {Farchi, Sara and Forastiere, Francesco and Vecchi Brumatti, Liza and Alviti, Sabrina and Arnofi, Antonio and Bernardini, Tommaso and Bin, Maura and Brescianini, Sonia and Colelli, Valentina and Cotichini, Rodolfo and Culasso, Martina and De Bartolo, Paolo and Felice, Laura and Fiano, Valentina and Fioritto, Alessandra and Frizzi, Alfio and Gagliardi, Luigi and Giorgi, Giulia and Grasso, Chiara and La Rosa, Francesca and Loganes, Claudia and Lorusso, Paola and Martini, Valentina and Merletti, Franco and Medda, Emanuela and Montelatici, Veronica and Mugelli, Isabella and Narduzzi, Silvia and Nistic{\`o}, Lorenza and Penna, Luana and Piscianz, Elisa and Piscicelli, Carlo and Poggesi, Giulia and Porta, Daniela and Ranieli, Antonella and Rapisardi, Gherardo and Rasulo, Assunta and Richiardi, Lorenzo and Rusconi, Franca and Serino, Laura and Stazi, Maria Antonietta and Toccaceli, Virgilia and Todros, Tullia and Tognin, Veronica and Trevisan, Morena and Valencic, Erica and Volpi, Patrizia and Ziroli, Valentina and Ronfani, Luca and Di Lallo, Domenico} } @article {3634, title = {Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders.}, journal = {Blood}, volume = {124}, year = {2014}, month = {2014 Aug 7}, pages = {e4-e10}, abstract = {

Abnormalities of platelet size are one of the distinguishing features of inherited thrombocytopenias (ITs), and evaluation of blood films is recommended as an essential step for differential diagnosis of these disorders. Nevertheless, what we presently know about this subject is derived mainly from anecdotal evidence. To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in platelet diameter distribution width and the percentage of platelets with increased or reduced diameters. On the basis of these findings, we propose a new classification of ITs according to platelet size. It distinguishes forms with giant platelets, with large platelets, with normal or slightly increased platelet size, and with normal or slightly decreased platelet size. We also measured platelet diameters in 87 patients with immune thrombocytopenia and identified cutoff values for mean platelet diameter and the percentage of platelets with increased or reduced size that have good diagnostic accuracy in differentiating ITs with giant platelets and with normal or slightly decreased platelet size from immune thrombocytopenia and all other forms of IT.

}, keywords = {Adolescent, Adult, Blood Platelets, Case-Control Studies, Cell Size, Child, Child, Preschool, Diagnosis, Differential, Female, Hearing Loss, Sensorineural, Humans, Infant, Male, Middle Aged, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Purpura, Thrombocytopenic, Idiopathic, Thrombocytopenia, Young Adult}, issn = {1528-0020}, doi = {10.1182/blood-2014-03-564328}, author = {Noris, Patrizia and Biino, Ginevra and Pecci, Alessandro and Civaschi, Elisa and Savoia, Anna and Seri, Marco and Melazzini, Federica and Loffredo, Giuseppe and Russo, Giovanna and Bozzi, Valeria and Notarangelo, Lucia Dora and Gresele, Paolo and Heller, Paula G and Pujol-Moix, N{\'u}ria and Kunishima, Shinji and Cattaneo, Marco and Bussel, James and De Candia, Erica and Cagioni, Claudia and Ramenghi, Ugo and Barozzi, Serena and Fabris, Fabrizio and Balduini, Carlo L} } @article {3570, title = {Potential role of circulating microRNAs as early markers of preeclampsia.}, journal = {Taiwan J Obstet Gynecol}, volume = {53}, year = {2014}, month = {2014 Jun}, pages = {232-4}, abstract = {

OBJECTIVE: To identify microRNAs (miRNAs) differentially expressed at early stages of gestation (12-14 weeks) in the serum of pregnant women, who later developed severe preeclampsia (sPE) in the third trimester of pregnancy (n~=~24) compared to women with normal pregnancy (n~=~24).

MATERIALS AND METHODS: Sera from 12-14-week-gestation whole blood were subjected to microarray analysis with TaqMan Low Density Array chips (human microRNA panel V3.0), and to quantitative real-time polymerase chain reaction.

RESULTS: By using the TaqMan Low Density Array chip technology, 19 mature miRNAs appeared differentially expressed in the group of women who later developed sPE as compared to normal women. The expression of four miRNAs (miR-1233, miR-520, miR-210, miR-144) was validated by quantitative real-time polymerase chain reaction analysis. MiR-1233 was the most overexpressed in the serum of women who later developed sPE.

CONCLUSION: Circulating miRNAs deserve further investigation in order to explore their potential role in the pathogenesis of preeclampsia. In particular, miR-1233 might represent a potential marker of early sPE.

}, keywords = {Adult, Biomarkers, Female, Gestational Age, Humans, MicroRNAs, Oligonucleotide Array Sequence Analysis, Pilot Projects, Pre-Eclampsia, Pregnancy, Retrospective Studies}, issn = {1875-6263}, doi = {10.1016/j.tjog.2014.03.001}, author = {Ura, Blendi and Feriotto, Giordana and Monasta, Lorenzo and Bilel, Sabrine and Zweyer, Marina and Celeghini, Claudio} } @article {3514, title = {A precordial rub in a boy with a severe attack of ulcerative colitis.}, journal = {Pediatr Emerg Care}, volume = {30}, year = {2014}, month = {2014 Apr}, pages = {268}, abstract = {

A case of a pneumomediastinum mimicking a pericarditis in a boy with an occult perforation due to ulcerative colitis is reported. Pneumomediastinum is a rare complication of severe attacks of ulcerative colitis, with or without the previous development of a toxic megacolon, that should be considered in the differential diagnosis.

}, keywords = {Adolescent, Colitis, Ulcerative, Diagnosis, Differential, Humans, Intestinal Perforation, Male, Mediastinal Emphysema, Pericarditis, Radiography, Thoracic}, issn = {1535-1815}, doi = {10.1097/PEC.0000000000000111}, author = {Badina, Laura and Ferrara, Giovanna and Guastalla, Pierpaolo and Barbi, Egidio} } @article {3595, title = {Promoting effective child development practices in the first year of life: does timing make a difference?}, journal = {BMC Pediatr}, volume = {14}, year = {2014}, month = {2014}, pages = {222}, abstract = {

BACKGROUND: There is an increasing need for parenting programs aimed at promoting parent-child interaction. A variety of interventions have been proposed. The use of audiovisual materials for parents has been shown to be effective but limited information is available on the optimal timing for its use, particularly for new parents during the first year of life of their children. The aim of this study is to compare the effectiveness of a video administered at two different times to first-time parents in modifying parental knowledge, attitudes and intentions with regards to effective care practices.

METHODS: Open randomized controlled trial carried out in a referral mother and child hospital. Eligible parents were randomly assigned to receive a video at one month (early intervention) or at seven months (late intervention) of age of their child. The video addressed four specific activities related to early child development: reading aloud to the baby, early exposure to music, promotion of early socialization for parents and for children. The primary outcome was the proportion of parents who declared that their knowledge, attitudes and intentions changed after having seen the video at one or seven months of age of the child.

RESULTS: One hundred and five families were randomly allocated either to the early (53) or to the late (52) intervention group. For 99 families (52 in the early and 47 in the late group) a complete outcome evaluation was available. Parents included in the early administration group more frequently reported modifications in their knowledge of the suggested practices while parents in the late group more frequently reported a change in their attitudes. This finding was consistent across all four practices. The video was found to influence parental intentions in the great majority of interviewed parents with no significant difference between groups (82.7\% and 87.2\% in the early and late intervention group, respectively).

CONCLUSIONS: Audiovisual materials can be an effective complementary tool in programs aimed at supporting parents, particularly those dealing with their first baby. The results provide some useful insights into the differential benefits of using audiovisual aids at different times during the first year of life of the baby.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02120430.

}, issn = {1471-2431}, doi = {10.1186/1471-2431-14-222}, author = {Roia, Anna and Paviotti, Elena and Ferluga, Valentina and Montico, Marcella and Monasta, Lorenzo and Ronfani, Luca and Tamburlini, Giorgio} } @article {3537, title = {Radiological contrast media in the breastfeeding woman: a position paper of the Italian Society of Radiology (SIRM), the Italian Society of Paediatrics (SIP), the Italian Society of Neonatology (SIN) and the Task Force on Breastfeeding, Ministry of Health}, journal = {Eur Radiol}, volume = {24}, year = {2014}, month = {2014 Aug}, pages = {2012-22}, abstract = {

OBJECTIVES: Breastfeeding is a well-recognised investment in the health of the mother-infant dyad. Nevertheless, many professionals still advise breastfeeding mothers to temporarily discontinue breastfeeding after contrast media imaging. Therefore, we performed this review to provide health professionals with basic knowledge and skills for appropriate use of contrast media.

METHODS: A joint working group of the Italian Society of Radiology (SIRM), Italian Society of Paediatrics (SIP), Italian Society of Neonatology (SIN) and Task Force on Breastfeeding, Ministry of Health, Italy prepared a review of the relevant medical literature on the safety profile of contrast media for the nursing infant/child.

RESULTS: Breastfeeding is safe for the nursing infant of any post-conceptional age after administration of the majority of radiological contrast media to the mother; only gadolinium-based agents considered at high risk of nephrogenic systemic fibrosis (gadopentetate dimeglumine, gadodiamide, gadoversetamide) should be avoided in the breastfeeding woman as a precaution; there is no need to temporarily discontinue breastfeeding or to express and discard breast milk following the administration of contrast media assessed as compatible with breastfeeding.

CONCLUSIONS: Breastfeeding women should receive unambiguous professional advice and clear encouragement to continue breastfeeding after imaging with the compatible contrast media.

KEY POINTS: {\textbullet} Breastfeeding is a well-known investment in the health of the mother-infant dyad. {\textbullet} Breastfeeding is safe after administration of contrast media to the mother. {\textbullet} There is no need to temporarily discontinue breastfeeding following administration of contrast media.

}, keywords = {Adult, Breast Feeding, Contrast Media, Female, Humans, Infant, Italy, Neonatology, Practice Guidelines as Topic, Radiology, Societies, Medical}, issn = {1432-1084}, doi = {10.1007/s00330-014-3198-6}, author = {Cova, Maria Assunta and Stacul, Fulvio and Quaranta, Roberto and Guastalla, Pierpaolo and Salvatori, Guglielmo and Banderali, Giuseppe and Fonda, Claudio and David, Vincenzo and Gregori, Massimo and Zuppa, Antonio Alberto and Davanzo, Riccardo} } @article {3538, title = {A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus.}, journal = {N Engl J Med}, volume = {370}, year = {2014}, month = {2014 Apr 3}, pages = {1316-26}, abstract = {

BACKGROUND: Congenital infection with human cytomegalovirus (CMV) is a major cause of morbidity and mortality. In an uncontrolled study published in 2005, administration of CMV-specific hyperimmune globulin to pregnant women with primary CMV infection significantly reduced the rate of intrauterine transmission, from 40\% to 16\%.

METHODS: We evaluated the efficacy of hyperimmune globulin in a phase 2, randomized, placebo-controlled, double-blind study. A total of 124 pregnant women with primary CMV infection at 5 to 26 weeks of gestation were randomly assigned within 6 weeks after the presumed onset of infection to receive hyperimmune globulin or placebo every 4 weeks until 36 weeks of gestation or until detection of CMV in amniotic fluid. The primary end point was congenital infection diagnosed at birth or by means of amniocentesis.

RESULTS: A total of 123 women could be evaluated in the efficacy analysis (1 woman in the placebo group withdrew). The rate of congenital infection was 30\% (18 fetuses or infants of 61 women) in the hyperimmune globulin group and 44\% (27 fetuses or infants of 62 women) in the placebo group (a difference of 14 percentage points; 95\% confidence interval, -3 to 31; P=0.13). There was no significant difference between the two groups or, within each group, between the women who transmitted the virus and those who did not, with respect to levels of virus-specific antibodies, T-cell-mediated immune response, or viral DNA in the blood. The clinical outcome of congenital infection at birth was similar in the two groups. The number of obstetrical adverse events was higher in the hyperimmune globulin group than in the placebo group (13\% vs. 2\%).

CONCLUSIONS: In this study involving 123 women who could be evaluated, treatment with hyperimmune globulin did not significantly modify the course of primary CMV infection during pregnancy. (Funded by Agenzia Italiana del Farmaco; CHIP ClinicalTrials.gov number, NCT00881517; EudraCT no. 2008-006560-11.).

}, keywords = {Adult, Amniocentesis, Cytomegalovirus, Cytomegalovirus Infections, Female, Fetal Diseases, Humans, Immunoglobulins, Infectious Disease Transmission, Vertical, Pregnancy, Pregnancy Complications, Infectious}, issn = {1533-4406}, doi = {10.1056/NEJMoa1310214}, author = {Revello, Maria Grazia and Lazzarotto, Tiziana and Guerra, Brunella and Spinillo, Arsenio and Ferrazzi, Enrico and Kustermann, Alessandra and Guaschino, Secondo and Vergani, Patrizia and Todros, Tullia and Frusca, Tiziana and Arossa, Alessia and Furione, Milena and Rognoni, Vanina and Rizzo, Nicola and Gabrielli, Liliana and Klersy, Catherine and Gerna, Giuseppe} } @article {3614, title = {Recommendations for self-monitoring in pediatric diabetes: a consensus statement by the ISPED.}, journal = {Acta Diabetol}, volume = {51}, year = {2014}, month = {2014 Apr}, pages = {173-84}, abstract = {

A panel of experts of the Italian Society of Pediatric Endocrinology and Diabetology comprehensively discussed and approved the Italian recommendations regarding self-monitoring of blood glucose, continuous glucose monitoring and other measures of glycemic control in children and adolescents with type 1 diabetes. After an extensive review of the literature, we took these issues into account: self-monitoring blood glucose, continuous glucose monitoring, glycemic variability, glycosuria, ketonuria, ketonemia, glycated hemoglobin, fructosamine and glycated albumin, logbook, data downloading, lancing devices, carbohydrate counting, and glycemic measurements at school. We concluded that clinical guidelines on self-management should be developed in every country with faithful adaptation to local languages and taking into account specific contexts and local peculiarities, without any substantial modifications to the international recommendations. We believe that the National Health Service should provide all necessary resources to ensure self-monitoring of blood glucose and possibly continuous glucose monitoring of all children and adolescents with type 1 diabetes, according to the standards of care provided by these recommendations and internationally.

}, issn = {1432-5233}, doi = {10.1007/s00592-013-0521-7}, author = {Scaramuzza, Andrea and Cherubini, Valentino and Tumini, Stefano and Bonfanti, Riccardo and Buono, Pietro and Cardella, Francesca and d{\textquoteright}Annunzio, Giuseppe and Frongia, Anna Paola and Lombardo, Fortunato and Monciotti, Anna Carla Maria and Rabbone, Ivana and Schiaffini, Riccardo and Toni, Sonia and Zucchini, Stefano and Frontino, Giulio and Iafusco, Dario} } @article {3539, title = {Rhythm perception and production predict reading abilities in developmental dyslexia.}, journal = {Front Hum Neurosci}, volume = {8}, year = {2014}, month = {2014}, pages = {392}, abstract = {

Rhythm organizes events in time and plays a major role in music, but also in the phonology and prosody of a language. Interestingly, children with developmental dyslexia-a learning disability that affects reading acquisition despite normal intelligence and adequate education-have a poor rhythmic perception. It has been suggested that an accurate perception of rhythmical/metrical structure, that requires accurate perception of rise time, may be critical for phonological development and subsequent literacy. This hypothesis is mostly based on results showing a high degree of correlation between phonological awareness and metrical skills, using a very specific metrical task. We present new findings from the analysis of a sample of 48 children with a diagnosis of dyslexia, without comorbidities. These children were assessed with neuropsychological tests, as well as specifically-devised psychoacoustic and musical tasks mostly testing temporal abilities. Associations were tested by multivariate analyses including data mining strategies, correlations and most importantly logistic regressions to understand to what extent the different auditory and musical skills can be a robust predictor of reading and phonological skills. Results show a strong link between several temporal skills and phonological and reading abilities. These findings are discussed in the framework of the neuroscience literature comparing music and language processing, with a particular interest in the links between rhythm processing in music and language.

}, issn = {1662-5161}, doi = {10.3389/fnhum.2014.00392}, author = {Flaugnacco, Elena and Lopez, Luisa and Terribili, Chiara and Zoia, Stefania and Buda, Sonia and Tilli, Sara and Monasta, Lorenzo and Montico, Marcella and Sila, Alessandra and Ronfani, Luca and Sch{\"o}n, Daniele} } @article {3629, title = {Risk of Essure microinsert abdominal migration: case report and review of literature.}, journal = {Ther Clin Risk Manag}, volume = {10}, year = {2014}, month = {2014}, pages = {963-8}, abstract = {

PURPOSE: To report a case of Essure microinsert abdominal migration and literature review.

METHODS: A 41-year-old woman was counseled to undergo Essure sterilization. The procedure was hampered by the presence of endometrial cavity adhesions, obscuring left tubal ostium. By using microscissors the adhesions were progressively lysed. Since the procedure had become very painful, the patient required general anesthesia. Once adhesion lysis was completed, the tubal ostium was well visible. Both devices were then easily introduced into the fallopian tubes. At the end of the procedure, five coils were visible on the right side and five coils on the left side, as recommended.

RESULTS: The 3-month hysterosalpingogram follow-up suspected abdominal migration of the left device. Laparoscopy confirmed the device displacement in the left lower abdominal quadrant. Both fallopian tubes and the uterus appeared normal. No signs of perforation were detected. The device was embedded into the omentum, but it was easily removed. Bilateral tubal sterilization was performed by bipolar coagulation.

CONCLUSION: There are only 13 cases, including the present, of Essure abdominal migration in the literature. In most cases, abdominal displacement of the microinsert is asymptomatic and does not induce tissue damage. However, in some cases, it may cause a severe adverse event, requiring major surgery. Therefore, removal of the migrated device should be performed as soon as possible. Moreover, during presterilization counseling, the patient should also be correctly informed about the risk of this rare but relevant complication, as well as about the surgical interventions that could be required to solve it.

}, issn = {1176-6336}, doi = {10.2147/TCRM.S65634}, author = {Ricci, Giuseppe and Restaino, Stefano and Di Lorenzo, Giovanni and Fanfani, Francesco and Scrimin, Federica and Mangino, Francesco P} } @article {3498, title = {Severe inflammatory bowel disease associated with congenital alteration of transforming growth factor beta signaling.}, journal = {J Crohns Colitis}, volume = {8}, year = {2014}, month = {2014 Aug}, pages = {770-4}, abstract = {

Transforming growth factor beta is a pleiotropic cytokine which plays a central role in the homeostasis of the immune system. A complex dysregulation of its signaling occurs in Loeys-Dietz syndrome, a monogenic disorder caused by mutations of transforming growth factor beta receptors type 1 or type 2, characterized by skeletal involvement, craniofacial abnormalities, and arterial tortuosity with a strong predisposition for aneurysm and dissection. In addition, several immunologic abnormalities have been described in these patients, including an increased risk of allergic disorders as well as eosinophilic gastrointestinal disorders. The occurrence of inflammatory bowel disorders has been also reported, but it is poorly documented. We describe two unrelated children with Loeys-Dietz syndrome affected by severe chronic inflammatory colitis appearing at an early age. The intestinal disease presented similar features in both patients, including a histopathological picture of non-eosinophilic chronic ulcerative colitis, striking elevation of inflammatory markers, and a distinctly severe clinical course leading to failure to thrive, with resistance to multiple immunosuppressive treatments. One of the patients also presented autoimmune thyroiditis. Our report confirms that chronic ulcerative colitis may be associated with Loeys-Dietz syndrome. This finding suggests that an alteration of transforming growth factor beta signaling may by itself predispose to inflammatory colitis in humans, and represent an invaluable model to understand inflammatory bowel diseases.

}, keywords = {Child, Preschool, Colon, Colonoscopy, Female, Humans, Infant, Inflammatory Bowel Diseases, Loeys-Dietz Syndrome, Male, Signal Transduction, Transforming Growth Factor beta}, issn = {1876-4479}, doi = {10.1016/j.crohns.2014.01.013}, author = {Naviglio, Samuele and Arrigo, Serena and Martelossi, Stefano and Villanacci, Vincenzo and Tommasini, Alberto and Loganes, Claudia and Fabretto, Antonella and Vignola, Silvia and Lonardi, Silvia and Ventura, Alessandro} } @article {3552, title = {Spectrum of the mutations in Bernard-Soulier syndrome.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Sep}, pages = {1033-45}, abstract = {

Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28\%), GP1BB (28\%), or GP9 (44\%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85\% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.

}, keywords = {Alleles, Bernard-Soulier Syndrome, Databases, Nucleic Acid, Founder Effect, Genetic Variation, Humans, Mutation, Platelet Glycoprotein GPIb-IX Complex, Polymorphism, Single Nucleotide, von Willebrand Diseases, Web Browser}, issn = {1098-1004}, doi = {10.1002/humu.22607}, author = {Savoia, Anna and Kunishima, Shinji and De Rocco, Daniela and Zieger, Barbara and Rand, Margaret L and Pujol-Moix, N{\'u}ria and Caliskan, Umran and Tokgoz, Huseyin and Pecci, Alessandro and Noris, Patrizia and Srivastava, Alok and Ward, Christopher and Morel-Kopp, Marie-Christine and Alessi, Marie-Christine and Bellucci, Sylvia and Beurrier, Philippe and de Maistre, Emmanuel and Favier, R{\'e}mi and H{\'e}zard, Nathalie and Hurtaud-Roux, Marie-Fran{\c c}oise and Latger-Cannard, V{\'e}ronique and Lavenu-Bombled, C{\'e}cile and Proulle, Val{\'e}rie and Meunier, Sandrine and N{\'e}grier, Claude and Nurden, Alan and Randrianaivo, Hanitra and Fabris, Fabrizio and Platokouki, Helen and Rosenberg, Nurit and HadjKacem, Basma and Heller, Paula G and Karimi, Mehran and Balduini, Carlo L and Pastore, Annalisa and Lanza, Francois} } @article {3583, title = {Teleradiology for remote consultation using iPad improves the use of health system human resources for paediatric fractures: prospective controlled study in a tertiary care hospital in Italy.}, journal = {BMC Health Serv Res}, volume = {14}, year = {2014}, month = {2014}, pages = {327}, abstract = {

BACKGROUND: The growing cost of health care and lack of specialised staff have set e-Health high on the European political agenda. In a prospective study we evaluated the effect of providing images for remote consultation through an iPad on the number of in-hospital orthopaedic consultations for children with bone fractures.

METHODS: Children from 0 to 18 years diagnosed with a bone fracture by the radiologist during the hours when an orthopaedic service is provided only on-call were eligible for enrollment. Cases were enrolled prospectively during September and October 2013. A standard approach (verbal information only, no X-Ray provided remotely) was compared to an experimental approach (standard approach plus the provision of X-ray for remote consultation through an iPad). The primary outcome was the number of orthopaedic in-hospital consultations that occurred. Other outcomes included: immediate activation of other services; time needed for decision-making; technical difficulties; quality of images and diagnostic confidence (on a likert scale of 1 to 10).

RESULTS: Forty-two children were enrolled in the study. Number of in-hospital consultancies dropped from 32/42 (76.1\%) when no X-ray was provided to 16/42 (38\%) when the X-rays was provided (p < 0.001). With remote X-ray consultation in 14/42 (33.3\%) cases services such as surgery and plaster room could be immediately activated, compared to no service activated without teleradiology (p < 0.001). Average time for decision making was 23.4 {\textpm} 21.8 minutes with remote X-ray consultation, compared to 56.2 {\textpm} 16.1 when the X-ray was not provided (p < 0.001). The comparison between images on the iPad and on the standard system for X- Ray visualisation resulted in a non statistically significant difference in the quality of images (average score 9.89 {\textpm} 0.37 vs 9.91 {\textpm} 0.30; p = 0.79), and in non statistically significant difference in diagnostic confidence (average score 9.91 {\textpm} 0.32 vs 9.92 {\textpm} 0.31; p = 0.88).

CONCLUSIONS: Remote X-ray consultation through Aycan OsiriX PRO and iPad should be considered as a means for reducing the need of in-hospital orthopaedic consultation during on-call times, and potentially decrease the cost of care for the health system. In the future, alternative systems less expensive than Aycan OsiriX PRO should be further developed and tested.

}, keywords = {Adolescent, Child, Child, Preschool, Computers, Handheld, Decision Making, Fractures, Bone, Humans, Infant, Infant, Newborn, Italy, Prospective Studies, Remote Consultation, Teleradiology, Time Factors}, issn = {1472-6963}, doi = {10.1186/1472-6963-14-327}, author = {Zennaro, Floriana and Grosso, Daniele and Fascetta, Riccardo and Marini, Marta and Odoni, Luca and Di Carlo, Valentina and Dibello, Daniela and Vittoria, Francesca and Lazzerini, Marzia} } @article {3524, title = {TNF-α SNP rs1800629 and risk of relapse in childhood acute lymphoblastic leukemia: relation to immunophenotype.}, journal = {Pharmacogenomics}, volume = {15}, year = {2014}, month = {2014 Apr}, pages = {619-27}, abstract = {

AIM: In the AIEOP-BFM ALL (Associazione Italiana Ematologia Oncologia Pediatrica-Berlin Frankfurt M{\"u}nster acute lymphoblastic leukemia) 2000 protocol, 70\% of relapsed patients had favorable prognostic features and fell within less intensive polychemotherapeutic regimens, suggesting the need for better assessing lower risk stratification.

MATERIALS \& METHODS: A novel two-phase study design selected 614 children to be genotyped for TNF-α SNP rs1800629 (-308G>A). A weighted Cox model was applied to evaluate the SNP effect on hazard of relapse, adjusting for immunophenotype, risk group, age and gender and including interaction terms.

RESULTS: Significant interaction was found with immunophenotypes (p = 0.0007, with minor allele genotypes being adverse genetic markers in B-cell acute lymphoblastic leukemia and protective ones in T-cell acute lymphoblastic leukemia), and also with risk protocols (p = 0.0041, with minor allele genotypes as prognostic factor of relapse for standard risk patients [only one T-cell acute lymphoblastic leukemia in the subgroup analyzed]).

CONCLUSION: The presence of at least one A allele in TNF-α SNP rs1800629 should suggest a closer monitoring in B-cell acute lymphoblastic leukemia standard risk patients.

}, keywords = {Adolescent, Antineoplastic Agents, Child, Child, Preschool, Drug Resistance, Neoplasm, Female, Genotype, Humans, Infant, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Phenotype, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Recurrence, Risk Assessment, Steroids, Tumor Necrosis Factor-alpha}, issn = {1744-8042}, doi = {10.2217/pgs.13.249}, author = {Franca, Raffaella and Rebora, Paola and Athanasakis, Emmanouil and Favretto, Diego and Verzegnassi, Federico and Basso, Giuseppe and Tommasini, Alberto and Valsecchi, Maria Grazia and Decorti, Giuliana and Rabusin, Marco} } @article {7724, title = {Trans-ethnic meta-analysis of white blood cell phenotypes.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Dec 20}, pages = {6944-60}, abstract = {

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

}, keywords = {African Americans, Asian Continental Ancestry Group, Bayes Theorem, European Continental Ancestry Group, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Leukocyte Count, Leukocytes, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1460-2083}, doi = {10.1093/hmg/ddu401}, author = {Keller, Margaux F and Reiner, Alexander P and Okada, Yukinori and van Rooij, Frank J A and Johnson, Andrew D and Chen, Ming-Huei and Smith, Albert V and Morris, Andrew P and Tanaka, Toshiko and Ferrucci, Luigi and Zonderman, Alan B and Lettre, Guillaume and Harris, Tamara and Garcia, Melissa and Bandinelli, Stefania and Qayyum, Rehan and Yanek, Lisa R and Becker, Diane M and Becker, Lewis C and Kooperberg, Charles and Keating, Brendan and Reis, Jared and Tang, Hua and Boerwinkle, Eric and Kamatani, Yoichiro and Matsuda, Koichi and Kamatani, Naoyuki and Nakamura, Yusuke and Kubo, Michiaki and Liu, Simin and Dehghan, Abbas and Felix, Janine F and Hofman, Albert and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Franco, Oscar H and Longo, Dan L and Singleton, Andrew B and Psaty, Bruce M and Evans, Michelle K and Cupples, L Adrienne and Rotter, Jerome I and O{\textquoteright}Donnell, Christopher J and Takahashi, Atsushi and Wilson, James G and Ganesh, Santhi K and Nalls, Mike A} } @article {3474, title = {Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Feb}, pages = {145-54}, abstract = {

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

}, keywords = {Analysis of Variance, European Continental Ancestry Group, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Glucose, Gout, Humans, Inhibins, Polymorphism, Single Nucleotide, Signal Transduction, Uric Acid}, issn = {1546-1718}, doi = {10.1038/ng.2500}, author = {K{\"o}ttgen, Anna and Albrecht, Eva and Teumer, Alexander and Vitart, Veronique and Krumsiek, Jan and Hundertmark, Claudia and Pistis, Giorgio and Ruggiero, Daniela and O{\textquoteright}Seaghdha, Conall M and Haller, Toomas and Yang, Qiong and Tanaka, Toshiko and Johnson, Andrew D and Kutalik, Zolt{\'a}n and Smith, Albert V and Shi, Julia and Struchalin, Maksim and Middelberg, Rita P S and Brown, Morris J and Gaffo, Angelo L and Pirastu, Nicola and Li, Guo and Hayward, Caroline and Zemunik, Tatijana and Huffman, Jennifer and Yengo, Loic and Zhao, Jing Hua and Demirkan, Ayse and Feitosa, Mary F and Liu, Xuan and Malerba, Giovanni and Lopez, Lorna M and van der Harst, Pim and Li, Xinzhong and Kleber, Marcus E and Hicks, Andrew A and Nolte, Ilja M and Johansson, {\r A}sa and Murgia, Federico and Wild, Sarah H and Bakker, Stephan J L and Peden, John F and Dehghan, Abbas and Steri, Maristella and Tenesa, Albert and Lagou, Vasiliki and Salo, Perttu and Mangino, Massimo and Rose, Lynda M and Lehtim{\"a}ki, Terho and Woodward, Owen M and Okada, Yukinori and Tin, Adrienne and M{\"u}ller, Christian and Oldmeadow, Christopher and Putku, Margus and Czamara, Darina and Kraft, Peter and Frogheri, Laura and Thun, Gian Andri and Grotevendt, Anne and Gislason, Gauti Kjartan and Harris, Tamara B and Launer, Lenore J and McArdle, Patrick and Shuldiner, Alan R and Boerwinkle, Eric and Coresh, Josef and Schmidt, Helena and Schallert, Michael and Martin, Nicholas G and Montgomery, Grant W and Kubo, Michiaki and Nakamura, Yusuke and Tanaka, Toshihiro and Munroe, Patricia B and Samani, Nilesh J and Jacobs, David R and Liu, Kiang and d{\textquoteright}Adamo, Pio and Ulivi, Sheila and Rotter, Jerome I and Psaty, Bruce M and Vollenweider, Peter and Waeber, Gerard and Campbell, Susan and Devuyst, Olivier and Navarro, Pau and Kolcic, Ivana and Hastie, Nicholas and Balkau, Beverley and Froguel, Philippe and Esko, T{\~o}nu and Salumets, Andres and Khaw, Kay Tee and Langenberg, Claudia and Wareham, Nicholas J and Isaacs, Aaron and Kraja, Aldi and Zhang, Qunyuan and Wild, Philipp S and Scott, Rodney J and Holliday, Elizabeth G and Org, Elin and Viigimaa, Margus and Bandinelli, Stefania and Metter, Jeffrey E and Lupo, Antonio and Trabetti, Elisabetta and Sorice, Rossella and D{\"o}ring, Angela and Lattka, Eva and Strauch, Konstantin and Theis, Fabian and Waldenberger, Melanie and Wichmann, H-Erich and Davies, Gail and Gow, Alan J and Bruinenberg, Marcel and Stolk, Ronald P and Kooner, Jaspal S and Zhang, Weihua and Winkelmann, Bernhard R and Boehm, Bernhard O and Lucae, Susanne and Penninx, Brenda W and Smit, Johannes H and Curhan, Gary and Mudgal, Poorva and Plenge, Robert M and Portas, Laura and Persico, Ivana and Kirin, Mirna and Wilson, James F and Mateo Leach, Irene and van Gilst, Wiek H and Goel, Anuj and Ongen, Halit and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Imboden, Medea and von Eckardstein, Arnold and Cucca, Francesco and Nagaraja, Ramaiah and Piras, Maria Grazia and Nauck, Matthias and Schurmann, Claudia and Budde, Kathrin and Ernst, Florian and Farrington, Susan M and Theodoratou, Evropi and Prokopenko, Inga and Stumvoll, Michael and Jula, Antti and Perola, Markus and Salomaa, Veikko and Shin, So-Youn and Spector, Tim D and Sala, Cinzia and Ridker, Paul M and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Hengstenberg, Christian and Nelson, Christopher P and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Singleton, Andrew B and Kamatani, Naoyuki and Zeller, Tanja and Burnier, Michel and Attia, John and Laan, Maris and Klopp, Norman and Hillege, Hans L and Kloiber, Stefan and Choi, Hyon and Pirastu, Mario and Tore, Silvia and Probst-Hensch, Nicole M and V{\"o}lzke, Henry and Gudnason, Vilmundur and Parsa, Afshin and Schmidt, Reinhold and Whitfield, John B and Fornage, Myriam and Gasparini, Paolo and Siscovick, David S and Polasek, Ozren and Campbell, Harry and Rudan, Igor and Bouatia-Naji, Nabila and Metspalu, Andres and Loos, Ruth J F and van Duijn, Cornelia M and Borecki, Ingrid B and Ferrucci, Luigi and Gambaro, Giovanni and Deary, Ian J and Wolffenbuttel, Bruce H R and Chambers, John C and M{\"a}rz, Winfried and Pramstaller, Peter P and Snieder, Harold and Gyllensten, Ulf and Wright, Alan F and Navis, Gerjan and Watkins, Hugh and Witteman, Jacqueline C M and Sanna, Serena and Schipf, Sabine and Dunlop, Malcolm G and T{\"o}njes, Anke and Ripatti, Samuli and Soranzo, Nicole and Toniolo, Daniela and Chasman, Daniel I and Raitakari, Olli and Kao, W H Linda and Ciullo, Marina and Fox, Caroline S and Caulfield, Mark and Bochud, Murielle and Gieger, Christian} } @article {1956, title = {A novel CRYBB2 missense mutation causing congenital autosomal dominant cataract in an Italian family.}, journal = {Ophthalmic Genet}, volume = {34}, year = {2013}, month = {2013 Mar-Jun}, pages = {115-7}, abstract = {

Congenital cataract is a leading cause of visual impairment in children and brings approximately 10\% of childhood blindness worldwide. Molecular analysis revealed ~60 loci to be associated with several phenotypes of childhood cataracts. Until now, more than 30 loci and 18 genes on different chromosomes have been associated with autosomal dominant congenital cataract (ADCC). Here, we present a three-generation Italian family with a non syndromic ADCC. A linkage analysis carried out using HumanCytoSNP-12 DNA Analysis BeadChip led us to identify ten genomic regions virtually involved in the disease. All the genes located in these regions were scored for possible relationship with ADCC and, according to a strict clinical and genetic selection, 4 genes have been analyzed. A novel sequence variant was found in the CRYBB2 gene (p.Ser143Phe). This variant affects a conserved aminoacid in the third Greek key motif of the protein, cosegregates with the disease phenotype in all affected individuals and is not present both in the unaffected family members and 100 healthy control subjects. Finally, we identified the first CRYBB2 mutation in an Italian family causing a clinical picture of ADCC.

}, keywords = {Amino Acid Sequence, beta-Crystallin B Chain, Cataract, DNA Mutational Analysis, Female, Genes, Dominant, Genetic Linkage, Genotype, Humans, Italy, Male, Molecular Sequence Data, Mutation, Missense, Pedigree, Phenotype}, issn = {1744-5094}, doi = {10.3109/13816810.2012.707273}, author = {Faletra, Flavio and d{\textquoteright}Adamo, Adamo Pio and Pensiero, Stefano and Athanasakis, Emmanouil and Catalano, Dario and Bruno, Irene and Gasparini, Paolo} } @article {1991, title = {Safety and efficacy of infliximab and adalimumab for refractory uveitis in juvenile idiopathic arthritis: 1-year followup data from the Italian Registry.}, journal = {J Rheumatol}, volume = {40}, year = {2013}, month = {2013 Jan}, pages = {74-9}, abstract = {

OBJECTIVE: To evaluate safety and efficacy of adalimumab (ADA) and infliximab (IFX) for the treatment of juvenile idiopathic arthritis-related anterior uveitis (JIA-AU).

METHODS: Starting January 2007, patients with JIA-AU treated with IFX and ADA were managed by a standard protocol and data were entered into the National Italian Registry (NIR). At baseline, all patients were refractory to standard immunosuppressive treatment and/or were corticosteroid-dependent. Data recorded every 3 months included uveitis course, number/type of ocular complications, drug-related adverse events (AE), treatment change or withdrawal, and laboratory measures. Data of patients treated for at least 1 year were retrieved from the NIR and analyzed using descriptive statistics. Treatment efficacy was based on change in uveitis course and in number of ocular complications.

RESULTS: Up to December 2009, data for 108 patients with JIA-AU treated with anti-tumor necrosis factor-α agents were recorded in the NIR and data from 91, with at least 12 months{\textquoteright} followup, were included in the study. Forty-eight patients were treated with IFX, 43 with ADA. Forty-seven patients (55.3\%) achieved remission of AU, 28 (32.9\%) had recurrent AU, and 10 (11.8\%) maintained a chronic course. A higher remission rate was observed with ADA (67.4\% vs 42.8\% with IFX; p = 0.025). Ocular complications decreased from 0.47 to 0.32 per subject. Five patients experienced resolution of structural complications. No patient reported serious AE; 8 (8.8\%) experienced 11 minor AE (9 with IFX, 2 with ADA).

CONCLUSION: IFX and ADA appear to be effective and safe for treatment of refractory JIA-related uveitis, with a better performance of ADA in the medium-term period.

}, keywords = {Adolescent, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antirheumatic Agents, Arthritis, Juvenile, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, Italy, Male, Registries, Treatment Outcome, Tumor Necrosis Factor-alpha, Uveitis}, issn = {0315-162X}, doi = {10.3899/jrheum.120583}, author = {Zannin, Maria E and Birolo, Carolina and Gerloni, Valeria M and Miserocchi, Elisabetta and Pontikaki, Irene and Paroli, Maria P and Bracaglia, Claudia and Shardlow, Alison and Parentin, Fulvio and Cimaz, Rolando and Simonini, Gabriele and Falcini, Fernanda and Corona, Fabrizia and Viola, Stefania and De Marco, Riccardo and Breda, Luciana and La Torre, Francesco and Vittadello, Fabio and Martini, Giorgia and Zulian, Francesco} } @article {1836, title = {Type 1 diabetes mellitus and celiac disease: usefulness of gluten-free diet.}, journal = {Acta Diabetol}, volume = {50}, year = {2013}, month = {2013 Oct}, pages = {821-2}, issn = {1432-5233}, doi = {10.1007/s00592-011-0316-7}, author = {Pascolo, Paola and Faleschini, Elena and Tonini, Giorgio and Ventura, Alessandro} } @article {1873, title = {Acute febrile cholestatic jaundice in children: keep in mind Kawasaki disease.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {55}, year = {2012}, month = {2012 Oct}, pages = {380-3}, abstract = {

Kawasaki disease (KD) is characterized by persistent fever in addition to 4 of 5 signs of mucocutaneous inflammation. Although gastrointestinal involvement does not belong to the classic diagnostic criteria, it has been often associated with KD onset. We reviewed patients who were admitted for febrile cholestatic jaundice between 2003 and 2010 in 2 tertiary pediatric care centers. KD was the second most frequent cause (21\%) after viral infections. Considering the relative high frequency of this condition, a high index of suspicion of KD should be maintained in patients presenting with febrile cholestatic jaundice.

}, keywords = {Child, Child, Preschool, Diagnosis, Differential, Female, Fever, Humans, Infant, Jaundice, Obstructive, Male, Mucocutaneous Lymph Node Syndrome, Virus Diseases}, issn = {1536-4801}, doi = {10.1097/MPG.0b013e31825513de}, author = {Taddio, Andrea and Pellegrin, Maria Chiara and Centenari, Chiara and Filippeschi, Irene Pellegrini and Ventura, Alessandro and Maggiore, Giuseppe} } @article {1795, title = {Allogeneic hematopoietic stem cell transplantation for Philadelphia-positive acute lymphoblastic leukemia in children and adolescents: a retrospective multicenter study of the Italian Association of Pediatric Hematology and Oncology (AIEOP).}, journal = {Biol Blood Marrow Transplant}, volume = {18}, year = {2012}, month = {2012 Jun}, pages = {852-60}, abstract = {

Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) still represents a major challenge. We report the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP) with allogeneic hematopoietic stem cell transplantation (HSCT) in children with Ph+ ALL from 1990 to 2008. Sixty-nine patients received HSCT from either a related (37, 54\%) or an unrelated (32, 46\%) donor. Twenty-five patients (36\%) underwent transplantation before 2000 and 44 (64\%) after 2000. Twenty-three patients (33\%) received Imatinib mesylate treatment before HSCT and seven (10\%) after HSCT. After a median follow-up of 56 months, the overall survival (OS) probability was 51\% (95\% confidence interval [CI], 38-63), the leukemia-free survival (LFS) was 47\% (95\% CI, 34-59), transplantation-related mortality (TRM) was 17\% (95\% CI, 10-30), and relapse incidence (RI) was 36\% (95\% CI, 26-50). Transplantation in first complete remission, female gender, and lower WBC count at diagnosis were associated with a better LFS in both univariate and multivariate analyses. Patients with p210 transcript had a trend for a worse prognosis compared with those who had the p190 transcript. Our series confirms the role of HSCT in the eradication of Ph+ ALL. Early HSCT is recommended once morphologic remission is obtained.

}, keywords = {Adolescent, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Child, Child, Preschool, Disease-Free Survival, Drug Administration Schedule, Female, Fusion Proteins, bcr-abl, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Humans, Infant, Italy, Male, Philadelphia Chromosome, Piperazines, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Pyrimidines, Remission Induction, Retrospective Studies, Secondary Prevention, Transplantation, Homologous, Young Adult}, issn = {1523-6536}, doi = {10.1016/j.bbmt.2011.10.015}, author = {Fagioli, Franca and Zecca, Marco and Rognoni, Carla and Lanino, Edoardo and Balduzzi, Adriana and Berger, Massimo and Messina, Chiara and Favre, Claudio and Rabusin, Marco and Lo Nigro, Luca and Masetti, Riccardo and Prete, Arcangelo and Locatelli, Franco} } @article {1921, title = {Alteration of liver enzymes is a feature of the MYH9-related disease syndrome.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e35986}, abstract = {

BACKGROUND: MYH9-related disease (MYH9-RD) is a rare autosomal dominant genetic syndrome characterized by congenital thrombocytopenia associated with the risk of developing progressive nephropathy, sensorineural deafness, and presenile cataract. During the collection of a large case-series of patients with MYH9-RD we noticed several cases with unexplained elevation of liver enzymes. Our aim was to evaluate if the alteration of liver tests is a feature of the MYH9-RD and to define its clinical significance.

METHODS AND FINDINGS: Data concerning liver tests, prospectively recorded in the Italian Registry for MYH9-RD, were collected and compared with those of three control populations: patients with autoimmune thrombocytopenia, patients with inherited thrombocytopenias other than MYH9-RD, and the participants to a large epidemiologic survey in an Italian geographic isolate. Thirty-eight of 75 evaluable MYH9-RD patients (50.7\%) showed an elevation of ALT and/or AST, and 17 of 63 (27.0\%) an increase of GGT. The increases ranged from 1.9 {\textpm} 0.7 to 2.7 {\textpm} 1.6 fold the upper normal limit. The prevalence of liver test alterations was significantly higher in MYH9-RD patients than in each of the control populations, with odds ratios ranging from 8.2 (95\% CIs 2.2-44.8) to 24.7 (14.8-40.8). Clinical follow-up and more detailed liver studies of a subset of patients, including ultrasound liver scan, liver elastography and liver biopsy in one case, did not show any significant structural damage or evolution towards liver insufficiency.

CONCLUSIONS: Elevation of liver enzymes is a frequent and previously unrecognized feature of the MYH9-RD syndrome; however, this defect does not appear to have poor prognostic value.

}, keywords = {Abnormalities, Multiple, Adolescent, Adult, Aged, Aged, 80 and over, Biopsy, Case-Control Studies, Child, Child, Preschool, Demography, Female, Follow-Up Studies, Humans, Immunohistochemistry, Infant, Liver, Liver Function Tests, Male, Middle Aged, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Odds Ratio, Syndrome, Young Adult}, issn = {1932-6203}, doi = {10.1371/journal.pone.0035986}, author = {Pecci, Alessandro and Biino, Ginevra and Fierro, Tiziana and Bozzi, Valeria and Mezzasoma, Annamaria and Noris, Patrizia and Ramenghi, Ugo and Loffredo, Giuseppe and Fabris, Fabrizio and Momi, Stefania and Magrini, Umberto and Pirastu, Mario and Savoia, Anna and Balduini, Carlo and Gresele, Paolo} } @article {1869, title = {Association of MBL2 gene exon 1 variants with autoimmune thyroid disease in Brazilian patients.}, journal = {Int J Immunogenet}, volume = {39}, year = {2012}, month = {2012 Aug}, pages = {357-61}, abstract = {

We investigated the association between MBL2 gene exon 1 functional polymorphisms and autoimmune thyroid disease (AITD) in 163 Brazilian patients (87 with Hashimoto thyroiditis, HT; 76 with Graves{\textquoteright} disease) and 214 healthy controls. Individuals carrying MBL2 O allele are at higher risk of developing AITD (OR = 1.58, 95\% CI: 1.11-2.26; P-value = 0.009) and HT (OR = 1.67, 95\% CI: 1.09-2.55; P-value = 0.013) as suggesting a possible role for mannose-binding lectin in influencing disease susceptibility.

}, keywords = {Adolescent, Adult, Brazil, Case-Control Studies, Child, Child, Preschool, Exons, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Graves Disease, Hashimoto Disease, Humans, Infant, Male, Mannose-Binding Lectin, Middle Aged, Polymorphism, Single Nucleotide, Young Adult}, issn = {1744-313X}, doi = {10.1111/j.1744-313X.2012.01102.x}, author = {Filho, C B and Rodrigues, F F and Segat, L and Fonseca, A M and Araujo, J and Arahata, C and Pontes, L and Vilar, L and de Lima Filho, J L and Crovella, S} } @article {1865, title = {A child with severe pneumomediastinum and ABCA3 gene mutation: a puzzling connection.}, journal = {Arch Bronconeumol}, volume = {48}, year = {2012}, month = {2012 Apr}, pages = {139-40}, keywords = {Anemia, ATP-Binding Cassette Transporters, Child, Preschool, Dyspnea, Genetic Predisposition to Disease, Heterozygote, Humans, Intensive Care, Leukocytosis, Male, Mediastinal Emphysema, Mutation, Missense, Point Mutation, Pulmonary Emphysema, Respiratory Tract Infections, Subcutaneous Emphysema, Tomography, X-Ray Computed}, issn = {1579-2129}, doi = {10.1016/j.arbres.2011.11.008}, author = {Copertino, Marco and Barbi, Egidio and Poli, Furio and Zennaro, Floriana and Ferrari, Maurizio and Carrera, Paola and Ventura, Alessandro} } @article {1893, title = {Cognitive assessment of very preterm infants at 2-year corrected age: performance of the Italian version of the PARCA-R parent questionnaire.}, journal = {Early Hum Dev}, volume = {88}, year = {2012}, month = {2012 Mar}, pages = {159-63}, abstract = {

BACKGROUND: Serial assessments of cognitive and language development are recommended for very preterm children, but standardized neuropsychological testing is time-consuming and expensive, as well as tiring for the child.

AIMS: To validate the Italian version of the PARCA-R parent questionnaire and test its clinical effectiveness in assessing cognitive development of very preterm children at 2 years of corrected age.

METHODS: 120 consecutive Italian very preterm children (mean gestational age 28.8 weeks, standard deviation 2.1) were assessed in four hospitals through the Mental Development Index (MDI) of the Bayley Scales of Infant Development (BSID-II). Parents completed the PARCA-R questionnaire, designed to measure children{\textquoteright}s non-verbal and verbal (vocabulary and sentence complexity) cognitive level. The correlation between the MDI and the PARCA-R Parent Report Composite (PRC) was tested through the Pearson correlation coefficient, and the receiver operating characteristic (ROC) curve was used to identify optimal PRC cut-offs.

RESULTS: Significant correlation between the PRC score and MDI (r=0.60, p<0.001) indicated good concurrent validity. The area under the ROC curve was 0.83, and the cut-off of 46 lead to 72.7\% sensitivity and 77.1\% specificity in identifying children with moderate/severe cognitive delay (MDI<70). Negative predictive value was 96.6 (90.3-99.3). Screening through PARCA-R would reduce the number of children with MDI>=70 undergoing BSID-II or equivalent standardized tool from 109 to 25.

CONCLUSIONS: The Italian version of PARCA-R retains good discriminative power for identifying cognitive delay in 2-year very preterm children. It is well accepted by parents, and represents a valid and efficient alternative for developmental screening and outcome measurement.

}, keywords = {Cognition, Female, Humans, Infant, Infant, Newborn, Infant, Premature, Italy, Male, Parents, Questionnaires, ROC Curve}, issn = {1872-6232}, doi = {10.1016/j.earlhumdev.2011.07.022}, author = {Cuttini, Marina and Ferrante, Pierpaolo and Mirante, Nadia and Chiandotto, Valeria and Fertz, Mariacristina and Dall{\textquoteright}Oglio, Anna Maria and Coletti, Maria Franca and Johnson, Samantha} } @article {1802, title = {Contribution of SNP arrays in diagnosis of deletion 2p11.2-p12.}, journal = {Gene}, volume = {492}, year = {2012}, month = {2012 Jan 15}, pages = {315-8}, abstract = {

Deletions of the short arm of chromosome 2 are exceedingly rare, having been reported in few patients. Furthermore most cases with deletion in 2p11.2-p12 have been studied using standard karyotype and so it is not possible to delineate the precise size of deletions. Here, we describe a 9-year-old girl with a 9.4 Mb de novo interstitial deletion of region 2p11.2-p12 identified by SNP array analysis. The deleted region encompasses over 40 known genes, including LRRTM1, CTNNA2 and REEP1, haploinsufficiency of which could explain some clinical features of this patient such as mental retardation, speech delay and gait abnormalities. A comparison of our case with previously reported patients who present deletions in 2p11.2-p12 was carried out. Our case adds new information to the deletion of 2p11.2-p12, improving the knowledge on this rearrangement.

}, keywords = {Abnormalities, Multiple, Child, Chromosomes, Human, Pair 2, Female, Humans, Intellectual Disability, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Sequence Deletion}, issn = {1879-0038}, doi = {10.1016/j.gene.2011.10.035}, author = {Rocca, Maria Santa and Fabretto, Antonella and Faletra, Flavio and Carlet, Ombretta and Skabar, Aldo and Gasparini, Paolo and Pecile, Vanna} } @article {1867, title = {De novo 6.9 Mb interstitial deletion on chromosome 4q31.1-q32.1 in a girl with severe speech delay and dysmorphic features.}, journal = {Am J Med Genet A}, volume = {158A}, year = {2012}, month = {2012 Apr}, pages = {882-7}, abstract = {

Deletion of the terminal part of long arm of chromosome 4 is a condition characterized by facial dysmorphisms, cardiac and limb defects, and developmental delay. Deletions usually involve the terminal part of the chromosome and most frequently are interstitial. Here, we report a de novo interstitial deletion resulting in a microdeletion of 6.9 Mb involving 4q31.3-q32.1 segment, detected by SNPs-Array technique in a 4-year-old female showing severe speech delay, mild facial dysmorphisms, and joint laxity. Phenotype-genotype relationships looking at the genes involved in this part of the chromosome were also carried out and data compared with those previously described.

}, keywords = {Abnormalities, Multiple, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 4, Developmental Disabilities, Female, Genotype, Humans, Language Development Disorders, Phenotype, Sequence Deletion}, issn = {1552-4833}, doi = {10.1002/ajmg.a.35239}, author = {Fabretto, Antonella and Santa Rocca, Maria and Perrone, Maria Dolores and Skabar, Aldo and Pecile, Vanna and Gasparini, Paolo} } @article {1804, title = {De novo 911 Kb interstitial deletion on chromosome 1q43 in a boy with mental retardation and short stature.}, journal = {Eur J Med Genet}, volume = {55}, year = {2012}, month = {2012 Feb}, pages = {117-9}, abstract = {

Patients with distal deletions of chromosome 1q have a recognizable syndrome that includes microcephaly, hypoplasia or agenesis of the corpus callosum, and psychomotor retardation. Although these symptoms have been attributed to deletions of 1q42-1q44, the minimal chromosomal region involved has not yet defined. In this report, we describe a 7 years old male with mental retardation, cryptorchid testes, short stature and alopecia carrying only an interstitial de novo deletion of 911 Kb in the 1q43 region (239,597,095-240,508,817) encompassing three genes CHRM3, RPS7P5 and FMN2.

}, keywords = {Child, Chromosomes, Human, Pair 1, Dwarfism, Humans, Intellectual Disability, Male, Sequence Deletion}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2011.11.004}, author = {Perrone, M D and Rocca, M S and Bruno, I and Faletra, F and Pecile, V and Gasparini, P} } @article {1785, title = {Delayed diagnosis of glycogen storage disease type III.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {54}, year = {2012}, month = {2012 Jan}, pages = {122-4}, keywords = {Delayed Diagnosis, Diagnostic Errors, Glycogen Storage Disease Type I, Glycogen Storage Disease Type III, Humans, Infant, Liver, Male}, issn = {1536-4801}, doi = {10.1097/MPG.0b013e318228d806}, author = {Minen, Federico and Cont, Gabriele and De Cunto, Angela and Martelossi, Stefano and Ventura, Alessandro and Maggiore, Giuseppe and Faletra, Flavio and Gasparini, Paolo and Cassandrini, Denise} } @article {1807, title = {Does the 1.5 Mb microduplication in chromosome band Xp22.31 have a pathogenetic role? New contribution and a review of the literature.}, journal = {Am J Med Genet A}, volume = {158A}, year = {2012}, month = {2012 Feb}, pages = {461-4}, keywords = {Chromosome Breakpoints, Chromosome Duplication, Chromosomes, Human, X, Hand Deformities, Congenital, Humans, Intellectual Disability, Karyotyping, Muscle Hypotonia, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatases}, issn = {1552-4833}, doi = {10.1002/ajmg.a.34398}, author = {Faletra, Flavio and d{\textquoteright}Adamo, Adamo Pio and Santa Rocca, Maria and Carrozzi, Marco and Perrone, Maria Dolores and Pecile, Vanna and Gasparini, Paolo} } @article {1927, title = {Endothelial cells obtained from patients affected by chronic venous disease exhibit a pro-inflammatory phenotype.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e39543}, abstract = {

BACKGROUND: The inflammatory properties of vein endothelium in relation to chronic venous disease (CVD) have been poorly investigated. Therefore, new insights on the characteristics of large vein endothelium would increase our knowledge of large vessel physiopathology.

METHODOLOGY/PRINCIPAL FINDINGS: Surgical specimens of veins were obtained from the tertiary venous network (R3) and/or saphenous vein (SF) of patients affected by CVD and from control individuals. Highly purified venous endothelial cell (VEC) cultures obtained from CVD patients were characterized for morphological, phenotypic and functional properties compared to control VEC. An increase of CD31/PECAM-1, CD146 and ICAM-1 surface levels was documented at flow cytometry in pathological VEC with respect to normal controls. Of note, the strongest expression of these pro-inflammatory markers was observed in VEC obtained from patients with more advanced disease. Similarly, spontaneous cell proliferation and resistance to starvation was higher in pathological than in normal VEC, while the migratory response of VEC showed an opposite trend, being significantly lower in VEC obtained from pathological specimens. In addition, in keeping with a higher baseline transcriptional activity of NF-kB, the release of the pro-inflammatory cytokines osteoprotegerin (OPG) and vascular endothelial growth factor (VEGF) was higher in pathological VEC cultures with respect to control VEC. Interestingly, there was a systemic correlation to these in vitro data, as demonstrated by higher serum OPG and VEGF levels in CVD patients with respect to normal healthy controls.

CONCLUSION/SIGNIFICANCE: Taken together, these data indicate that large vein endothelial cells obtained from CVD patients exhibit a pro-inflammatory phenotype, which might significantly contribute to systemic inflammation in CVD patients.

}, keywords = {Adult, Antigens, CD146, Antigens, CD31, Body Mass Index, Cell Culture Techniques, Endothelial Cells, Female, Flow Cytometry, Humans, Inflammation, Intercellular Adhesion Molecule-1, Kinetics, Male, Microscopy, Electron, Scanning, Middle Aged, Phenotype, Saphenous Vein, Vascular Diseases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0039543}, author = {Tisato, Veronica and Zauli, Giorgio and Voltan, Rebecca and Gianesini, Sergio and di Iasio, Maria Grazia and Volpi, Ilaria and Fiorentini, Guido and Zamboni, Paolo and Secchiero, Paola} } @article {1958, title = {Evidence of inbreeding depression on human height.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002655}, abstract = {

Stature is a classical and highly heritable complex trait, with 80\%-90\% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ(2) = 83.89, df = 1; p = 5.2 {\texttimes} 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

}, keywords = {Adult, Aged, Body Height, Consanguinity, Databases, Genetic, Family, Female, Genes, Recessive, Genetic Heterogeneity, Genome-Wide Association Study, Homozygote, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002655}, author = {McQuillan, Ruth and Eklund, Niina and Pirastu, Nicola and Kuningas, Maris and McEvoy, Brian P and Esko, T{\~o}nu and Corre, Tanguy and Davies, Gail and Kaakinen, Marika and Lyytik{\"a}inen, Leo-Pekka and Kristiansson, Kati and Havulinna, Aki S and G{\"o}gele, Martin and Vitart, Veronique and Tenesa, Albert and Aulchenko, Yurii and Hayward, Caroline and Johansson, {\r A}sa and Boban, Mladen and Ulivi, Sheila and Robino, Antonietta and Boraska, Vesna and Igl, Wilmar and Wild, Sarah H and Zgaga, Lina and Amin, Najaf and Theodoratou, Evropi and Polasek, Ozren and Girotto, Giorgia and Lopez, Lorna M and Sala, Cinzia and Lahti, Jari and Laatikainen, Tiina and Prokopenko, Inga and Kals, Mart and Viikari, Jorma and Yang, Jian and Pouta, Anneli and Estrada, Karol and Hofman, Albert and Freimer, Nelson and Martin, Nicholas G and K{\"a}h{\"o}nen, Mika and Milani, Lili and Heli{\"o}vaara, Markku and Vartiainen, Erkki and R{\"a}ikk{\"o}nen, Katri and Masciullo, Corrado and Starr, John M and Hicks, Andrew A and Esposito, Laura and Kolcic, Ivana and Farrington, Susan M and Oostra, Ben and Zemunik, Tatijana and Campbell, Harry and Kirin, Mirna and Pehlic, Marina and Faletra, Flavio and Porteous, David and Pistis, Giorgio and Widen, Elisabeth and Salomaa, Veikko and Koskinen, Seppo and Fischer, Krista and Lehtim{\"a}ki, Terho and Heath, Andrew and McCarthy, Mark I and Rivadeneira, Fernando and Montgomery, Grant W and Tiemeier, Henning and Hartikainen, Anna-Liisa and Madden, Pamela A F and d{\textquoteright}Adamo, Pio and Hastie, Nicholas D and Gyllensten, Ulf and Wright, Alan F and van Duijn, Cornelia M and Dunlop, Malcolm and Rudan, Igor and Gasparini, Paolo and Pramstaller, Peter P and Deary, Ian J and Toniolo, Daniela and Eriksson, Johan G and Jula, Antti and Raitakari, Olli T and Metspalu, Andres and Perola, Markus and J{\"a}rvelin, Marjo-Riitta and Uitterlinden, Andr{\'e} and Visscher, Peter M and Wilson, James F} } @article {1899, title = {Extra-large letter spacing improves reading in dyslexia.}, journal = {Proc Natl Acad Sci U S A}, volume = {109}, year = {2012}, month = {2012 Jul 10}, pages = {11455-9}, abstract = {

Although the causes of dyslexia are still debated, all researchers agree that the main challenge is to find ways that allow a child with dyslexia to read more words in less time, because reading more is undisputedly the most efficient intervention for dyslexia. Sophisticated training programs exist, but they typically target the component skills of reading, such as phonological awareness. After the component skills have improved, the main challenge remains (that is, reading deficits must be treated by reading more--a vicious circle for a dyslexic child). Here, we show that a simple manipulation of letter spacing substantially improved text reading performance on the fly (without any training) in a large, unselected sample of Italian and French dyslexic children. Extra-large letter spacing helps reading, because dyslexics are abnormally affected by crowding, a perceptual phenomenon with detrimental effects on letter recognition that is modulated by the spacing between letters. Extra-large letter spacing may help to break the vicious circle by rendering the reading material more easily accessible.

}, keywords = {Attention, Awareness, Child, Dyslexia, Form Perception, France, Humans, Italy, Language, Pattern Recognition, Visual, Phonetics, Reading, Vision, Ocular, Visual Fields}, issn = {1091-6490}, doi = {10.1073/pnas.1205566109}, author = {Zorzi, Marco and Barbiero, Chiara and Facoetti, Andrea and Lonciari, Isabella and Carrozzi, Marco and Montico, Marcella and Bravar, Laura and George, Florence and Pech-Georgel, Catherine and Ziegler, Johannes C} } @article {1823, title = {Febrile urinary tract infections in young children: recommendations for the diagnosis, treatment and follow-up.}, journal = {Acta Paediatr}, volume = {101}, year = {2012}, month = {2012 May}, pages = {451-7}, abstract = {

UNLABELLED: We report the recommendations for the diagnosis, treatment, imaging evaluation and use of antibiotic prophylaxis in children with the first febrile urinary tract infection, aged 2 months to 3 years. They were prepared by a working group of the Italian Society of Pediatric Nephrology after careful review of the available literature and a consensus decision, when clear evidence was not available.

CONCLUSION: These recommendations are endorsed by the Italian Society of Pediatric Nephrology. They can also be a tool of comparison with other existing guidelines in issues in which much controversy still exists.

}, keywords = {Anti-Bacterial Agents, Child, Preschool, Female, Fever, Follow-Up Studies, Humans, Infant, Male, Urinary Tract Infections}, issn = {1651-2227}, doi = {10.1111/j.1651-2227.2011.02549.x}, author = {Ammenti, Anita and Cataldi, Luigi and Chimenz, Roberto and Fanos, Vassilios and La Manna, Angela and Marra, Giuseppina and Materassi, Marco and Pecile, Paolo and Pennesi, Marco and Pisanello, Lorena and Sica, Felice and Toffolo, Antonella and Montini, Giovanni} } @article {1891, title = {Frequency of human papillomavirus types 16, 18, 31, and 33 and sites of cervical lesions in gynecological patients from Recife, Brazil.}, journal = {Genet Mol Res}, volume = {11}, year = {2012}, month = {2012}, pages = {462-6}, abstract = {

Human papilloma virus (HPV) is a well-established cause of cervical cancer. While many studies have been performed so far on HPV viral biology, mode of infection and prevention measures, scanty information is available on lesion sites of infected women and the incidence of viral types at specific locations. We looked for a possible relationship between the most common viral types (HPVs 16, 18, 31, 33) found in Recife, PE, Brazil, and lesion sites. We examined 396 HPV-positive women at the Gynecological Unit of the IMIP at Recife; 288 women were positive for HPV 16, 18, 31, or 33, present as a single-virus type or as co-infection. HPV 16 was the most frequent virus type found in the vulva, vagina, uterine cervix-vagina, and uterine cervix. HPV 31 was the second prevalent virus type in vulva, vagina, uterine cervix-vagina, uterine cervix, and mole. HPVs 18 and 33 were present with similar frequencies in the mole-vulva region. Among the co-infections, HPV 16/18 and HPV16/31 were the most frequent in our study group, followed by HPV 16/33.

}, keywords = {Adolescent, Adult, Brazil, Cervix Uteri, DNA, Viral, Female, Human papillomavirus 16, Human papillomavirus 18, Human papillomavirus 31, Humans, Papillomavirus Infections, Uterine Cervical Diseases, Young Adult}, issn = {1676-5680}, doi = {10.4238/2012.March.1.3}, author = {Baldez da Silva, M F P T and Guimar{\~a}es, V and Silva, M A R and Medeiros do Amaral, C M and Be{\c c}ak, W and Stocco, R C and Freitas, A C and Crovella, S} } @article {1907, title = {Genome-wide association and functional follow-up reveals new loci for kidney function.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002584}, abstract = {

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

}, keywords = {African Americans, Aged, Animals, Caspase 9, Cyclin-Dependent Kinases, DEAD-box RNA Helicases, DNA Helicases, European Continental Ancestry Group, Female, Follow-Up Studies, Gene Knockdown Techniques, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Male, Middle Aged, Phosphoric Diester Hydrolases, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002584}, author = {Pattaro, Cristian and K{\"o}ttgen, Anna and Teumer, Alexander and Garnaas, Maija and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Taliun, Daniel and Li, Man and Gao, Xiaoyi and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and O{\textquoteright}Seaghdha, Conall M and Glazer, Nicole and Isaacs, Aaron and Liu, Ching-Ti and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Johnson, Andrew D and Gierman, Hinco J and Feitosa, Mary and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, {\r A}sa and T{\"o}njes, Anke and Dehghan, Abbas and Chouraki, Vincent and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Kollerits, Barbara and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Cavalieri, Margherita and Rao, Madhumathi and Hu, Frank B and Demirkan, Ayse and Oostra, Ben A and de Andrade, Mariza and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Koenig, Wolfgang and Illig, Thomas and D{\"o}ring, Angela and Wichmann, H-Erich and Kolcic, Ivana and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Endlich, Karlhans and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Ketkar, Shamika and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Giulianini, Franco and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Metzger, Marie and Mitchell, Paul and Ciullo, Marina and Kim, Stuart K and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Siscovick, David S and van Duijn, Cornelia M and Borecki, Ingrid and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline C M and Hayward, Caroline and Ridker, Paul and Parsa, Afshin and Bochud, Murielle and Heid, Iris M and Goessling, Wolfram and Chasman, Daniel I and Kao, W H Linda and Fox, Caroline S} } @article {1919, title = {Genomic profiling by whole-genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse.}, journal = {Genes Chromosomes Cancer}, volume = {51}, year = {2012}, month = {2012 Jul}, pages = {644-53}, abstract = {

Despite the excellent survival rate of Wilms tumor (WT) patients, only approximately one-half of children who suffer tumor recurrence reach second durable remission. This underlines the need for novel markers to optimize initial treatment. We investigated 77 tumors using Illumina 370CNV-QUAD genotyping BeadChip arrays and compared their genomic profiles to detect copy number (CN) abnormalities and allelic ratio anomalies associated with the following clinicopathological variables: relapse (yes vs. no), age at diagnosis (<= 24 months vs. >24 months), and disease stage (low stage, I and II, vs. high stage, III and IV). We found that CN gains at chromosome region 1q21.1-q31.3 were significantly associated with relapse. Additional genetic events, including allelic imbalances at chromosome arms 1p, 1q, 3p, 3q, and 14q were also found to occur at higher frequency in relapsing tumors. Interestingly, allelic imbalances at 1p and 14q also showed a borderline association with higher tumor stages. No genetic events were found to be associated with age at diagnosis. This is the first genome wide analysis with single nucleotide polymorphism (SNP) arrays specifically investigating the role of genetic anomalies in predicting WT relapse on cases prospectively enrolled in the same clinical trial. Our study, besides confirming the role of 1q gains, identified a number of additional candidate genetic markers, warranting further molecular investigations.

}, keywords = {Adolescent, Allelic Imbalance, Child, Child, Preschool, Chromosome Aberrations, DNA Copy Number Variations, Female, Genetic Markers, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Infant, Kaplan-Meier Estimate, Male, Polymorphism, Single Nucleotide, Prospective Studies, Recurrence, Wilms Tumor}, issn = {1098-2264}, doi = {10.1002/gcc.21951}, author = {Perotti, Daniela and Spreafico, Filippo and Torri, Federica and Gamba, Beatrice and d{\textquoteright}Adamo, Pio and Pizzamiglio, Sara and Terenziani, Monica and Catania, Serena and Collini, Paola and Nantron, Marilina and Pession, Andrea and Bianchi, Maurizio and Indolfi, Paolo and D{\textquoteright}Angelo, Paolo and Fossati-Bellani, Franca and Verderio, Paolo and Macciardi, Fabio and Radice, Paolo} } @article {1791, title = {Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation.}, journal = {Bone Marrow Transplant}, volume = {47}, year = {2012}, month = {2012 Jun}, pages = {770-90}, abstract = {

In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized.

}, keywords = {Autoimmune Diseases, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, European Union, Female, Hematopoietic Stem Cell Transplantation, Humans, Male, Risk Factors, Safety, Severity of Illness Index}, issn = {1476-5365}, doi = {10.1038/bmt.2011.185}, author = {Snowden, J A and Saccardi, R and Allez, M and Ardizzone, S and Arnold, R and Cervera, R and Denton, C and Hawkey, C and Labopin, M and Mancardi, G and Martin, R and Moore, J J and Passweg, J and Peters, C and Rabusin, M and Rovira, M and van Laar, J M and Farge, D} } @article {1825, title = {HIV-1 induces NALP3-inflammasome expression and interleukin-1β secretion in dendritic cells from healthy individuals but not from HIV-positive patients.}, journal = {AIDS}, volume = {26}, year = {2012}, month = {2012 Jan 2}, pages = {11-8}, abstract = {

OBJECTIVE: NALP3-inflammasome is an innate mechanism, alternative to type-1 interferon, which is able to recognize nucleic acids and viruses in the cytoplasm and to induce pro-inflammatory response. Here, we hypothesized the involvement of inflammasome in the early defense against HIV-1 and in the full maturation of dendritic cells: for this, we evaluated the response of dendritic cells pulsed with HIV-1 in terms of inflammasome activation in healthy donors. Moreover, inflammasome response to HIV was evaluated in HIV-infected individuals.

DESIGN AND METHODS: Monocyte-derived dendritic cells isolated from 20 healthy individuals (HC-DC) and 20 HIV-1-infected patients (HIV-DC) were pulsed with alditrithiol-2-inactivated HIV-1. We then analyzed inflammasome genes expression and interleukin-1β (IL-1β) secretion.

RESULTS: In HC-DC, HIV-1 induced higher NLRP3/NALP3 mRNA expression compared with other inflammasome genes such as NALP1/NLRP1 or IPAF/NLRC4 (P < 0.001). This augmented expression was accompanied by CASP1-increased and IL1B-increased mRNA levels and by a significant increment of IL-1β secretion (P < 0.05). Otherwise, HIV-1 failed to activate inflammasome and cytokine production in HIV-DC. HIV-DC showed an increased NLRP3/NALP3 basal expression, suggesting a chronic inflammatory profile of patients{\textquoteright} immune cells.

CONCLUSION: HIV-1 was able to induce a NALP3-inflammasome response in healthy individuals, indicating that this inflammasome could play a role in the first steps of HIV-1 infection; the consequent inflammatory process may be important for directing host immune response against the virus and/or disease progression. HIV-DC seemed to be chronically activated, but unresponsive against pathogens. Our findings could be of interest considering the ongoing research about dendritic cell manipulation and therapeutic strategies for AIDS involving dendritic cell-based immune-vaccines.

}, keywords = {Acquired Immunodeficiency Syndrome, Adult, Brazil, Carrier Proteins, Caspase 1, Cells, Cultured, Dendritic Cells, DNA, Viral, Female, HIV-1, Humans, Immunity, Innate, Inflammasomes, Interleukin-1beta, Male, Tumor Necrosis Factor-alpha}, issn = {1473-5571}, doi = {10.1097/QAD.0b013e32834d697f}, author = {Pontillo, Alessandra and Silva, Lais T and Oshiro, Telma M and Finazzo, Claudia and Crovella, Sergio and Duarte, Alberto J S} } @article {1954, title = {Identification of a New Mutation (L46P) in the Human NOG Gene in an Italian Patient with Symphalangism Syndrome.}, journal = {Mol Syndromol}, volume = {3}, year = {2012}, month = {2012 Jun}, pages = {21-24}, abstract = {

Proximal symphalangism (SYM1) is a joint morphogenesis disorder characterized by stapes ankylosis, proximal interphalangeal joint fusion, skeletal anomalies and conductive hearing loss. Noggin is a bone morphogenetic protein (BMP) antagonist essential for normal bone and joint development in humans and mice. Autosomal dominant mutations have been described in the NOG gene, encoding the noggin protein. We analyzed an Italian sporadic patient with SYM1 due to a novel NOG mutation (L46P) based on a c.137T>C transition. A different pathogenic mutation in the same codon (L46D) has been previously described in an in vivo chicken model. An in silico model shows a decreased binding affinity between noggin and BMP7 for both L46D and L46P compared to the wild type. Therefore, this codon should play an important role in BMP7 binding activity of the noggin protein and consequently to the joint morphogenesis.

}, issn = {1661-8769}, doi = {000337928}, author = {Athanasakis, E and Biarn{\'e}s, X and Bonati, M T and Gasparini, P and Faletra, F} } @article {1980, title = {Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.}, journal = {Hum Mol Genet}, volume = {21}, year = {2012}, month = {2012 Dec 15}, pages = {5329-43}, abstract = {

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 {\texttimes} 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 {\texttimes} 10(-4)-2.2 {\texttimes} 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

}, keywords = {Amino Acid Transport Systems, Basic, Antigens, CD98 Heavy Chain, Genetic Predisposition to Disease, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Inhibin-beta Subunits, Intracellular Signaling Peptides and Proteins, Low Density Lipoprotein Receptor-Related Protein-2, Membrane Proteins, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/dds369}, author = {Chasman, Daniel I and Fuchsberger, Christian and Pattaro, Cristian and Teumer, Alexander and B{\"o}ger, Carsten A and Endlich, Karlhans and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Taliun, Daniel and Li, Man and Gao, Xiaoyi and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and O{\textquoteright}Seaghdha, Conall M and Glazer, Nicole and Isaacs, Aaron and Liu, Ching-Ti and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Johnson, Andrew D and Gierman, Hinco J and Feitosa, Mary F and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, {\r A}sa and T{\"o}njes, Anke and Dehghan, Abbas and Lambert, Jean-Charles and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Coassin, Stefan and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Cavalieri, Margherita and Rao, Madhumathi and Hu, Frank and Demirkan, Ayse and Oostra, Ben A and de Andrade, Mariza and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Giulianini, Franco and Koenig, Wolfgang and Illig, Thomas and Meisinger, Christa and Gieger, Christian and Zgaga, Lina and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Stengel, B{\'e}n{\'e}dicte and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Ketkar, Shamika and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Mitchell, Paul and Ciullo, Marina and Kim, Stuart K and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Siscovick, David S and van Duijn, Cornelia M and Borecki, Ingrid B and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline and Hayward, Caroline and Ridker, Paul M and Parsa, Afshin and Bochud, Murielle and Heid, Iris M and Kao, W H Linda and Fox, Caroline S and K{\"o}ttgen, Anna} } @article {1845, title = {Lutein and zeaxanthin supplementation in preterm infants to prevent retinopathy of prematurity: a randomized controlled study.}, journal = {J Matern Fetal Neonatal Med}, volume = {25}, year = {2012}, month = {2012 May}, pages = {523-7}, abstract = {

OBJECTIVES: Lutein and its isomer zeaxanthin (L/Z) function in the eye as antioxidant agents and blue-light filters. Our aim was to evaluate whether their administration could help decrease the occurrence of retinopathy of prematurity (ROP) in preterm infants.

METHODS: Infants with gestational age <=32 weeks were randomly assigned to receive a daily dose of L/Z (0.14 + 0.006 mg) or placebo until discharge.

RESULTS: ROP occurrence was similar in the L/Z (11/58; 19\%) and placebo (15/56; 27\%) groups, as the occurrence of ROP at each stage and the need of eye surgery.

CONCLUSION: L/Z supplementation was ineffective in preventing ROP in preterm infants and did not affect the outcome at discharge of our patients.

}, keywords = {Antioxidants, Drug Administration Schedule, Drug Combinations, Female, Humans, Infant, Newborn, Infant, Premature, Logistic Models, Lutein, Male, Retinopathy of Prematurity, Risk Factors, Treatment Outcome, Xanthophylls, Zeaxanthins}, issn = {1476-4954}, doi = {10.3109/14767058.2011.629252}, author = {Dani, Carlo and Lori, Ilaria and Favelli, Federica and Frosini, Saverio and Messner, Hubert and Wanker, Petra and De Marini, Sergio and Oretti, Chiara and Boldrini, Antonio and Massimiliano, Ciantelli and Bragetti, Patrizia and Germini, Cristiana} } @article {1812, title = {Mannose-binding lectin and MBL-associated serine protease-2 gene polymorphisms in a Brazilian population from Rio de Janeiro.}, journal = {Int J Immunogenet}, volume = {39}, year = {2012}, month = {2012 Feb}, pages = {32-8}, abstract = {

Mannose-binding lectin (MBL) is a protein able to bind to carbohydrate patterns on pathogen membranes; upon MBL binding, its{\textquoteright} associated serine protease MBL-associated serine protease type 2 (MASP2) is autoactivated, promoting the activation of complement via the lectin pathway. For both MBL2 and MASP2 genes, the frequencies of polymorphisms are extremely variable between different ethnicities, and this aspect has to be carefully considered when performing genetic studies. While polymorphisms in the MBL-encoding gene (MBL2) have been associated, depending upon ethnicity, with several diseases in different populations, little is known about the distribution of MASP2 gene polymorphisms in human populations. The aim of our study was thus to determine the frequencies of MBL2 (exon 1 and promoter) and MASP2 (p.D371Y) polymorphisms in a Brazilian population from Rio de Janeiro. A total of 294 blood donor samples were genotyped for 27 polymorphisms in the MBL2 gene by direct sequencing of a region spanning from the promoter polymorphism H/L rs11003125 to the rs1800451 polymorphism (at codon 57 in the first exon of the gene). Genotyping for MASP2 p.D371Y was carried out using fluorogenic probes. To our knowledge, this is the first study reporting the prevalence of the MASP2 p.D371Y polymorphism in a Brazilian population. The C allele frequency 39\% is something intermediate between the reported 14\% in Europeans and 90\% in Sub-Saharan Africans. MBL2 polymorphisms frequencies were quite comparable to those previously reported for admixed Brazilians. Both MBL2 and MASP2 polymorphisms frequencies reported in our study for the admixed Brazilian population are somehow intermediate between those reported in Europeans and Africans, reflecting the ethnic composition of the southern Brazilian population, estimated to derive from an admixture of Caucasian (31\%), African (34\%) and Native American (33\%) populations. In conclusion, our population genetic study describes the frequencies of MBL2 and MASP2 functional SNPs in a population from Rio de Janeiro, with the aim of adding new information concerning the distribution of these SNPs in a previously unanalysed Brazilian population, thus providing a new genetic tool for the evaluation of the association of MBL2 and MASP2 functional SNPs with diseases in Brazil, with particular emphasis on the state of Rio de Janeiro.

}, keywords = {Adolescent, Adult, Brazil, Ethnic Groups, Exons, Female, Fluorescent Dyes, Gene Frequency, Genetics, Population, Genome, Human, HapMap Project, Humans, Male, Mannose-Binding Lectin, Mannose-Binding Protein-Associated Serine Proteases, Middle Aged, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Sequence Analysis, DNA, Young Adult}, issn = {1744-313X}, doi = {10.1111/j.1744-313X.2011.01052.x}, author = {Ferraroni, N R and Segat, L and Guimar{\~a}es, R L and Brand{\~a}o, L A C and Crovella, S and Constantino-Silva, R N and Loja, C and da Silva Duarte, A J and Grumach, A S} } @article {1906, title = {Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Mar}, pages = {260-8}, abstract = {

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 {\texttimes} 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

}, keywords = {Age Factors, DNA Helicases, DNA Primase, DNA Repair, DNA Repair Enzymes, DNA-Directed DNA Polymerase, European Continental Ancestry Group, Exodeoxyribonucleases, Female, Genetic Loci, Genome-Wide Association Study, Humans, Immunity, Menopause, Polymorphism, Single Nucleotide, Proteins}, issn = {1546-1718}, doi = {10.1038/ng.1051}, author = {Stolk, Lisette and Perry, John R B and Chasman, Daniel I and He, Chunyan and Mangino, Massimo and Sulem, Patrick and Barbalic, Maja and Broer, Linda and Byrne, Enda M and Ernst, Florian and Esko, T{\~o}nu and Franceschini, Nora and Gudbjartsson, Daniel F and Hottenga, Jouke-Jan and Kraft, Peter and McArdle, Patrick F and Porcu, Eleonora and Shin, So-Youn and Smith, Albert V and van Wingerden, Sophie and Zhai, Guangju and Zhuang, Wei V and Albrecht, Eva and Alizadeh, Behrooz Z and Aspelund, Thor and Bandinelli, Stefania and Lauc, Lovorka Barac and Beckmann, Jacques S and Boban, Mladen and Boerwinkle, Eric and Broekmans, Frank J and Burri, Andrea and Campbell, Harry and Chanock, Stephen J and Chen, Constance and Cornelis, Marilyn C and Corre, Tanguy and Coviello, Andrea D and d{\textquoteright}Adamo, Pio and Davies, Gail and de Faire, Ulf and de Geus, Eco J C and Deary, Ian J and Dedoussis, George V Z and Deloukas, Panagiotis and Ebrahim, Shah and Eiriksdottir, Gudny and Emilsson, Valur and Eriksson, Johan G and Fauser, Bart C J M and Ferreli, Liana and Ferrucci, Luigi and Fischer, Krista and Folsom, Aaron R and Garcia, Melissa E and Gasparini, Paolo and Gieger, Christian and Glazer, Nicole and Grobbee, Diederick E and Hall, Per and Haller, Toomas and Hankinson, Susan E and Hass, Merli and Hayward, Caroline and Heath, Andrew C and Hofman, Albert and Ingelsson, Erik and Janssens, A Cecile J W and Johnson, Andrew D and Karasik, David and Kardia, Sharon L R and Keyzer, Jules and Kiel, Douglas P and Kolcic, Ivana and Kutalik, Zolt{\'a}n and Lahti, Jari and Lai, Sandra and Laisk, Triin and Laven, Joop S E and Lawlor, Debbie A and Liu, Jianjun and Lopez, Lorna M and Louwers, Yvonne V and Magnusson, Patrik K E and Marongiu, Mara and Martin, Nicholas G and Klaric, Irena Martinovic and Masciullo, Corrado and McKnight, Barbara and Medland, Sarah E and Melzer, David and Mooser, Vincent and Navarro, Pau and Newman, Anne B and Nyholt, Dale R and Onland-Moret, N Charlotte and Palotie, Aarno and Par{\'e}, Guillaume and Parker, Alex N and Pedersen, Nancy L and Peeters, Petra H M and Pistis, Giorgio and Plump, Andrew S and Polasek, Ozren and Pop, Victor J M and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Rehnberg, Emil and Rotter, Jerome I and Rudan, Igor and Sala, Cinzia and Salumets, Andres and Scuteri, Angelo and Singleton, Andrew and Smith, Jennifer A and Snieder, Harold and Soranzo, Nicole and Stacey, Simon N and Starr, John M and Stathopoulou, Maria G and Stirrups, Kathleen and Stolk, Ronald P and Styrkarsdottir, Unnur and Sun, Yan V and Tenesa, Albert and Thorand, Barbara and Toniolo, Daniela and Tryggvadottir, Laufey and Tsui, Kim and Ulivi, Sheila and van Dam, Rob M and van der Schouw, Yvonne T and van Gils, Carla H and van Nierop, Peter and Vink, Jacqueline M and Visscher, Peter M and Voorhuis, Marlies and Waeber, Gerard and Wallaschofski, Henri and Wichmann, H Erich and Widen, Elisabeth and Wijnands-van Gent, Colette J M and Willemsen, Gonneke and Wilson, James F and Wolffenbuttel, Bruce H R and Wright, Alan F and Yerges-Armstrong, Laura M and Zemunik, Tatijana and Zgaga, Lina and Zillikens, M Carola and Zygmunt, Marek and Arnold, Alice M and Boomsma, Dorret I and Buring, Julie E and Crisponi, Laura and Demerath, Ellen W and Gudnason, Vilmundur and Harris, Tamara B and Hu, Frank B and Hunter, David J and Launer, Lenore J and Metspalu, Andres and Montgomery, Grant W and Oostra, Ben A and Ridker, Paul M and Sanna, Serena and Schlessinger, David and Spector, Tim D and Stefansson, Kari and Streeten, Elizabeth A and Thorsteinsdottir, Unnur and Uda, Manuela and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and V{\"o}lzke, Henry and Murray, Anna and Murabito, Joanne M and Visser, Jenny A and Lunetta, Kathryn L} } @article {1985, title = {Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Aug}, pages = {904-9}, abstract = {

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 {\texttimes} 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of \~{}110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

}, keywords = {Asian Continental Ancestry Group, Blood Urea Nitrogen, Cohort Studies, Creatinine, Genetic Predisposition to Disease, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic, Uric Acid}, issn = {1546-1718}, doi = {10.1038/ng.2352}, author = {Okada, Yukinori and Sim, Xueling and Go, Min Jin and Wu, Jer-Yuarn and Gu, Dongfeng and Takeuchi, Fumihiko and Takahashi, Atsushi and Maeda, Shiro and Tsunoda, Tatsuhiko and Chen, Peng and Lim, Su-Chi and Wong, Tien-Yin and Liu, Jianjun and Young, Terri L and Aung, Tin and Seielstad, Mark and Teo, Yik-Ying and Kim, Young Jin and Lee, Jong-Young and Han, Bok-Ghee and Kang, Daehee and Chen, Chien-Hsiun and Tsai, Fuu-Jen and Chang, Li-Ching and Fann, S-J Cathy and Mei, Hao and Rao, Dabeeru C and Hixson, James E and Chen, Shufeng and Katsuya, Tomohiro and Isono, Masato and Ogihara, Toshio and Chambers, John C and Zhang, Weihua and Kooner, Jaspal S and Albrecht, Eva and Yamamoto, Kazuhiko and Kubo, Michiaki and Nakamura, Yusuke and Kamatani, Naoyuki and Kato, Norihiro and He, Jiang and Chen, Yuan-Tsong and Cho, Yoon Shin and Tai, E-Shyong and Tanaka, Toshihiro} } @article {1928, title = {Mevalonate kinase deficiency: disclosing the role of mevalonate pathway modulation in inflammation.}, journal = {Curr Pharm Des}, volume = {18}, year = {2012}, month = {2012}, pages = {5746-52}, abstract = {

Inflammation is a highly regulated process involved both in the response to pathogens as well as in tissue homeostasis. In recent years, a complex network of proteins in charge of inflammation control has been revealed by the study of hereditary periodic fever syndromes. Most of these proteins belong to a few families and share the capability of sensing pathogen-associated and damageassociated molecular patterns. By interacting with each other, these proteins participate in the assembly of molecular platforms, called inflammasomes, which ultimately lead to the activation of cytokines, to the transcription of inflammatory genes or to the induction of cell apoptosis. Among hereditary periodic fever syndromes, mevalonate kinase deficiency (MKD) is the sole in which the phenotype did not directly associate with a deficiency of these proteins, but with a metabolic defect of the mevalonate pathway, highlighting the importance of this metabolic pathway in the inflammation control. Noteworthy, drugs acting on this pathway can greatly influence the inflammatory response. The modulation of inflammation by mevalonate pathway is of interest, since it may involve mechanisms not directly referable to inflammasomes. MKD provides a model to study these mechanisms and possibly to develop new classes of anti-inflammatory drugs.

}, keywords = {Animals, Anti-Inflammatory Agents, Apoptosis, Cytokines, Drug Design, Hereditary Autoinflammatory Diseases, Humans, Inflammasomes, Inflammation, Mevalonate Kinase Deficiency, Mevalonic Acid}, issn = {1873-4286}, author = {Marcuzzi, Annalisa and Crovella, Sergio and Monasta, Lorenzo and Vecchi Brumatti, Liza and Gattorno, Marco and Frenkel, Joost} } @article {1984, title = {miR-EdiTar: a database of predicted A-to-I edited miRNA target sites.}, journal = {Bioinformatics}, volume = {28}, year = {2012}, month = {2012 Dec 1}, pages = {3166-8}, abstract = {

MOTIVATION: A-to-I RNA editing is an important mechanism that consists of the conversion of specific adenosines into inosines in RNA molecules. Its dysregulation has been associated to several human diseases including cancer. Recent work has demonstrated a role for A-to-I editing in microRNA (miRNA)-mediated gene expression regulation. In fact, edited forms of mature miRNAs can target sets of genes that differ from the targets of their unedited forms. The specific deamination of mRNAs can generate novel binding sites in addition to potentially altering existing ones.

RESULTS: This work presents miR-EdiTar, a database of predicted A-to-I edited miRNA binding sites. The database contains predicted miRNA binding sites that could be affected by A-to-I editing and sites that could become miRNA binding sites as a result of A-to-I editing.

AVAILABILITY: miR-EdiTar is freely available online at http://microrna.osumc.edu/mireditar.

CONTACT: alessandro.lagana@osumc.edu or carlo.croce@osumc.edu

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

}, keywords = {Adenosine, Binding Sites, Databases, Genetic, Gene Expression Regulation, Humans, Inosine, Internet, MicroRNAs, Nucleic Acid Conformation, RNA Editing}, issn = {1367-4811}, doi = {10.1093/bioinformatics/bts589}, author = {Lagan{\`a}, Alessandro and Paone, Alessio and Veneziano, Dario and Cascione, Luciano and Gasparini, Pierluigi and Carasi, Stefania and Russo, Francesco and Nigita, Giovanni and Macca, Valentina and Giugno, Rosalba and Pulvirenti, Alfredo and Shasha, Dennis and Ferro, Alfredo and Croce, Carlo M} } @article {1967, title = {Molecular diagnosis of Usher syndrome: application of two different next generation sequencing-based procedures.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e43799}, abstract = {

Usher syndrome (USH) is a clinically and genetically heterogeneous disorder characterized by visual and hearing impairments. Clinically, it is subdivided into three subclasses with nine genes identified so far. In the present study, we investigated whether the currently available Next Generation Sequencing (NGS) technologies are already suitable for molecular diagnostics of USH. We analyzed a total of 12 patients, most of which were negative for previously described mutations in known USH genes upon primer extension-based microarray genotyping. We enriched the NGS template either by whole exome capture or by Long-PCR of the known USH genes. The main NGS sequencing platforms were used: SOLiD for whole exome sequencing, Illumina (Genome Analyzer II) and Roche 454 (GS FLX) for the Long-PCR sequencing. Long-PCR targeting was more efficient with up to 94\% of USH gene regions displaying an overall coverage higher than 25{\texttimes}, whereas whole exome sequencing yielded a similar coverage for only 50\% of those regions. Overall this integrated analysis led to the identification of 11 novel sequence variations in USH genes (2 homozygous and 9 heterozygous) out of 18 detected. However, at least two cases were not genetically solved. Our result highlights the current limitations in the diagnostic use of NGS for USH patients. The limit for whole exome sequencing is linked to the need of a strong coverage and to the correct interpretation of sequence variations with a non obvious, pathogenic role, whereas the targeted approach suffers from the high genetic heterogeneity of USH that may be also caused by the presence of additional causative genes yet to be identified.

}, keywords = {Child, Preschool, Exome, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Molecular Diagnostic Techniques, Pilot Projects, Sequence Analysis, DNA, Usher Syndromes}, issn = {1932-6203}, doi = {10.1371/journal.pone.0043799}, author = {Licastro, Danilo and Mutarelli, Margherita and Peluso, Ivana and Neveling, Kornelia and Wieskamp, Nienke and Rispoli, Rossella and Vozzi, Diego and Athanasakis, Emmanouil and D{\textquoteright}Eustacchio, Angela and Pizzo, Mariateresa and D{\textquoteright}Amico, Francesca and Ziviello, Carmela and Simonelli, Francesca and Fabretto, Antonella and Scheffer, Hans and Gasparini, Paolo and Banfi, Sandro and Nigro, Vincenzo} } @article {1930, title = {NF-κB as a target for modulating inflammatory responses.}, journal = {Curr Pharm Des}, volume = {18}, year = {2012}, month = {2012}, pages = {5735-45}, abstract = {

The inflammatory response is of major importance in host defence, but is involved in all acute and chronic diseases. Multiple inflammatory cells and molecules are involved. Among the latter, the Nuclear Factor -κB (NF-κB) has been found to be most important and present in all cell types. NF-B regulates the expression of a large number of genes involved in inflammation. NF-κB plays a key role in the orchestration of the multifaceted inflammatory response, not only in the first pro-inflammatory phase, but also later in the regulation of the resolution of inflammation, when anti-inflammatory genes are expressed and apoptosis is induced. The review describes NF-κB and its two pathways: the canonical, mediated by the p65 and p50 subunits, and the non-canonical, mediated by the subunits RelB, p52 and p50. The relevance of the kinases and interactions leading to NF-κB activation is considered in different primary cells (i.e. macrophages, dendritic cells, fibroblasts, cells from inflammatory tissues), together with the response induced and the ligand involved. Then we overview the different steps to NF-B activation that can be targeted (IKKs, IκBα or NF-κB subunits themselves) with various technologies available i.e. small molecules peptides or nucleic acids. A rationale is provided for possible targets to consider, in the light that NF-κB signaling pathways regulates both pro-inflammatory and anti-inflammatory responses. The possibility of using NF-κB targeted dendritic cells in immunotherapy is considered.

}, keywords = {Acute Disease, Animals, Chronic Disease, Dendritic Cells, Gene Expression Regulation, Humans, Immunotherapy, Inflammation, NF-kappa B, Signal Transduction}, issn = {1873-4286}, author = {Gasparini, Chiara and Feldmann, Marc} } @article {1933, title = {Personalized therapies in pediatric inflammatory and autoimmune diseases.}, journal = {Curr Pharm Des}, volume = {18}, year = {2012}, month = {2012}, pages = {5766-75}, abstract = {

Pediatric inflammatory and autoimmune diseases are a wide array of systemic or organ-specific conditions, characterized by an exaggerated immune reactivity, which generally occurs in immunogenetically predisposed children. Among the most important ones, in terms of their diffusion and morbidity in the population worldwide, pediatric inflammatory bowel disease (IBD) and juvenile rheumatoid arthritis (JRA) have to be considered. The aim of personalized therapy is to give to each patient the most appropriate drug and dose regimen, in order to maximize treatment response and reduce the risk of adverse events. In general, several therapeutic options exist for pediatric inflammatory and autoimmune conditions, therefore the perspective of pharmacological tools that allow identification of patients with increased risk of treatment issues related to a particular medication, in terms of lack of efficacy or increased probability of adverse events, is particularly desirable and promising. The present review will be focused on the personalized therapy approaches already available or in development for pediatric patients with IBD or JRA, comprising pharmacokinetic, pharmacodynamic and pharmacogenetic assays.

}, keywords = {Arthritis, Rheumatoid, Autoimmune Diseases, Child, Genetic Predisposition to Disease, Humans, Immunogenetic Phenomena, Individualized Medicine, Inflammation, Inflammatory Bowel Diseases, Pharmacogenetics}, issn = {1873-4286}, author = {Stocco, Gabriele and De Iudicibus, Sara and Franca, Raffaella and Addobbati, Riccardo and Decorti, Giuliana} } @article {1988, title = {Phylloid pattern of hypomelanosis closely related to chromosomal abnormalities in the 13q detected by SNP array analysis.}, journal = {Dermatology}, volume = {225}, year = {2012}, month = {2012}, pages = {294-7}, abstract = {

Phylloid hypomelanosis is a distinct type of pigmentary mosaicism characterized by congenital hypochromic macules resembling a floral ornament with various elements such as round or oval patches, asymmetrical macules similar to begonia leaves, or oblong lesions. It has been found to be predominantly associated with abnormalities in chromosome 13 and sometimes as-sociated with different extracutaneous abnormalities. Here, we report 2 new cases of phylloid hypomelanosis due to mosaicism involving chromosome 13. The first one is a mosaicism for a supernumerary marker belonging to chromosome 13 and the second one is the first report of phylloid hypomelanosis associated with a mosaic deletion of 13q. Because of the extremely low level of mosaicism in these 2 cases, SNP array analysis on skin fibroblasts was carried out, showing a 13q21.33-q34 duplication (71,024,411-115,103,529) and a 13q13.3-q34 (38,368,012-115,103,529) deletion. Both cases underline on the one hand the strict connection between phylloid hypomelanosis and anomalies of chromosome 13, and on the other hand the relevance of the SNP array analysis on skin fibroblasts in the detection of low-level mosaicism.

}, keywords = {Chromosomes, Human, Pair 13, Humans, Hypopigmentation, Male, Mosaicism, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide}, issn = {1421-9832}, doi = {10.1159/000342884}, author = {Faletra, F and Berti, I and Tommasini, A and Pecile, V and Cleva, L and Alberini, E and Bruno, I and Gasparini, P} } @article {1966, title = {A red baby should not be taken too lightly.}, journal = {Acta Paediatr}, volume = {101}, year = {2012}, month = {2012 Dec}, pages = {e573-7}, abstract = {

AIM: To identify clinical and laboratory features that can drive the differential diagnosis of a primary immunodeficiency diseases in patients with ectodermal defects.

METHODS: Analysis of selected teaching cases.

RESULTS: We identified four exemplary cases that allowed to point out specific clues.

CONCLUSIONS: A careful evaluation of immune and ectodermal signs is the key to the diagnosis. Therefore, a multidisciplinary approach can lead to diagnosis and to an appropriate treatment in most of the cases.

}, keywords = {Child, Preschool, Dermatitis, Ectodermal Dysplasia, Female, Humans, Immunologic Deficiency Syndromes, Infant, Male, Netherton Syndrome, Severe Combined Immunodeficiency, Skin}, issn = {1651-2227}, doi = {10.1111/apa.12018}, author = {Faletra, Flavio and Bruno, Irene and Berti, Irene and Pastore, Serena and Pirrone, Angela and Tommasini, Alberto} } @article {1832, title = {Relation between maternal thrombophilia and stillbirth according to causes/associated conditions of death.}, journal = {Early Hum Dev}, volume = {88}, year = {2012}, month = {2012 Apr}, pages = {251-4}, abstract = {

OBJECTIVE: To investigate maternal thrombophilia in cases of Stillbirth (SB), also an uncertain topic because most case series were not characterised for cause/associated conditions of death.

STUDY DESIGN: In a consecutive, prospective, multicentre design, maternal DNA was obtained in 171 cases of antenatal SB and 326 controls (uneventful pregnancy at term, 1:2 ratio). Diagnostic work-up of SB included obstetric history, neonatologist inspection, placenta histology, autopsy, microbiology/chromosome evaluations. Results audited in each centre were classified by two of us by using CoDAC. Cases were subdivided into explained SB where a cause of death was identified and although no defined cause was detected in the remnants, 64 cases found conditions associated with placenta-vascular disorders (including preeclampsia, growth restriction and placenta abruption - PVD). In the remnant 79 cases, no cause of death or associated condition was found. Antithrombin activity, Factor V Leiden, G20210A Prothrombin mutation (FII mutation) and acquired thrombophilia were analysed.

RESULTS: Overall, the presence of a thrombophilic defect was significantly more prevalent in mothers with SBs compared to controls. In particular, SB mothers showed an increased risk of carrying Factor II mutation (OR=3.2, 95\% CI: 1.3-8.3, p=0.01), namely in unexplained cases. Such mutation was significantly associated also with previous SB (OR=8.9, 95\%CI 1.2-70.5). At multiple logistic regression, Factor II mutation was the only significantly associated variable with SB (adj OR=3.8, 95\% CI: 1.3-13.5).

CONCLUSION: These data suggest that Factor II mutation is the only condition specifically associated with unexplained SB and could represents a risk of recurrence. PVD-associated condition is unrelated to thrombophilia.

}, keywords = {Adult, Case-Control Studies, Cause of Death, Female, Fetal Diseases, Fetal Mortality, Humans, Infant, Newborn, Male, Placenta Diseases, Pre-Eclampsia, Pregnancy, Pregnancy Complications, Hematologic, Socioeconomic Factors, Stillbirth, Thrombophilia, Young Adult}, issn = {1872-6232}, doi = {10.1016/j.earlhumdev.2011.08.013}, author = {Monari, F and Alberico, S and Avagliano, L and Cetin, I and Cozzolino, S and Gargano, G and Marozio, L and Mecacci, F and Neri, I and Tranquilli, A L and Venturini, P and Facchinetti, F} } @article {1938, title = {Role of high molecular weight hyaluronic acid in postmenopausal vaginal discomfort.}, journal = {Minerva Ginecol}, volume = {64}, year = {2012}, month = {2012 Aug}, pages = {321-9}, abstract = {

AIM: Aim of the present study was to quantify the intensity of vulvovaginal symptoms before and after treatment with high molecular weight hyaluronic acid (HA), to test the tolerability and safety of the product, to evaluate the effect on the quality of life and the compliance to the treatment.

METHODS: This was a double-blind randomized placebo-controlled study. In seven months we enrolled 36 post-menopausal women, equally distributed in placebo and active group. The evaluation was based on at least three atrophy-related signs and on the patient reported symptoms. After the written informed consent, the participants were instructed to apply the gel (drug or placebo) daily. Three days after the end of the treatment the patients received a final examination to evaluate the progress of symptoms, the presence of any adverse events and their correlation with the treatment.

RESULTS: Self-evaluation scales and investigator evaluation showed that the vaginal dryness was significantly reduced both in placebo and in the active group; however, high molecular weight HA was the only active treatment in reducing significantly itching and burning (P<0.02 and <0.04 respectively). Both treatments significantly reduced vaginal atrophy (P<0.001), erythema (P<0.01 placebo and P<0.001 HA) and vaginal dryness (P<0.001), but HA treatment was significantly more effective on the first two symptoms. Both treatments were very well tolerated and compliance of the treatment was very high.

CONCLUSION: High molecular weight HA could be effective in subjective and objective improvement of postmenopausal vaginal atrophy providing a good compliance. No adverse events occurred during the entire period of the study.

}, keywords = {Atrophy, Double-Blind Method, Female, Humans, Hyaluronic Acid, Middle Aged, Molecular Weight, Postmenopause, Vagina, Vaginal Diseases}, issn = {0026-4784}, author = {Grimaldi, E F and Restaino, S and Inglese, S and Foltran, L and Sorz, A and Di Lorenzo, G and Guaschino, S} } @article {1887, title = {Sedation with intranasal midazolam of Angolan children undergoing invasive procedures.}, journal = {Acta Paediatr}, volume = {101}, year = {2012}, month = {2012 Jul}, pages = {e296-8}, abstract = {

AIM: Ambulatory surgery is a daily requirement in poor countries, and limited means and insufficient trained staff lead to the lack of attention to the patient{\textquoteright}s pain. Midazolam is a rapid-onset, short-acting benzodiazepine which is used safely to reduce pain in children. We evaluated the practicability of intranasal midazolam sedation in a suburban hospital in Luanda (Angola), during the surgical procedures.

METHODS: Intranasal midazolam solution was administered at a dose of 0.5 mg/kg. Using the Ramsay{\textquoteright}s reactivity score, we gave a score to four different types of children{\textquoteright}s behaviour: moaning, shouting, crying and struggling, and the surgeon evaluated the ease of completing the surgical procedure using scores from 0 (very easy) to 3 (managing with difficulty).

RESULTS: Eighty children (median age, 3 years) were recruited, and 140 surgical procedures were performed. Fifty-two children were treated with midazolam during 85 procedures, and 28 children were not treated during 55 procedures. We found a significant difference between the two groups on the shouting, crying and struggling parameters (p < 0.001). The mean score of the ease of completing the procedures was significantly different among the two groups (p < 0.0001).

CONCLUSION: These results provide a model of procedural sedation in ambulatory surgical procedures in poor countries, thus abolishing pain and making the surgeon{\textquoteright}s job easier.

}, keywords = {Administration, Intranasal, Adolescent, Ambulatory Surgical Procedures, Angola, Child, Child Behavior, Child, Preschool, Conscious Sedation, Crying, Female, Humans, Hypnotics and Sedatives, Infant, Male, Midazolam, Prospective Studies}, issn = {1651-2227}, doi = {10.1111/j.1651-2227.2012.02691.x}, author = {Kawanda, Lumana and Capobianco, Ivan and Starc, Meta and Felipe, Daniel and Zanon, Davide and Barbi, Egidio and Munkela, Nadine and Rodrigues, Ver{\'o}nica and Malundo, L{\'u}is and Not, Tarcisio} } @article {1909, title = {Specific protein profile in cerebrospinal fluid from HIV-1-positive cART-treated patients affected by neurological disorders.}, journal = {J Neurovirol}, volume = {18}, year = {2012}, month = {2012 Oct}, pages = {416-22}, abstract = {

Cytokines/chemokines are involved in the immune response of infections, including HIV-1. We defined the profile of 48 cytokines/chemokines in cerebrospinal fluid from 18 cART patients with chronic HIV-1 infection by Luminex technology. Nine patients were affected with leukoencephalopathies: five with John Cunningham virus (JCV) + progressive multifocal leukoencephalopathy (PML) and four with JCV-not determined leukoencephalopathy (NDLE). In addition, nine HIV-1-positive patients with no neurological signs (NND) and five HIV-1-negative patients affected with acute disseminated encephalomyelitis (ADEM) were enrolled. Ten cytokines (IL-15, IL-3, IL-16, IL-18, CTACK, GRO1, SCF, MCP-1, MIF, SDF) were highly expressed in HIV-1-positive patients while IL-1Ra and IL-17 were present at a lower level. In addition, the levels of IL-17, IL-9, FGF-basic, MIP-1β, and MCP-1 were significantly higher (p < 0.05) in patients with neurological diseases (PML, NDLE, ADEM) with respect to NND. Focusing the attention to the cytokine profile in JCV + PML patients with respect to JCV-NDLE patients, only TNF-β was significantly downregulated (p < 0.05) in JCV + PML patients. This pilot study emphasized the role of immunoregulation in HIV-1-related neurological disorders during cART treatment.

}, keywords = {Adult, Aged, Anti-HIV Agents, Cytokines, Encephalomyelitis, Acute Disseminated, Female, HIV Infections, HIV-1, Humans, Leukoencephalopathy, Progressive Multifocal, Male, Middle Aged, Pilot Projects}, issn = {1538-2443}, doi = {10.1007/s13365-012-0109-y}, author = {Zanin, Valentina and Delbue, Serena and Marcuzzi, Annalisa and Tavazzi, Eleonora and Del Savio, Rossella and Crovella, Sergio and Marchioni, Enrico and Ferrante, Pasquale and Comar, Manola} } @article {1889, title = {Stem cell ageing and apoptosis.}, journal = {Curr Pharm Des}, volume = {18}, year = {2012}, month = {2012}, pages = {1694-717}, abstract = {

Ageing has been defined as the process of deterioration of many body functions over the lifespan of an individual. In spite of the number of different theories about ageing, there is a general consensus in identifying ageing effects in a reduced capacity to regenerate injured tissues or organs and an increased propensity to infections and cancer. In recent years the stem cell theory of ageing has gained much attention. Adult stem cells residing in mammalian tissues are essential for tissue homeostasis and repair throughout adult life. With advancing age, the highly regulated molecular signalling necessary to ensure proper cellular, tissue, and organ homeostasis loses coordination and leads, as a consequence, to a compromised potential of regeneration and repair of damaged cells and tissues. Although a complete comprehension of the molecular mechanisms involved in stem cell ageing and apoptosis is far to be reached, recent studies are beginning to unravel the processes involved in stem cell ageing, particularly in adult skeletal muscle stem cells, namely satellite cells. Thus, the focus of this review is to analyse the relationship between stem cell ageing and apoptosis with a peculiar attention to human satellite cells as compared to haematopoietic stem cells. Undoubtedly, the knowledge of age-related changes of stem cells will help in understanding the ageing process itself and will provide novel therapeutic challenges for improved tissue regeneration.

}, keywords = {Adult, Apoptosis, Cell Aging, Humans, Stem Cells}, issn = {1873-4286}, author = {Fulle, Stefania and Centurione, Lucia and Mancinelli, Rosa and Sancilio, Silvia and Manzoli, Francesco Antonio and Di Pietro, Roberta} } @article {1990, title = {The submerged dyslexia iceberg: how many school children are not diagnosed? Results from an Italian study.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e48082}, abstract = {

BACKGROUND: Although dyslexia is one of the most common neurobehavioral disorders affecting children, prevalence is uncertain and available data are scanty and dated. The objective of this study is to evaluate the prevalence of dyslexia in an unselected school population using clearly defined and rigorous diagnostic criteria and methods.

METHODS: Cross sectional study. We selected a random cluster sample of 94 fourth grade elementary school classes of Friuli Venezia Giulia, a Region of North Eastern Italy. We carried out three consecutive levels of screening: the first two at school and the last at the Neuropsychiatry Unit of a third level Mother and Child Hospital. The main outcome measure was the prevalence of dyslexia, defined as the number of children positive to the third level of screening divided by the total number of children enrolled.

RESULTS: We recruited 1774 children aged 8-10 years, of which 1528 received parents{\textquoteright} consent to participate. After applying exclusion criteria, 1357 pupils constituted the final working sample. The prevalence of dyslexia in the enrolled population ranged from 3.1\% (95\% CI 2.2-4.1\%) to 3.2\% (95\% CI 2.4-4.3\%) depending on different criteria adopted. In two out of three children with dyslexia the disorder had not been previously diagnosed.

CONCLUSIONS: This study shows that dyslexia is largely underestimated in Italy and underlines the need for reliable information on prevalence, in order to better allocate resources both to Health Services and Schools.

}, keywords = {Area Under Curve, Child, Cross-Sectional Studies, Delayed Diagnosis, Dyslexia, Female, Humans, Italy, Male, Neuropsychological Tests, Prevalence, Questionnaires, ROC Curve}, issn = {1932-6203}, doi = {10.1371/journal.pone.0048082}, author = {Barbiero, Chiara and Lonciari, Isabella and Montico, Marcella and Monasta, Lorenzo and Penge, Roberta and Vio, Claudio and Tressoldi, Patrizio Emanuele and Ferluga, Valentina and Bigoni, Anna and Tullio, Alessia and Carrozzi, Marco and Ronfani, Luca} } @article {1911, title = {TNF-related apoptosis-inducing ligand significantly attenuates metabolic abnormalities in high-fat-fed mice reducing adiposity and systemic inflammation.}, journal = {Clin Sci (Lond)}, volume = {123}, year = {2012}, month = {2012 Nov}, pages = {547-55}, abstract = {

TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] has recently been shown to ameliorate the natural history of DM (diabetes mellitus). It has not been determined yet whether systemic TRAIL delivery would prevent the metabolic abnormalities due to an HFD [HF (high-fat) diet]. For this purpose, 27 male C57bl6 mice aged 8 weeks were randomly fed on a standard diet, HFD or HFD+TRAIL for 12 weeks. TRAIL was delivered weekly by intraperitoneal injection. Body composition was evaluated; indirect calorimetry studies, GTT (glucose tolerance test) and ITT (insulin tolerance test) were performed. Pro-inflammatory cytokines, together with adipose tissue gene expression and apoptosis, were measured. TRAIL treatment reduced significantly the increased adiposity associated with an HFD. Moreover, it reduced significantly hyperglycaemia and hyperinsulinaemia during a GTT and it improved significantly the peripheral response to insulin. TRAIL reversed the changes in substrate utilization induced by the HFD and ameliorated skeletal muscle non-esterified fatty acids oxidation rate. This was associated with a significant reduction of pro-inflammatory cytokines together with a modulation of adipose tissue gene expression and apoptosis. These findings shed light on the possible anti-adipogenic and anti-inflammatory effects of TRAIL and open new therapeutic possibilities against obesity, systemic inflammation and T2DM (Type 2 DM).

}, keywords = {Adiposity, Animals, Apoptosis, Calorimetry, Cytokines, Dietary Fats, Energy Intake, Glucose Tolerance Test, Hyperglycemia, Hyperinsulinism, Inflammation, Inflammation Mediators, Male, Mice, Mice, Inbred C57BL, Oxidation-Reduction, Palmitic Acid, Real-Time Polymerase Chain Reaction, TNF-Related Apoptosis-Inducing Ligand}, issn = {1470-8736}, doi = {10.1042/CS20120176}, author = {Bernardi, Stella and Zauli, Giorgio and Tikellis, Christos and Candido, Riccardo and Fabris, Bruno and Secchiero, Paola and Cooper, Mark E and Thomas, Merlin C} } @article {1917, title = {TRAIL as biomarker and potential therapeutic tool for cardiovascular diseases.}, journal = {Curr Drug Targets}, volume = {13}, year = {2012}, month = {2012 Aug}, pages = {1215-21}, abstract = {

This review focuses on TNF-related apoptosis-inducing ligand (TRAIL), also called Apo2 ligand, a protein belonging to the TNF superfamily. TRAIL can be found either in its transmembrane or circulating form, and its mostly studied peripheral effect is the induction of cellular apoptosis. Here, we discuss the evidences supporting the use of TRAIL as biomarker of cardiovascular diseases as well as the evidences showing the potential beneficial therapeutic effects of TRAIL on cardiovascular diseases and diabetes.

}, keywords = {Biological Markers, Cardiovascular Diseases, Humans, Prognosis, TNF-Related Apoptosis-Inducing Ligand}, issn = {1873-5592}, author = {Bernardi, Stella and Milani, Daniela and Fabris, Bruno and Secchiero, Paola and Zauli, Giorgio} } @article {1709, title = {TRAIL shows potential cardioprotective activity.}, journal = {Invest New Drugs}, volume = {30}, year = {2012}, month = {2012 Jun}, pages = {1257-60}, abstract = {

Recent clinical trials carried out in patients with advanced cancer have shown that recombinant TRAIL administration is usually safe and well tolerated when used either alone or in association with chemotherapeutic drugs. Notably, anticancer chemotherapy can be associated to cardiomiopathy. We have here demonstrated that TRAIL (administrated as either recombinant soluble TRAIL or as AAV-TRAIL expression viral vector) reduced the development of cardiomyopathy in the ApoE(-/-) diabetic mouse model. These data suggest, for the first time, that therapeutically administration of TRAIL might have a cardioprotective effect.

}, keywords = {Animals, Apolipoproteins E, Apoptosis, Cardiotonic Agents, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Diabetic Cardiomyopathies, Fibrosis, Male, Mice, Mice, Knockout, Recombinant Proteins, TNF-Related Apoptosis-Inducing Ligand}, issn = {1573-0646}, doi = {10.1007/s10637-010-9627-8}, author = {Toffoli, Barbara and Bernardi, Stella and Candido, Riccardo and Zacchigna, Serena and Fabris, Bruno and Secchiero, Paola} } @article {1953, title = {Two Novel COH1 Mutations in an Italian Patient with Cohen Syndrome.}, journal = {Mol Syndromol}, volume = {3}, year = {2012}, month = {2012 Jun}, pages = {30-33}, abstract = {

Cohen syndrome (CS) is an autosomal recessive disease caused by mutations in the COH1 gene. It is characterized by intellectual disability, hypotonia, joint hyperlaxity, severe myopia, characteristic facial dysmorphisms and, in some cases, intermittent isolated neutropenia. We investigated an Italian patient with CS together with his family. Genetic analysis disclosed 2 novel mutations: the first is an intronic mutation (c.8697-9A>G) creating a new splice site 8 nucleotides upstream, and the second is a duplication of 1 base (c.10156dupA) generating a premature stop codon. The compound heterozygous mutations explain the proband{\textquoteright}s phenotype and improved the knowledge of genotype-phenotype correlation.

}, issn = {1661-8769}, doi = {000338816}, author = {Athanasakis, E and Fabretto, A and Faletra, F and Mocenigo, M and Morgan, A and Gasparini, P} } @article {1987, title = {Use of specific antiretroviral regimens among HIV-infected women in Italy at time of conception: 2001-2011.}, journal = {AIDS Patient Care STDS}, volume = {26}, year = {2012}, month = {2012 Aug}, pages = {439-43}, keywords = {Anti-HIV Agents, Drug Administration Schedule, Female, Fertilization, HIV Protease Inhibitors, HIV Seropositivity, Humans, Infectious Disease Transmission, Vertical, Italy, Pregnancy, Reverse Transcriptase Inhibitors, Sentinel Surveillance}, issn = {1557-7449}, doi = {10.1089/apc.2012.0116}, author = {Floridia, Marco and Ravizza, Marina and Guaraldi, Giovanni and Pinnetti, Carmela and Martinelli, Pasquale and Tamburrini, Enrica} } @article {1602, title = {The active Zot domain (aa 288-293) increases ZO-1 and myosin 1C serine/threonine phosphorylation, alters interaction between ZO-1 and its binding partners, and induces tight junction disassembly through proteinase activated receptor 2 activation.}, journal = {FASEB J}, volume = {25}, year = {2011}, month = {2011 Jan}, pages = {144-58}, abstract = {

Vibrio cholerae-derived zonula occludins toxin (Zot) is a multifunctional protein that reversibly disassembles intestinal tight junctions (tjs). Zot structure-function analysis has mapped this activity to aa 288-293, named AT1002. AT1002 reduced transepithelial electrical resistance across rat small intestine, ex vivo, as did Zot and its processed mature form, ΔG. AT1002 increased in vivo permeability to sugar tracers, whereas scrambled control peptides did not. Binding and barrier assays in proteinase activated receptor (PAR)(2)-expressing and PAR(2)-null cells established AT1002 activity to be PAR(2) dependent. Coincident with the increased intestinal permeability, confocal microscopy of AT1002-exposed rat intestinal IEC6 cells revealed displacement of ZO-1 and occludin from intercellular boundaries. In coimmunoprecipitation assays, AT1002 decreased ZO-1-occludin and ZO-1-claudin 1 interactions coincident with PKCα-dependent ZO-1 serine/threonine phosphorylation. Further, AT1002 increased serine phosphorylation of myosin 1C and, at the same time, transiently diminished its association with ZO-1. The COOH-terminal domain of ZO-1 was required for its association with myosin 1C. These data indicate that the NH(2)-terminal portion of active Zot contains a PAR(2)-activating motif, FCIGRL, that increases PKCα-dependent ZO-1 and myosin 1C serine/threonine phosphorylation. These modifications provoke selective disengagement of ZO-1 from its binding partners, occludin, claudin 1, and myosin 1C, coincident with opening of tjs.

}, keywords = {Amino Acid Sequence, Animals, Caco-2 Cells, Cell Line, Cells, Cultured, Cholera Toxin, Epithelial Cells, Humans, Immunoblotting, Male, Membrane Proteins, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Myosins, Oligopeptides, Phosphoproteins, Phosphorylation, Protein Binding, Protein Kinase C-alpha, Rats, Rats, Wistar, Receptor, PAR-2, RNA Interference, Serine, Threonine, Tight Junctions, Zonula Occludens-1 Protein}, issn = {1530-6860}, doi = {10.1096/fj.10-158972}, author = {Goldblum, Simeon E and Rai, Usha and Tripathi, Amit and Thakar, Manjusha and De Leo, Luigina and Di Toro, Nicola and Not, Tarcisio and Ramachandran, Rithwik and Puche, Adam C and Hollenberg, Morley D and Fasano, Alessio} } @article {1612, title = {Association of tumor necrosis factor-related apoptosis-inducing ligand with total and cardiovascular mortality in older adults.}, journal = {Atherosclerosis}, volume = {215}, year = {2011}, month = {2011 Apr}, pages = {452-8}, abstract = {

OBJECTIVE: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits biological activity on vascular cells in vitro. Rapid variation of circulating TRAIL levels occurs during acute coronary ischemia, suggesting that biological pathways involving TRAIL may be activated during ischemic heart disease. However, whether differential levels of soluble TRAIL in normal individuals are associated with adverse health outcomes has not been investigated. We tested the hypothesis that TRAIL levels predict mortality in a population based sample of community dwelling men and women.

METHODS: Plasma TRAIL level was measured by ELISA at baseline in 1282 adults (mean age 68 years) enrolled in the InCHIANTI study. Vital status was ascertained over the six-year follow-up.

RESULTS: In multivariable Cox regression analysis adjusted for potential confounders including prevalent cardiovascular diseases (CVD), ankle-brachial index, electrocardiogram abnormalities, and inflammatory markers, baseline TRAIL levels were inversely related to all-cause mortality (p=0.008). In stratified analyses, the prognostic effect of TRAIL level was strong and highly significant in participants with prevalent CVD (N=321), (lowest versus highest quartile: HR 3.1; 95\% CI 1.5-6.5) while it was negligible in those free of CVD (p value for the interaction term between CVD status and TRAIL levels=0.038). Similar findings were obtained when CVD mortality was considered as the outcome of interest.

CONCLUSIONS: In older patients with CVD, low levels of TRAIL were associated with increased risk of death over a period of 6 years. Lower concentration of circulating TRAIL may be related to the clinical evolution of older adults with CVD.

}, keywords = {Adult, Aged, Ankle Brachial Index, Cardiovascular Diseases, Female, Follow-Up Studies, Humans, Italy, Male, Middle Aged, TNF-Related Apoptosis-Inducing Ligand}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2010.11.004}, author = {Volpato, Stefano and Ferrucci, Luigi and Secchiero, Paola and Corallini, Federica and Zuliani, Giovanni and Fellin, Renato and Guralnik, Jack M and Bandinelli, Stefania and Zauli, Giorgio} } @article {1775, title = {Comparison of propofol versus propofol-ketamine combination in pediatric oncologic procedures performed by non-anesthesiologists.}, journal = {Pediatr Blood Cancer}, volume = {57}, year = {2011}, month = {2011 Dec 15}, pages = {1163-7}, abstract = {

BACKGROUND: Limited data are available on the best option (short acting sedatives, opioids, or ketamine) in oncologic procedural sedation performed by non-anesthesiologists. The aim of the present prospective study is to compare the safety and efficacy of propofol-ketamine versus propofol alone, managed by trained pediatricians, in children with cancer undergoing painful procedures.

PROCEDURES: Data on 121 children with acute lymphatic leukemia (ALL) undergoing procedural sedations (lumbar punctures and bone marrow aspirations) were prospectively collected and included drug doses, side effects, pain assessment, and sedation degree. Children were randomly assigned to one of the two groups: P (n = 62) receiving propofol alone and K (n = 59) in whom a ketamine-propofol combination was used.

RESULTS: In group K, the total dose of propofol required was significantly lower than in group P (3.9 {\textpm} 3.6 mg/kg vs. 5.1 {\textpm} 3.6 mg/kg; P < 0.001). The incidence of hypotension was also significantly lower (11\% vs. 39\%; P < 0.001). Major O(2) desaturations (defined as SatO(2) < 88\%) occurred principally in group P (7 vs. 1; P = 0.05). Both best analgesia and shorter recovery time were obtained with the propofol-ketamine association. No differences were observed in the degree of sedation and in the awakening quality score between the two groups.

CONCLUSIONS: The combination of propofol and ketamine produced statistically significant clinical advantages combined with a higher profile of safety in children with cancer undergoing painful procedures.

}, keywords = {Biopsy, Needle, Bone Marrow Examination, Child, Conscious Sedation, Female, Humans, Hypnotics and Sedatives, Ketamine, Male, Neoplasms, Pediatrics, Physicians, Propofol, Spinal Puncture}, issn = {1545-5017}, doi = {10.1002/pbc.23170}, author = {Chiaretti, Antonio and Ruggiero, Antonio and Barbi, Egidio and Pierri, Filomena and Maurizi, Palma and Fantacci, Claudia and Bersani, Giulia and Riccardi, Riccardo} } @article {1741, title = {Cryptic genetic gluten intolerance revealed by intestinal antitransglutaminase antibodies and response to gluten-free diet.}, journal = {Gut}, volume = {60}, year = {2011}, month = {2011 Nov}, pages = {1487-93}, abstract = {

BACKGROUND AND OBJECTIVE: Antitransglutaminase (anti-TG2) antibodies are synthesised in the intestine and their presence seems predictive of future coeliac disease (CD). This study investigates whether mucosal antibodies represent an early stage of gluten intolerance even in the absence of intestinal damage and serum anti-TG2 antibodies.

METHODS: This study investigated 22 relatives of patients with CD genetically predisposed to gluten intolerance but negative for both serum anti-TG2 antibodies and intestinal abnormalities. Fifteen subjects were symptomatic and seven were asymptomatic. The presence of immunoglobulin A anti-TG2 antibodies in the intestine was studied by creating phage-antibody libraries against TG-2. The presence of intestinal anti-TG2 antibodies was compared with the serum concentration of the intestinal fatty acid-binding protein (I-FABP), a marker for early intestinal mucosal damage. The effects of a 12-month gluten-free diet on anti-TG2 antibody production and the subjects{\textquoteright} clinical condition was monitored. Twelve subjects entered the study as controls.

RESULTS: The intestinal mucosa appeared normal in 18/22; 4 had a slight increase in intraepithelial lymphocytes. Mucosal anti-TG2 antibodies were isolated in 15/22 subjects (68\%); in particular symptomatic subjects were positive in 13/15 cases and asymptomatic subjects in 2/7 cases (p=0.01). No mucosal antibodies were selected from the controls{\textquoteright} biopsies. There was significant correlation between the presence of intestinal anti-TG2 antibodies and positive concentrations of I-FABP (p=0.0008). After a gluten-free diet, 19/22 subjects underwent a second intestinal biopsy, which showed that anti-TG2 antibodies had disappeared in 12/15 (p=0.002), while I-FABP decreased significantly (p<0.0001). The diet resolved both extraintestinal and intestinal symptoms.

CONCLUSIONS: A new form of genetic-dependent gluten intolerance has been described in which none of the usual diagnostic markers is present. Symptoms and intestinal anti-TG2 antibodies respond to a gluten free-diet. The detection of intestinal anti-TG2 antibodies by the phage-antibody libraries has an important diagnostic and therapeutic impact for the subjects with gluten-dependent intestinal or extraintestinal symptoms. Clinical trial number NCT00677495.

}, keywords = {Adolescent, Adult, Antibodies, Anti-Idiotypic, Asymptomatic Diseases, Celiac Disease, Child, Child, Preschool, Diet, Gluten-Free, Fatty Acid-Binding Proteins, Female, Genetic Predisposition to Disease, GTP-Binding Proteins, Health Status, Humans, Intestinal Mucosa, Male, Middle Aged, Peptide Library, Transglutaminases, Young Adult}, issn = {1468-3288}, doi = {10.1136/gut.2010.232900}, author = {Not, Tarcisio and Ziberna, Fabiana and Vatta, Serena and Quaglia, Sara and Martelossi, Stefano and Villanacci, Vincenzo and Marzari, Roberto and Florian, Fiorella and Vecchiet, Monica and Sulic, Ana-Marija and Ferrara, Fortunato and Bradbury, Andrew and Sblattero, Daniele and Ventura, Alessandro} } @article {1753, title = {Endothelial progenitor cells, bronchopulmonary dysplasia and other short-term outcomes of extremely preterm birth.}, journal = {Early Hum Dev}, volume = {87}, year = {2011}, month = {2011 Jul}, pages = {461-5}, abstract = {

AIM: To evaluate the impact of endothelial progenitor cells (EPCs), a subset of committed circulatory stem cells, on the development of bronchopulmonary dysplasia (BPD) and other short term outcomes in a cohort of extremely premature newborns.

METHODS: Progenitor cells were quantified by flow cytometry at birth in 36 neonates born <=28 weeks of gestation and at 36 postmenstrual weeks in 18 of them. Cells expressing the stemness markers CD34, CD133, or both were defined as circulating progenitor cells (CPCs). EPCs were defined as CPCs co-expressing the endothelial marker KDR.

RESULTS: Mean (SD) gestational age and birth weight of the infants studied were 26.2(1.5) weeks and 761.6(171.8) grams, respectively. EPC levels at birth did not differ between infants who subsequently developed BPD (n=9) and those who did not (n=24) [CD34(+)KDR(+) EPCs: 81(34-41) vs 80(56-110), p=0.7] and were not correlated with the duration of mechanical ventilation or O2-dependence, nor with the need of surfactant replacement. Infants with a hemodynamically significant patent ductus arteriosus (PDA) (n=22) had significantly lower EPC levels at birth than those with no PDA (n=11) [CD34(+)KDR(+) cells: 47(34-92) vs 142(84.5-221), p=0.008]. Data from the 18 infants studied both at birth and at 36 postmenstrual weeks showed that, while CPCs sharply decline over time, levels of all EPCs phenotypes are preserved after delivery.

CONCLUSIONS: Levels of EPCs at birth did not affect the risk of developing BPD in our group of extremely premature neonates. However, the association between low EPC counts at birth and PDA may be clinically relevant, and deserves further studies.

}, keywords = {Blood Cell Count, Bronchopulmonary Dysplasia, Cohort Studies, Ductus Arteriosus, Patent, Endothelial Cells, Female, Flow Cytometry, Humans, Infant, Newborn, Infant, Premature, Italy, Pregnancy, Prospective Studies, Regression Analysis, Stem Cells}, issn = {1872-6232}, doi = {10.1016/j.earlhumdev.2011.03.011}, author = {Paviotti, Giulia and Fadini, Gian Paolo and Boscaro, Elisa and Agostini, Carlo and Avogaro, Angelo and Chiandetti, Lino and Baraldi, Eugenio and Filippone, Marco} } @article {1821, title = {Frequency of HLA B*5701 allele carriers in abacavir treated-HIV infected patients and controls from northeastern Brazil.}, journal = {Clinics (Sao Paulo)}, volume = {66}, year = {2011}, month = {2011}, pages = {1485-8}, keywords = {Adolescent, Adult, Anti-HIV Agents, Brazil, Case-Control Studies, Dideoxynucleosides, Drug Hypersensitivity, Female, Gene Frequency, Genotype, HIV Infections, HLA-B Antigens, Humans, Male, Middle Aged, Real-Time Polymerase Chain Reaction, Young Adult}, issn = {1980-5322}, author = {Crovella, Sergio and Biller, Lara and Santos, Sergio and Salustiano, Ana and Brand{\~a}o, Lucas and Guimar{\~a}es, Rafael and Segat, Ludovica and Lima Filho, Jose Luiz de and Arraes, Luiz Claudio} } @article {1724, title = {Gastroesophageal reflux disease at any cost: a dangerous paediatric attitude.}, journal = {Acta Paediatr}, volume = {100}, year = {2011}, month = {2011 Oct}, pages = {e178-80}, keywords = {Diagnostic Errors, Gastroesophageal Reflux, Humans, Inappropriate Prescribing, Infant, Infant, Newborn, Male, Proton Pump Inhibitors, Spasms, Infantile}, issn = {1651-2227}, doi = {10.1111/j.1651-2227.2011.02315.x}, author = {Taddio, Andrea and Bersanini, Chiara and Basile, Lucio and Fontana, Massimo and Ventura, Alessandro} } @article {1610, title = {Gastrointestinal Foxp3 expression in normal, inflammatory and neoplastic conditions.}, journal = {Pathology}, volume = {43}, year = {2011}, month = {2011 Aug}, pages = {465-71}, abstract = {

BACKGROUND: Foxp3(+) regulatory T lymphocytes (T-regs) represent an important regulatory cell subset in inflammatory, preneoplastic and neoplastic conditions of the gastrointestinal tract.

METHODS: Inflammatory, preneoplastic and neoplastic conditions of the gastrointestinal tract (189 cases) were studied with the evaluation of Foxp3 regulatory T cells based on immunohistochemistry.

RESULTS: Few Foxp3(+) cells were found in controls and inflammatory conditions (oesophagitis, gastritis, coeliac disease, inflammatory bowel disease); in preneoplastic and neoplastic conditions the number of Foxp3(+) cells was significatively increased.

CONCLUSIONS: In normal conditions the number of mucosal lymphocytes is very low throughout the gastro-intestinal tract; in active coeliac disease patients or on a gluten-free diet, only a slight increase in Foxp3(+) cells may be found. Gastrointestinal cancers are associated with higher Foxp3(+) cell proportion, compared with microscopically normal tissue and with precancerous conditions. However, it is uncertain whether the increase in these regulatory cells is a cause or a consequence of tumour progression.

}, keywords = {Adult, Aged, Celiac Disease, Cell Count, Disease Progression, Esophagitis, Female, Forkhead Transcription Factors, Gastric Mucosa, Gastritis, Humans, Inflammatory Bowel Diseases, Lymphocytes, Male, Middle Aged, Precancerous Conditions, Stomach Diseases, Stomach Neoplasms, Young Adult}, issn = {1465-3931}, doi = {10.1097/PAT.0b013e3283485e37}, author = {Villanacci, Vincenzo and Not, Tarcisio and Nascimbeni, Riccardo and Ferrara, Fortunato and Tommasini, Alberto and Manenti, Stefania and Antonelli, Elisabetta and Bassotti, Gabrio} } @article {1760, title = {A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity.}, journal = {Leukemia}, volume = {25}, year = {2011}, month = {2011 Jan}, pages = {66-74}, abstract = {

Asparaginase is an important component for treatment of childhood acute lymphoblastic leukemia (ALL). The basis for interindividual differences in asparaginase sensitivity remains unclear. To comprehensively identify genetic variants important in the cytotoxicity of asparaginase, we used a genome-wide association approach using the HapMap lymphoblastoid cell lines (87 CEU trio members) and 54 primary ALL leukemic blast samples at diagnosis. Asparaginase sensitivity was assessed as the drug concentration necessary to inhibit 50\% of growth (inhibitory concentration (IC)(50)). In CEU lines, we tested 2,390,203 single-nucleotide polymorphism (SNP) genotypes at the individual SNP (P<0.001) and gene level (P<0.05), and identified 329 SNPs representing 94 genes that were associated with asparaginase IC(50). The aspartate metabolism pathway was the most overrepresented among 199 pathways evaluated (P=8.1 {\texttimes} 10(-3)), with primary involvement of adenylosuccinate lyase and aspartyl-tRNA synthetase genes. We validated that SNPs in the aspartate metabolism pathway were also associated with asparaginase sensitivity in primary ALL leukemic blast samples (P=5.5 {\texttimes} 10(-5)). Our genome-wide interrogation of CEU cell lines and primary ALL blasts revealed that inherited genomic interindividual variation in a plausible candidate pathway can contribute to asparaginase sensitivity.

}, keywords = {Antineoplastic Agents, Asparaginase, Aspartic Acid, Cell Line, Genome-Wide Association Study, Humans, Multivariate Analysis, Polymorphism, Single Nucleotide, Precursor Cell Lymphoblastic Leukemia-Lymphoma}, issn = {1476-5551}, doi = {10.1038/leu.2010.256}, author = {Chen, S-H and Yang, W and Fan, Y and Stocco, G and Crews, K R and Yang, J J and Paugh, S W and Pui, C-H and Evans, W E and Relling, M V} } @article {1840, title = {Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Oct}, pages = {1005-11}, abstract = {

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 {\texttimes} 10(-8) to P = 2.3 {\texttimes} 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

}, keywords = {Arteries, Blood Pressure, Case-Control Studies, Follow-Up Studies, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Linkage Disequilibrium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.922}, author = {Wain, Louise V and Verwoert, Germaine C and O{\textquoteright}Reilly, Paul F and Shi, Gang and Johnson, Toby and Johnson, Andrew D and Bochud, Murielle and Rice, Kenneth M and Henneman, Peter and Smith, Albert V and Ehret, Georg B and Amin, Najaf and Larson, Martin G and Mooser, Vincent and Hadley, David and D{\"o}rr, Marcus and Bis, Joshua C and Aspelund, Thor and Esko, T{\~o}nu and Janssens, A Cecile J W and Zhao, Jing Hua and Heath, Simon and Laan, Maris and Fu, Jingyuan and Pistis, Giorgio and Luan, Jian{\textquoteright}an and Arora, Pankaj and Lucas, Gavin and Pirastu, Nicola and Pichler, Irene and Jackson, Anne U and Webster, Rebecca J and Zhang, Feng and Peden, John F and Schmidt, Helena and Tanaka, Toshiko and Campbell, Harry and Igl, Wilmar and Milaneschi, Yuri and Hottenga, Jouke-Jan and Vitart, Veronique and Chasman, Daniel I and Trompet, Stella and Bragg-Gresham, Jennifer L and Alizadeh, Behrooz Z and Chambers, John C and Guo, Xiuqing and Lehtim{\"a}ki, Terho and Kuhnel, Brigitte and Lopez, Lorna M and Polasek, Ozren and Boban, Mladen and Nelson, Christopher P and Morrison, Alanna C and Pihur, Vasyl and Ganesh, Santhi K and Hofman, Albert and Kundu, Suman and Mattace-Raso, Francesco U S and Rivadeneira, Fernando and Sijbrands, Eric J G and Uitterlinden, Andr{\'e} G and Hwang, Shih-Jen and Vasan, Ramachandran S and Wang, Thomas J and Bergmann, Sven and Vollenweider, Peter and Waeber, Gerard and Laitinen, Jaana and Pouta, Anneli and Zitting, Paavo and McArdle, Wendy L and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Glazer, Nicole L and Taylor, Kent D and Harris, Tamara B and Alavere, Helene and Haller, Toomas and Keis, Aime and Tammesoo, Mari-Liis and Aulchenko, Yurii and Barroso, In{\^e}s and Khaw, Kay-Tee and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Eyheramendy, Susana and Org, Elin and S{\~o}ber, Siim and Lu, Xiaowen and Nolte, Ilja M and Penninx, Brenda W and Corre, Tanguy and Masciullo, Corrado and Sala, Cinzia and Groop, Leif and Voight, Benjamin F and Melander, Olle and O{\textquoteright}Donnell, Christopher J and Salomaa, Veikko and d{\textquoteright}Adamo, Adamo Pio and Fabretto, Antonella and Faletra, Flavio and Ulivi, Sheila and Del Greco, Fabiola M and Facheris, Maurizio and Collins, Francis S and Bergman, Richard N and Beilby, John P and Hung, Joseph and Musk, A William and Mangino, Massimo and Shin, So-Youn and Soranzo, Nicole and Watkins, Hugh and Goel, Anuj and Hamsten, Anders and Gider, Pierre and Loitfelder, Marisa and Zeginigg, Marion and Hernandez, Dena and Najjar, Samer S and Navarro, Pau and Wild, Sarah H and Corsi, Anna Maria and Singleton, Andrew and de Geus, Eco J C and Willemsen, Gonneke and Parker, Alex N and Rose, Lynda M and Buckley, Brendan and Stott, David and Orru, Marco and Uda, Manuela and van der Klauw, Melanie M and Zhang, Weihua and Li, Xinzhong and Scott, James and Chen, Yii-Der Ida and Burke, Gregory L and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and D{\"o}ring, Angela and Meitinger, Thomas and Davies, Gail and Starr, John M and Emilsson, Valur and Plump, Andrew and Lindeman, Jan H and Hoen, Peter A C {\textquoteright}t and K{\"o}nig, Inke R and Felix, Janine F and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Breteler, Monique and Debette, St{\'e}phanie and Destefano, Anita L and Fornage, Myriam and Mitchell, Gary F and Smith, Nicholas L and Holm, Hilma and Stefansson, Kari and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Samani, Nilesh J and Preuss, Michael and Rudan, Igor and Hayward, Caroline and Deary, Ian J and Wichmann, H-Erich and Raitakari, Olli T and Palmas, Walter and Kooner, Jaspal S and Stolk, Ronald P and Jukema, J Wouter and Wright, Alan F and Boomsma, Dorret I and Bandinelli, Stefania and Gyllensten, Ulf B and Wilson, James F and Ferrucci, Luigi and Schmidt, Reinhold and Farrall, Martin and Spector, Tim D and Palmer, Lyle J and Tuomilehto, Jaakko and Pfeufer, Arne and Gasparini, Paolo and Siscovick, David and Altshuler, David and Loos, Ruth J F and Toniolo, Daniela and Snieder, Harold and Gieger, Christian and Meneton, Pierre and Wareham, Nicholas J and Oostra, Ben A and Metspalu, Andres and Launer, Lenore and Rettig, Rainer and Strachan, David P and Beckmann, Jacques S and Witteman, Jacqueline C M and Erdmann, Jeanette and van Dijk, Ko Willems and Boerwinkle, Eric and Boehnke, Michael and Ridker, Paul M and J{\"a}rvelin, Marjo-Riitta and Chakravarti, Aravinda and Abecasis, Goncalo R and Gudnason, Vilmundur and Newton-Cheh, Christopher and Levy, Daniel and Munroe, Patricia B and Psaty, Bruce M and Caulfield, Mark J and Rao, Dabeeru C and Tobin, Martin D and Elliott, Paul and van Duijn, Cornelia M} } @article {1834, title = {Glutamine-enriched nutrition does not reduce mucosal morbidity or complications after stem-cell transplantation for childhood malignancies: a prospective randomized study.}, journal = {Transplantation}, volume = {91}, year = {2011}, month = {2011 Jun 27}, pages = {1321-5}, abstract = {

BACKGROUND: Intravenous glutamine-enriched solution seems to be effective in posttransplant period in decreasing the severity and duration of mucositis. The aim of this randomized study was to determine the benefit of glutamine supplementation both on mucosal morbidity and in posttransplant associated complications.

METHODS: Children undergoing allogeneic hematopoietic stem-cell transplantation (HSCT) for malignant hematological diseases were randomly assigned to standard total parenteral nutrition (S-TPN) or glutamine-enriched (GE)-TPN solution consisting of 0.4 g/kg/day of l-alanine-glutamine dipeptide. This treatment started on the day of HSCT and ended when the patients could orally cover more than 50\% of their daily energy requirements. The severity and the rate of post-HSCT mucositis were based on World Health Organization criteria. All the analyses were conducted on intention-to-treat principle.

RESULTS: One hundred twenty consecutive patients (83 men; median age, 8.1 years) were enrolled. The mean duration of treatment was 23.5 and 23 days in the two treatment arms. The mean calorie intake was 1538 kcal/d in the S-TPN group and 1512 kcal/d in GE-TPN group. All patients were well nourished before and after HSCT. Mucositis occurred in 91.4\% and 91.7\% of patients in S-TPN and GE-TPN arm, respectively (P=0.98). Odds ratio adjusted by type of HSCT was 0.98 (95\% confidence interval, 0.26-2.63). Type and duration of analgesic treatment, clinical outcome (engraftment, graft versus host disease, early morbidity, and mortality, relapse rate up to 180 days post-HSCT) were not significantly different in the two treatment arms.

CONCLUSION: GE-TPN solution does not affect mucositis and outcome in well-nourished HSCT allogeneic patients.

}, keywords = {Adolescent, Analgesia, Child, Child, Preschool, Double-Blind Method, Female, Glutamine, Hematopoietic Stem Cell Transplantation, Humans, Infant, Male, Mucositis, Mucous Membrane, Neoplasms, Odds Ratio, Parenteral Nutrition, Prospective Studies, Recurrence, Stem Cells, Treatment Outcome}, issn = {1534-6080}, doi = {10.1097/TP.0b013e31821ab959}, author = {Uderzo, Cornelio and Rebora, Paola and Marrocco, Emanuela and Varotto, Stefania and Cichello, Francesca and Bonetti, Maurizio and Maximova, Natalia and Zanon, Davide and Fagioli, Franca and Nesi, Francesca and Masetti, Riccardo and Masetti, Roberto and Rovelli, Attilio and Rondelli, Roberto and Valsecchi, Maria Grazia and Cesaro, Simone} } @article {1824, title = {High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study.}, journal = {Arthritis Rheum}, volume = {63}, year = {2011}, month = {2011 Nov}, pages = {3625-32}, abstract = {

OBJECTIVE: Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in \~{}40\% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome.

METHODS: An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations.

RESULTS: Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2\%). Estimates of the level of mosaicism ranged from 4.2\% to 35.8\% (mean {\textpm} SD 12.1 {\textpm} 7.9\%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms.

CONCLUSION: Somatic NLRP3 mutations were identified in 69.2\% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.

}, keywords = {Adolescent, Adult, Carrier Proteins, Case-Control Studies, Child, Child, Preschool, Cryopyrin-Associated Periodic Syndromes, Female, Genetic Association Studies, Humans, Infant, Male, Mosaicism}, issn = {1529-0131}, doi = {10.1002/art.30512}, author = {Tanaka, Naoko and Izawa, Kazushi and Saito, Megumu K and Sakuma, Mio and Oshima, Koichi and Ohara, Osamu and Nishikomori, Ryuta and Morimoto, Takeshi and Kambe, Naotomo and Goldbach-Mansky, Raphaela and Aksentijevich, Ivona and de Saint Basile, Genevi{\`e}ve and Neven, B{\'e}n{\'e}dicte and van Gijn, Mari{\"e}lle and Frenkel, Joost and Ar{\'o}stegui, Juan I and Yag{\"u}e, Jordi and Merino, Rosa and Iba{\~n}ez, Mercedes and Pontillo, Alessandra and Takada, Hidetoshi and Imagawa, Tomoyuki and Kawai, Tomoki and Yasumi, Takahiro and Nakahata, Tatsutoshi and Heike, Toshio} } @article {1661, title = {HLA-G 14 bp deletion/insertion polymorphism in celiac disease.}, journal = {Am J Gastroenterol}, volume = {106}, year = {2011}, month = {2011 Jan}, pages = {139-44}, abstract = {

OBJECTIVES: Nonclassical major histocompatibility class I HLA-G antigen is a tolerogenic molecule that inhibits lytic activity of natural killer (NK) cells and cytotoxic T lymphocytes. Because of its immunomodulatory and tolerogenic properties, HLA-G molecules may have a role in celiac disease (CD). We analyzed the HLA-G 14 bp deletion/insertion polymorphism, known to have a functional effect on mRNA stability, in a group of 522 CD patients, stratified for the presence of HLA-DQ2 genotype, and 400 healthy individuals to evaluate the possible effect of the polymorphism on the risk to develop the disease.

METHODS: HLA-G 14 bp deletion/insertion polymorphism (rs1704) was detected by polymerase chain reaction and double-checked by direct sequencing.

RESULTS: The 14 bp inserted (I) allele and the homozygous I/I genotype were significantly more frequent in CD patients than in healthy controls. The presence of I allele was associated with an increased risk of CD (OR 1.35) and the effect of I allele was consistent with a recessive genetic model (P<0.001).

CONCLUSIONS: Our results also indicate that the effect of the HLA-G D/I polymorphism is restricted for HLA-DQ2, and not simply due to the presence of linkage disequilibrium with the major known risk factor; moreover we found that the presence of the I allele confers an increased risk of CD in addition to the risk conferred by HLA-DQ2 alone and that subjects that carry both DQ2 and HLA-G I alleles have an increased risk of CD than subjects that carry DQ2 but not the I allele.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Case-Control Studies, Celiac Disease, Child, Child, Preschool, Confidence Intervals, Female, Genetic Predisposition to Disease, Genotype, Histocompatibility Antigens Class I, HLA Antigens, HLA-DQ Antigens, HLA-G Antigens, Humans, Male, Middle Aged, Mutagenesis, Insertional, Odds Ratio, Polymerase Chain Reaction, Polymorphism, Genetic, Reference Values, RNA Stability, Sequence Deletion, Young Adult}, issn = {1572-0241}, doi = {10.1038/ajg.2010.340}, author = {Fabris, Annalisa and Segat, Ludovica and Catamo, Eulalia and Morgutti, Marcello and Vendramin, Anna and Crovella, Sergio} } @article {1720, title = {Horizontal gaze palsy and progressive scoliosis without ROBO3 mutations.}, journal = {Ophthalmic Genet}, volume = {32}, year = {2011}, month = {2011 Nov}, pages = {212-6}, abstract = {

BACKGROUND: To describe clinical and genetic observations in a patient with horizontal gaze palsy and progressive scoliosis (HGPPS) without identified mutations in the ROBO3 gene.

MATERIALS AND METHODS: Neurologic and orthopedic evaluation of the proband; sequencing all exons, exon-intron boundaries, and promoter region of ROBO3 in the proband and his mother. Array CGH was also carried out in the proband and his mother to evaluate possible chromosomal deletion(s) and/or duplication(s).

RESULTS: The proband had complete horizontal gaze restriction with full vertical gaze and small amplitude horizontal pendular nystagmus. He also had severe scoliosis and brainstem hypoplasia pathognomonic of HGPPS. However, complete sequencing of ROBO3 twice in both forward and reverse directions did not reveal any mutations. Array CGH investigation revealed no chromosomal abnormalities.

CONCLUSIONS: This patient had clinical and neuroimaging characteristics considered pathognomonic of HGPPS and yet did not have ROBO3 mutations. A clinical misdiagnosis is unlikely in the absence of facial weakness (typical of Moebius syndrome), deafness (typical of the HOXA1 spectrum), or mental retardation (typical of other central decussation abnormalities). It is perhaps more likely that a phenotype identical to HGPPS can be caused by abnormalities in ROBO3 splice variant expression, by mutations of a gene other than ROBO3, or by some environmental or epigenetic factor(s) inhibiting the action of ROBO3 or its protein product in the developing brainstem.

}, keywords = {Child, Humans, Kyphosis, Magnetic Resonance Imaging, Male, Mutation, Ocular Motility Disorders, Oculomotor Nerve Diseases, Pedigree, Receptors, Immunologic, Scoliosis}, issn = {1744-5094}, doi = {10.3109/13816810.2011.574186}, author = {Abu-Amero, Khaled K and Faletra, Flavio and Gasparini, Paolo and Parentin, Fulvio and Pensiero, Stefano and Alorainy, Ibrahim A and Hellani, Ali M and Catalano, Dario and Bosley, Thomas M} } @article {1755, title = {Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene.}, journal = {Arthritis Rheum}, volume = {63}, year = {2011}, month = {2011 Apr}, pages = {1141-50}, abstract = {

OBJECTIVE: To analyze the long-term impact of the R92Q mutation of TNFRSF1A in children with periodic fever, in comparison with children with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) with TNFRSF1A structural mutations and children with periodic fever of unknown origin fulfilling the criteria for periodic fever, aphthosis, pharyngitis, and adenitis syndrome (PFAPA).

METHODS: The extracellular region of TNFRSF1A was analyzed in 720 consecutive children with periodic fever, using denaturing high-performance liquid chromatography and DNA sequencing. Followup data on 11 pediatric patients with TNFRSF1A structural mutations (cysteine or T50M), 23 pediatric patients with an R92Q substitution, and 64 pediatric patients with PFAPA were collected during routine clinic visits. The 50-item Child Health Questionnaire was used to assess health-related quality of life (HRQOL).

RESULTS: The frequency of typical TRAPS-related clinical manifestations was significantly lower and the impact of the disease on HRQOL was significantly reduced in patients with the R92Q mutation compared with TRAPS patients carrying structural mutations of TNFRSF1A. Followup data on 11 TRAPS patients with TNFRSF1A structural mutations (mean followup 7.9 years), 16 patients with theR92Q substitution (mean followup 7.3 years), and 64 patients with PFAPA (mean followup 5.2 years) were available. Patients with R92Q mutations and patients with PFAPA displayed a higher rate of self-resolution or amelioration of the fever episodes than did TRAPS patients with structural mutations.

CONCLUSION: Although some cases may progress to a more chronic disease course, the majority of children with an R92Q mutation of the TNFRSFA1 gene show a milder disease course than that in children with TNFRSFA1 structural mutations and have a high rate of spontaneous resolution and amelioration of the recurrent fever episodes.

}, keywords = {Adolescent, Antirheumatic Agents, Biological Therapy, Child, Child, Preschool, Familial Mediterranean Fever, Female, Fever, Follow-Up Studies, Genotype, Health Surveys, Humans, Infant, Interleukin 1 Receptor Antagonist Protein, Longitudinal Studies, Lymphadenitis, Male, Mutation, Pharyngitis, Quality of Life, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Recurrence, Retrospective Studies, Steroids, Syndrome}, issn = {1529-0131}, doi = {10.1002/art.30237}, author = {Pelagatti, M A and Meini, A and Caorsi, R and Cattalini, M and Federici, S and Zulian, F and Calcagno, G and Tommasini, A and Bossi, G and Sormani, M P and Caroli, F and Plebani, A and Ceccherini, I and Martini, A and Gattorno, M} } @article {1835, title = {Management of the adnexal mass.}, journal = {Obstet Gynecol}, volume = {118}, year = {2011}, month = {2011 Oct}, pages = {956; author reply 956-7}, keywords = {Female, Humans, Ovarian Neoplasms}, issn = {1873-233X}, doi = {10.1097/AOG.0b013e318230dde3}, author = {Ricci, Giuseppe and Zito, Gabriella and Fischer-Tamaro, Leo} } @article {1829, title = {Mast cells are critically involved in serum-mediated vascular leakage in chronic urticaria beyond high-affinity IgE receptor stimulation.}, journal = {Allergy}, volume = {66}, year = {2011}, month = {2011 Dec}, pages = {1538-45}, abstract = {

BACKGROUND: Chronic urticaria (CU) is one of the most common skin disorders whose pathogenic mechanisms are not fully clarified. Autoimmune aetiology can be ascribed to 45\% of patients with CU, and basophil histamine release is positive in 40\% of cases. Our aim was to use a novel approach to evaluate the serum permeabilizing effect to identify the mediators of endothelial cell (EC) leakage and to define the role of mast cells (MCs) in the process.

METHODS: Permeabilizing activity of sera from 19 patients with CU and 11 healthy blood donors was evaluated by measuring serum-induced degranulation of two MC lines, expressing (LAD2) or lacking (HMC-1) the IgE receptor. Mast cell supernatant (SN) was then incubated with an EC monolayer, and endothelial permeability was evaluated by Fluorescein isothiocyanate-bovine serum albumin leakage in a transwell system.

RESULTS: All 19 patient sera failed to induce direct EC leakage, but 15/19 and 17/19 promoted degranulation of HMC-1 and LAD2, respectively. Interestingly, 85\% of autologous serum skin test-negative sera were able to cause MC degranulation. Also, 17/19 SNs from HMC-1 and all SNs from LAD2 incubated with CU sera increased endothelial permeability. Endothelial cell leakage remained unchanged after Ig depletion and was prevented by antihistamine, platelet-activating factor or leukotriene antagonist.

CONCLUSIONS: Our study shows that CU sera are able to degranulate MCs through an IgE- and IgG-independent mechanism. The nature of histamine-releasing factors involved is still unclear, but our finding opens new ways to the understanding of the pathogenesis of CU, particularly in patients not showing circulating autoantibodies to FcεRI or IgE.

}, keywords = {Adult, Aged, Capillary Permeability, Chronic Disease, Endothelial Cells, Female, Histamine Release, Humans, Male, Mast Cells, Middle Aged, Receptors, IgE, Serum, Urticaria, Young Adult}, issn = {1398-9995}, doi = {10.1111/j.1398-9995.2011.02704.x}, author = {Bossi, F and Frossi, B and Radillo, O and Cugno, M and Tedeschi, A and Riboldi, P and Asero, R and Tedesco, F and Pucillo, C} } @article {1690, title = {The missense variation Q705K in CIAS1/NALP3/NLRP3 gene and an NLRP1 haplotype are associated with celiac disease.}, journal = {Am J Gastroenterol}, volume = {106}, year = {2011}, month = {2011 Mar}, pages = {539-44}, abstract = {

OBJECTIVES: Celiac disease (CD) is a multifactorial common disorder with several susceptibility loci. Variations in the NALP1/NLRP1 and NALP3/NLRP3 genes have been reported to confer risk for several autoimmune conditions. We hypothesized that polymorphisms in these genes, due to their role in innate immunity and inflammatory processes, may affect susceptibility to CD.

METHODS: Two single-nucleotide polymorphisms (SNPs) in NLRP1 (rs12150220, rs2670660) and two SNPs (rs10754558, rs35829419) in NLRP3 genes were genotyped in 504 CD Italian patients and 256 healthy controls.

RESULTS: The minor A allele of NLRP3 rs35829419 (Q705K) polymorphism appeared to exert a protective role against the development of CD (P=0.029; odds ratio (OR)=0.56). Moreover, a particular NLRP1 haplotype was associated with predisposition to CD (P=0.003; OR=1.38), even more when present in combination with the rs35829419 major C allele (P=0.002; OR=1.42).

CONCLUSIONS: We hypothesized that the deregulation of CIAS1/NALP3/NLRP3 and NALP1/NLRP1 inflammasomes could have a role in CD pathogenesis.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Apoptosis Regulatory Proteins, Carrier Proteins, Celiac Disease, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Genotype, Glutamine, Haplotypes, Humans, Inflammasomes, Italy, Lysine, Male, Mutation, Missense, Polymorphism, Single Nucleotide}, issn = {1572-0241}, doi = {10.1038/ajg.2010.474}, author = {Pontillo, Alessandra and Vendramin, Anna and Catamo, Eulalia and Fabris, Annalisa and Crovella, Sergio} } @article {1742, title = {Molecular mechanism of glucocorticoid resistance in inflammatory bowel disease.}, journal = {World J Gastroenterol}, volume = {17}, year = {2011}, month = {2011 Mar 7}, pages = {1095-108}, abstract = {

Natural and synthetic glucocorticoids (GCs) are widely employed in a number of inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in moderate to severe active Crohn{\textquoteright}s disease and ulcerative colitis. Despite their extensive therapeutic use and the proven effectiveness, considerable clinical evidence of wide inter-individual differences in GC efficacy among patients has been reported, in particular when these agents are used in inflammatory diseases. In recent years, a detailed knowledge of the GC mechanism of action and of the genetic variants affecting GC activity at the molecular level has arisen from several studies. GCs interact with their cytoplasmic receptor, and are able to repress inflammatory gene expression through several distinct mechanisms. The glucocorticoid receptor (GR) is therefore crucial for the effects of these agents: mutations in the GR gene (NR3C1, nuclear receptor subfamily 3, group C, member 1) are the primary cause of a rare, inherited form of GC resistance; in addition, several polymorphisms of this gene have been described and associated with GC response and toxicity. However, the GR is not self-standing in the cell and the receptor-mediated functions are the result of a complex interplay of GR and many other cellular partners. The latter comprise several chaperonins of the large cooperative hetero-oligomeric complex that binds the hormone-free GR in the cytosol, and several factors involved in the transcriptional machinery and chromatin remodeling, that are critical for the hormonal control of target genes transcription in the nucleus. Furthermore, variants in the principal effectors of GCs (e.g. cytokines and their regulators) have also to be taken into account for a comprehensive evaluation of the variability in GC response. Polymorphisms in genes involved in the transport and/or metabolism of these hormones have also been suggested as other possible candidates of interest that could play a role in the observed inter-individual differences in efficacy and toxicity. The best-characterized example is the drug efflux pump P-glycoprotein, a membrane transporter that extrudes GCs from cells, thereby lowering their intracellular concentration. This protein is encoded by the ABCB1/MDR1 gene; this gene presents different known polymorphic sites that can influence its expression and function. This editorial reviews the current knowledge on this topic and underlines the role of genetics in predicting GC clinical response. The ambitious goal of pharmacogenomic studies is to adapt therapies to a patient{\textquoteright}s specific genetic background, thus improving on efficacy and safety rates.

}, keywords = {Drug Resistance, Glucocorticoids, Humans, Inflammatory Bowel Diseases, P-Glycoproteins, Polymorphism, Genetic, Receptors, Glucocorticoid, Signal Transduction, Transcription, Genetic}, issn = {2219-2840}, doi = {10.3748/wjg.v17.i9.1095}, author = {De Iudicibus, Sara and Franca, Raffaella and Martelossi, Stefano and Ventura, Alessandro and Decorti, Giuliana} } @article {1658, title = {A multicenter, case-control study on risk factors for antepartum stillbirth.}, journal = {J Matern Fetal Neonatal Med}, volume = {24}, year = {2011}, month = {2011 Mar}, pages = {407-10}, abstract = {

OBJECTIVE: As the influence of socio-demographic variables, lifestyle and medical conditions on the epidemiology of stillbirth (SB) is modified by population features, we aimed at investigating the role played by these factors on the incidence of SB in a developed country.

STUDY DESIGN: Multivariate logistic regression analysis (OR with 95\% CI) was utilized in a prospective multicentre nested case-control study to compare in a 1:2 ratio stillborn of >22 weeks gestation with matched for gestational age live-born (LB) infants. Intrapartum SB were excluded.

RESULTS: Two hundred fifty-four consecutive SBs and 497 LBs were enrolled. Socio-demographic variables were equally distributed. Fetal malformations (7.96, 2.69-23.55), severe intrauterine growth restriction (IUGR) (birthweight <= 5(th) \%ile) (4.32, 2.27?8.24), BMI > 25 (2.87, 1.90-4.33), and preeclampsia (PE, 0.40, 0.21-0.77) were recognized as independent predictors for SB. At term, only BMI > 25 was associated with SB (7.70, 2.9-20.5).

CONCLUSION: Fetal malformations, severe IUGR and maternal BMI > 25 were associated with a significant increase in the risk of SB; PE presented instead a protective role. Maternal BMI > 25 was the only risk factor for SB identified in term pregnancies.

}, keywords = {Adult, Case-Control Studies, Cause of Death, Congenital Abnormalities, Female, Fetal Death, Fetal Growth Retardation, Humans, Infant, Newborn, Male, Obstetric Labor Complications, Pre-Eclampsia, Pregnancy, Risk Factors, Stillbirth, Young Adult}, issn = {1476-4954}, doi = {10.3109/14767058.2010.496880}, author = {Facchinetti, Fabio and Alberico, Salvatore and Benedetto, Chiara and Cetin, Irene and Cozzolino, Sabrina and Di Renzo, Gian Carlo and Del Giovane, Cinzia and Ferrari, Francesca and Mecacci, Federico and Menato, Guido and Tranquilli, Andrea L and Baronciani, Dante} } @article {1609, title = {A multicenter, randomized, placebo-controlled trial of levetiracetam in children and adolescents with newly diagnosed absence epilepsy.}, journal = {Epilepsia}, volume = {52}, year = {2011}, month = {2011 Apr}, pages = {802-9}, abstract = {

PURPOSE: To evaluate the potential efficacy of levetiracetam as an antiabsence agent in children and adolescents with newly diagnosed childhood or juvenile absence epilepsy.

METHODS: Patients were randomized in a 2:1 ratio to receive de novo monotherapy with levetiracetam (up to 30 mg/kg/day) or placebo for 2 weeks under double-blind conditions. Responder status (primary end point) was defined as freedom from clinical seizures on days 13 and 14 and from electroencephalographic (EEG) seizures during a standard EEG recording with hyperventilation and intermittent photic stimulation on day 14. The double-blind phase was followed by an open-label follow-up.

KEY FINDINGS: Nine of 38 patients (23.7\%) were responders in the levetiracetam group, compared with one of 21 (4.8\%) in the placebo group (p = 0.08). Seven of 38 patients (18.4\%) were free from clinical and EEG seizures during the last 4 days of the trial (including 24-h EEG monitoring on day 14) compared with none of the patients treated with placebo (p = 0.04). Seventeen patients remained seizure-free on levetiracetam after 1 year follow-up. Of the 41 patients who discontinued levetiracetam due to lack of efficacy (n = 39) or adverse events (n = 2), 34 became seizure-free on other treatments.

SIGNIFICANCE: Although superiority to placebo just failed to reach statistical significance for the primary end point, the overall findings are consistent with levetiracetam having modest efficacy against absence seizures. Further controlled trials exploring larger doses and an active comparator are required to determine the role of levetiracetam in the treatment of absence epilepsy.

}, keywords = {Adolescent, Age Factors, Anticonvulsants, Child, Child, Preschool, Double-Blind Method, Drug Resistance, Epilepsy, Absence, Female, Humans, Male, Outcome Assessment (Health Care), Piracetam}, issn = {1528-1167}, doi = {10.1111/j.1528-1167.2010.02976.x}, author = {Fattore, Cinzia and Boniver, Clementina and Capovilla, Giuseppe and Cerminara, Caterina and Citterio, Antonietta and Coppola, Giangennaro and Costa, Paola and Darra, Francesca and Vecchi, Marilena and Perucca, Emilio} } @article {1790, title = {Multiple loci are associated with white blood cell phenotypes.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Jun}, pages = {e1002113}, abstract = {

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

}, keywords = {Genetic Loci, Genome-Wide Association Study, Humans, Leukocyte Count, Leukocytes, Molecular Epidemiology, Multigene Family, Phenotype, Polymorphism, Single Nucleotide, Ubiquitin-Protein Ligases}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002113}, author = {Nalls, Michael A and Couper, David J and Tanaka, Toshiko and van Rooij, Frank J A and Chen, Ming-Huei and Smith, Albert V and Toniolo, Daniela and Zakai, Neil A and Yang, Qiong and Greinacher, Andreas and Wood, Andrew R and Garcia, Melissa and Gasparini, Paolo and Liu, Yongmei and Lumley, Thomas and Folsom, Aaron R and Reiner, Alex P and Gieger, Christian and Lagou, Vasiliki and Felix, Janine F and V{\"o}lzke, Henry and Gouskova, Natalia A and Biffi, Alessandro and D{\"o}ring, Angela and V{\"o}lker, Uwe and Chong, Sean and Wiggins, Kerri L and Rendon, Augusto and Dehghan, Abbas and Moore, Matt and Taylor, Kent and Wilson, James G and Lettre, Guillaume and Hofman, Albert and Bis, Joshua C and Pirastu, Nicola and Fox, Caroline S and Meisinger, Christa and Sambrook, Jennifer and Arepalli, Sampath and Nauck, Matthias and Prokisch, Holger and Stephens, Jonathan and Glazer, Nicole L and Cupples, L Adrienne and Okada, Yukinori and Takahashi, Atsushi and Kamatani, Yoichiro and Matsuda, Koichi and Tsunoda, Tatsuhiko and Tanaka, Toshihiro and Kubo, Michiaki and Nakamura, Yusuke and Yamamoto, Kazuhiko and Kamatani, Naoyuki and Stumvoll, Michael and T{\"o}njes, Anke and Prokopenko, Inga and Illig, Thomas and Patel, Kushang V and Garner, Stephen F and Kuhnel, Brigitte and Mangino, Massimo and Oostra, Ben A and Thein, Swee Lay and Coresh, Josef and Wichmann, H-Erich and Menzel, Stephan and Lin, JingPing and Pistis, Giorgio and Uitterlinden, Andr{\'e} G and Spector, Tim D and Teumer, Alexander and Eiriksdottir, Gudny and Gudnason, Vilmundur and Bandinelli, Stefania and Frayling, Timothy M and Chakravarti, Aravinda and van Duijn, Cornelia M and Melzer, David and Ouwehand, Willem H and Levy, Daniel and Boerwinkle, Eric and Singleton, Andrew B and Hernandez, Dena G and Longo, Dan L and Soranzo, Nicole and Witteman, Jacqueline C M and Psaty, Bruce M and Ferrucci, Luigi and Harris, Tamara B and O{\textquoteright}Donnell, Christopher J and Ganesh, Santhi K} } @article {1688, title = {Mutations in the 5{\textquoteright} UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2.}, journal = {Am J Hum Genet}, volume = {88}, year = {2011}, month = {2011 Jan 7}, pages = {115-20}, abstract = {

THC2, an autosomal-dominant thrombocytopenia described so far in only two families, has been ascribed to mutations in MASTL or ACBD5. Here, we show that ANKRD26, another gene within the THC2 locus, and neither MASTL nor ACBD5, is mutated in eight unrelated families. ANKRD26 was also found to be mutated in the family previously reported to have an ACBD5 mutation. We identified six different ANKRD26 mutations, which were clustered in a highly conserved 19~bp sequence located in the 5{\textquoteright} untranslated region. Mutations were not detected in 500 controls and are absent from the 1000 Genomes database. Available data from an animal model and Dr.~Watson{\textquoteright}s genome give evidence against haploinsufficiency as the pathogenetic mechanism for ANKRD26-mediated thrombocytopenia. The luciferase reporter assay suggests that these 5{\textquoteright} UTR mutations might enhance ANKRD26 expression. ANKRD26 is the ancestor of a family of primate-specific genes termed POTE, which have been recently identified as a family of proapoptotic proteins. Dysregulation of apoptosis might therefore be the pathogenetic mechanism, as demonstrated for another thrombocytopenia, THC4. Further investigation is needed to provide evidence supporting this hypothesis.

}, keywords = {Ankyrin Repeat, Base Sequence, Chromosome Breakage, Chromosome Disorders, Conserved Sequence, Female, Genes, Dominant, Genetic Loci, Haploinsufficiency, Humans, Male, Molecular Sequence Data, Mutation, Pedigree, Thrombocytopenia}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2010.12.006}, author = {Pippucci, Tommaso and Savoia, Anna and Perrotta, Silverio and Pujol-Moix, N{\'u}ria and Noris, Patrizia and Castegnaro, Giovanni and Pecci, Alessandro and Gnan, Chiara and Punzo, Francesca and Marconi, Caterina and Gherardi, Samuele and Loffredo, Giuseppe and De Rocco, Daniela and Scianguetta, Saverio and Barozzi, Serena and Magini, Pamela and Bozzi, Valeria and Dezzani, Luca and Di Stazio, Mariateresa and Ferraro, Marcella and Perini, Giovanni and Seri, Marco and Balduini, Carlo L} } @article {1662, title = {A new case of duplication of the MDS region identified by high-density SNP arrays and a review of the literature.}, journal = {J Appl Genet}, volume = {52}, year = {2011}, month = {2011 Feb}, pages = {77-80}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Child, Female, Gene Duplication, Humans, Microtubule-Associated Proteins, Myelodysplastic Syndromes, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Prognosis}, issn = {2190-3883}, doi = {10.1007/s13353-010-0004-2}, author = {Faletra, Flavio and Devescovi, Raffaella and Pecile, Vanna and Fabretto, Antonella and Carrozzi, Marco and Gasparini, Paolo} } @article {1710, title = {Osteoprotegerin induces morphological and functional alterations in mouse pancreatic islets.}, journal = {Mol Cell Endocrinol}, volume = {331}, year = {2011}, month = {2011 Jan 1}, pages = {136-42}, abstract = {

Although serum osteoprotegerin (OPG) is significantly increased in diabetic subjects, its potential role in beta cell dysfunction has not been investigated. This study aimed to assess the effect of full-length OPG administered in vivo in mice on pancreatic islet structure and function and its interaction with the renin-angiotensin system (RAS). OPG-treated mice showed increased islet monocyte/macrophage infiltration, fibrosis and apoptosis with reduction of islet function. The remodeling of islet architecture was associated with increased pancreatic expression of components of the RAS, growth factor genes (transforming growth factor β and connective tissue growth factor) and inflammatory molecules (monocyte chemotactic protein-1 and vascular adhesion molecule type 1). Prevention of these changes with improvement of insulin secretion was observed in ramipril treated animals. Our data suggest that OPG might play an important role in promoting beta cell dysfunction and that the upregulation of the local RAS represents one possible mechanism responsible for the OPG-induced beta cell dysfunction.

}, keywords = {Animals, Apoptosis, Blood Glucose, Blood Pressure, Body Weight, Cell Lineage, Cell Movement, Chemokine CCL2, Connective Tissue Growth Factor, Fibrosis, Gene Expression Regulation, Humans, Insulin, Islets of Langerhans, Macrophages, Mice, Monocytes, Organ Size, Osteoprotegerin, Peptidyl-Dipeptidase A, Receptor, Angiotensin, Type 1, Systole, Transforming Growth Factor beta, Vascular Cell Adhesion Molecule-1}, issn = {1872-8057}, doi = {10.1016/j.mce.2010.08.019}, author = {Toffoli, Barbara and Bernardi, Stella and Candido, Riccardo and Sabato, Nicoletta and Carretta, Renzo and Corallini, Federica and Secchiero, Paola and Zauli, Giorgio and Fabris, Bruno} } @article {1784, title = {Osteoprotegerin promotes vascular fibrosis via a TGF-β1 autocrine loop.}, journal = {Atherosclerosis}, volume = {218}, year = {2011}, month = {2011 Sep}, pages = {61-8}, abstract = {

BACKGROUND: This study was designed to evaluate the potential role of osteoprotegerin (OPG) in arterial fibrosis.

METHODS: Aortic samples were analyzed after in vivo treatment of ApoE(-/-) mice with recombinant human OPG. Mouse vascular smooth muscle cells (VSMC) were exposed in vitro to recombinant OPG and analyzed for markers of inflammation and fibrosis, such as fibronectin, collagen I, III, IV and transforming growth factor-β1 (TGF-β1). Conversely, the potential modulation of endogenous OPG expression and release by VSMC was analyzed in response to different pro-atherosclerotic cytokines, TGF-β1, platelet derived growth factor (PDGF) and angiogensin II (Ang II).

RESULTS: In vivo treatment with human OPG induced signs of fibrosis and up-regulated the arterial expression of TGF-β1. Consistently, in vitro treatment of VSMC with human OPG induced the expression of fibronectin, collagen type I, III, IV, metalloprotein-2 (MMP-2) and MMP-9, as well as of TGF-β1. On the other hand, exposure to recombinant TGF-β1 promoted the expression/release of endogenous OPG and mediated the increase of OPG release induced by PDGF and Ang II in VSMC.

CONCLUSIONS: Taken together, these data support a pathogenic role for OPG in the development and progression of atherosclerotic lesions and suggest the existence of a vicious circle between TGF-β1 and OPG.

}, keywords = {Animals, Apolipoproteins E, Cell Proliferation, Collagen, Fibronectins, Fibrosis, Gene Expression Regulation, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Osteoprotegerin, Platelet-Derived Growth Factor, Transforming Growth Factor beta1}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2011.05.019}, author = {Toffoli, Barbara and Pickering, Raelene J and Tsorotes, Despina and Wang, Bo and Bernardi, Stella and Kantharidis, Phillip and Fabris, Bruno and Zauli, Giorgio and Secchiero, Paola and Thomas, Merlin C} } @article {1745, title = {A Phase II study on the safety and efficacy of a single dose of pegfilgrastim for mobilization and transplantation of autologous hematopoietic stem cells in pediatric oncohematology patients.}, journal = {Transfusion}, volume = {51}, year = {2011}, month = {2011 Nov}, pages = {2480-7}, abstract = {

BACKGROUND: Limited data are available on the use of pegfilgrastim in pediatric patients as a mobilizing agent in association with chemotherapy.

STUDY DESIGN AND METHODS: This was a prospective, multicenter, Phase II study to evaluate the safety and efficacy of a single dose of 100 {\textmu}g/kg pegfilgrastim in mobilizing peripheral blood stem cells (PBSCs) in pediatric patients. The primary endpoint of the study was the percentage of good mobilizers with pegfilgrastim (blood peak of CD34+ cells >= 20 {\texttimes} 10(6) /L). The results were compared with a historical control group.

RESULTS: Thirty of 36 recruited patients were classified as good mobilizers (83\%). The median value of circulating CD34+ at leukapheresis was 143 {\texttimes} 10(6) /L (range, 20 {\texttimes} 10(6) -1988 {\texttimes} 10(6) /L). No significant adverse effects were associated with the use of pegfilgrastim and no patient was withdrawn from using the drug. A blood peak of 20 {\texttimes} 10(6) /L or more CD34+ was observed in 33 of 36 control patients (92\%) and the median CD34+ count at leukapheresis was 158 {\texttimes} 10(6) /kg (range, 28 {\texttimes} 10(6) -4529 {\texttimes} 10(6) /kg; p = 0.7). No significant differences were found between the two groups in terms of toxicity or other variables of mobilization. As at October 2008, 23 patients of the pegfilgrastim group and 32 patients of the filgrastim group underwent autologous transplant. No significant differences were found in terms of early toxicity, myeloid recovery, and Day 100 survival.

CONCLUSION: A single dose of 100 {\textmu}g/kg pegfilgrastim was safe and effective for PBSC collection in pediatric patients. We suggest that these results support the use of pegfilgrastim for pediatric patients.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Female, Granulocyte Colony-Stimulating Factor, Hematopoietic Stem Cell Mobilization, Humans, Infant, Male, Neoplasms, Peripheral Blood Stem Cell Transplantation, Prospective Studies, Recombinant Proteins, Transplantation, Autologous}, issn = {1537-2995}, doi = {10.1111/j.1537-2995.2011.03157.x}, author = {Cesaro, Simone and Zanazzo, Andrea Giulio and Frenos, Stefano and Luksch, Roberto and Pegoraro, Anna and Tridello, Gloria and Dallorso, Sandro} } @article {1789, title = {Procalcitonin in detecting neonatal nosocomial sepsis.}, journal = {Arch Dis Child Fetal Neonatal Ed}, year = {2011}, month = {2011 Mar 15}, abstract = {

OBJECTIVE: To investigate the accuracy of procalcitonin (PCT) as a diagnostic marker of nosocomial sepsis (NS) and define the most accurate cut-off to distinguish infected from uninfected neonates. SETTING: Six neonatal intensive care units (NICUs). PATIENTS: 762 neonates admitted to six NICUs during a 28-month observational study for whom at least one serum sample was taken on admission. MAIN OUTCOME MEASURES: Positive and negative predictive values at different PCT cut-off levels. RESULTS: The overall probability of an NS was doubled or more if PCT was >0.5 ng/ml. In very-low-birth-weight (VLBW) infants, a cut-off of >2.4 ng/ml gave a positive predictive value of NS near to 50\% with a probability of a false-positive diagnosis of NS in about 10\% of the patients. CONCLUSIONS: In VLBW neonates, a serum PCT value >2.4 ng/ml prompts early empirical antibiotic therapy, while in normal-birth-weight infants, a PCT value <=2.4 ng/ml carries a low risk of missing an NS.

}, issn = {1468-2052}, doi = {10.1136/adc.2010.194100}, author = {Auriti, Cinzia and Fiscarelli, Ersilia and Ronchetti, Maria Paola and Argentieri, Marta and Marrocco, Gabriella and Quondamcarlo, Anna and Seganti, Giulio and Bagnoli, Francesco and Buonocore, Giuseppe and Serra, Giovanni and Bacolla, Gianfranco and Mastropasqua, Savino and Mari, Annibale and Corchia, Carlo and Prencipe, Giusi and Piersigilli, Fiammetta and Rav{\`a}, Lucilla and Di Ciommo, Vincenzo} } @article {1852, title = {Rubella susceptibility profile in pregnant women with HIV.}, journal = {Clin Infect Dis}, volume = {52}, year = {2011}, month = {2011 Apr 1}, pages = {960-2}, keywords = {Female, HIV Infections, Humans, Pregnancy, Pregnancy Complications, Infectious, Rubella}, issn = {1537-6591}, doi = {10.1093/cid/cir040}, author = {Floridia, Marco and Pinnetti, Carmela and Ravizza, Marina and Tibaldi, Cecilia and Sansone, Matilde and Fiscon, Marta and Guaraldi, Giovanni and Guerra, Brunella and Alberico, Salvatore and Spinillo, Arsenio and Castelli, Paula and Dalzero, Serena and Cavaliere, Anna Franca and Tamburrini, Enrica} } @article {1756, title = {Shwachman-Diamond syndrome and type 1 diabetes mellitus: more than a chance association?}, journal = {Exp Clin Endocrinol Diabetes}, volume = {119}, year = {2011}, month = {2011 Nov}, pages = {610-2}, abstract = {

Shwachman-Diamond syndrome is a rare clinical condition consisting of exocrine pancreatic dysfunction, various degree of pancytopenia, and metaphyseal dysplasia. The majority of Shwachman-Diamond syndrome cases result from mutations in the Shwachman-Bodian-Diamond Syndrome gene. To date, type 1 diabetes mellitus has only been reported in 4 independent cases presenting with Shwachman-Diamond syndrome, 3 of them with molecular confirmation of the diagnosis. We describe 2 unrelated patients with clinical and molecular features typical of Shwachman-Diamond syndrome and type 1 diabetes mellitus. In addition, we report the occurrence rate of type 1 diabetes mellitus in the Italian registry for Shwachman-Diamond syndrome, which is low (3.23\%) but increased at least 30-fold over the type 1 diabetes mellitus occurrence rate in the general population. No evidence of a direct correlation between Shwachman-Diamond syndrome and type 1 diabetes mellitus have been reported, therefore the presence of both diseases in the same patient might be a chance association, however we suggest that the defects in immune regulation of Shwachman-Diamond syndrome might play a role in the development of type 1 diabetes mellitus.

}, keywords = {Bone Marrow Diseases, CD4-CD8 Ratio, Diabetes Mellitus, Type 1, Exocrine Pancreatic Insufficiency, Female, Heterozygote, Humans, Immune System, Infant, Italy, Lipomatosis, Male, Mutation, Prevalence, Proteins, Registries}, issn = {1439-3646}, doi = {10.1055/s-0031-1275699}, author = {Gana, S and Sainati, L and Frau, M R and Monciotti, C and Poli, F and Cannioto, Z and Comelli, M and Danesino, C and Minelli, A} } @article {1854, title = {Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Dec}, pages = {1256-61}, abstract = {

Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87\% of enchondromas (benign cartilage tumors) and in 70\% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81\%) subjects with Ollier disease and 10 of 13 (77\%) with Maffucci syndrome carried IDH1 (98\%) or IDH2 (2\%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40\% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.

}, keywords = {Adult, Case-Control Studies, Cell Line, Tumor, DNA Methylation, Enchondromatosis, Female, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Humans, Isocitrate Dehydrogenase, Male, Middle Aged, Mosaicism, Mutation, Missense, Sequence Analysis, DNA, Transcription, Genetic, Young Adult}, issn = {1546-1718}, doi = {10.1038/ng.1004}, author = {Pansuriya, Twinkal C and van Eijk, Ronald and d{\textquoteright}Adamo, Pio and van Ruler, Maayke A J H and Kuijjer, Marieke L and Oosting, Jan and Cleton-Jansen, Anne-Marie and van Oosterwijk, Jolieke G and Verbeke, Sofie L J and Meijer, Dani{\"e}lle and van Wezel, Tom and Nord, Karolin H and Sangiorgi, Luca and Toker, Berkin and Liegl-Atzwanger, Bernadette and San-Julian, Mikel and Sciot, Raf and Limaye, Nisha and Kindblom, Lars-Gunnar and Daugaard, Soeren and Godfraind, Catherine and Boon, Laurence M and Vikkula, Miikka and Kurek, Kyle C and Szuhai, Karoly and French, Pim J and Bov{\'e}e, Judith V M G} } @article {1611, title = {Tag-single nucleotide polymorphism-based human leukocyte antigen genotyping in celiac disease patients from northeastern Italy.}, journal = {Hum Immunol}, volume = {72}, year = {2011}, month = {2011 Jun}, pages = {499-502}, abstract = {

We genotyped celiac disease (CD)-associated haplotypes DQ2.5, DQ8, DQ2.2, and DQ7 in 1005 CD patients from North Eastern Italy using a Tag-single nucleotide polymorphism (SNPs) approach and real time PCR platform, checking the accuracy and reliability of the method and comparing it to traditional PCR-SSP. Only 14 of 2010 chromosomes analyzed (0.7\%) showed discrepancies between the Tag-SNPs real-time polymerase chain reaction (PCR) method and the PCR-single-strand polymorphism (SSP) technique, indicating a high sensitivity and specificity (ranging from 0.987 to 1 and from 0.998 to 0.999, respectively) for tagging with respect to corresponding human leukocyte antigen (HLA) alleles identified by PCR-SSP. Moreover, the overall cost of the Tag-SNPs HLA typing method was low (3 to 4 {\texteuro}/sample instead of 35 to 70 {\texteuro}/sample with commercial kits), making it suitable for mass screenings. Hence, we believe that the Tag-SNPs HLA typing could be used to complement or replace classic HLA typing in at high-risk groups, for research purposes and eventually in population screening programs.

}, keywords = {Adolescent, Adult, Aged, Celiac Disease, Child, Child, Preschool, Female, Humans, Infant, Italy, Male, Mass Screening, Middle Aged, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, Sensitivity and Specificity}, issn = {1879-1166}, doi = {10.1016/j.humimm.2011.03.008}, author = {Vatta, Serena and Fabris, Annalisa and Segat, Ludovica and Not, Tarcisio and Crovella, Sergio} } @article {1838, title = {Therapeutic approaches in the treatment of juvenile dermatomyositis in patients with recent-onset disease and in those experiencing disease flare: an international multicenter PRINTO study.}, journal = {Arthritis Rheum}, volume = {63}, year = {2011}, month = {2011 Oct}, pages = {3142-52}, abstract = {

OBJECTIVE: To evaluate response to therapy over a 24-month period in a large prospective international cohort of patients with juvenile dermatomyositis (DM).

METHODS: The study included 145 patients with recent-onset juvenile DM and 130 juvenile DM patients experiencing disease flare, all of whom were <18 years old. Disease activity parameters and therapeutic approaches in 4 geographic areas were analyzed at baseline and at 6, 12, and 24 months. Response was assessed according to the Pediatric Rheumatology International Trials Organization (PRINTO) juvenile DM response criteria, and data were reported "as observed" and in the intent-to-treat (ITT) population.

RESULTS: Patients with recent-onset juvenile DM at baseline had higher baseline disease activity and greater improvement over 24 months when compared to juvenile DM patients experiencing disease flare at baseline. Methotrexate (MTX) or high-dose corticosteroids were administered more frequently to patients with recent-onset juvenile DM, compared to juvenile DM patients experiencing disease flare, who were more likely to receive cyclosporine. Compared to patients from Western and Eastern Europe, a higher proportion of patients from South and Central America and North America received pulse steroids, and the average steroid dosage was higher in the North American and South and Central American patients. The use of MTX was similar in all 4 regions, while cyclosporin A was more frequently used in Western Europe. In the "as observed" analysis, 57.9\% of the patients with recent-onset juvenile DM and 36.4\% of the patients experiencing disease flare (P<0.001) reached at least a 70\% response by PRINTO criteria at 6 months; these proportions had increased at month 24 to 78.4\% and 51.2\%, respectively (P<0.001). Corresponding results of the ITT analysis were much lower, with only one-third of the patients able to maintain the initial assigned therapy over 24 months.

CONCLUSION: Patients with recent-onset juvenile DM are more likely to achieve significant clinical improvement over 24 months, when compared to patients experiencing flares of juvenile DM. Internationally, various therapeutic approaches are used to treat this disease.

}, keywords = {Adolescent, Adrenal Cortex Hormones, Child, Dermatologic Agents, Dermatomyositis, Female, Humans, Longitudinal Studies, Male, Methotrexate, Prospective Studies, Treatment Outcome}, issn = {1529-0131}, doi = {10.1002/art.30475}, author = {Hasija, Rachana and Pistorio, Angela and Ravelli, Angelo and Demirkaya, Erkan and Khubchandani, Raju and Guseinova, Dinara and Malattia, Clara and Canhao, Helena and Harel, Liora and Foell, Dirk and Wouters, Carine and De Cunto, Carmen and Huemer, Christian and Kimura, Yukiko and Mangge, Harald and Minetti, Carlo and Nordal, Ellen Berit and Philippet, Pierre and Garozzo, Rosaria and Martini, Alberto and Ruperto, Nicolino} } @article {1787, title = {Vertebral defects in patients with Peters plus syndrome and mutations in B3GALTL.}, journal = {Ophthalmic Genet}, volume = {32}, year = {2011}, month = {2011 Nov}, pages = {256-8}, keywords = {Abnormalities, Multiple, Alternative Splicing, Child, Preschool, Cleft Lip, Consanguinity, Cornea, Female, Galactosyltransferases, Glucosyltransferases, Growth Disorders, Humans, Limb Deformities, Congenital, Point Mutation, Spine}, issn = {1744-5094}, doi = {10.3109/13816810.2011.587082}, author = {Faletra, Flavio and Athanasakis, Emmanouil and Minen, Federico and Fornasier, Federico and Marchetti, Federico and Gasparini, Paolo} } @article {1815, title = {X-ray fluorescence elemental mapping and microscopy to follow hepatic disposition of a Gd-based magnetic resonance imaging contrast agent.}, journal = {Clin Exp Pharmacol Physiol}, volume = {38}, year = {2011}, month = {2011 Dec}, pages = {834-45}, abstract = {

1. Spatially resolved X-ray fluorescence (XRF) spectroscopy with synchrotron radiation is a technique that allows imaging and quantification of chemical elements in biological specimens with high sensitivity. In the present study, we applied XRF techniques at a macro and micro level to carry out drug distribution studies on ex vivo models to confirm the hepatobiliary disposition of the Gd-based magnetic resonance imaging contrast agent B22956/1. 2. Gd presence was selectively quantified allowing the determination of the time dependent disappearance of the drug from blood and its hepatic accumulation in mice after administration. Elemental mapping highlighted the drug distribution differences between healthy and diseased livers. XRF microanalyses showed that in CCl(4) -induced hepatitis, B22956/1 has greatly reduced hepatic accumulation, shown as a 20-fold reduction of Gd presence. Furthermore, a significant increase of Fe presence was found in steatotic compared with healthy livers, in line with the disease features. 3. The present results show that XRF might be useful in preclinical pharmacological studies with drugs containing exogenous elements. Furthermore, quantitative and high-sensitivity elemental mapping allows simultaneous detection of chemical variation, showing pathological conditions. This approach was useful in suggesting reduced B22956/1 accumulation in steatotic livers, thus opening possible new diagnostic perspectives for this drug.

}, keywords = {Animals, Contrast Media, Fatty Liver, Female, Gadolinium, Hepatitis, Iron, Liver, Magnetic Resonance Imaging, Mice, Mice, Inbred CBA, Organometallic Compounds, Spectrometry, X-Ray Emission}, issn = {1440-1681}, doi = {10.1111/j.1440-1681.2011.05618.x}, author = {Delfino, Riccarda and Altissimo, Matteo and Menk, Ralf Hendrik and Alberti, Roberto and Klatka, Tomasz and Frizzi, Tommaso and Longoni, Antonio and Salom{\`e}, Murielle and Tromba, Giuliana and Arfelli, Fulvia and Clai, Milan and Vaccari, Lisa and Lorusso, Vito and Tiribelli, Claudio and Pascolo, Lorella} } @article {1694, title = {Abatacept improves health-related quality of life, pain, sleep quality, and daily participation in subjects with juvenile idiopathic arthritis.}, journal = {Arthritis Care Res (Hoboken)}, volume = {62}, year = {2010}, month = {2010 Nov}, pages = {1542-51}, abstract = {

OBJECTIVE: To assess health-related quality of life (HRQOL) in abatacept-treated children/adolescents with juvenile idiopathic arthritis (JIA).

METHODS: In this phase III, double-blind, placebo-controlled trial, subjects with active polyarticular course JIA and an inadequate response/intolerance to >=1 disease-modifying antirheumatic drug (including biologics) received abatacept 10 mg/kg plus methotrexate (MTX) during the 4-month open-label period (period A). Subjects achieving the American College of Rheumatology Pediatric 30 criteria for improvement (defined "responders") were randomized to abatacept or placebo (plus MTX) in the 6-month double-blind withdrawal period (period B). HRQOL assessments included 15 Child Health Questionnaire (CHQ) health concepts plus the physical (PhS) and psychosocial summary scores (PsS), pain (100-mm visual analog scale), the Children{\textquoteright}s Sleep Habits Questionnaire, and a daily activity participation questionnaire.

RESULTS: A total of 190 subjects from period A and 122 from period B were eligible for analysis. In period A, there were substantial improvements across all of the CHQ domains (greatest improvement was in pain/discomfort) and the PhS (8.3 units) and PsS (4.3 units) with abatacept. At the end of period B, abatacept-treated subjects had greater improvements versus placebo in all domains (except behavior) and both summary scores. Similar improvement patterns were seen with pain and sleep. For participation in daily activities, an additional 2.6 school days/month and 2.3 parents{\textquoteright} usual activity days/month were gained in period A responders with abatacept, and further gains were made in period B (1.9 versus 0.9 [P = 0.033] and 0.2 versus -1.3 [P = 0.109] school days/month and parents{\textquoteright} usual activity days/month, respectively, in abatacept- versus placebo-treated subjects).

CONCLUSION: Improvements in HRQOL were observed with abatacept, providing real-life tangible benefits to children with JIA and their parents/caregivers.

}, keywords = {Adolescent, Arthritis, Juvenile, Child, Double-Blind Method, Female, Health Status, Humans, Immunoconjugates, Male, Pain, Quality of Life, Questionnaires, Sleep Stages}, issn = {2151-4658}, doi = {10.1002/acr.20283}, author = {Ruperto, Nicolino and Lovell, Daniel J and Li, Tracy and Sztajnbok, Flavio and Goldenstein-Schainberg, Claudia and Scheinberg, Morton and Penades, Inmaculada Calvo and Fischbach, Michael and Alcala, Javier Orozco and Hashkes, Philip J and Hom, Christine and Jung, Lawrence and Lepore, Loredana and Oliveira, Sheila and Wallace, Carol and Alessio, Maria and Quartier, Pierre and Cortis, Elisabetta and Eberhard, Anne and Simonini, Gabriele and Lemelle, Irene and Chalom, Elizabeth Candell and Sigal, Leonard H and Block, Alan and Covucci, Allison and Nys, Marleen and Martini, Alberto and Giannini, Edward H} } @article {1737, title = {Acute respiratory failure in a child after talc inhalation.}, journal = {Respiration}, volume = {79}, year = {2010}, month = {2010}, pages = {340}, keywords = {Female, Humans, Infant, Inhalation Exposure, Respiratory Insufficiency, Talc}, issn = {1423-0356}, doi = {10.1159/000181013}, author = {Patarino, Federica and Norbedo, Stefania and Barbi, Egidio and Poli, Furio and Furlan, Stefano and Savron, Fabio} } @article {1626, title = {Anti transglutaminase antibodies cause ataxia in mice.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010}, pages = {e9698}, abstract = {

BACKGROUND: Celiac disease (CD) is an autoimmune gastrointestinal disorder characterized by the presence of anti-transglutaminase 2 (TG2) and anti-gliadin antibodies. Amongst the neurological dysfunctions associated with CD, ataxia represents the most common one.

METHODS: We analyzed by immunohistochemistry, the anti-neural reactivity of the serum from 20 CD patients. To determine the role of anti-TG2 antibodies in ataxia, two anti-TG2 single chain variable fragments (scFv), isolated from a phage-display IgA antibody library, were characterized by immunohistochemistry and ELISA, and injected in mice to study their effects on motor coordination. We found that 75\% of the CD patient population without evidence of neurological involvement, has circulating anti-neural IgA and/or IgG antibodies. Two anti-TG2 scFvs, cloned from one CD patient, stained blood vessels but only one reacted with neurons. This anti-TG2 antibody showed cross reactivity with the transglutaminase isozymes TG3 and TG6. Intraventricular injection of the anti-TG2 or the anti-TG2/3/6 cross-reactive scFv provoked transient, equally intensive ataxia in mice.

CONCLUSION: The serum from CD patients contains anti-TG2, TG3 and TG6 antibodies that may potentially cause ataxia.

}, keywords = {Adult, Animals, Antibodies, Ataxia, Autoimmune Diseases, Brain, Celiac Disease, Female, Gliadin, Humans, Isoenzymes, Male, Mice, Mice, Inbred C57BL, Middle Aged, Motor Skills, Rats, Rats, Sprague-Dawley, Transglutaminases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0009698}, author = {Boscolo, Sabrina and Lorenzon, Andrea and Sblattero, Daniele and Florian, Fiorella and Stebel, Marco and Marzari, Roberto and Not, Tarcisio and Aeschlimann, Daniel and Ventura, Alessandro and Hadjivassiliou, Marios and Tongiorgi, Enrico} } @article {1701, title = {Beta defensin-1 gene (DEFB1) polymorphisms are not associated with atopic dermatitis in children and adolescents from northeast Brazil (Recife, Pernambuco).}, journal = {Int J Dermatol}, volume = {49}, year = {2010}, month = {2010 Jun}, pages = {653-7}, abstract = {

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease resulting from the interplay between environmental, immunological and genetic factors. In our study, we investigated the role of three single nucleotide polymorphisms (SNPs) at 5{\textquoteright}-UTR of DEFB1 gene, encoding for the human beta defensin-1, on the susceptibility to develop AD in a group of Brazilian children and adolescents.

METHODS: Three SNPs, -20 G/A (rs11362), -44 C/G (rs1800972), and -52 G/A (rs1799946) at 5{\textquoteright}-UTR of DEFB1 gene were genotyped in two groups of children and adolescents, one affected by AD (96 subjects), the other healthy (191 individuals), from northeast Brazil.

RESULTS: -44 C/G frequencies were comparable between the two groups. The -20 GG genotype was more frequent in AD subjects than in healthy controls; the -52 GG, conversely, was more frequent in healthy controls than in AD. However, both these differences did not reach statistical significance. Also, association between SNPs and AD severity has been shown. The analysis of DEFB1 haplotypes did not highlight any association of the three SNPs with AD development or disease severity.

CONCLUSIONS: Our results seem to exclude a role for the -44 C/G DEFB1 SNPs on the pathogenesis and severity of AD, while for the -20 C/G and -52 G/A, even if not statistically significant, we evidenced a slight trend for susceptibility (-20 GG) and protection (-52 GG) for the development of AD. However, as controversial findings have been reported in the literature, the role of DEFB1 in the development of AD and in the severity of the phenotype deserves further investigation.

}, keywords = {Adolescent, beta-Defensins, Brazil, Child, Child, Preschool, Dermatitis, Atopic, Female, Gene Frequency, Genetic Predisposition to Disease, Haplotypes, Humans, Infant, Male, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1365-4632}, doi = {10.1111/j.1365-4632.2009.04343.x}, author = {Segat, Ludovica and Guimar{\~a}es, Rafael L and Brand{\~a}o, Lucas A C and Rocha, Cintia R C and Zanin, Valentina and Trevisiol, Chiara and de Lima Filho, Jos{\'e} Luiz and Crovella, Sergio} } @article {1660, title = {A case of lymphedema-distichiasis syndrome carrying a new de novo frameshift FOXC2 mutation.}, journal = {Ophthalmic Genet}, volume = {31}, year = {2010}, month = {2010 Jun}, pages = {98-100}, abstract = {

PURPOSE: Lymphedema-Distichiasis (LD, OMIM 153400) is an autosomal dominant disorder with variable expression. The mutated gene implicated is FOXC2, which encodes for a forkhead transcription factor involved in the development of the lymphatic and vascular system. LD is characterized by late childhood or pubertal onset lymphedema of the limbs and distichiasis. Other associations have been reported, including congenital heart disease, ptosis, scoliosis.

CONCLUSIONS: Here we describe a case of LD carrying a de novo frameshift mutation of FOXC2 who presented a prepubertal onset of lower limbs lymphedema and mild distichiasis associated with other anomalies such as webbing neck and ptosis.

}, keywords = {Abnormalities, Multiple, Adolescent, Eye Abnormalities, Eyelashes, Face, Forkhead Transcription Factors, Frameshift Mutation, Humans, Lymphedema, Male, Syndrome}, issn = {1744-5094}, doi = {10.3109/13816811003620517}, author = {Fabretto, Antonella and Shardlow, Alison and Faletra, Flavio and Lepore, Loredana and Hladnik, Uros and Gasparini, Paolo} } @article {1663, title = {Declining HCV seroprevalence in pregnant women with HIV.}, journal = {Epidemiol Infect}, volume = {138}, year = {2010}, month = {2010 Sep}, pages = {1317-21}, abstract = {

We assessed recent trends in hepatitis C virus (HCV) prevalence in pregnant women with HIV using data from a large national study. Based on 1240 pregnancies, we observed a 3.4-fold decline in HCV seroprevalence in pregnant women with HIV between 2001 (29.3\%) and 2008 (8.6\%). This decline was the net result of two components: a progressively declining HCV seroprevalence in non-African women (from 35.7\% in 2001 to 16.7\% in 2008), sustained by a parallel reduction in history of injecting drug use (IDU) in this population, and a significantly growing presence (from 21.2\% in 2001 to 48.6\% in 2008) of women of African origin, at very low risk of being HCV-infected [average HCV prevalence 1\%, adjusted odds ratio (aOR) for HCV 0.09, 95\% CI 0.03-0.29]. Previous IDU was the stronger determinant of HCV co-infection in pregnant women with HIV (aOR 30.9, 95\% CI 18.8-51.1). The observed trend is expected to translate into a reduced number of cases of vertical HCV transmission.

}, keywords = {Chi-Square Distribution, Female, Hepatitis C, HIV Infections, Humans, Italy, Logistic Models, Pregnancy, Risk Factors, Seroepidemiologic Studies}, issn = {1469-4409}, doi = {10.1017/S0950268810000129}, author = {Floridia, M and Tamburrini, E and Anzidei, G and Tibaldi, C and Muggiasca, M L and Guaraldi, G and Fiscon, M and Vimercati, A and Martinelli, P and Donisi, A and Dalzero, S and Ravizza, M} } @article {1687, title = {Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations.}, journal = {Blood}, volume = {116}, year = {2010}, month = {2010 Dec 23}, pages = {5832-7}, abstract = {

Platelet transfusion is currently the primary medical treatment for reducing thrombocytopenia in patients with inherited thrombocytopenias. To evaluate whether stimulating megakaryopoiesis could increase platelet count in these conditions, we treated patients with a severe thrombocytopenia induced by MYH9 mutations (MYH9-related disease) with a nonpeptide thrombopoietin receptor agonist, eltrombopag. Twelve adult patients with MYH9-RD and platelet counts of less than 50 {\texttimes} 10(9)/L received 50 mg of eltrombopag orally per day for 3 weeks. Patients who achieved a platelet count higher than 150 {\texttimes} 10(9)/L stopped therapy, those with 100 to 150 platelets {\texttimes} 10(9)/L continued treatment at the same eltrombopag dose for 3 additional weeks, while those with less than 100 platelets {\texttimes} 10(9)/L increased the eltrombopag dose to 75 mg for 3 weeks. Major responses (platelet count of at least 100 {\texttimes} 10(9)/L or 3 times the baseline value) were obtained in 8 patients, minor responses (platelet counts at least twice the baseline value) in 3. One patient did not respond. Bleeding tendency disappeared in 8 of 10 patients with bleeding symptoms at baseline. Mild adverse events were reported in 2 patients. The availability of thrombopoietin mimetics opened new prospects in the treatment of inherited thrombocytopenias. This study is registered at www.clinicaltrials.gov as NCT01133860 (European Union Drug Regulating Authorities Clinical Trials number 2008-001903-42).

}, keywords = {Administration, Oral, Adolescent, Adult, Benzoates, Dose-Response Relationship, Drug, Female, Genetic Predisposition to Disease, Humans, Hydrazines, Male, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Platelet Aggregation, Platelet Count, Pyrazoles, Receptors, Thrombopoietin, Survival Rate, Thrombocytopenia, Treatment Outcome, Young Adult}, issn = {1528-0020}, doi = {10.1182/blood-2010-08-304725}, author = {Pecci, Alessandro and Gresele, Paolo and Klersy, Catherine and Savoia, Anna and Noris, Patrizia and Fierro, Tiziana and Bozzi, Valeria and Mezzasoma, Anna Maria and Melazzini, Federica and Balduini, Carlo L} } @article {1628, title = {Emx2 and Foxg1 inhibit gliogenesis and promote neuronogenesis.}, journal = {Stem Cells}, volume = {28}, year = {2010}, month = {2010 Jul}, pages = {1206-18}, abstract = {

Neural stem cells (NSCs) give rise to all cell types forming the cortex: neurons, astrocytes, and oligodendrocytes. The transition from the former to the latter ones takes place via lineage-restricted progenitors in a highly regulated way. This process is mastered by large sets of genes, among which some implicated in central nervous system pattern formation. The aim of this study was to disentangle the kinetic and histogenetic roles exerted by two of these genes, Emx2 and Foxg1, in cortico-cerebral precursors. For this purpose, we set up a new integrated in vitro assay design. Embryonic cortical progenitors were transduced with lentiviral vectors driving overexpression of Emx2 and Foxg1 in NSCs and neuronal progenitors. Cells belonging to different neuronogenic and gliogenic compartments were labeled by spectrally distinguishable fluoroproteins driven by cell type-specific promoters and by cell type-specific antibodies and were scored via multiplex cytofluorometry and immunocytofluorescence. A detailed picture of Emx2 and Foxg1 activities in cortico-cerebral histogenesis resulted from this study. Unexpectedly, we found that both genes inhibit gliogenesis and promote neuronogenesis, through distinct mechanisms, and Foxg1 also dramatically stimulates neurite outgrowth. Remarkably, such activities, alone or combined, may be exploited to ameliorate the neuronal output obtainable from neural cultures, for purposes of cell-based brain repair.

}, keywords = {Animals, Cell Differentiation, Cell Enlargement, Cells, Cultured, Female, Forkhead Transcription Factors, Homeodomain Proteins, Mice, Nerve Tissue Proteins, Neurogenesis, Neuroglia, Neurons, Stem Cells, Transcription Factors}, issn = {1549-4918}, doi = {10.1002/stem.443}, author = {Brancaccio, Marco and Pivetta, Chiara and Granzotto, Marilena and Filippis, Carol and Mallamaci, Antonello} } @article {1695, title = {EULAR/PRINTO/PRES criteria for Henoch-Sch{\"o}nlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part I: Overall methodology and clinical characterisation.}, journal = {Ann Rheum Dis}, volume = {69}, year = {2010}, month = {2010 May}, pages = {790-7}, abstract = {

OBJECTIVES: To report methodology and overall clinical, laboratory and radiographic characteristics for Henoch-Sch{\"o}nlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) classification criteria.

METHODS: The preliminary Vienna 2005 consensus conference, which proposed preliminary criteria for paediatric vasculitides, was followed by a EULAR/PRINTO/PRES - supported validation project divided into three main steps. Step 1: retrospective/prospective web-data collection for HSP, c-PAN, c-WG and c-TA, with age at diagnosis

RESULTS: A total of 1183/1398 (85\%) samples collected were available for analysis: 827 HSP, 150 c-PAN, 60 c-WG, 87 c-TA and 59 c-other. Prevalence, signs/symptoms, laboratory, biopsy and imaging reports were consistent with the clinical picture of the four c-vasculitides. A representative subgroup of 280 patients was blinded to the treating physician diagnosis and classified by a consensus panel, with a kappa-agreement of 0.96 for HSP (95\% CI 0.84 to 1), 0.88 for c-WG (95\% CI 0.76 to 0.99), 0.84 for c-TA (95\% CI 0.73 to 0.96) and 0.73 for c-PAN (95\% CI 0.62 to 0.84), with an overall kappa of 0.79 (95\% CI 0.73 to 0.84).

CONCLUSION: EULAR/PRINTO/PRES propose validated classification criteria for HSP, c-PAN, c-WG and c-TA, with substantial/almost perfect agreement with the final consensus classification or original treating physician diagnosis.

}, keywords = {Adolescent, Biopsy, Child, Delphi Technique, Granulomatosis with Polyangiitis, Humans, International Cooperation, Internet, Polyarteritis Nodosa, Purpura, Schoenlein-Henoch, Reproducibility of Results, Takayasu Arteritis}, issn = {1468-2060}, doi = {10.1136/ard.2009.116624}, author = {Ruperto, Nicolino and Ozen, Seza and Pistorio, Angela and Dolezalova, Pavla and Brogan, Paul and Cabral, David A and Cuttica, Ruben and Khubchandani, Raju and Lovell, Daniel J and O{\textquoteright}Neil, Kathleen M and Quartier, Pierre and Ravelli, Angelo and Iusan, Silvia M and Filocamo, Giovanni and Magalh{\~a}es, Claudia Saad and Unsal, Erbil and Oliveira, Sheila and Bracaglia, Claudia and Bagga, Arvind and Stanevicha, Valda and Manzoni, Silvia Magni and Pratsidou, Polyxeni and Lepore, Loredana and Espada, Graciela and Kone-Paut, Isabella and Paut, Isabelle Kone and Zulian, Francesco and Barone, Patrizia and Bircan, Zelal and Maldonado, Maria del Rocio and Russo, Ricardo and Vilca, Iris and Tullus, Kjell and Cimaz, Rolando and Horneff, Gerd and Anton, Jordi and Garay, Stella and Nielsen, Susan and Barbano, Giancarlo and Martini, Alberto} } @article {1631, title = {First case in Italy of acquired resistance to oseltamivir in an immunocompromised patient with influenza A/H1N1v infection.}, journal = {J Clin Virol}, volume = {48}, year = {2010}, month = {2010 Jul}, pages = {220-2}, abstract = {

A pandemic influenza A/H1N1v strain with the neuraminidase H274Y mutation was detected in nasal secretions of a 2-year-old leukemic patient with influenza-like illness after 18 days of treatment with oseltamivir. At baseline, no drug-resistant virus was found, while 4 days after treatment initiation a mixture of wild-type and mutated virus was detected. After treatment interruption, the wild type influenza virus re-emerged and became prevalent in nasal secretions after a few days, suggesting the lower fitness of the mutated virus strain. The patient slowly improved concurrently with a decrease in virus load, which resulted negative 42 days after diagnosis. No other drug-resistant influenza A/H1N1v virus strains have been detected in Italy (up to the end of November 2009) since the first case of the novel A/H1N1v virus was identified in the country (May 2009).

}, keywords = {Amino Acid Substitution, Antiviral Agents, Bodily Secretions, Child, Preschool, Drug Resistance, Viral, Female, Humans, Immunocompromised Host, Influenza A Virus, H1N1 Subtype, Influenza, Human, Italy, Molecular Sequence Data, Mutation, Missense, Neuraminidase, Nose, Oseltamivir, RNA, Viral, Sequence Analysis, DNA, Treatment Outcome, Viral Load, Viral Proteins, Withholding Treatment}, issn = {1873-5967}, doi = {10.1016/j.jcv.2010.03.027}, author = {Campanini, Giulia and Piralla, Antonio and Rovida, Francesca and Puzelli, Simona and Facchini, Marzia and Locatelli, Franco and Minoli, Lorenzo and Percivalle, Elena and Donatelli, Isabella and Baldanti, Fausto} } @article {1715, title = {Five new OTOF gene mutations and auditory neuropathy.}, journal = {Int J Pediatr Otorhinolaryngol}, volume = {74}, year = {2010}, month = {2010 May}, pages = {494-8}, abstract = {

OBJECTIVE: Purpose of this paper is to analyse OTOF gene in a series of subjects affected by auditory neuropathy.

METHODS: Four children showing mild to profound prelingual deafness, confirmed by the absence of a clear and detectable responses at auditory brainstem responses (ABR), associated with the presence of bilateral OAE, were enrolled in the study.

RESULTS AND CONCLUSIONS: Genetic analysis identified five new mutations (a nonsense, a small and a large deletion and two splicing site mutations), and one missense mutation (F1795C) previously described. These results further confirm the role of OTOF gene in auditory neuropathy. In the absence of a context of neurological syndrome, the combination of absent ABR and positive OAE responses should lead to an auditory neuropathy diagnosis and to a mutational screening in OTOF.

}, keywords = {Auditory Diseases, Central, Deafness, Evoked Potentials, Auditory, Brain Stem, Female, Humans, Male, Membrane Proteins, Mutation, Otoacoustic Emissions, Spontaneous, Polymerase Chain Reaction}, issn = {1872-8464}, doi = {10.1016/j.ijporl.2010.02.004}, author = {Zadro, Cristina and Ciorba, Andrea and Fabris, Annalisa and Morgutti, Marcello and Trevisi, Patrizia and Gasparini, Paolo and Martini, Alessandro} } @article {1712, title = {A G to C transversion at the last nucleotide of exon 25 of the MYH9 gene results in a missense mutation rather than in a splicing defect.}, journal = {Eur J Med Genet}, volume = {53}, year = {2010}, month = {2010 Sep-Oct}, pages = {256-60}, abstract = {

MYH9-related disease (MYH9-RD) is a rare autosomal dominant disorder caused by mutations in MYH9, the gene encoding the heavy chain of non-muscle myosin IIA. Patients present with congenital macrothrombocytopenia and inclusion bodies in neutrophils and might develop sensorineural deafness, presenile cataract, and/or progressive nephropathy leading to end-stage renal failure. In two families with macrothrombocytopenia we identified a novel c.3485G~>~C mutation in the last nucleotide of exon 25. Bioinformatic tools for splice site prediction and minigene functional test predicted splicing anomalies of exon 25. However, analysis of RNA purified from patient{\textquoteright}s peripheral blood did not allowed us to detect any anomalies, suggesting that RNA processing is correct at least in this tissue. Therefore, we concluded that c.3485G~>~C leads to a novel missense mutation (p.Arg1162Thr) of myosin-9, which resulted to be slightly degraded in patient platelets. A precise definition of the effect of mutations is fundamental to improve our knowledge into the pathogenetic mechanisms responsible for the disease.

}, keywords = {Adolescent, Adult, Blood Platelets, Computational Biology, Exons, Female, Humans, Inclusion Bodies, Kidney Failure, Chronic, Molecular Motor Proteins, Mutation, Missense, Myosin Heavy Chains, Neutrophils, Nonmuscle Myosin Type IIA, Nucleotides, RNA Splicing, Thrombocytopenia}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2010.06.010}, author = {Vettore, Silvia and De Rocco, Daniela and Gerber, Bernhard and Scandellari, Raffaella and Bianco, Anna Monica and Balduini, Carlo L and Pecci, Alessandro and Fabris, Fabrizio and Savoia, Anna} } @article {1629, title = {Hepatic glycogenosis in an adolescent with diabetes.}, journal = {J Pediatr}, volume = {157}, year = {2010}, month = {2010 Dec}, pages = {1042}, keywords = {Adolescent, Diabetes Mellitus, Type 1, Female, Glycogen Storage Disease, Humans, Liver Diseases}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2010.06.018}, author = {Bua, Jenny and Marchetti, Federico and Faleschini, Elena and Ventura, Alessandro and Bussani, Rossana} } @article {1700, title = {HLA-G*0105N allele is associated with augmented risk for HIV infection in white female patients.}, journal = {AIDS}, volume = {24}, year = {2010}, month = {2010 Jul 31}, pages = {1961-4}, abstract = {

We analyzed HLA-G 3777G > C, HLA-G 14 bp deletion/insertion and HLA-G*0105N polymorphisms in HIV-positive white adult participants, infected through horizontal heterosexual transmission, and unexposed uninfected individuals, all from north eastern Italy. We report a new association between the HLA-G*0105N allele and HIV infection in adult white female participants, being HLA-G*0105N null allele correlated with an augmented risk (odds ratio = 4.35, 95\% confidence interval = 1.38-18.07, P = 0.005) for HIV infection.

}, keywords = {Adolescent, Adult, Aged, Female, Genetic Predisposition to Disease, Histocompatibility Antigens Class I, HIV Infections, HIV-1, Humans, Middle Aged, Polymorphism, Genetic, Young Adult}, issn = {1473-5571}, doi = {10.1097/QAD.0b013e32833c3324}, author = {Segat, Ludovica and Catamo, Eulalia and Fabris, Annalisa and Morgutti, Marcello and D{\textquoteright}Agaro, Pierlanfranco and Campello, Cesare and Crovella, Sergio} } @article {1759, title = {[Human papillomavirus cervical infection: viral genotyping and risk factors for high-grade squamous intraepithelial lesion and cervix cancer].}, journal = {Rev Bras Ginecol Obstet}, volume = {32}, year = {2010}, month = {2010 Oct}, pages = {476-85}, abstract = {

PURPOSE: to analyze the characteristics of viral infection and the risk factors for high-grade squamous intraepithelial lesion and cervical carcinoma in women with cervical HPV infection.

METHODS: a case-control study was conducted on women with cervical HPV at a Gynecology reference service enrolled at the Public Health System, located in Recife, Northeastern Brazil. The groups of cases (72 women with high-grade squamous intraepithelial lesion or cervical cancer) and controls (176 women with normal Pap smear or benign alterations) were investigated for six viral genotypes (HPV 16, 18, 31, 33, 6, 11) in ecto- and endocervical material using MY09/MY11 primers. The independent variables were ranked in three levels of determination: distal (sociodemographic), intermediate (behavioral) and proximal (previous Pap smear). The homogeneity of proportions was tested (χ2), unadjusted Odds Ratios (OR) were obtained and hierarchical logistic regression was applied to the final model, with adjustment of the effect of each variable to the outcome based on the variables in the same and previous levels of causality.

RESULTS: the viral genotype of cervical infection was identified in 76.6\% of the 248 women participating in the study. High-risk HPV genotypes (83.4\% of cases and 67.1\% of controls) were predominant, especially HPV 16 and 31. The distal risk factors identified were: living in a rural area (OR=2.71, 95\%CI: 1.18-6.23), less than three years of study (OR=3.97, 95\%CI: 2.09-7.54) and family income below two minimum wages (OR=3.30, 95\%CI: 1.04-10.51); intermediate: four or more pregnancies (OR=2.00, 95\%CI: 1.06-3.76); and proximal: absence of a previous Pap smear (OR=9.74, 95\%CI: 2.48-38.28).

CONCLUSIONS: genotypes 16 and 31 of cervical HPV infection are predominant among women assisted by the Public Health System in Northeastern Brazil. Socioeconomic and reproductive factors, as well as the absence of cytological screening, represent risk factors for the progression of infection to high-grade squamous intraepithelial lesion and cervical cancer.

}, keywords = {Adult, Carcinoma in Situ, Case-Control Studies, Female, Genotype, Humans, Papillomaviridae, Papillomavirus Infections, Risk Factors, Socioeconomic Factors, Uterine Cervical Neoplasms}, issn = {1806-9339}, author = {de Mendon{\c c}a, Vilma Guimar{\~a}es and Guimar{\~a}es, Maria Jos{\'e} Bezerra and de Lima Filho, Jos{\'e} Luiz and de Mendon{\c c}a, Carolina Guimar{\~a}es and Martins, Danyelly Bruneska Gondim and Crovella, Sergio and de Alencar, Luiz Cl{\'a}udio Arraes} } @article {1635, title = {Incidence of bacteremias and invasive mycoses in children with acute non-lymphoblastic leukemia: results from a multi-center Italian study.}, journal = {Pediatr Blood Cancer}, volume = {55}, year = {2010}, month = {2010 Dec 1}, pages = {1103-7}, abstract = {

BACKGROUND: Data on the epidemiology of bacteremias and invasive fungal diseases (IFD) in children with acute myeloid leukemia (AML) are scarce.

DESIGN AND METHODS: In a multi-center, retrospective study, we analyzed proportion, rate per 1,000 person-days at risk, and cumulative risk of bacteremias and IFD in children with AML.

RESULTS: Between January 1998 and December 2005, 240 children were treated for AML at 8 Italian Centers, for a total of 521 treatment courses and 63,232 person-days at risk. Bacteremia was observed in 32\% of treatment courses and IFD was seen in 10\% (P < 0.0001), with rates of 2.62 and 0.84, respectively (P < 0.001). There was a significantly higher frequency of IFD during relapse treatment: proportion 15\% versus 9\% (P = 0.05), rate 2.10 versus 0.64 (P = 0.008) and cumulative risk 32\% versus 12\% (P = 0.007), while there were no differences in the proportion, rate and cumulative risk of bacteremia during front-line or relapse treatment. The epidemiology of bacteremias and IFD was different during front-line therapy for M3 as compared to other types of AML, but the differences were not statistically significant.

CONCLUSIONS: Severe infectious complications are frequent during the treatment of pediatric AML, especially during relapse treatment, and bacteremias are more frequent than IFD.

}, keywords = {Antineoplastic Combined Chemotherapy Protocols, Bacteremia, Child, Female, Follow-Up Studies, Humans, Incidence, Italy, Leukemia, Myeloid, Acute, Male, Mycoses, Neoplasm Recurrence, Local, Retrospective Studies}, issn = {1545-5017}, doi = {10.1002/pbc.22750}, author = {Castagnola, Elio and Rossi, Mario R and Cesaro, Simone and Livadiotti, Susanna and Giacchino, Mareva and Zanazzo, Giulio and Fioredda, Francesca and Beretta, Chiara and Ciocchello, Francesca and Carli, Modesto and Putti, Maria Caterina and Pansini, Valeria and Berger, Massimo and Licciardello, Maria and Farina, Silvia and Caviglia, Ilaria and Haupt, Riccardo} } @article {1597, title = {Long-term observational, non-randomized study of enzyme replacement therapy in late-onset glycogenosis type II.}, journal = {J Inherit Metab Dis}, volume = {33}, year = {2010}, month = {2010 Dec}, pages = {727-35}, abstract = {

OBJECTIVES: Type II glycogenosis (GSDII) is a lysosomal storage disorder due to acid alpha-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase (rhGAA) has been demonstrated to be effective in the treatment of infantile forms of GSDII, but little information is available concerning late-onset phenotypes. Long-term follow-up studies are not available at present. The aim of this study was to evaluate the ERT long-term effects in late-onset GSDII.

METHODS: Twenty-four patients, including 7 juveniles and 17 adults, received bi-weekly infusion of rhGAA (20 mg/kg) for at least 36 months. Clinical conditions, muscular function (6-min walking test, 6MWT; Walton scale, WS), respiratory function (vital capacity, VC; forced expiratory volume, FEV1; arterial pCO(2)), and muscle enzymes were assessed every 6 months.

RESULTS: The 6MWT improved in both juvenile and adult patients (p = 0.01, p = 0.0002, respectively), as well as in patients with moderate to severe muscle function impairment (WS >3.5; p = 0.002). An overall improvement in WS was also observed (p = 0.0003). VC and FEV1 remained unchanged, while pCO(2) decreased (p = 0.017). Muscle enzymes decreased significantly (p < 0.0001). Two patients (8\%) showed transient secondary events during ERT.

CONCLUSIONS: Long-term ERT with rhGAA was shown to be safe, well tolerated, and effective in improving motor function and in stabilizing respiratory function in late-onset GSDII. The response pattern showed a progressive clinical improvement during the follow-up period in juvenile patients, while in adults it reached and maintained a plateau after the first year of treatment.

}, keywords = {Adolescent, Adult, Age of Onset, Aged, alpha-Glucosidases, Child, Enzyme Replacement Therapy, Female, Follow-Up Studies, Glycogen Storage Disease Type II, Humans, Male, Middle Aged, Observation, Time Factors, Treatment Outcome, Young Adult}, issn = {1573-2665}, doi = {10.1007/s10545-010-9201-8}, author = {Bembi, Bruno and Pisa, Federica Edith and Confalonieri, Marco and Ciana, Giovanni and Fiumara, Agata and Parini, Rossella and Rigoldi, Miriam and Moglia, Arrigo and Costa, Alfredo and Carlucci, Annalisa and Danesino, Cesare and Pittis, Maria Gabriela and Dardis, Andrea and Ravaglia, Sabrina} } @article {1664, title = {Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial.}, journal = {JAMA}, volume = {303}, year = {2010}, month = {2010 Apr 7}, pages = {1266-73}, abstract = {

CONTEXT: Novel therapies have improved the remission rate in chronic inflammatory disorders including juvenile idiopathic arthritis (JIA). Therefore, strategies of tapering therapy and reliable parameters for detecting subclinical inflammation have now become challenging questions.

OBJECTIVES: To analyze whether longer methotrexate treatment during remission of JIA prevents flares after withdrawal of medication and whether specific biomarkers identify patients at risk for flares.

DESIGN, SETTING, AND PATIENTS: Prospective, open, multicenter, medication-withdrawal randomized clinical trial including 364 patients (median age, 11.0 years) with JIA recruited in 61 centers from 29 countries between February 2005 and June 2006. Patients were included at first confirmation of clinical remission while continuing medication. At the time of therapy withdrawal, levels of the phagocyte activation marker myeloid-related proteins 8 and 14 heterocomplex (MRP8/14) were determined.

INTERVENTION: Patients were randomly assigned to continue with methotrexate therapy for either 6 months (group 1 [n = 183]) or 12 months (group 2 [n = 181]) after induction of disease remission.

MAIN OUTCOME MEASURES: Primary outcome was relapse rate in the 2 treatment groups; secondary outcome was time to relapse. In a prespecified cohort analysis, the prognostic accuracy of MRP8/14 concentrations for the risk of flares was assessed.

RESULTS: Intention-to-treat analysis of the primary outcome revealed relapse within 24 months after the inclusion into the study in 98 of 183 patients (relapse rate, 56.7\%) in group 1 and 94 of 181 (55.6\%) in group 2. The odds ratio for group 1 vs group 2 was 1.02 (95\% CI, 0.82-1.27; P = .86). The median relapse-free interval after inclusion was 21.0 months in group 1 and 23.0 months in group 2. The hazard ratio for group 1 vs group 2 was 1.07 (95\% CI, 0.82-1.41; P = .61). Median follow-up duration after inclusion was 34.2 and 34.3 months in groups 1 and 2, respectively. Levels of MRP8/14 during remission were significantly higher in patients who subsequently developed flares (median, 715 [IQR, 320-1 110] ng/mL) compared with patients maintaining stable remission (400 [IQR, 220-800] ng/mL; P = .003). Low MRP8/14 levels indicated a low risk of flares within the next 3 months following the biomarker test (area under the receiver operating characteristic curve, 0.76; 95\% CI, 0.62-0.90).

CONCLUSIONS: In patients with JIA in remission, a 12-month vs 6-month withdrawal of methotrexate did not reduce the relapse rate. Higher MRP8/14 concentrations were associated with risk of relapse after discontinuing methotrexate.

TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN18186313.

}, keywords = {Adolescent, Antirheumatic Agents, Arthritis, Juvenile, ATP-Binding Cassette Transporters, Calgranulin B, Child, Child, Preschool, Female, Humans, Infant, Male, Methotrexate, Predictive Value of Tests, Prospective Studies, Recurrence, Remission Induction}, issn = {1538-3598}, doi = {10.1001/jama.2010.375}, author = {Foell, Dirk and Wulffraat, Nico and Wedderburn, Lucy R and Wittkowski, Helmut and Frosch, Michael and Gerss, Joachim and Stanevicha, Valda and Mihaylova, Dimitrina and Ferriani, Virginia and Tsakalidou, Florence Kanakoudi and Foeldvari, Ivan and Cuttica, Ruben and Gonzalez, Benito and Ravelli, Angelo and Khubchandani, Raju and Oliveira, Sheila and Armbrust, Wineke and Garay, Stella and Vojinovic, Jelena and Norambuena, Ximena and Gamir, Mar{\'\i}a Luz and Garc{\'\i}a-Consuegra, Julia and Lepore, Loredana and Susic, Gordana and Corona, Fabrizia and Dolezalova, Pavla and Pistorio, Angela and Martini, Alberto and Ruperto, Nicolino and Roth, Johannes} } @article {1693, title = {Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1.}, journal = {J Nephrol}, volume = {23}, year = {2010}, month = {2010 Nov-Dec}, pages = {667-76}, abstract = {

INTRODUCTION: Mutations of the AGXT gene encoding the alanine:glyoxylate aminotransferase liver enzyme (AGT) cause primary hyperoxaluria type 1 (PH1). Here we report a molecular modeling study of selected missense AGXT mutations: the common Gly170Arg and the recently described Gly47Arg and Ser81Leu variants, predicted to be pathogenic using standard criteria.

METHODS: Taking advantage of the refined 3D structure of AGT, we computed the dimerization energy of the wild-type and mutated proteins.

RESULTS: Molecular modeling predicted that Gly47Arg affects dimerization with a similar effect to that shown previously for Gly170Arg through classical biochemical approaches. In contrast, no effect on dimerization was predicted for Ser81Leu. Therefore, this probably demonstrates pathogenic properties via a different mechanism, similar to that described for the adjacent Gly82Glu mutation that affects pyridoxine binding.

CONCLUSION: This study shows that the molecular modeling approach can contribute to evaluating the pathogenicity of some missense variants that affect dimerization. However, in silico studies--aimed to assess the relationship between structural change and biological effects--require the integrated use of more than 1 tool.

}, keywords = {Amino Acid Sequence, Female, Humans, Male, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Protein Multimerization, Transaminases}, issn = {1121-8428}, author = {Robbiano, Angela and Frecer, Vladimir and Miertus, Jan and Zadro, Cristina and Ulivi, Sheila and Bevilacqua, Elena and Mandrile, Giorgia and De Marchi, Mario and Miertus, Stanislav and Amoroso, Antonio} } @article {1692, title = {Molecular surveillance of pandemic influenza A(H1N1) viruses circulating in Italy from May 2009 to February 2010: association between haemagglutinin mutations and clinical outcome.}, journal = {Euro Surveill}, volume = {15}, year = {2010}, month = {2010}, abstract = {

Haemagglutinin sequences of pandemic influenza A(H1N1) viruses circulating in Italy were examined, focusing on amino acid changes at position 222 because of its suggested pathogenic relevance. Among 169 patients, the D222G substitution was detected in three of 52 (5.8\%) severe cases and in one of 117 (0.9\%) mild cases, whereas the D222E mutation was more frequent and evenly distributed in mild (31.6\%) and severe cases (38.4\%). A cluster of D222E viruses among school children confirms reported human-to-human transmission of viruses mutated at amino acid position 222.

}, keywords = {Adolescent, Adult, Age Distribution, Aged, Amino Acid Substitution, Child, Child, Preschool, Female, Hemagglutinins, Humans, Infant, Influenza A Virus, H1N1 Subtype, Influenza, Human, Italy, Male, Middle Aged, Mutation, Pandemics, Population Surveillance, Reverse Transcriptase Polymerase Chain Reaction, Severity of Illness Index, Sex Distribution, Young Adult}, issn = {1560-7917}, author = {Puzelli, S and Facchini, M and De Marco, M A and Palmieri, A and Spagnolo, D and Boros, S and Corcioli, F and Trotta, D and Bagnarelli, P and Azzi, A and Cassone, A and Rezza, G and Pompa, M G and Oleari, F and Donatelli, I} } @article {1636, title = {Morbidity of pandemic H1N1 influenza in children with cancer.}, journal = {Pediatr Blood Cancer}, volume = {55}, year = {2010}, month = {2010 Aug}, pages = {226-8}, abstract = {

BACKGROUND: To define the mortality and the current impact of the H1N1 pandemic in pediatric hematology-oncology centers, we performed a specific survey.

PROCEDURE: Pharyngeal swabs from patients with fevers of unknown origin, flu-like symptoms or bronchopneumonia were screened for H1N1 using PCR.

RESULTS: Sixty-two patients with documented H1N1 infection were reported: 16 had recently stopped therapy, 2 were at the diagnosis stage, and 44 were receiving therapy. The clinical course was severe (requiring ICU admission) in only 1 patient, moderate (requiring hospital admission) in 38, and mild in the remaining 23 (37\%), treated as outpatients. While none of the patients died of H1N1-related complications, two patients died of progressive cancer; in all of the remaining cases, symptoms resolved within 11 days. The clinical course was complicated by respiratory distress or bronchopneumonia in 10 cases. Oseltamivir was given to 82\% of patients. Chemotherapy was temporarily withdrawn in 54\% of cases for a median time of 21 days (range, 4-43 days).

CONCLUSION: H1N1 infection in children with cancer was not reported as the cause of death in any case but resulted in reduced intensity of anti-cancer therapy.

}, keywords = {Adolescent, Antineoplastic Agents, Cause of Death, Child, Child, Preschool, Data Collection, Disease Outbreaks, Humans, Influenza A Virus, H1N1 Subtype, Influenza, Human, Leukemia, Lymphoma, Non-Hodgkin, Morbidity, Neoplasms, Treatment Outcome, Young Adult}, issn = {1545-5017}, doi = {10.1002/pbc.22619}, author = {Caselli, D{\'e}sir{\'e}e and Carraro, Francesca and Castagnola, Elio and Ziino, Ottavio and Frenos, Stefano and Milano, Giuseppe Maria and Livadiotti, Susanna and Cesaro, Simone and Marra, Nicoletta and Zanazzo, Giulio and Meazza, Cristina and Cellini, Monica and Aric{\`o}, Maurizio} } @article {1637, title = {Multidrug resistant Pseudomonas aeruginosa infection in children undergoing chemotherapy and hematopoietic stem cell transplantation.}, journal = {Haematologica}, volume = {95}, year = {2010}, month = {2010 Sep}, pages = {1612-5}, abstract = {

Pseudomonas aeruginosa is one leading gram-negative organism associated with nosocomial infections. Bacteremia is life-threatening in the immunocompromised host. Increasing frequency of multi-drug-resistant (MDRPA) strains is concerning. We started a retrospective survey in the pediatric hematology oncology Italian network. Between 2000 and 2008, 127 patients with Pseudomonas aeruginosa bacteremia were reported from 12 centers; 31.4\% of isolates were MDRPA. Death within 30 days of a positive blood culture occurred in 19.6\% (25/127) of total patients; in patients with MDRPA infection it occurred in 35.8\% (14/39). In the multivariate analysis, only MDRPA had significant association with infection-related death. This is the largest series of Pseudomonas aeruginosa bacteremia cases from pediatric hematology oncology centers. Monitoring local bacterial isolates epidemiology is mandatory and will allow empiric antibiotic therapy to be tailored to reduce fatalities.

}, keywords = {Adolescent, Antineoplastic Agents, Bacteremia, Child, Child, Preschool, Drug Resistance, Multiple, Female, Hematopoietic Stem Cell Transplantation, Humans, Immunocompromised Host, Infant, Infant, Newborn, Italy, Male, Pseudomonas aeruginosa, Pseudomonas Infections, Retrospective Studies, Young Adult}, issn = {1592-8721}, doi = {10.3324/haematol.2009.020867}, author = {Caselli, D{\'e}sir{\'e}e and Cesaro, Simone and Ziino, Ottavio and Zanazzo, Giulio and Manicone, Rosaria and Livadiotti, Susanna and Cellini, Monica and Frenos, Stefano and Milano, Giuseppe M and Cappelli, Barbara and Licciardello, Maria and Beretta, Chiara and Aric{\`o}, Maurizio and Castagnola, Elio} } @article {1714, title = {Predictors of poor response to methotrexate in polyarticular-course juvenile idiopathic arthritis: analysis of the PRINTO methotrexate trial.}, journal = {Ann Rheum Dis}, volume = {69}, year = {2010}, month = {2010 Aug}, pages = {1479-83}, abstract = {

OBJECTIVES: To determine whether baseline demographic, clinical, articular and laboratory variables predict methotrexate (MTX) poor response in polyarticular-course juvenile idiopathic arthritis.

METHODS: Patients newly treated for 6 months with MTX enrolled in the Paediatric Rheumatology International Trials Organization (PRINTO) MTX trial. Bivariate and logistic regression analyses were used to identify baseline predictors of poor response according to the American College of Rheumatology pediatric (ACR-ped) 30 and 70 criteria.

RESULTS: In all, 405/563 (71.9\%) of patients were women; median age at onset and disease duration were 4.3 and 1.4 years, respectively, with anti-nuclear antibody (ANA) detected in 259/537 (48.2\%) patients. With multivariate logistic regression analysis, the most important determinants of ACR-ped 70 non-responders were: disease duration > 1.3 years (OR 1.93), ANA negativity (OR 1.77), Childhood Health Assessment Questionnaire (CHAQ) disability index > 1.125 (OR 1.65) and the presence of right and left wrist activity (OR 1.55). Predictors of ACR-ped 30 non-responders were: ANA negativity (OR 1.92), CHAQ disability index > 1.14 (OR 2.18) and a parent{\textquoteright}s evaluation of child{\textquoteright}s overall well-being < or = 4.69 (OR 2.2).

CONCLUSION: The subgroup of patients with longer disease duration, ANA negativity, higher disability and presence of wrist activity were significantly associated with a poorer response to a 6-month MTX course.

}, keywords = {Adolescent, Antibodies, Antinuclear, Antirheumatic Agents, Arthritis, Juvenile, Child, Child, Preschool, Disability Evaluation, Female, Follow-Up Studies, Humans, Immunosuppressive Agents, Male, Methotrexate, Prognosis, Treatment Outcome}, issn = {1468-2060}, doi = {10.1136/ard.2009.120840}, author = {Vilca, Iris and Munitis, Pablo Garcia and Pistorio, Angela and Ravelli, Angelo and Buoncompagni, Antonella and Bica, Blanca and Campos, Lucia and H{\"a}fner, Renate and Hofer, Michael and Ozen, Seza and Huemer, Christian and Bae, Sang Cheol and Sztajnbok, Flavio and Arguedas, Olga and Foeldvari, Ivan and Huppertz, Hans Iko and Gamir, Mar{\'\i}a Luz and Magnusson, Bo and Dressler, Frank and Uziel, Yosef and van Rossum, Marion A J and Hollingworth, Peter and Cawkwell, Gail and Martini, Alberto and Ruperto, Nicolino} } @article {1639, title = {Screening for GJB2 and GJB6 gene mutations in patients from Campania region with sensorineural hearing loss.}, journal = {Int J Audiol}, volume = {49}, year = {2010}, month = {2010 Apr}, pages = {326-31}, abstract = {

The aim of this study was to screen 349 patients affected by sensorineural hearing loss (SNHL), mostly from the Campania region (southern Italy), for GJB2 gene mutations and for two deletions of the GJB6 gene (del GJB6 -D13S1830 and del GJB6 -D13S1854). We identified pathogenetic GJB2 mutations in 51 cases (15\% of patients). No GJB6 mutation was found. We also examined the audiologic features of the patients for whom we had an etiologic diagnosis, in order to identify correlations between the severity of hearing loss and the type of mutation.

}, keywords = {Acoustic Stimulation, Adolescent, Adult, Audiometry, Auditory Perception, Child, Child, Preschool, Connexins, Genetic Predisposition to Disease, Genetic Testing, Hearing Loss, Sensorineural, Heterozygote, Homozygote, Humans, Italy, Mass Screening, Middle Aged, Mutation, Phenotype, Risk Factors, Severity of Illness Index, Young Adult}, issn = {1708-8186}, doi = {10.3109/14992021003601756}, author = {Chinetti, Viviana and Iossa, Sandra and Auletta, Gennaro and Laria, Carla and De Luca, Maria and Di Leva, Francesca and Riccardi, Pasquale and Giannini, Pasquale and Gasparini, Paolo and Ciccodicola, Alfredo and Marciano, Elio and Franz{\`e}, Annamaria} } @article {1665, title = {Therapeutic strategy in p47-phox deficient chronic granulomatous disease presenting as inflammatory bowel disease.}, journal = {J Allergy Clin Immunol}, volume = {125}, year = {2010}, month = {2010 Apr}, pages = {943-946.e1}, keywords = {Age of Onset, Anti-Bacterial Agents, Antibodies, Monoclonal, Child, Drug Therapy, Combination, Gene Deletion, Granulomatous Disease, Chronic, Humans, Inflammatory Bowel Diseases, Male, NADPH Oxidase, Steroids, Treatment Outcome, Vidarabine}, issn = {1097-6825}, doi = {10.1016/j.jaci.2010.01.035}, author = {Freudenberg, Folke and Wintergerst, Uwe and Roesen-Wolff, Angela and Albert, Michael H and Prell, Christine and Strahm, Brigitte and Koletzko, Sibylle and Ehl, Stephan and Roos, Dirk and Tommasini, Alberto and Ventura, Alessandro and Belohradsky, Bernd H and Seger, Reinhard and Roesler, Joachim and G{\"u}ng{\"o}r, Tayfun} } @article {1734, title = {Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Dec}, pages = {1077-85}, abstract = {

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 {\texttimes} 10$^{-}$$^{6}$$^{0}$) and 9q31.2 (P = 2.2 {\texttimes} 10$^{-}${\textthreesuperior}{\textthreesuperior}), we identified 30 new menarche loci (all P < 5 {\texttimes} 10$^{-}$$^{8}$) and found suggestive evidence for a further 10 loci (P < 1.9 {\texttimes} 10$^{-}$$^{6}$). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

}, keywords = {Adolescent, Aging, Body Height, Body Size, Child, DNA Copy Number Variations, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inheritance Patterns, Menarche, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reproducibility of Results, Time Factors}, issn = {1546-1718}, doi = {10.1038/ng.714}, author = {Elks, Cathy E and Perry, John R B and Sulem, Patrick and Chasman, Daniel I and Franceschini, Nora and He, Chunyan and Lunetta, Kathryn L and Visser, Jenny A and Byrne, Enda M and Cousminer, Diana L and Gudbjartsson, Daniel F and Esko, T{\~o}nu and Feenstra, Bjarke and Hottenga, Jouke-Jan and Koller, Daniel L and Kutalik, Zolt{\'a}n and Lin, Peng and Mangino, Massimo and Marongiu, Mara and McArdle, Patrick F and Smith, Albert V and Stolk, Lisette and van Wingerden, Sophie H and Zhao, Jing Hua and Albrecht, Eva and Corre, Tanguy and Ingelsson, Erik and Hayward, Caroline and Magnusson, Patrik K E and Smith, Erin N and Ulivi, Shelia and Warrington, Nicole M and Zgaga, Lina and Alavere, Helen and Amin, Najaf and Aspelund, Thor and Bandinelli, Stefania and Barroso, In{\^e}s and Berenson, Gerald S and Bergmann, Sven and Blackburn, Hannah and Boerwinkle, Eric and Buring, Julie E and Busonero, Fabio and Campbell, Harry and Chanock, Stephen J and Chen, Wei and Cornelis, Marilyn C and Couper, David and Coviello, Andrea D and d{\textquoteright}Adamo, Pio and de Faire, Ulf and de Geus, Eco J C and Deloukas, Panos and D{\"o}ring, Angela and Smith, George Davey and Easton, Douglas F and Eiriksdottir, Gudny and Emilsson, Valur and Eriksson, Johan and Ferrucci, Luigi and Folsom, Aaron R and Foroud, Tatiana and Garcia, Melissa and Gasparini, Paolo and Geller, Frank and Gieger, Christian and Gudnason, Vilmundur and Hall, Per and Hankinson, Susan E and Ferreli, Liana and Heath, Andrew C and Hernandez, Dena G and Hofman, Albert and Hu, Frank B and Illig, Thomas and J{\"a}rvelin, Marjo-Riitta and Johnson, Andrew D and Karasik, David and Khaw, Kay-Tee and Kiel, Douglas P and Kilpel{\"a}inen, Tuomas O and Kolcic, Ivana and Kraft, Peter and Launer, Lenore J and Laven, Joop S E and Li, Shengxu and Liu, Jianjun and Levy, Daniel and Martin, Nicholas G and McArdle, Wendy L and Melbye, Mads and Mooser, Vincent and Murray, Jeffrey C and Murray, Sarah S and Nalls, Michael A and Navarro, Pau and Nelis, Mari and Ness, Andrew R and Northstone, Kate and Oostra, Ben A and Peacock, Munro and Palmer, Lyle J and Palotie, Aarno and Par{\'e}, Guillaume and Parker, Alex N and Pedersen, Nancy L and Peltonen, Leena and Pennell, Craig E and Pharoah, Paul and Polasek, Ozren and Plump, Andrew S and Pouta, Anneli and Porcu, Eleonora and Rafnar, Thorunn and Rice, John P and Ring, Susan M and Rivadeneira, Fernando and Rudan, Igor and Sala, Cinzia and Salomaa, Veikko and Sanna, Serena and Schlessinger, David and Schork, Nicholas J and Scuteri, Angelo and Segr{\`e}, Ayellet V and Shuldiner, Alan R and Soranzo, Nicole and Sovio, Ulla and Srinivasan, Sathanur R and Strachan, David P and Tammesoo, Mar-Liis and Tikkanen, Emmi and Toniolo, Daniela and Tsui, Kim and Tryggvadottir, Laufey and Tyrer, Jonathon and Uda, Manuela and van Dam, Rob M and van Meurs, Joyce B J and Vollenweider, Peter and Waeber, Gerard and Wareham, Nicholas J and Waterworth, Dawn M and Weedon, Michael N and Wichmann, H Erich and Willemsen, Gonneke and Wilson, James F and Wright, Alan F and Young, Lauren and Zhai, Guangju and Zhuang, Wei Vivian and Bierut, Laura J and Boomsma, Dorret I and Boyd, Heather A and Crisponi, Laura and Demerath, Ellen W and van Duijn, Cornelia M and Econs, Michael J and Harris, Tamara B and Hunter, David J and Loos, Ruth J F and Metspalu, Andres and Montgomery, Grant W and Ridker, Paul M and Spector, Tim D and Streeten, Elizabeth A and Stefansson, Kari and Thorsteinsdottir, Unnur and Uitterlinden, Andr{\'e} G and Widen, Elisabeth and Murabito, Joanne M and Ong, Ken K and Murray, Anna} } @article {1691, title = {Transmission of hemagglutinin D222G mutant strain of pandemic (H1N1) 2009 virus.}, journal = {Emerg Infect Dis}, volume = {16}, year = {2010}, month = {2010 May}, pages = {863-5}, abstract = {

A pandemic (H1N1) 2009 virus strain carrying the D222G mutation was identified in a severely ill man and was transmitted to a household contact. Only mild illness developed in the contact, despite his obesity and diabetes. The isolated virus reacted fully with an antiserum against the pandemic vaccine strain.

}, keywords = {Adult, Amino Acid Substitution, Disease Outbreaks, Hemagglutinin Glycoproteins, Influenza Virus, Humans, Influenza A Virus, H1N1 Subtype, Influenza, Human, Male, Middle Aged, Mutation, Missense, Phylogeny, Retrospective Studies, RNA, Viral, Sequence Analysis, RNA, Severity of Illness Index}, issn = {1080-6059}, doi = {10.3201/eid1605.091815}, author = {Puzelli, Simona and Facchini, Marzia and Spagnolo, Domenico and De Marco, Maria A and Calzoletti, Laura and Zanetti, Alessandro and Fumagalli, Roberto and Tanzi, Maria L and Cassone, Antonio and Rezza, Giovanni and Donatelli, Isabella} } @article {1718, title = {Treatment with recombinant tumor necrosis factor-related apoptosis-inducing ligand alleviates the severity of streptozotocin-induced diabetes.}, journal = {Diabetes}, volume = {59}, year = {2010}, month = {2010 May}, pages = {1261-5}, abstract = {

OBJECTIVE: To evaluate the potential therapeutic effect of recombinant human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) treatment in a model of type 1 diabetes.

RESEARCH DESIGN AND METHODS: Recombinant TRAIL was added in vitro to primary human and mouse peripheral blood mononuclear cells (PBMCs) and isolated human islets to evaluate the expression of the immunoregulatory gene SOCS1. Diabetes was induced by five consecutive daily injections of low-concentration (50 mg/kg) streptozotocin (STZ) in C57 black mice (n = 24). A group of these mice (n = 12) was co-injected with recombinant TRAIL (20 microg/day) for 5 days, and the diabetic status (glycemia and body weight) was followed over time. After 6 weeks, circulating levels of insulin, TNF-alpha, and osteoprotegerin (OPG) were measured, and animals were killed to perform the histological analysis of the pancreas.

RESULTS: The in vitro exposure of both PBMCs and human islets to recombinant TRAIL significantly upregulated the expression of SOCS1. With respect to STZ-treated animals, mice co-injected with STZ+TRAIL were characterized by 1) lower levels of hyperglycemia, 2) higher levels of body weight and insulinemia, 3) a partial preservation of pancreatic islets with normal morphology, and 4) a lower expression of both systemic (TNF-alpha and OPG) and pancreatic (vascular cell adhesion molecule [VCAM]-1) inflammatory markers.

CONCLUSIONS: Overall, these data demonstrate that the administration of recombinant TRAIL ameliorates the severity of STZ-induced type 1 diabetes, and this effect was accompanied by the upregulation of SOCS1 expression.

}, keywords = {Animals, Cells, Cultured, Diabetes Mellitus, Experimental, Gene Expression, Humans, Islets of Langerhans, Leukocytes, Mononuclear, Mice, Recombinant Proteins, Suppressor of Cytokine Signaling Proteins, TNF-Related Apoptosis-Inducing Ligand}, issn = {1939-327X}, doi = {10.2337/db09-1771}, author = {Zauli, Giorgio and Toffoli, Barbara and di Iasio, Maria Grazia and Celeghini, Claudio and Fabris, Bruno and Secchiero, Paola} } @article {1659, title = {Two cases of Noonan syndrome with severe respiratory and gastroenteral involvement and the SOS1 mutation F623I.}, journal = {Eur J Med Genet}, volume = {53}, year = {2010}, month = {2010 Sep-Oct}, pages = {322-4}, abstract = {

Noonan syndrome (NS) is an autosomal dominant, inherited disorder characterized by facial dysmorphism, congenital heart defects, and reduced postnatal growth. Dysregulated RAS-MAPK signalling is the common molecular basis for NS, a genetically heterogeneous disease. Germline mutations in genes encoding small GTPases of the RAS family (KRAS and NRAS), modulators of RAS function (PTPN11, SOS1 and SHOC2) or downstream signal transducers (RAF1) are causative for NS. SOS1 is the second major gene for NS after PTPN11. Compared to patients with mutations in other genes, SOS1 mutation-positive individuals in general tend to have a more favorable outcome, with less short stature and cognitive impairment. We describe two unrelated patients with NS carrying the same heterozygous SOS1 missense mutation (c.1867T > A/p.F623I). The phenotype of both patients is remarkable as they show uncommon clinical features such as pulmonary lymphangiectasis, congenital pleural effusions, severe feeding problems, and laryngomalacia. These findings may be related to the specific mutation present in our two patients, or be part of the SOS1 phenotype. Detailed clinical assessment of large cohorts of patients with NS and SOS1 mutation is required to clarify this initial observation.

}, keywords = {Child, Preschool, Genes, ras, Germ-Line Mutation, Heterozygote, Humans, Infant, Infant, Newborn, Male, Mutation, Missense, Noonan Syndrome, Phenotype, SOS1 Protein}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2010.07.011}, author = {Fabretto, Antonella and Kutsche, Kerstin and Harmsen, May-Britt and Demarini, Sergio and Gasparini, Paolo and Fertz, Maria Cristina and Zenker, Martin} }