@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 {10763, title = {Cervico-vaginal secretion cytokine profile: A non-invasive approach to study the endometrial receptivity in IVF cycles.}, journal = {Am J Reprod Immunol}, volume = {81}, year = {2019}, month = {2019 Jan}, pages = {e13064}, abstract = {

PROBLEM: Cytokines have a significant role in the process of embryo implantation, trophoblast growth, and differentiation by modulating the immune and endocrine system. The aim of this study was to investigate the profile of a large set of cytokines in the cervico-vaginal washing of women undergoing IVF, to explore the association of these proteins with a good receptive endometrium.

METHOD OF STUDY: A cohort of 155 women scheduled for IVF cycle was recruited. All patients were asymptomatic for genitourinary infections and had been screened for chlamydia, mycoplasma, and other bacterial infections. All IVF subjects were treated according to standard clinical and laboratory protocols. A panel of 48 immune factors was analyzed on cervico-vaginal washing, using magnetic bead-based multiplex immunoassays (Bio-Plex, BIO-RAD Laboratories, Milano, Italy).

RESULTS: A total of 99 patients reached embryo transfer, of which 31 had a clinical pregnancy. A pattern of four pro-inflammatory immune molecules, IL-12p40, IFN-a, MIF, and MCP3 (P~<~0.001), was found significantly up-regulated in the cervico-vaginal fluid of women with clinical pregnancy. A significantly increased expression of IL-9, Gro , and SDF-1 (P~<~0.05) was observed in the presence of endometriosis, while high levels of IL-13 and L-15 were associated with ovulatory infertility factor (P~<~0.05).

CONCLUSION: In this pilot study, we demonstrated that the expression of specific cytokines in the cervico-vaginal washing on the day of oocyte retrieval might have a positive correlation with the potential clinical pregnancy. Therefore, cervico-vaginal secretion cytokine profiling might be a new, non-invasive approach to study the endometrial receptivity in IVF management.

}, issn = {1600-0897}, doi = {10.1111/aji.13064}, author = {Zanotta, Nunzia and Monasta, Lorenzo and Skerk, Kristina and Luppi, Stefania and Martinelli, Monica and Ricci, Giuseppe and Comar, Manola} } @article {10755, title = {An evaluation of the Movement ABC-2 Test for use in Italy: A comparison of data from Italy and the UK.}, journal = {Res Dev Disabil}, volume = {84}, year = {2019}, month = {2019 Jan}, pages = {43-56}, abstract = {

BACKGROUND: The standardized test within the Movement Assessment Battery for Children-2nd edition (MABC-2) is used worldwide to assess motor problems in children. Ideally, any country using a test developed in another country should produce national norms to ensure that it functions effectively in the new context.

AIM: The first objective of this study was to explore the differences in motor performance between Italian and British children. The second was to examine the structural validity of the test for the Italian sample.

METHOD: A total of 718 Italian (IT) and 765 British (UK) children, aged 3-10 years, were individually tested on the age-appropriate items of the MABC-2 Test.

RESULTS: Developmental trends emerged on every task and differences between IT and UK children were obtained on 11 of 27 task comparisons. Interactions between age and country indicated that differences were not consistently in favor of one culture. Confirmatory factor analysis generally supported the proposed structure of the MABC-2 Test.

CONCLUSION: Although the differences between the IT and the UK children were relatively few, those that did emerge emphasize the need for population specific norms and suggest that cultural diversity in motor experiences should be considered when evaluating motor abilities in children.

}, issn = {1873-3379}, doi = {10.1016/j.ridd.2018.04.013}, author = {Zoia, Stefania and Biancotto, Marina and Guicciardi, Marco and Lecis, Romina and Lucidi, Fabio and Pelamatti, Giovanna M and Carrozzi, Marco and Skabar, Aldo and Sugden, David A and Barnett, Anna L and Henderson, Sheila E} } @article {10780, title = {First urinary tract infections in children: the role of the risk factors proposed by the Italian recommendations.}, journal = {Acta Paediatr}, volume = {108}, year = {2019}, month = {2019 Mar}, pages = {544-550}, abstract = {

AIM: In 2009, the Italian society for paediatric nephrology suggested the need for cystography, following a first febrile urinary tract infection (UTI), only in children at high risk for dilating vesicoureteral reflux or in the event of a second infection. The aim of this study was to evaluate the adequacy of the risk factors proposed by the Italian guidelines.

METHODS: Children aged 2-36~months, managed by 10 Italian hospitals between 2009 and 2013, with a first febrile UTI were retrospectively evaluated.

RESULTS: Four hundred and fourteen children were included: 51\% female, mean age eight months. Escherichia coli was responsible of 84\% UTIs. 269 children (65\%) presented at least one risk factor, thus were further investigated: 44\% had a reflux. The presence of a pathogen other than E.~coli significantly predicted high-grade reflux, both in the univariate (Odd Ratio 2.52, 95\% Confidence Interval 1.32-4.81, p~<~0.005) and multivariate analysis (OR 2.74, 95\% CI: 1.39-5.41, p: 0.003). 26/145 children (18\%) with no risk factors experienced a second UTI, which prompted the execution of cystography, showing a dilating reflux in 11.

CONCLUSION: Among the risk factors proposed by the Italian guidelines, only the presence of a pathogen other than E.~coli significantly predicted reflux. Cystography can be postponed in children with no risk factors.

}, issn = {1651-2227}, doi = {10.1111/apa.14506}, author = {Alberici, I and La Manna, A and Pennesi, M and Starc, M and Scozzola, F and Nicolini, G and Toffolo, A and Marra, G and Chimenz, R and Sica, F and Maringhini, S and Monasta, L and Montini, G} } @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 {10812, title = {Management of endometrial, ovarian and cervical cancer in the elderly: current approach to a challenging condition.}, journal = {Arch Gynecol Obstet}, volume = {299}, year = {2019}, month = {2019 Feb}, pages = {299-315}, abstract = {

PURPOSE: Gynaecological cancer management in older people represents a current challenge. Therefore, in the present paper, we aimed to gather all the evidence reported in the literature concerning gynecological cancers in the elderly, illustrating the state of art and the future perspectives.

METHODS: We searched MEDLINE (PubMed), EMBASE, Cochrane Central Register of Controlled Trials, IBECS, BIOSIS, Web of Science, SCOPUS and Grey literature (Google Scholar; British Library) from January 1952 to May 2017, using the terms "ovarian cancer", "endometrial cancer", "cervical cancer", "gynecological cancers" combined with {\textquoteright}elderly{\textquoteright}, {\textquoteright}cancer{\textquoteright}, {\textquoteright}clinical trial{\textquoteright} and {\textquoteright}geriatric assessment{\textquoteright}.

RESULTS: The search identified 81 citations, of which 65 were potentially relevant after initial evaluation and met the criteria for inclusion and were analyzed. We divided all included studies into three different issue: "Endometrial cancer", "Ovarian cancer" and "Cervical cancer".

CONCLUSIONS: The present literature review shows that, in spite of the higher burden of comorbidities, elderly patients can also benefit from standard treatment to manage their gynecological cancers. It is important to overcome the common habit of undertreating the elderly patients because they are more fragile and with a lower life expectancy than their younger counterpart. Further trials with elderly women are warranted.

}, issn = {1432-0711}, doi = {10.1007/s00404-018-5006-z}, author = {Vitale, Salvatore Giovanni and Capriglione, Stella and Zito, Gabriella and Lopez, Salvatore and Gulino, Ferdinando Antonio and Di Guardo, Federica and Vitagliano, Amerigo and Noventa, Marco and La Rosa, Valentina Lucia and Sapia, Fabrizio and Valenti, Gaetano and Rapisarda, Agnese Maria Chiara and Peterlunger, Isabel and Rossetti, Diego and Lagan{\`a}, Antonio Simone} } @article {10820, title = {MYH9-Related Thrombocytopenia: Four Novel Variants Affecting the Tail Domain of the Non-Muscle Myosin Heavy Chain IIA Associated with a Mild Clinical Evolution of the Disorder.}, journal = {Hamostaseologie}, volume = {39}, year = {2019}, month = {2019 Feb}, pages = {87-94}, abstract = {

-related disease (-RD) is an autosomal-dominant thrombocytopenia caused by mutations in the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA). Patients present congenital macrothrombocytopenia and inclusions of NMMHC-IIA in leukocytes, and have a variable risk of developing kidney damage, sensorineural deafness, presenile cataracts and/or liver enzymes abnormalities. The spectrum of mutations found in -RD patients is limited and the incidence and severity of the non-congenital features are predicted by the causative variant. In particular, different alterations of the C-terminal tail domain of NMMHC-IIA associate with remarkably different disease evolution. We report four novel mutations affecting the tail domain of NMMHC-IIA and responsible for -RD in four families. Two variants cause amino acid substitutions in the coiled-coil region of NMMHC-IIA, while the other two are a splicing variant and a single nucleotide deletion both resulting in frameshift alterations of the short non-helical tailpiece. Characterization of phenotypes of affected individuals shows that all of these novel variants are associated with a mild clinical evolution of the disease.

}, issn = {2567-5761}, doi = {10.1055/s-0038-1645840}, author = {Zaninetti, Carlo and De Rocco, Daniela and Giangregorio, Tania and Bozzi, Valeria and Demeter, Judit and Leoni, Pietro and Noris, Patrizia and Ryh{\"a}nen, Samppa and Barozzi, Serena and Pecci, Alessandro and Savoia, Anna} } @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 {10756, title = {Anaphylaxis in atypical cold urticaria: case report and review of literature.}, journal = {Ital J Pediatr}, volume = {44}, year = {2018}, month = {2018 Nov 13}, pages = {135}, abstract = {

BACKGROUND: Cold-induced urticaria is a kind of physical urticaria characterized by the appearance of wheals after exposure to cold. The atypical form is a rare sub-type characterized by appearance of hives even in areas not directly exposed to the cold and by a negative cold stimulation test. Its diagnosis is often challenging because of the lack of specific tests and it is usually based on the patient{\textquoteright}s clinical history. Hypotension due to generalized exposure to the cold is described both in the typical and the atypical forms.

CASE PRESENTATION: We describe a 9-year-old boy who, at the beginning of the summer after the first swim in the sea, developed generalized urticaria, dyspnea, conjunctival hyperemia, blurred vision and loss of strength. The child was treated with intramuscular steroid and intravenous antihistamine, and the symptoms quickly resolved. Insect bite, contact with fish and drug ingestion were denied, and no unusual food had been eaten before the swim. A tentative diagnosis was made of either aquagenic urticaria or cold urticaria, but the specific tests were negative. Although the cause was unknown, prophylactic treatment with antihistamines was prescribed but in spite of this, wheals developed all over the body, after every swim in the sea. The child then came to our attention and relying on clinical history a diagnosis of atypical cold urticaria was made: development of hives even in areas not directly exposed to cold and a negative response to the cold stimulation test, are the characteristic features of this rare form of cold urticaria.

CONCLUSION: Atypical cold urticaria should be suspected in all cases of anaphylaxis related to cold exposure (i.e. contact with water) with a negative cold stimulation test.

}, keywords = {Anaphylaxis, Child, Cold Temperature, Humans, Male, Swimming, Urticaria}, issn = {1824-7288}, doi = {10.1186/s13052-018-0578-6}, author = {Benelli, Elisa and Longo, Giorgio and Barbi, Egidio and Berti, Irene} } @article {10759, title = {Benign hereditary chorea and deletions outside NKX2-1: What{\textquoteright}s the role of MBIP?}, journal = {Eur J Med Genet}, volume = {61}, year = {2018}, month = {2018 Oct}, pages = {581-584}, abstract = {

Heterozygous point mutations or deletions of the NKX2-1 gene cause benign hereditary chorea (BHC) or a various combinations of primary hypothyroidism, respiratory distress and neurological disorders. Deletions proximal to, but not encompassing, NKX2-1 have been described in few subjects with brain-lung-thyroid syndrome. We report on a three-generation Italian family, with 6 subjects presenting BHC and harboring a genomic deletion adjacent to NKX2-1 and including the gene MBIP, recently proposed to be relevant for the pathogenesis of brain-lung-thyroid syndrome. We observed a clear reduction of NKX2-1 transcript levels in fibroblasts from our patients compared to controls; this finding suggests that MBIP deletion affects NKX2-1 expression, mimicking haploinsufficiency caused by classical NKX2-1 related mutations.

}, keywords = {Cells, Cultured, Chorea, Haploinsufficiency, Humans, Intracellular Signaling Peptides and Proteins, Pedigree, Sequence Deletion, Thyroid Nuclear Factor 1}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2018.03.011}, author = {Invernizzi, Federica and Zorzi, Giovanna and Legati, Andrea and Coppola, Giovanni and d{\textquoteright}Adamo, Pio and Nardocci, Nardo and Garavaglia, Barbara and Ghezzi, Daniele} } @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 {10766, title = {Complete Remission of a Refractory Acute Myeloid Leukemia with Myelodysplastic- and Monosomy 7-Related Changes after a Combined Conditioning Regimen of Plerixafor, Cytarabine and Melphalan in a 4-Year-Old Boy: A Case Report and Review of Literature.}, journal = {Cancers (Basel)}, volume = {10}, year = {2018}, month = {2018 Aug 27}, abstract = {

Acute myeloid leukemia with myelodysplastic changes and monosomy 7 is a rare form of pediatric leukemia associated with very poor disease-free survival. The refractoriness of the disease is due to the protection offered by the bone marrow niche, making leukemic stem cells impervious to whatever chemotherapy or myeloablative regimen is chosen. Using a mobilizing agent for haematopoietic stem cells, Plerixafor, could sensitise leukemic cells to the myeloablative therapy. This approach was not previously used in a pediatric population, and in adult populations, was used in combination with busulphan with no difference in overall survival. We describe the case of a 4-year-old boy affected by refractory acute myeloid leukemia with myelodysplastic changes and monosomy 7. The child had never achieved a remission. We proposed a combined time-scheduled scheme of therapy with plerixafor and melphalan. Combining pharmacokinetics of plerixafor with pharmacokinetics and rapid and elevated myeloablative potential of melphalan in high dosage (200 mg/m{\texttwosuperior}), we succeeded in mobilizing more than 85\% of stem blasts immediately before infusion of Melphalan. The count of residual blasts after 8 h from melphalan infusion was only 1.3 cells/μL. The child achieved an engraftment at day +32 with full donor chimerism. Sixteen months after haematopoietic stem cell transplantation (HSCT), he is well and in complete remission. Our case suggests that the use of plerixafor before a conditioning therapy with melphalan could induce remission in acute myeloid leukemia refractory to the usual conditioning therapy in pediatric patients. This work adds strength to the body of knowledge regarding the "personalized" conditioning regimen for high-risk leukemic patients.

}, issn = {2072-6694}, doi = {10.3390/cancers10090291}, author = {Grasso, Antonio G and Granzotto, Marilena and Zanon, Davide and Maestro, Alessandra and Loiacono, Stefano and Maximova, Natalia} } @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 {10771, title = {Effectiveness of the facility-based maternal near-miss case reviews in improving maternal and newborn quality of care in low-income and middle-income countries: a systematic review.}, journal = {BMJ Open}, volume = {8}, year = {2018}, month = {2018 04 19}, pages = {e019787}, abstract = {

OBJECTIVES: The maternal near-miss case review (NMCR) has been promoted by WHO as an approach to improve quality of care (QoC) at facility level. This systematic review synthesises evidence on the effectiveness of the NMCR on QoC and maternal and perinatal health outcomes in low-income and middle-income countries (LMICs).

METHODS: Studies were searched for in six electronic databases (MEDLINE, Index Medicus, Web of Science, the Cochrane library, Embase, LILACS), with no language restrictions. Two authors independently screened papers and selected them for inclusion and independently extracted data. Maternal mortality was the primary outcome. Secondary outcomes included any outcome informing on any of the six dimensions of QoC: efficacy, safety, efficiency, equity, accessibility and timely care, acceptability and patient-centred care.

RESULTS: Out of 24 822 papers retrieved, 17 studies from 11 countries were included. Maternal mortality measured before and after the implementation of the NMCR cycle significantly decreased (OR 0.77, 95\% CI 0.61 to 0.98, eight studies, 55 573 043 women; I=39\%). A statistically significant reduction in the incidence of uterine rupture, postpartum haemorrhage and maternal sepsis was observed in three out of six studies. Ten studies reporting on maternal care process all showed some significant improvement when measured against predefined standards. All studies reported that the NMCR resulted in some amelioration of the facility structure (physical structure, staffing, equipment, training, organisation of care). Newborn outcomes were overall poorly reported; four studies showed no significant difference in perinatal mortality. Patient satisfaction and equity were also poorly reported.

CONCLUSIONS: Policy makers may consider implementing the maternal NMCR cycle approach among strategies aiming at improving QoC and reducing maternal mortality and morbidity in LMIC. Future studies should better document the effectiveness of the NMCR cycle particularly on outcomes reflecting patient-centred care and cost-effectiveness.

}, keywords = {Developing Countries, Female, Humans, Infant, Newborn, Maternal Mortality, Near Miss, Healthcare, Parturition, Patient Satisfaction, Perinatal Mortality, Postpartum Hemorrhage, Poverty, Pregnancy, Quality of Health Care, Uterine Rupture}, issn = {2044-6055}, doi = {10.1136/bmjopen-2017-019787}, author = {Lazzerini, Marzia and Richardson, Sonia and Ciardelli, Valentina and Erenbourg, Anna} } @article {10424, title = {Efficacy and Safety of Adalimumab in Pediatric Ulcerative Colitis: A Real-life Experience from the SIGENP-IBD Registry.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {66}, year = {2018}, month = {2018 Jun}, pages = {920-925}, abstract = {

OBJECTIVES: The aim of this study was to evaluate the effectiveness and safety of adalimumab (ADA) in children with ulcerative colitis (UC) previously treated with infliximab (IFX).

METHODS: Retrospective study including children with UC from a national registry who received ADA therapy. The primary endpoint was the rate of corticosteroid-free remission at week 52. Secondary outcomes were the rate of sustained clinical remission, primary nonresponse, and loss of response at weeks 12, 30, and 52 and rate of mucosal healing and side effects at week 52.

RESULTS: Thirty-two children received ADA (median age 10 {\textpm} 4 years). Median disease duration before ADA therapy was 27 months. All patients received previous IFX (43\% intolerant, 50\% nonresponders [37.5\% primary, 42.5\% secondary nonresponders], 6.7\% positive anti-IFX antibodies). Fifty-two weeks after ADA initiation, 13 patients (41\%) were in corticosteroid-free remission. Mucosal healing occurred in 9 patients (28\%) at 52 weeks. The cumulative probability of a clinical relapse-free course was 69\%, 59\%, and 53\% at 12, 30, and 52 weeks, respectively. Ten patients (31\%) had a primary failure and 5 (15\%) a loss of response to ADA. No significant differences in efficacy were reported between not-responders and intolerant to IFX (P = 1.0). Overall, 19 patient (59\%) maintained ADA during 52-week follow-up. Seven patients (22\%) experienced an adverse event, no serious side effects were observed and none resulted in ADA discontinuation.

CONCLUSIONS: Based on our data, ADA seems to be effective in children with UC, allowing to recover a significant percentage of patients intolerant or not-responding to IFX. The safety profile was good.

}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000001883}, author = {Aloi, Marina and Bramuzzo, Matteo and Arrigo, Serena and Romano, Claudio and D{\textquoteright}Arcangelo, Giulia and Lacorte, Doriana and Gatti, Simona and Illiceto, Maria T and Zucconi, Francesca and Dilillo, Dario and Zuin, Giovanna and Knafelz, Daniela and Ravelli, Alberto and Cucchiara, Salvatore and Alvisi, Patrizia} } @article {10772, title = {Emergency extracorporeal shockwave lithotripsy as opposed to delayed shockwave lithotripsy for the treatment of acute renal colic due to obstructive ureteral stone: a prospective randomized trial.}, journal = {Minerva Urol Nefrol}, volume = {70}, year = {2018}, month = {2018 Oct}, pages = {526-533}, abstract = {

BACKGROUND: The aim of this study was to assess the efficacy of emergency extracorporeal shockwave lithotripsy (eSWL) as first-line treatment in patients with acute colic due to obstructive ureteral stone.

METHODS: Seventy-four patients were randomized to emergency SWL within 12 hours (eSWL group) and deferred SWL later than 3 days (dSWL group). Follow-up included ultrasound, KUB (kidney-ureter-bladder) radiography and CT (computed tomography) scan at 24 hours, 7 days, 1 and 3 months from the treatment. When necessary, repeated SWL (re-SWL) or ureteroscopy (auxiliary-URS) was performed. Preoperative and postoperative data were compared and stone free rates (SFR) and efficiency quotients (EQ) were evaluated. Analyses were performed using SAS software.

RESULTS: Complete data of 70 patients were collected. 36 underwent eSWL and 34 dSWL. The mean patient age was 48.7. Mean stone size was 9.8 mm (CI 95\%: 8.9-10.8). 25 (35.7\%) were proximal and 45 (64.3\%) distal. Mean SWL energy was 19.2 kV (CI 95\%: 18.5-19.9) and mean number of shocks was 2657 (CI 95\%: 2513-2802). eSWL patients needs less auxiliary-URS than dSWL patients (13.9\% vs. 44.1\%, P=0.039) and less re-SWL sessions (8.3\% vs. 32.4\%, P=0.093). SFR at 24 hours was 52.8\% and 11.8\% (P<0.001) and the EQ at 3 months was 79.1\% and 57.5\% in the eSWL and dSWL group respectively. Patients from the dSWL group spent more time in the hospital (2.21 vs. 1.36 days, P=0.046) and complication rates between the two groups were similar.

CONCLUSIONS: eSWL is a safe procedure and delivers high SFR even within 24 hours especially for <10 mm stones. It is able to reduce the number of auxiliary procedures and hospitalization.

}, keywords = {Aged, Calculi, Emergency Medical Services, Female, Humans, Length of Stay, Lithotripsy, Male, Middle Aged, Prospective Studies, Renal Colic, Time-to-Treatment, Tomography, X-Ray Computed, Ureteral Obstruction}, issn = {1827-1758}, doi = {10.23736/S0393-2249.18.03084-9}, author = {Bucci, Stefano and Umari, Paolo and Rizzo, Michele and Pavan, Nicola and Liguori, Giovanni and Barbone, Fabio and Trombetta, Carlo} } @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 {10776, title = {Facilitators and barriers to the effective implementation of the individual maternal near-miss case reviews in low/middle-income countries: a systematic review of qualitative studies.}, journal = {BMJ Open}, volume = {8}, year = {2018}, month = {2018 Jun 30}, pages = {e021281}, abstract = {

BACKGROUND: The maternal near-miss cases review (NMCR), a type of clinical audit, proved to be effective in improving quality of care and decreasing maternal mortality in low/middle-income countries (LMICs). However, challenges in its implementation have been described.

OBJECTIVES: Synthesising the evidence on facilitators and barriers to the effective implementation of NMCR in LMICs.

DESIGN: Systematic review of qualitative studies.

DATA SOURCES: MEDLINE, LILACS, Global Health Library, SCI-EXPANDED, SSCI, Cochrane library and Embase were searched in December 2017.

ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Qualitative studies exploring facilitators and/or barriers of implementing NMCR in LMIC were included.

DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data, performed thematic analysis and assessed risk of bias.

RESULTS: Out of 25 361 papers retrieved, 9 studies from Benin, Brazil, Burkina Faso, Cote D{\textquoteright}Ivoire, Ghana, Malawi, Morocco, Tanzania, Uganda could be included in the review. The most frequently reported barriers to NMCR implementation were the following: absence of national guidelines and local protocols; insufficient training on how to perform the audit; lack of leadership, coordination, monitoring and supervision; lack of resources and work overload; fear of blame and punishment; poor knowledge of evidenced-based medicine; hierarchical differences among staff and poor understating of the benefits of the NMCR. Major facilitators to NMCR implementation included: good leadership and coordination; training of all key staff; a good cultural environment; clear staff{\textquoteright}s perception on the benefits of conducting audit; patient empowerment and the availability of external support.

CONCLUSIONS: In planning the NMCR implementation in LMICs, policy-makers should consider actions to prevent and mitigate common challenges to successful NMCR implementation. Future studies should aim at documenting facilitators and barriers to NMCR outside the African Region.

}, issn = {2044-6055}, doi = {10.1136/bmjopen-2017-021281}, author = {Lazzerini, Marzia and Ciuch, Margherita and Rusconi, Silvia and Covi, Benedetta} } @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 {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 {10434, title = {A Giant Ovarian Cyst in an Adolescent.}, journal = {J Pediatr}, volume = {199}, year = {2018}, month = {2018 08}, pages = {279}, keywords = {Child, Cystadenoma, Serous, Female, Humans, Ovarian Neoplasms}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2018.03.015}, author = {Corrias, Francesca and Pederiva, Federica and Cozzi, Giorgio and Ammar, Lydie and Cattaruzzi, Elisabetta and Lembo, Maria Antonietta 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 {10795, title = {How to predict response to anti-tumour necrosis factor agents in inflammatory bowel disease.}, journal = {Expert Rev Gastroenterol Hepatol}, volume = {12}, year = {2018}, month = {2018 Aug}, pages = {797-810}, abstract = {

INTRODUCTION: Anti-tumor necrosis factor (TNF) agents have changed the therapeutic approach to inflammatory bowel disease (IBD). However, a considerable proportion of patients either do not primarily respond or lose response to treatment. Despite the long-standing experience in the use of these drugs, still there is the need of identifying the possible predictors of efficacy. Areas covered: We critically review the current knowledge on predictors of response to anti-TNF therapy - both those available in clinical practice and those still under investigation. Multiple factors are involved in treatment success, including disease phenotype and severity, adherence to medications, and pharmacogenomic, pharmacokinetic, and immunologic factors. Literature search was conducted in PubMed using keywords {\textquoteright}inflammatory bowel disease,{\textquoteright} {\textquoteright}Crohn{\textquoteright}s disease,{\textquoteright} and {\textquoteright}ulcerative colitis,{\textquoteright} matched with {\textquoteright}antitumor necrosis factor,{\textquoteright} {\textquoteright}biologic therapy,{\textquoteright} {\textquoteright}clinical response,{\textquoteright} {\textquoteright}predictors,{\textquoteright} and {\textquoteright}efficacy,{\textquoteright} Relevant articles were selected for review. Expert commentary: While the role of several factors in clinical practice is clearly established, other investigational markers have been proposed, mostly in small studies, yet for many of them little external validation exists. Therapeutic drug monitoring is emerging as a pivotal strategy to guide decisions in clinical practice. In the near future, novel markers could improve our ability to direct treatment and personalize therapy.

}, keywords = {Antibodies, Monoclonal, Biological Therapy, Gastrointestinal Agents, Humans, Inflammatory Bowel Diseases, Patient Selection, Prognosis, Treatment Outcome, Tumor Necrosis Factor-alpha}, issn = {1747-4132}, doi = {10.1080/17474124.2018.1494573}, author = {Naviglio, Samuele and Giuffrida, Paolo and Stocco, Gabriele and Lenti, Marco Vincenzo and Ventura, Alessandro and Corazza, Gino Roberto and Di Sabatino, Antonio} } @article {10799, title = {In vivo microbiome and associated immune markers: New insights into the pathogenesis of vaginal dysbiosis.}, journal = {Sci Rep}, volume = {8}, year = {2018}, month = {2018 02 02}, pages = {2307}, abstract = {

The microbiota fulfils a key role in the training and function of the immune system, which contributes to the symbiosis between the host and complex microbial communities. In this study, we characterized the interplay between vaginal bacteria and local immune mediators during dysbiosis in selected women of reproductive age who were grouped according to Nugent{\textquoteright}s criteria. The abundance of Gardnerella vaginalis and Bifidobacterium breve was increased in the intermediate dysbiotic status, while the presence of a plethora of non-resident bacteria characterized the group with overt vaginosis. In response to these increases, the anti-inflammatory IL1ra and pro-inflammatory IL2 increased, while the embryo trophic factors FGFβ and GMCSF decreased compared to the healthy milieu. A specific pattern, including IL1α, IL1β, IL8, MIG, MIP1α and RANTES, distinguished the intermediate group from the vaginosis group, while IL5 and IL13, which are secreted by Th2 cells, were significantly associated with the perturbation of the commensals Lactobacilli, Gardnerella and Ureaplasma. Summarizing, we postulate that although the dysbiotic condition triggers a pro-inflammatory process, the presence of a steady state level of Th2 may influence clinical manifestations. These results raise clinically relevant questions regarding the use of vaginal immunological markers as efficacious tools to monitor microbial alterations.

}, keywords = {Adult, Biomarkers, Cytokines, Dysbiosis, Female, Humans, Microbiota, Th2 Cells, Vagina}, issn = {2045-2322}, doi = {10.1038/s41598-018-20649-x}, author = {Campisciano, Giuseppina and Zanotta, Nunzia and Licastro, Danilo and De Seta, Francesco and Comar, Manola} } @article {10807, title = {Joint Data Analysis in Nutritional Epidemiology: Identification of Observational Studies and Minimal Requirements.}, journal = {J Nutr}, volume = {148}, year = {2018}, month = {2018 02 01}, pages = {285-297}, abstract = {

Background: Joint data analysis from multiple nutrition studies may improve the ability to answer complex questions regarding the role of nutritional status and diet in health and disease.

Objective: The objective was to identify nutritional observational studies from partners participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) Consortium, as well as minimal requirements for joint data analysis.

Methods: A predefined template containing information on study design, exposure measurements (dietary intake, alcohol and tobacco consumption, physical activity, sedentary behavior, anthropometric measures, and sociodemographic and health status), main health-related outcomes, and laboratory measurements (traditional and omics biomarkers) was developed and circulated to those European research groups participating in the ENPADASI under the strategic research area of "diet-related chronic diseases." Information about raw data disposition and metadata sharing was requested. A set of minimal requirements was abstracted from the gathered information.

Results: Studies (12 cohort, 12 cross-sectional, and 2 case-control) were identified. Two studies recruited children only and the rest recruited adults. All studies included dietary intake data. Twenty studies collected blood samples. Data on traditional biomarkers were available for 20 studies, of which 17 measured lipoproteins, glucose, and insulin and 13 measured inflammatory biomarkers. Metabolomics, proteomics, and genomics or transcriptomics data were available in 5, 3, and 12 studies, respectively. Although the study authors were willing to share metadata, most refused, were hesitant, or had legal or ethical issues related to sharing raw data. Forty-one descriptors of minimal requirements for the study data were identified to facilitate data integration.

Conclusions: Combining study data sets will enable sufficiently powered, refined investigations to increase the knowledge and understanding of the relation between food, nutrition, and human health. Furthermore, the minimal requirements for study data may encourage more efficient secondary usage of existing data and provide sufficient information for researchers to draft future multicenter research proposals in nutrition.

}, keywords = {Adult, Biomarkers, Blood Glucose, Case-Control Studies, Child, Chronic Disease, Cohort Studies, Cross-Sectional Studies, Diet, Epidemiology, Europe, Genomics, Health Status, Humans, Inflammation, Insulin, Life Style, Lipoproteins, Longitudinal Studies, Metabolomics, Nutritional Status, Observational Studies as Topic, Statistics as Topic}, issn = {1541-6100}, doi = {10.1093/jn/nxx037}, author = {Pinart, Mariona and Nimptsch, Katharina and Bouwman, Jildau and Dragsted, Lars O and Yang, Chen and De Cock, Nathalie and Lachat, Carl and Perozzi, Giuditta and Canali, Raffaella and Lombardo, Rosario and D{\textquoteright}Archivio, Massimo and Guillaume, Mich{\`e}le and Donneau, Anne-Fran{\c c}oise and Jeran, Stephanie and Linseisen, Jakob and Kleiser, Christina and N{\"o}thlings, Ute and Barbaresko, Janett and Boeing, Heiner and Stelmach-Mardas, Marta and Heuer, Thorsten and Laird, Eamon and Walton, Janette and Gasparini, Paolo and Robino, Antonietta and Casta{\~n}o, Luis and Rojo-Mart{\'\i}nez, Gemma and Merino, Jordi and Masana, Luis and Standl, Marie and Schulz, Holger and Biagi, Elena and Nurk, Eha and Matthys, Christophe and Gobbetti, Marco and de Angelis, Maria and Windler, Eberhard and Zyriax, Birgit-Christiane and Tafforeau, Jean and Pischon, Tobias} } @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 {10428, title = {Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications.}, journal = {Clin Immunol}, volume = {191}, year = {2018}, month = {2018 Jun}, pages = {75-80}, abstract = {

Leukocyte Adhesion Deficiency type 1 (LAD-1) is a rare primary immunodeficiency due to mutations in the gene encoding for the common β-chain of the β2 integrin family (CD18). Herein, we describe clinical manifestations and long-term complications of eight LAD-1 patients. Four LAD-1 patients were treated with hematopoietic stem cell transplantation (HSCT), while the remaining four, including two with moderate LAD-1 deficiency, received continuous antibiotic prophylaxis. Untreated patients presented numerous infections and autoimmune manifestations. In particular, two of them developed renal and intestinal autoimmune diseases, despite the expression of Beta-2 integrin was partially conserved. Other two LAD-1 patients developed type 1 diabetes and autoimmune cytopenia after HSCT, suggesting that HSCT is effective for preventing infections in LAD-1, but does not prevent the risk of the autoimmune complications.

}, issn = {1521-7035}, doi = {10.1016/j.clim.2018.03.005}, author = {De Rose, Domenico Umberto and Giliani, Silvia and Notarangelo, Lucia Dora and Lougaris, Vassilios and Lanfranchi, Arnalda and Moratto, Daniele and Martire, Baldassarre and Specchia, Fernando and Tommasini, Alberto and Plebani, Alessandro and Badolato, Raffaele} } @article {10811, title = {Low-dose sirolimus in two cousins with autoimmune lymphoproliferative syndrome-associated infection.}, journal = {Pediatr Int}, volume = {60}, year = {2018}, month = {2018 Mar}, pages = {315-317}, keywords = {Anti-Bacterial Agents, Autoimmune Lymphoproliferative Syndrome, Child, Child, Preschool, Dose-Response Relationship, Drug, Female, Humans, Immunosuppressive Agents, Infant, Male, Otitis Media, Pneumonia, Bacterial, Sirolimus}, issn = {1442-200X}, doi = {10.1111/ped.13494}, author = {Nocerino, Agostino and Valencic, Erica and Loganes, Claudia and Pelos, Giorgio and Tommasini, Alberto} } @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 {10440, title = {Neuronal Dysfunction Associated with Cholesterol Deregulation.}, journal = {Int J Mol Sci}, volume = {19}, year = {2018}, month = {2018 May 19}, abstract = {

Cholesterol metabolism is crucial for cells and, in particular, its biosynthesis in the central nervous system occurs in situ, and its deregulation involves morphological changes that cause functional variations and trigger programmed cell death. The pathogenesis of rare diseases, such as Mevalonate Kinase Deficiency or Smith$^{-}$Lemli$^{-}$Opitz Syndrome, arises due to enzymatic defects in the cholesterol metabolic pathways, resulting in a shortage of downstream products. The most severe clinical manifestations of these diseases appear as neurological defects. Expanding the knowledge of this biological mechanism will be useful for identifying potential targets and preventing neuronal damage. Several studies have demonstrated that deregulation of the cholesterol pathway induces mitochondrial dysfunction as the result of respiratory chain damage. We set out to determine whether mitochondrial damage may be prevented by using protective mitochondria-targeted compounds, such as MitoQ, in a neuronal cell line treated with a statin to induce a biochemical block of the cholesterol pathway. Evidence from the literature suggests that mitochondria play a crucial role in the apoptotic mechanism secondary to blocking the cholesterol pathway. Our study shows that MitoQ, administered as a preventive agent, could counteract the cell damage induced by statins in the early stages, but its protective role fades over time.

}, keywords = {Anticholesteremic Agents, Cell Line, Tumor, Cholesterol, Electron Transport, Humans, Lovastatin, Mitochondria, Neurons, Neuroprotective Agents, Organophosphorus Compounds, Ubiquinone}, issn = {1422-0067}, doi = {10.3390/ijms19051523}, author = {Marcuzzi, Annalisa and Loganes, Claudia and Valencic, Erica and Piscianz, Elisa and Monasta, Lorenzo and Bilel, Sabrine and Bortul, Roberta and Celeghini, Claudio and Zweyer, Marina and Tommasini, Alberto} } @article {10535, title = {A new form of inherited thrombocytopenia due to monoallelic loss of function mutation in the thrombopoietin gene.}, journal = {Br J Haematol}, volume = {181}, year = {2018}, month = {2018 Jun}, pages = {698-701}, issn = {1365-2141}, doi = {10.1111/bjh.14694}, author = {Noris, Patrizia and Marconi, Caterina and De Rocco, Daniela and Melazzini, Federica and Pippucci, Tommaso and Loffredo, Giuseppe and Giangregorio, Tania and Pecci, Alessandro and Seri, Marco and Savoia, Anna} } @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 {10829, title = {Pain Intensity and Risk of Bone Fracture in Children With Minor Extremity Injuries.}, journal = {Pediatr Emerg Care}, year = {2018}, month = {2018 Jan 23}, abstract = {

OBJECTIVES: Injuries are one of the most common causes of pediatric emergency department (ED) visit. The aim of this study was to investigate the relationship between the intensity of pain at the ED visit of children presenting with an extremity injury and the risk of fracture.

METHODS: We conducted a retrospective study, considering all patients presenting to the ED of a children{\textquoteright}s hospital in Italy, with an accidental extremity injury, between May and December 2015. We selected all children aged 8 to 17 years who underwent an x-ray. Children with major, multiple, or nonextremity injuries were excluded. Age, sex, spontaneous and palpation pain, local swelling, time between injury, and medical evaluation were recorded. Sensibility and specificity of spontaneous and palpation pain in detecting a fracture were calculated.

RESULTS: We reviewed 994 medical records; of these, 344 (34.6\%) reported a fracture. Children{\textquoteright}s median age was 12 years (interquartile range [IQR], 10-14). Median spontaneous pain at the ED visit was not significantly different between children with and without a fracture: 4.0 (1.0-6.0) and 5 (1.0-6.0), respectively (P = 0.129). Children with mild palpation pain and children without an increase of pain of at least 2 points between spontaneous and palpation pain were fractured in 3.2\% and 0.97\% of cases, respectively.

CONCLUSIONS: In this series, pain intensity in children with a minor extremity injury was not a good marker of fracture. Nevertheless, children with mild palpation pain or with a mild increase of pain between spontaneous and palpation pain had a low risk of fracture.

}, issn = {1535-1815}, doi = {10.1097/PEC.0000000000001418}, author = {Zanchi, Chiara and Giangreco, Manuela and Ronfani, Luca and Germani, Claudio and Giorgi, Rita and Calligaris, Lorenzo and Norbedo, Stefania and Liccari, Giulio and Cozzi, Giorgio and Barbi, Egidio} } @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 {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 {10836, title = {Predictive value of the number of adverse reaction episodes for the IgE-mediated food allergy diagnosis.}, journal = {Allergol Immunopathol (Madr)}, year = {2018}, month = {2018 Dec 17}, abstract = {

INTRODUCTION AND OBJECTIVES: The reproducibility of the adverse reaction increases the suggestiveness of a history of food allergy. However, the positive predictive value (PPV) of multiple adverse reaction episodes for the diagnosis of IgE-mediated food allergy is not known. This evaluation was the objective of our study.

PATIENTS AND METHODS: We retrospectively studied 180 children with a history of non-anaphylactic adverse reactions after the ingestion of a food. All children had the prick test positive for the offending food and performed the oral food challenge (OFC) within 12 months after the last adverse reaction episode (ARE). We have evaluated whether increasing the number of ARE increased the probability that the OFC would be positive (failed).

RESULTS: 93 patients (52\%) presented one ARE, 49 (27\%) presented two ARE, 24 (13\%) presented three ARE, 14 (8\%) patients presented>=four ARE. The OFC was positive in 94/180 (52\%). The outcome of the OFC was found to be positively correlated with the number of ARE (OR=1.56; 95\% CI=1.16-2.09; p=0.003). A PPV=100\% was observed with a number of ARE>=five.

CONCLUSIONS: The number of ARE is an important predictor of the diagnosis of food allergy, although less than we would have imagined. The number of ARE could be used to increase the predictability of the diagnostic tests currently in use, to define clinical prediction rules alternative to OFC and easy to use in clinical practice.

}, issn = {1578-1267}, doi = {10.1016/j.aller.2018.10.006}, author = {Miceli Sopo, S and Gurnari, G and Monaco, S and Romano, A and Liotti, L and Cuomo, B and Dello Iacono, I and Badina, L and Longo, G and Calvani, M and Giannone, A and Calabr{\`o}, C and Scala, G and Verga, M C} } @article {10863, title = {Quality of care for children with acute malnutrition at health center level in Uganda: a cross sectional study in West Nile region during the refugee crisis.}, journal = {BMC Health Serv Res}, volume = {18}, year = {2018}, month = {2018 07 17}, pages = {561}, abstract = {

BACKGROUND: Arua district, in Uganda, hosts some of the largest refugee camps in the country. The estimated prevalence of moderate and severe acute malnutrition in children is higher than the national estimates (10.4 and 5.6\% respectively, compared to 3.6 and 1.3\%). This study aimed at assessing the quality of care provided to children with acute malnutrition at out-patient level in such a setting.

METHODS: Six facilities with the highest number of children with malnutrition were selected. The main tool used was the National Nutrition Service Delivery Assessment Tool, assessing 10 key areas of service delivery and assigned a score as either poor, fair, good or excellent. Health outcomes, quality of case management and data quality were assessed from the health management information system and from the official nutrition registers.

RESULTS: All facilities except two scored either poor or fair under all the 10 assessment areas. Overall, 33/60 (55\%) areas scored as poor, 25/60 (41\%) as fair, 2/60 (3.3\%) as good, and none as excellent. Main gaps identified included: lack of trained staff; disorganised patient flow; poor case management; stock out of essential supplies including ready-to-use therapeutic foods; weak community linkage. A sample coverage of 45.4\% (1020/2248) of total children admitted in the district during the 2016 financial year were included. The overall mean cure rate was 52.9\% while the default rate was 38.3\%. There was great heterogeneity across health facilities in health outcomes, quality of case management, and data quality.

CONCLUSION: This study suggests that quality of care provided to children with malnutrition at health center level is substandard with unacceptable low cure rates. It is essential to identify effective approaches to enhance adherence to national guidelines, provision of essential nutritional commodities, regular monitoring of services and better linkage with the community through village health teams.

}, keywords = {Child Nutrition Disorders, Child, Preschool, Cross-Sectional Studies, Health Facilities, Humans, Nutrition Assessment, Nutritional Status, Prevalence, Quality of Health Care, Refugee Camps, Refugees, Uganda}, issn = {1472-6963}, doi = {10.1186/s12913-018-3366-5}, author = {Wanzira, Humphrey and Muyinda, Richard and Lochoro, Peter and Putoto, Giovanni and Segafredo, Giulia and Wamani, Henry and Lazzerini, Marzia} } @article {10843, title = {Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice.}, journal = {Curr Med Chem}, volume = {25}, year = {2018}, month = {2018}, pages = {2783-2796}, abstract = {

BACKGROUND: Mevalonate Kinase Deficiency (MKD, OMIM $\#$610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome.

OBJECTIVE: Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints{\textquoteright} conditions and their quality of life.

METHODS: MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block.

RESULTS: A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile.

CONCLUSIONS: Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases.

}, keywords = {Acyl Coenzyme A, Cholesterol, Drug Repositioning, Farnesyl-Diphosphate Farnesyltransferase, Humans, Hypercholesterolemia, Mevalonate Kinase Deficiency, Oxazepines, Phosphotransferases (Alcohol Group Acceptor), Piperidines}, issn = {1875-533X}, doi = {10.2174/0929867324666170911161417}, author = {Marcuzzi, Annalisa and Loganes, Claudia and Celeghini, Claudio and Kleiner, Giulio} } @article {10850, title = {The Role of Oxidative Stress and Membrane Transport Systems during Endometriosis: A Fresh Look at a Busy Corner.}, journal = {Oxid Med Cell Longev}, volume = {2018}, year = {2018}, month = {2018}, pages = {7924021}, abstract = {

Endometriosis is a condition characterized by the presence of endometrial tissue outside the uterine cavity, leading to a chronic inflammatory reaction. It is one of the most widespread gynecological diseases with a 10-15\% prevalence in the general female population, rising up to 30-45\% in patients with infertility. Although it was first described in 1860, its etiology and pathogenesis are still unclear. It is now accepted that inflammation plays a central role in the development and progression of endometriosis. In particular, it is marked by an inflammatory process associated with the overproduction of an array of inflammatory mediators such as prostaglandins, metalloproteinases, cytokines, and chemokines. In addition, the growth and adhesion of endometrial cells in the peritoneal cavity due to reactive oxygen species (ROS) and free radicals lead to disease onset, its ensuing symptoms-among which pain and infertility. The aim of our review is to evaluate the role of oxidative stress and ROS in the pathogenesis of endometriosis and the efficacy of antioxidant therapy in the treatment and mitigation of its symptoms.

}, keywords = {Endometriosis, Female, Humans, Oxidative Stress}, issn = {1942-0994}, doi = {10.1155/2018/7924021}, author = {Vitale, Salvatore Giovanni and Capriglione, Stella and Peterlunger, Isabel and La Rosa, Valentina Lucia and Vitagliano, Amerigo and Noventa, Marco and Valenti, Gaetano and Sapia, Fabrizio and Angioli, Roberto and Lopez, Salvatore and Sarpietro, Giuseppe and Rossetti, Diego and Zito, Gabriella} } @article {10510, title = {Role of the Long Non-Coding RNA Growth Arrest-Specific 5 in Glucocorticoid Response in Children with Inflammatory Bowel Disease.}, journal = {Basic Clin Pharmacol Toxicol}, volume = {122}, year = {2018}, month = {2018 Jan}, pages = {87-93}, abstract = {

Glucocorticoids (GCs) are widely employed in inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in inflammatory bowel disease (IBD). Given the high incidence of suboptimal response, associated with a significant number of side-effects, that are particularly severe in paediatric patients, the identification of subjects that are most likely to respond poorly to GCs is extremely important. Recent evidence suggests that the long non-coding RNA (lncRNA) GAS5 could be a potential marker of GC resistance. To address this issue, we evaluated the association between the lncRNA GAS5 and the efficacy of steroids, in terms of inhibition of proliferation, in two cell lines derived from colon and ovarian cancers, to confirm the sensitivity and specificity of these lncRNAs. These cells showed a different sensitivity to GCs and revealed differential expression of GAS5 after treatment. GAS5 was up-regulated in GC-resistant cells and accumulated more in the cytoplasm compared to the nucleus in response to the drug. The functions of GAS5 were assessed by silencing, and we found that GAS5 knock-down reduced the proliferation during GC treatment. Furthermore, for the first time, we measured GAS5 levels in 19 paediatric IBD patients at diagnosis and after the first cycle of GCs, and we demonstrated an up-regulation of the lncRNA in patients with unfavourable steroid response. Our preliminary results indicate that GAS5 could be considered a novel pharmacogenomic marker useful for the personalization of GC therapy.

}, keywords = {Biomarkers, Cell Line, Tumor, Cell Proliferation, Child, Drug Resistance, Female, Gene Knockdown Techniques, Glucocorticoids, Humans, Inflammatory Bowel Diseases, Male, Patient Selection, Pharmacogenomic Testing, Precision Medicine, RNA, Long Noncoding, RNA, Small Interfering, Treatment Outcome, Up-Regulation}, issn = {1742-7843}, doi = {10.1111/bcpt.12851}, author = {Lucaf{\`o}, Marianna and Di Silvestre, Alessia and Romano, Maurizio and Avian, Alice and Antonelli, Roberta and Martelossi, Stefano and Naviglio, Samuele and Tommasini, Alberto and Stocco, Gabriele and Ventura, Alessandro and Decorti, Giuliana and De Iudicibus, Sara} } @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 {10846, title = {Secondary prevention of early-onset sepsis: a less invasive Italian approach for managing neonates at risk.}, journal = {Ital J Pediatr}, volume = {44}, year = {2018}, month = {2018 Jun 28}, pages = {73}, abstract = {

Strategies to prevent early-onset sepsis (EOS) have led to a substantial decline in many countries. However, one of the most controversial topics in neonatology is the management of asymptomatic full-term and late preterm neonates at risk for EOS, and guidelines lack substantial consensus regarding this issue. A strategy for managing neonates, entirely based on serial physical examinations, has been developed in two Italian regions. This strategy seems safe, while reducing laboratory tests and unnecessary antibiotics. In the current commentary we provide area-based data concerning the prevention of EOS in 2 northern Italian regions, and we detail the results of their strategy for managing healthy-appearing newborns at risk for EOS.

}, issn = {1824-7288}, doi = {10.1186/s13052-018-0515-8}, author = {Berardi, Alberto and Tzialla, Chryssoula and Travan, Laura and Bua, Jenny and Santori, Daniele and Azzalli, Milena and Spada, Caterina and Lucaccioni, Laura} } @article {10847, title = {Serum Stem Cell Growth Factor Beta for the Prediction of Therapy Response in Hepatocellular Carcinoma.}, journal = {Biomed Res Int}, volume = {2018}, year = {2018}, month = {2018}, pages = {6435482}, abstract = {

Introduction: Chronic inflammatory response is one of major contributors in the development of hepatocellular carcinoma (HCC). Inflammatory molecules, such as cytokines and growth factors in the circulation, can be useful in the diagnosis and prognosis of the patients. The stem cell growth factor beta (SCGF), a newly found protein, is a secreted sulfated glycoprotein and it functions as a growth factor for primitive hematopoietic progenitor cells. The level of SCGF had been reported to be elevated in several cancer types. However, there is very few or even no information on this protein in the study of HCC, even more in clinical studies.

Methods: A multiplex immunoassay panel of 48 cytokines and growth factors were utilized to screen 68 sera from 29 HCC patients at pretreatment (T0), 1 month (T1), and 6 months (T6) after treatment by either radiofrequency ablation (RF) or transarterial chemoembolization (TACE). Treatment response was evaluated according to mRECIST criteria.

Results: Immunoassay screening showed that the levels of IL-17, CTACK, TNF, IL-2R, IL-8, and SCGF were different in Complete Responders (CR) and Nonresponders (NR) groups. At T0 and T1, the SCGF level was significantly the highest in NR (23.8 and 40.7 ng/mL, respectively), followed by early recurrence (25.4 and 25.0 ng/mL), and CR (6.7 and 5.3 ng/mL), independently from HCV, stages, and treatment type. Low basal SCGF level was associated with longer disease-free survival compared to high SCGF.

Conclusion: In this study, for the first time, we demonstrate that the high level of serum SCGF at pre- and posttreatment is associated with HCC nonresponsiveness.

}, keywords = {Aged, Carcinoma, Hepatocellular, Chemoembolization, Therapeutic, Female, Hematopoietic Cell Growth Factors, Humans, Liver Neoplasms, Male, Middle Aged, Neoplasm Recurrence, Local, Retrospective Studies, Stem Cells, Treatment Outcome}, issn = {2314-6141}, doi = {10.1155/2018/6435482}, author = {Sukowati, Caecilia H C and Patti, Riccardo and Pascut, Devis and Ladju, Rusdina B and Tarchi, Paola and Zanotta, Nunzia and Comar, Manola and Tiribelli, Claudio and Croc{\`e}, Lory S} } @article {10851, title = {Theophylline as a precision therapy in a young girl with PIK3R1 immunodeficiency.}, journal = {J Allergy Clin Immunol Pract}, volume = {6}, year = {2018}, month = {2018 Nov - Dec}, pages = {2165-2167}, issn = {2213-2201}, doi = {10.1016/j.jaip.2018.02.029}, author = {Valencic, Erica and Grasso, Antonio Giacomo and Conversano, Ester and Lucaf{\`o}, Marianna and Piscianz, Elisa and Gregori, Massimo and Conti, Francesca and Cancrini, Caterina and Tommasini, Alberto} } @article {10855, title = {What is the quality of the maternal near-miss case reviews in WHO European Region? Cross-sectional study in Armenia, Georgia, Latvia, Republic of Moldova and Uzbekistan.}, journal = {BMJ Open}, volume = {8}, year = {2018}, month = {2018 04 12}, pages = {e017696}, abstract = {

OBJECTIVES: The maternal near-miss case review (NMCR) cycle is a type of clinical audit aiming at improving quality of maternal healthcare by discussing near-miss cases. In several countries this approach has been introduced and supported by WHO and partners since 2004, but information on the quality of its implementation is missing. This study aimed at evaluating the quality of the NMCR implementation in selected countries within WHO European Region.

DESIGN: Cross-sectional study.

SETTINGS: Twenty-three maternity units in Armenia, Georgia, Latvia, Moldova and Uzbekistan.

ASSESSMENT TOOLS: A predefined checklist including 50 items, according to WHO methodology. Quality in the NMCR implementation was defined by summary scores ranging from 0 (totally inappropriate) to 3 (appropriate).

RESULTS: Quality of the NMCR implementation was heterogeneous among different countries, and within the same country. Overall, the first part of the audit cycle (from case identification to case analysis) was fairly well performed (mean score 2.00, 95\% CI 1.94 to 2.06), with the exception of the {\textquoteright}inclusion of users{\textquoteright} views{\textquoteright} (mean score 0.66, 95\% CI 0.11 to 1.22), while the second part (developing recommendations, implementing them and ensuring quality) was poorly performed (mean score 0.66, 95\% CI 0.11 to 1.22). Each country had at least one champion facility, where quality of the NMCR cycle was acceptable. Quality of the implementation was not associated with its duration. Gaps in implementation were of technical, organisational and attitudinal nature.

CONCLUSIONS: Ensuring quality in the NMCR may be difficult but achievable. The high heterogeneity in results within the same country suggests that quality of the NMCR implementation depends, to a large extent, from hospital factors, including staff{\textquoteright}s commitment, managerial support and local coordination. Efforts should be put in preventing and mitigating common barriers that hamper successful NMCR implementation.

}, keywords = {Armenia, Checklist, Cross-Sectional Studies, Female, Georgia, Humans, Latvia, Maternal Mortality, Medical Audit, Moldova, Near Miss, Healthcare, Pregnancy, Pregnancy Complications, Quality Improvement, Uzbekistan}, issn = {2044-6055}, doi = {10.1136/bmjopen-2017-017696}, author = {Bacci, Alberta and Hodorogea, Stelian and Khachatryan, Henrik and Babojonova, Shohida and Irsa, Signe and Jansone, Maira and Dondiuc, Iurie and Matarazde, George and Lazdane, Gunta and Lazzerini, Marzia} } @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 {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 {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 {10463, title = {CCR5Δ32 and the genetic susceptibility to rheumatoid arthritis in admixed populations: a multicentre study.}, journal = {Rheumatology (Oxford)}, volume = {56}, year = {2017}, month = {2017 03 01}, pages = {495-497}, keywords = {Arthritis, Rheumatoid, Brazil, Case-Control Studies, Consanguinity, Gene Frequency, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide, Receptors, CCR5}, issn = {1462-0332}, doi = {10.1093/rheumatology/kew398}, author = {Toson, Bruno and Dos Santos, Eduardo Jos{\'e} and Adelino, Jos{\'e} Eduardo and Sandrin-Garcia, Paula and Crovella, Sergio and Louzada-J{\'u}nior, Paulo and Oliveira, Ren{\^e} Donizete Ribeiro and Pedroza, Larysse Santa Rosa Aquino and de F{\'a}tima Lobato Cunha Sauma, Maria and de Lima, Clayton Pereira Silva and Barbosa, Fabiola Brasil and Brenol, Claiton Viegas and Xavier, Ricardo Machado and Chies, Jos{\'e} Artur Bogo and Veit, Tiago Degani} } @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 {10541, title = {Climate change, emerging infections and blood donations.}, journal = {J Travel Med}, volume = {24}, year = {2017}, month = {2017 05 01}, keywords = {Blood Transfusion, Climate Change, Communicable Diseases, Emerging, Global Health, Humans, Travel}, issn = {1708-8305}, doi = {10.1093/jtm/taw098}, author = {Cegolon, L and Heymann, W C and Lange, J H} } @article {10552, title = {Combined use of AFM and soft X-ray microscopy to reveal fibres{\textquoteright} internalization in mesothelial cells.}, journal = {Analyst}, volume = {142}, year = {2017}, month = {2017 May 30}, pages = {1982-1992}, abstract = {

Nanotoxicology and nanomedicine investigations often require the probing of nano-objects such as fibres and particles in biological samples and cells, whilst internalization and intracellular destiny are the main issues for in vitro cellular studies. Various high resolution microscopy techniques are well suited for providing this highly sought-after information. However, sample preparation, nanomaterial composition and sectioning challenges make it often difficult to establish whether the fibres or particles have been internalized or they are simply overlaying or underlying the biological matter. In this paper we suggest a novel suitable combination of two different microscopic techniques to reveal in intact cells the uptake of asbestos fibres by mesothelial cells. After exposure to asbestos fibres and fixation, cells were first analysed under the AFM instrument and then imaged under the TwinMic soft X-ray microscope at Elettra Sincrotrone. The suggested approach combines standard soft X-ray microscopy imaging and AFM microscopy, with a common non-invasive sample preparation protocol which drastically reduces the experimental uncertainty and provides a quick and definitive answer to the nanoparticle cellular and tissue uptake.

}, keywords = {Asbestos, Cell Line, Epithelial Cells, Epithelium, Humans, Microscopy, Atomic Force, X-Rays}, issn = {1364-5528}, doi = {10.1039/c6an02661c}, author = {Gianoncelli, Alessandra and Kourousias, George and Cammisuli, Francesca and Cassese, Damiano and Rizzardi, Clara and Radillo, Oriano and Lazzarino, Marco and Pascolo, Lorella} } @article {10568, title = {Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine.}, journal = {Pflugers Arch}, volume = {469}, year = {2017}, month = {2017 01}, pages = {91-103}, abstract = {

The nature and importance of genetic factors regulating the differential handling of Ca and Mg by the renal tubule in the general population are poorly defined. We conducted a genome-wide meta-analysis of urinary magnesium-to-calcium ratio to identify associated common genetic variants. We included 9320 adults of European descent from four genetic isolates and three urban cohorts. Urinary magnesium and calcium concentrations were measured centrally in spot urine, and each study conducted linear regression analysis of urinary magnesium-to-calcium ratio on ~2.5 million single-nucleotide polymorphisms (SNPs) using an additive model. We investigated, in mouse, the renal expression profile of the top candidate gene and its variation upon changes in dietary magnesium. The genome-wide analysis evidenced a top locus (rs172639, p~=~1.7~{\texttimes}~10), encompassing CLDN14, the gene coding for claudin-14, that was genome-wide significant when using urinary magnesium-to-calcium ratio, but not either one taken separately. In mouse, claudin-14 is expressed in the distal nephron segments specifically handling magnesium, and its expression is regulated by chronic changes in dietary magnesium content. A genome-wide approach identified common variants in the CLDN14 gene exerting a robust influence on the differential excretion of Mg over Ca in urine. These data highlight the power of urinary electrolyte ratios to unravel genetic determinants of renal tubular function. Coupled with mouse experiments, these results support a major role for claudin-14, a gene associated with kidney stones, in the differential paracellular handling of divalent cations by the renal tubule.

}, keywords = {Animals, Calcium, Claudins, Humans, Kidney Tubules, Magnesium, Polymorphism, Single Nucleotide, Urine}, issn = {1432-2013}, doi = {10.1007/s00424-016-1913-7}, author = {Corre, Tanguy and Olinger, Eric and Harris, Sarah E and Traglia, Michela and Ulivi, Sheila and Lenarduzzi, Stefania and Belge, Hendrica and Youhanna, Sonia and Tokonami, Natsuko and Bonny, Olivier and Houillier, Pascal and Polasek, Ozren and Deary, Ian J and Starr, John M and Toniolo, Daniela and Gasparini, Paolo and Vollenweider, Peter and Hayward, Caroline and Bochud, Murielle and Devuyst, Olivier} } @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 {10518, title = {Curcumin Anti-Apoptotic Action in a Model of Intestinal Epithelial Inflammatory Damage.}, journal = {Nutrients}, volume = {9}, year = {2017}, month = {2017 Jun 06}, abstract = {

The purpose of this study is to determine if a preventive treatment with curcumin can protect intestinal epithelial cells from inflammatory damage induced by IFNγ. To achieve this goal we have used a human intestinal epithelial cell line (HT29) treated with IFNγ to undergo apoptotic changes that can reproduce the damage of intestinal epithelia exposed to inflammatory cytokines. In this model, we measured the effect of curcumin (curcuminoid from ) added as a pre-treatment at different time intervals before stimulation with IFNγ. Curcumin administration to HT29 culture before the inflammatory stimulus IFNγ reduced the cell apoptosis rate. This effect gradually declined with the reduction of the curcumin pre-incubation time. This anti-apoptotic action by curcumin pre-treatment was paralleled by a reduction of secreted IL7 in the HT29 culture media, while there was no relevant change in the other cytokine levels. Even though curcumin pre-administration did not impact the activation of the NF-κB pathway, a slight effect on the phosphorylation of proteins in this inflammatory signaling pathway was observed. In conclusion, curcumin pre-treatment can protect intestinal cells from inflammatory damage. These results can be the basis for studying the preventive role of curcumin in inflammatory bowel diseases.

}, keywords = {Anti-Inflammatory Agents, Non-Steroidal, Apoptosis, Cell Survival, Curcuma, Curcumin, Cytokines, Epithelial Cells, HT29 Cells, Humans, Inflammation, Interferon-gamma, Interleukin-7, Intestinal Mucosa, NF-kappa B, Phosphorylation, Signal Transduction}, issn = {2072-6643}, doi = {10.3390/nu9060578}, author = {Loganes, Claudia and Lega, Sara and Bramuzzo, Matteo and Vecchi Brumatti, Liza and Piscianz, Elisa and Valencic, Erica and Tommasini, Alberto and Marcuzzi, Annalisa} } @article {10558, title = {CYP3A genes and the association between prenatal methylmercury exposure and neurodevelopment.}, journal = {Environ Int}, volume = {105}, year = {2017}, month = {2017 08}, pages = {34-42}, abstract = {

BACKGROUND: Results on the association between prenatal exposure to methylmercury (MeHg) and child neuropsychological development are heterogeneous. Underlying genetic differences across study populations could contribute to this varied response to MeHg. Studies in Drosophila have identified the cytochrome p450 3A (CYP3A) family as candidate MeHg susceptibility genes.

OBJECTIVES: We evaluated whether genetic variation in CYP3A genes influences the association between prenatal exposure to MeHg and child neuropsychological development.

METHODS: The study population included 2639 children from three birth cohort studies: two subcohorts in Seychelles (SCDS) (n=1160, 20 and 30months of age, studied during the years 2001-2012), two subcohorts from Spain (INMA) (n=625, 14months of age, 2003-2009), and two subcohorts from Italy and Greece (PHIME) (n=854, 18months of age, 2006-2011). Total mercury, as a surrogate of MeHg, was analyzed in maternal hair and/or cord blood samples. Neuropsychological development was evaluated using Bayley Scales of Infant Development (BSID). Three functional polymorphisms in the CYP3A family were analyzed: rs2257401 (CYP3A7), rs776746 (CYP3A5), and rs2740574 (CYP3A4).

RESULTS: There was no association between CYP3A polymorphisms and cord mercury concentrations. The scores for the BSID mental scale improved with increasing cord blood mercury concentrations for carriers of the most active alleles (β[95\% CI]:=2.9[1.53,4.27] for CYP3A7 rs2257401 GG+GC, 2.51[1.04,3.98] for CYP3A5 rs776746 AA+AG and 2.31[0.12,4.50] for CYP3A4 rs2740574 GG+AG). This association was near the null for CYP3A7 CC, CYP3A5 GG and CYP3A4 AA genotypes. The interaction between the CYP3A genes and total mercury was significant (p<0.05) in European cohorts only.

CONCLUSIONS: Our results suggest that the polymorphisms in CYP3A genes may modify the response to dietary MeHg exposure during early life development.

}, keywords = {Adult, Child Development, Child, Preschool, Cohort Studies, Cytochrome P-450 CYP3A, Female, Fetal Blood, Genotype, Greece, Humans, Infant, Italy, Male, Mercury, Methylmercury Compounds, Neurodevelopmental Disorders, Neuropsychological Tests, Polymorphism, Genetic, Pregnancy, Prenatal Exposure Delayed Effects, Seychelles, Spain}, issn = {1873-6750}, doi = {10.1016/j.envint.2017.04.013}, author = {Llop, Sabrina and Tran, Van and Ballester, Ferran and Barbone, Fabio and Sofianou-Katsoulis, Aikaterini and Sunyer, Jordi and Engstr{\"o}m, Karin and Alhamdow, Ayman and Love, Tanzy M and Watson, Gene E and Bustamante, Mariona and Murcia, Mario and I{\~n}iguez, Carmen and Shamlaye, Conrad F and Rosolen, Valentina and Mariuz, Marika and Horvat, Milena and Tratnik, Janja S and Mazej, Darja and van Wijngaarden, Edwin and Davidson, Philip W and Myers, Gary J and Rand, Matthew D and Broberg, Karin} } @article {8483, title = {Describing Kawasaki shock syndrome: results from a retrospective study and literature review.}, journal = {Clin Rheumatol}, volume = {36}, year = {2017}, month = {2017 Jan}, pages = {223-228}, abstract = {

Kawasaki shock syndrome (KSS) is a rare manifestation of Kawasaki disease (KD) characterized by systolic hypotension or clinical signs of poor perfusion. The objectives of the study are to describe the main clinical presentation, echocardiographic, and laboratory findings, as well as the treatment options and clinical outcomes of KSS patients when compared with KD patients. This is a retrospective study. All children referred to two pediatric rheumatology units from January 1, 2012, to December 31, 2014, were enrolled. Patients were divided into patients with or without KSS. We compared the two groups according to the following variables: sex, age, type of KD (classic, with less frequent manifestations, or incomplete), clinical manifestations, cardiac involvement, laboratory findings, therapy administered, response to treatment, and outcome. Eighty-four patients with KD were enrolled. Of these, five (6~\%) met the criteria for KSS. Patients with KSS had higher values of C-reactive protein (p = 0.005), lower hemoglobin levels (p = 0.003); more frequent hyponatremia (p = 0.004), hypoalbuminemia (p = 0.004), and coagulopathy (p = 0.003); and increase in cardiac troponins (p = 0.000). Among the KSS patients, three had a coronary artery involvement, but none developed a permanent aneurysm. Intravenous immunoglobulin resistance was more frequent in the KSS group, although not significantly so (3/5, 60~\% vs. 23/79, 30~\%, P = NS). None of the five cases was fatal, and all recovered without sequelae. KSS patients are more likely to have higher rates of cardiac involvement. However, most cardiovascular abnormalities resolved promptly with therapy.

}, keywords = {C-Reactive Protein, Child, Child, Preschool, Echocardiography, Female, Heart Failure, Hemoglobins, Humans, Immunoglobulins, Intravenous, Male, Mucocutaneous Lymph Node Syndrome, Retrospective Studies, Shock, Syndrome}, issn = {1434-9949}, doi = {10.1007/s10067-016-3316-8}, author = {Taddio, Andrea and Rossi, Eleonora Dei and Monasta, Lorenzo and Pastore, Serena and Tommasini, Alberto and Lepore, Loredana and Bronzetti, Gabriele and Marrani, Edoardo and Mottolese, Biancamaria D{\textquoteright}Agata and Simonini, Gabriele and Cimaz, Rolando and Ventura, Alessandro} } @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 {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 {10587, title = {Histoproteomic Characterization of Localized Cutaneous Amyloidosis in X-Linked Reticulate Pigmentary Disorder.}, journal = {Skin Pharmacol Physiol}, volume = {30}, year = {2017}, month = {2017}, pages = {90-93}, keywords = {Amyloidosis, Genetic Diseases, X-Linked, Humans, Pigmentation Disorders, Proteomics, Skin Diseases}, issn = {1660-5535}, doi = {10.1159/000464336}, author = {L{\textquoteright}Imperio, Vincenzo and Bruno, Irene and Rabach, Ingrid and Smith, Andrew and Chinello, Clizia and Stella, Martina and Magni, Fulvio and Pagni, Fabio} } @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 {10473, title = {Impact of the 13-Valent Pneumococcal Conjugate Vaccine on Clinical and Hypoxemic Childhood Pneumonia over Three Years in Central Malawi: An Observational Study.}, journal = {PLoS One}, volume = {12}, year = {2017}, month = {2017}, pages = {e0168209}, abstract = {

BACKGROUND: The pneumococcal conjugate vaccine{\textquoteright}s (PCV) impact on childhood pneumonia during programmatic conditions in Africa is poorly understood. Following PCV13 introduction in Malawi in November 2011, we evaluated the case burden and rates of childhood pneumonia.

METHODS AND FINDINGS: Between January 1, 2012-June 30, 2014 we conducted active pneumonia surveillance in children <5 years at seven hospitals, 18 health centres, and with 38 community health workers in two districts, central Malawi. Eligible children had clinical pneumonia per Malawi guidelines, defined as fast breathing only, chest indrawing +/- fast breathing, or, >=1 clinical danger sign. Since pulse oximetry was not in the Malawi guidelines, oxygenation <90\% defined hypoxemic pneumonia, a distinct category from clinical pneumonia. We quantified the pneumonia case burden and rates in two ways. We compared the period immediately following vaccine introduction (early) to the period with >75\% three-dose PCV13 coverage (post). We also used multivariable time-series regression, adjusting for autocorrelation and exploring seasonal variation and alternative model specifications in sensitivity analyses. The early versus post analysis showed an increase in cases and rates of total, fast breathing, and indrawing pneumonia and a decrease in danger sign and hypoxemic pneumonia, and pneumonia mortality. At 76\% three-dose PCV13 coverage, versus 0\%, the time-series model showed a non-significant increase in total cases (+47\%, 95\% CI: -13\%, +149\%, p = 0.154); fast breathing cases increased 135\% (+39\%, +297\%, p = 0.001), however, hypoxemia fell 47\% (-5\%, -70\%, p = 0.031) and hospital deaths decreased 36\% (-1\%, -58\%, p = 0.047) in children <5 years. We observed a shift towards disease without danger signs, as the proportion of cases with danger signs decreased by 65\% (-46\%, -77\%, p<0.0001). These results were generally robust to plausible alternative model specifications.

CONCLUSIONS: Thirty months after PCV13 introduction in Malawi, the health system burden and rates of the severest forms of childhood pneumonia, including hypoxemia and death, have markedly decreased.

}, keywords = {Child, Child Mortality, Cost of Illness, Dose-Response Relationship, Immunologic, Geography, Humans, Hypoxia, Malawi, Pneumococcal Vaccines, Pneumonia, Pneumococcal, Time Factors, Vaccines, Conjugate}, issn = {1932-6203}, doi = {10.1371/journal.pone.0168209}, author = {McCollum, Eric D and Nambiar, Bejoy and Deula, Rashid and Zadutsa, Beatiwel and Bondo, Austin and King, Carina and Beard, James and Liyaya, Harry and Mankhambo, Limangeni and Lazzerini, Marzia and Makwenda, Charles and Masache, Gibson and Bar-Zeev, Naor and Kazembe, Peter N and Mwansambo, Charles and Lufesi, Norman and Costello, Anthony and Armstrong, Ben and Colbourn, Tim} } @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 {10522, title = {Improving the quality of hospital care for children by supportive supervision: a cluster randomized trial, Kyrgyzstan.}, journal = {Bull World Health Organ}, volume = {95}, year = {2017}, month = {2017 Jun 01}, pages = {397-407}, abstract = {

OBJECTIVE: To determine whether periodic supportive supervision after a training course improved the quality of paediatric hospital care in Kyrgyzstan, where inappropriate care was common but in-hospital postnatal mortality was low.

METHODS: In a cluster, randomized, parallel-group trial, 10 public hospitals were allocated to a 4-day World Health Organization (WHO) course on hospital care for children followed by periodic supportive supervision by paediatricians for 1~year, while 10 hospitals had no intervention. We assessed prospectively 10 key indicators of inappropriate paediatric case management, as indicated by WHO guidelines. The primary indicator was the combination of the three indicators: unnecessary hospitalization, increased iatrogenic risk and unnecessary painful procedures. An independent team evaluated the overall quality of care.

FINDINGS: We prospectively reviewed the medical records of 4626 hospitalized children aged 2 to 60~months. In the intervention hospitals, the mean proportion of the primary indicator decreased from 46.9\% (95\% confidence interval, CI: 24.2 to 68.9) at baseline to 6.8\% (95\% CI: 1.1 to 12.1) at 1~year, but was unchanged in the control group (45.5\%, 95\% CI: 25.2 to 67.9, to 64.7\%, 95\% CI: 43.3 to 86.1). At 1~year, the risk ratio for the primary indicator in the intervention versus the control group was 0.09 (95\% CI: 0.06 to 0.13). The proportions of the other nine indicators also decreased in the intervention group ( < 0.0001 for all). Overall quality of care improved significantly in intervention hospitals.

CONCLUSION: Periodic supportive supervision for 1~year after a training course improved both adherence to WHO guidelines on hospital care for children and the overall quality of paediatric care.

}, keywords = {Child, Child Care, Cluster Analysis, Hospitalization, Hospitals, Public, Humans, Kyrgyzstan, Medical Audit, Pediatricians, Professional Role, Prospective Studies, Quality Improvement}, issn = {1564-0604}, doi = {10.2471/BLT.16.176982}, author = {Lazzerini, Marzia and Shukurova, Venera and Davletbaeva, Marina and Monolbaev, Kubanychbek and Kulichenko, Tatiana and Akoev, Yuri and Bakradze, Maya and Margieva, Tea and Mityushino, Ilya and Namazova-Baranova, Leyla and Boronbayeva, Elnura and Kuttumuratova, Aigul and Weber, Martin Willy and Tamburlini, Giorgio} } @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 {10567, title = {Intranasal Dexmedetomidine Sedation as Adjuvant Therapy in Acute Asthma Exacerbation With Marked Anxiety and Agitation.}, journal = {Ann Emerg Med}, volume = {69}, year = {2017}, month = {2017 01}, pages = {125-127}, abstract = {

We describe 2 patients with acute asthma exacerbation who were admitted to the emergency department (ED) with severe~agitation and restlessness as a prominent finding, for which bedside asthma treatment sedation with intranasal dexmedetomidine was performed. In both cases, dexmedetomidine allowed the patients to rest and improved tolerance to treatment. Dexmedetomidine is a unique sedative with an excellent safety profile and minimal effect on respiratory function. These properties render it particularly promising for the management of severe agitation in children admitted to the ED with acute asthma exacerbation.

}, keywords = {Acute Disease, Administration, Intranasal, Anxiety, Asthma, Child, Preschool, Dexmedetomidine, Emergency Service, Hospital, Female, Humans, Hypnotics and Sedatives, Infant, Psychomotor Agitation}, issn = {1097-6760}, doi = {10.1016/j.annemergmed.2016.08.005}, author = {Cozzi, Giorgio and Lega, Sara and Giorgi, Rita and Barbi, Egidio} } @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 {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 {10809, title = {Long-Term Survival After Hematopoietic Stem Cell Transplantation for Complete STAT1 Deficiency.}, journal = {J Clin Immunol}, volume = {37}, year = {2017}, month = {2017 Oct}, pages = {701-706}, abstract = {

PURPOSE: Complete signal transducer and activator of transcription 1 (STAT1) deficiency is a rare autosomal recessive condition characterized by impairment of intracellular signaling from both type I and type II interferons (IFN). Affected patients are prone to early severe mycobacterial and viral infections, which usually result in death before 18~months of age. We previously reported a patient affected by complete STAT1 deficiency who underwent hematopoietic stem cell transplantation (HSCT). Here, we describe the transplantation procedures and long-term outcomes.

METHODS: The patient, who had suffered multiple life-threatening mycobacterial and viral infections in the first years of life, underwent HSCT at 4~years of age from a partially matched (HLA compatibility 8/10) unrelated donor after a myeloablative conditioning regimen consisting of busulfan, cyclophosphamide, and anti-thymocyte globulin.

RESULTS: Hematological reconstitution was detected at d+15, with full donor engraftment demonstrated by molecular analysis of leukocytes. Several complications occurred in the post-transplantation phase, including acute graft versus host disease, posterior reversible encephalopathy, thrombotic thrombocytopenic purpura, bilateral keratoconjunctivitis with complete loss of vision, and chronic lower limb lymphedema. Analysis of STAT1 in CD3 cells at 90 and 120~days after HSCT by flow cytometry showed normal STAT1 phosphorylation levels in response to IFN-α.

CONCLUSIONS: Notably, no severe infections occurred after discharge (day + 90) during a 9-year follow-up, suggesting that normal response to IFNs in hematopoietic cells is sufficient to provide protection in humans.

}, keywords = {Child, Preschool, Hematopoietic Stem Cell Transplantation, Humans, Immunologic Deficiency Syndromes, Male, STAT1 Transcription Factor, Treatment Outcome}, issn = {1573-2592}, doi = {10.1007/s10875-017-0430-6}, author = {Naviglio, Samuele and Soncini, Elena and Vairo, Donatella and Lanfranchi, Arnalda and Badolato, Raffaele and Porta, Fulvio} } @article {8340, title = {Metastatic neuroblastoma in infants: are survival rates excellent only within the stringent framework of clinical trials?}, journal = {Clin Transl Oncol}, volume = {19}, year = {2017}, month = {2017 Jan}, pages = {76-83}, abstract = {

INTRODUCTION: SIOPEN INES protocol yielded excellent 5-year survival rates for MYCN-non-amplified metastatic~neuroblastoma. Patients deemed ineligible due to lack or delay of MYCN status or late registration were treated, but not included in the study. Our goal was to analyse survival at 10~years among the whole population.

MATERIALS AND METHODS: Italian and Spanish metastatic INES patients{\textquoteright} data are reported. SPSS 20.0 was used for statistical analysis.

RESULTS: Among 98 infants, 27 had events and 19 died, while 79 were disease free. Five- and 10-year event-free survival (EFS) were 73 and 70~\%, and overall survival (OS) was 81 and 74~\%, respectively. MYCN status was significant for EFS, but not for OS in multivariate analysis.

CONCLUSIONS: The survival rates of patients who complied with all the inclusion criteria for INES trials are higher compared to those that included also not registered patients. Five-year EFS and OS for INES 99.2 were 87.8 and 95.7~\%, while our stage 4s population obtained 78 and 87~\%. Concerning 99.3, 5-year EFS and OS were 86.7 and 95.6~\%, while for stage 4 we registered 61 and 68~\%. MYCN amplification had a strong impact on prognosis and therefore we consider it unacceptable that many patients were not studied for MYCN and probably inadequately treated. Ten-year survival rates were shown to decrease: EFS from 73 to 70~\% and OS from 81 to 74~\%, indicating a risk of late events, particularly in stage 4s. Population-based registries like European ENCCA WP 11-task 11 will possibly clarify these data.

}, keywords = {Biomarkers, Tumor, Child, Child, Preschool, Clinical Trials as Topic, Combined Modality Therapy, Female, Follow-Up Studies, Gene Amplification, Humans, Infant, Infant, Newborn, Male, N-Myc Proto-Oncogene Protein, Neoplasm Staging, Neuroblastoma, Prognosis, Survival Rate}, issn = {1699-3055}, doi = {10.1007/s12094-016-1505-1}, author = {Di Cataldo, A and Agodi, A and Balaguer, J and Garaventa, A and Barchitta, M and Segura, V and Bianchi, M and Castel, V and Castellano, A and Cesaro, S and Couselo, J M and Cruz, O and D{\textquoteright}Angelo, P and De Bernardi, B and Donat, J and de Andoin, N G and Hernandez, M I and La Spina, M and Lillo, M and Lopez-Almaraz, R and Luksch, R and Mastrangelo, S and Mateos, E and Molina, J and Moscheo, C and Mura, R and Porta, F and Russo, G and Tondo, A and Torrent, M and Vetrella, S and Villegas, J A and Viscardi, E and Zanazzo, G A and Ca{\~n}ete, A} } @article {10462, title = {Is middle cerebral artery Doppler related to neonatal and 2-year infant outcome in early fetal growth restriction?}, journal = {Am J Obstet Gynecol}, volume = {216}, year = {2017}, month = {2017 05}, pages = {521.e1-521.e13}, abstract = {

BACKGROUND: Reduced fetal middle cerebral artery Doppler impedance is associated with hypoxemia in fetal growth restriction. It remains unclear as to whether this finding could be useful in timing delivery, especially in the third trimester. In this regard there is a paucity of evidence from prospective studies.

OBJECTIVES: The aim of this study was to determine whether there is an association between middle cerebral artery Doppler impedance and its ratio with the umbilical artery in relation to neonatal and 2 year infant outcome in early fetal growth restriction (26-31 weeks of gestation). Additionally we sought to explore which ratio is more informative for clinical use.

STUDY DESIGN: This is a secondary analysis from the Trial of Randomized Umbilical and Fetal Flow in Europe, a prospective, multicenter, randomized management study on different antenatal monitoring strategies (ductus venosus Doppler changes and computerized cardiotocography short-term variation) in fetal growth restriction diagnosed between 26 and 31 weeks. We analyzed women with middle cerebral artery Doppler measurement at study entry and within 1 week before delivery and with complete postnatal follow-up (374 of 503). The primary outcome was survival without neurodevelopmental impairment at 2 years corrected for prematurity. Neonatal outcome was defined as survival until first discharge home without severe neonatal morbidity. Z-scores were calculated for~middle cerebral artery pulsatility index and both umbilicocerebral and cerebroplacental ratios. Odds ratios of Doppler parameter Z-scores for neonatal and 2 year infant outcome were calculated by multivariable logistic~regression analysis adjusted for gestational age and birthweight p50~ratio.

RESULTS: Higher middle cerebral artery pulsatility index at inclusion but not within 1 week before delivery was associated with neonatal survival without severe morbidity (odds ratio, 1.24; 95\% confidence interval, 1.02-1.52). Middle cerebral artery pulsatility index Z-score and umbilicocerebral ratio Z-score at inclusion were associated with~2~year survival with normal neurodevelopmental outcome (odds ratio, 1.33; 95\% confidence interval, 1.03-1.72, and odds ratio, 0.88; 95\% confidence interval, 0.78-0.99, respectively) as were gestation at delivery and birthweight p50 ratio (odds ratio, 1.41; 95\% confidence interval, 1.20-1.66, and odds ratio, 1.86; 95\% confidence interval, 1.33-2.60, respectively). When comparing cerebroplacental ratio against umbilicocerebral ratio, the incremental range of the cerebroplacental ratio tended toward zero, whereas the umbilicocerebral ratio tended toward infinity as the values became more abnormal.

CONCLUSION: In a monitoring protocol based on ductus venosus and cardiotocography in early fetal growth restriction (26-31 weeks of gestation), the impact of middle cerebral artery Doppler and its ratios on outcome is modest and less marked than birthweight and delivery gestation. It is unlikely that middle cerebral artery Doppler and its ratios are informative in optimizing the timing of delivery in fetal growth restriction before 32 weeks of gestation. The umbilicocerebral ratio allows for a better differentiation in the abnormal range than the cerebroplacental ratio.

}, keywords = {Birth Weight, Child Development, Child, Preschool, Delivery, Obstetric, Female, Fetal Growth Retardation, Gestational Age, Humans, Middle Cerebral Artery, Pregnancy, Prospective Studies, Pulsatile Flow, Ultrasonography, Doppler, Ultrasonography, Prenatal, Umbilical Arteries}, issn = {1097-6868}, doi = {10.1016/j.ajog.2017.01.001}, author = {Stampalija, Tamara and Arabin, Birgit and Wolf, Hans and Bilardo, Caterina M and Lees, Christoph} } @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 {10506, title = {Polymorphisms in key bone modulator cytokines genes influence bisphosphonates therapy in postmenopausal women.}, journal = {Inflammopharmacology}, volume = {25}, year = {2017}, month = {2017 Apr}, pages = {191-201}, abstract = {

Osteoporosis is a multifactorial and debilitating disease resulting from decreased bone mineral density (BMD) and loss of tissue microarchitecture. Ineffective therapies may lead to bone fractures and subsequent death. Single nucleotide polymorphisms (SNPs) in key immune regulator genes have been associated with therapeutic response to bisphosphonates, which are the first therapeutic line of choice for osteoporosis. However, cytokine pathways and their relation with therapeutic adhesion remain to be fully elucidated. Aimed at better understanding these processes, we investigated the response to bisphosphonate therapy in postmenopausal women and four SNPs in key proinflammatory cytokines genes: IL23R +2284 (C>A) (rs10889677), IL17A +672 (G>A) (rs7747909), IL12B +1188 (T>G) (rs3212227) and INF-γ -1616 (G>A) (rs2069705). A total of 69 patients treated with bisphosphonate were followed for a period of 1 up to 4~years, genotyped and compared according to their changes in bone mineral density (BMD) and level of biochemical markers during their treatment. The INF-γ -1616 G/G associated with increased BMD values in femoral neck (GG/AA, p~=~0.016) and decreased BMD values in total hip (GG/GA, p~=~0.019; GG/AA, p~=~0.011). In relation to biochemical markers, INF-γ -1616 SNP associated with increased alkaline phosphatase (GG/AA; p~<~0.0001) and parathyroid hormone levels (AA/GA; p~=~0.017). Vitamin D values changes were related to IL17A +672 (GG/GA, p~=~0.034) and to IL12B +1188 (TT/TG, p~=~0.046) SNPs. Besides, significant differences in changes of calcium levels correlated with IL23R +2284 (CC/CA, p~=~0.016) genotypes. Altogether, we suggest that these polymorphisms may play an important role for therapeutic decisions in osteoporosis treatment.

}, keywords = {Aged, Bone Density, Bone Remodeling, Cytokines, Diphosphonates, Female, Humans, Middle Aged, Osteoporosis, Postmenopausal, Polymorphism, Single Nucleotide, Postmenopause}, issn = {1568-5608}, doi = {10.1007/s10787-017-0322-7}, author = {Lima, C A D and Javorski, N R and Souza, A P O and Barbosa, A D and Valen{\c c}a, A P M C and Crovella, S and Souza, P R E and de Azev{\^e}do Silva, J and Sandrin-Garcia, P} } @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 {10573, title = {A premenarcheal girl with urogenital bleeding.}, journal = {Arch Dis Child}, volume = {102}, year = {2017}, month = {2017 May}, pages = {472}, issn = {1468-2044}, doi = {10.1136/archdischild-2016-311730}, author = {Lora, Angela and Scrimin, Federica and Taddio, Andrea and Ventura, Alessandro and Barbi, Egidio} } @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 {10580, title = {Surgery for distal hypospadias: what about the catheter?}, journal = {Pediatr Med Chir}, volume = {39}, year = {2017}, month = {2017 Sep 28}, pages = {145}, abstract = {

No agreed recommendations exist for timing of urethral stent removal, after distal hypospadias surgery. We compared our preliminary case series with outcomes from literature: 18/44 patients were treated with catheter and 26/44 without it. The surgical outcome was comparable in the two groups. After hypospadias surgery, the main advantage of the immediate postoperative catheter removal was the shorter hospital stay without negatively affecting the care and home management.

}, keywords = {Child, Child, Preschool, Device Removal, Humans, Hypospadias, Infant, Length of Stay, Male, Retrospective Studies, Stents, Treatment Outcome, Urinary Catheterization}, issn = {2420-7748}, doi = {10.4081/pmc.2017.145}, author = {Scarpa, Maria-Grazia and Perin, Giordano and Di Grazia, Massimo and Codrich, Daniela and Pederiva, Federica and Guida, Edoardo and Lembo, Maria Antonietta and Giannotta, Antonio and Schleef, Jurgen} } @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 {10534, title = {Targeted sequencing identifies novel variants involved in autosomal recessive hereditary hearing loss in Qatari families.}, journal = {Mutat Res}, volume = {800-802}, year = {2017}, month = {2017 08}, pages = {29-36}, abstract = {

Hereditary hearing loss is characterized by a very high genetic heterogeneity. In the Qatari population the role of GJB2, the worldwide HHL major player, seems to be quite limited compared to Caucasian populations. In this study we analysed 18 Qatari families affected by non-syndromic hearing loss using a targeted sequencing approach that allowed us to analyse 81 genes simultaneously. Thanks to this approach, 50\% of these families (9 out of 18) resulted positive for the presence of likely causative alleles in 6 different genes: CDH23, MYO6, GJB6, OTOF, TMC1 and OTOA. In particular, 4 novel alleles were detected while the remaining ones were already described to be associated to HHL in other ethnic groups. Molecular modelling has been used to further investigate the role of novel alleles identified in CDH23 and TMC1 genes demonstrating their crucial role in Ca2+ binding and therefore possible functional role in proteins. Present study showed that an accurate molecular diagnosis based on next generation sequencing technologies might largely improve molecular diagnostics outcome leading to benefits for both genetic counseling and definition of recurrence risk.

}, keywords = {Adolescent, Alleles, Cadherins, Child, Child, Preschool, Connexins, Female, GPI-Linked Proteins, Hearing Loss, Sensorineural, Humans, Infant, Male, Membrane Proteins, Models, Molecular, Mutation, Myosin Heavy Chains, Pedigree, Protein Conformation, Qatar, Sequence Analysis, DNA}, issn = {1873-135X}, doi = {10.1016/j.mrfmmm.2017.05.001}, author = {Alkowari, Moza K and Vozzi, Diego and Bhagat, Shruti and Krishnamoorthy, Navaneethakrishnan and Morgan, Anna and Hayder, Yousra and Logendra, Barathy and Najjar, Nehal and Gandin, Ilaria and Gasparini, Paolo and Badii, Ramin and Girotto, Giorgia and Abdulhadi, Khalid} } @article {10487, title = {Thrombogenesis in Thrombophilic Pregnancy: Evaluation of Low-Molecular-Weight Heparin Prophylaxis.}, journal = {Acta Haematol}, volume = {137}, year = {2017}, month = {2017}, pages = {201-206}, abstract = {

The aim of this study is to investigate thrombogenesis and the hypercoagulable changes in pregnant women affected by thrombophilia who received low-molecular-weight heparin (LWMH) prophylaxis. We included 21 pregnant women affected by thrombophilia treated with LWMH and 20 nontreated normal pregnant women as the control group. The sample group of thrombophilic pregnant women included different conditions (factor V Leiden mutation, protein C deficiency, protein S deficiency, antiphospholipid antibodies syndrome, and combined defects). Three blood samples were collected during pregnancy (i.e., at 16, 20, and 24 weeks) and tested for activated partial thromboplastin time and prothrombin fragment F1 + 2 (F1 + 2); anti-FXa activity was tested only in treated thrombophilic pregnant women. F1 + 2 levels progressively increased during pregnancy in both study groups. However, the F1 + 2 increase in women exposed to heparin prophylaxis was significantly lower than that in normal pregnant women in all 3 measurements carried out during gestation (p < 0.05); a statistically significant inverse correlation between F1 + 2 levels and anti-Xa activity (R = -0.8575, p < 0.05) was observed in treated women during pregnancy. Our findings suggest that F1 + 2 in addition to anti-Xa measurement could be used to adjust LWMH prophylaxis, at least in high-risk pregnant women.

}, keywords = {Adult, Anticoagulants, Case-Control Studies, Factor Xa Inhibitors, Female, Heparin, Low-Molecular-Weight, Humans, Nadroparin, Partial Thromboplastin Time, Peptide Fragments, Pilot Projects, Pregnancy, Pregnancy Complications, Hematologic, Prothrombin, Thrombophilia, Thrombosis}, issn = {1421-9662}, doi = {10.1159/000467385}, author = {Simeone, Roberto and Giacomello, Roberta and Bruno, Germano and Parco, Sergio and Maximova, Natalia and Martinelli, Monica and Zito, Gabriella and Luppi, Stefania and Cervi, Gina and Ricci, Giuseppe} } @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 {10538, title = {Training in Occupational Medicine: Jurisprudential Malfunctions in the Italian System and European Perspectives.}, journal = {Ann Ig}, volume = {29}, year = {2017}, month = {2017 May-Jun}, pages = {197-205}, abstract = {

BACKGROUND: To practice occupational health in Europe, a medical doctor must qualify in occupational medicine. This requires a period of postgraduate specialist medical training lasting a minimum of four years, in conformity with European regulations, to obtain a certificate of completion of training which is then mutually recognized within the entire European Union.

DISCUSSION: In 2002 an Italian law allowed doctors specialized in public health medicine and legal/forensic medicine to also practice as consultants in occupational medicine in the country. However a subsequent law in 2008 determined that only physicians specialized in occupational medicine could freely practice as consultants in this discipline. The other two categories (consultants in public health medicine and consultants in legal/forensic medicine) were required to undertake additional training (a Master course) to qualify as consultants in occupational medicine.

CONCLUSIONS: Doctors who entered postgraduate training in public health or legal/forensic medicine before 2008, with the option to practice also as consultants in occupational medicine upon completion of their training, suffered an unprecedented and legally questionable retroactive application of this new law which stripped them of previously acquired rights. Moreover, even after qualifying by undertaking this extra training in occupational medicine, the latter two categories of doctors do not have their training recognized in other member states of the European Union. To disallow the rights of doctors qualified in occupational medicine to work as consultants in the latter medical discipline elsewhere within the European Union seems a clear violation of professional rights and, as such, legal action could be taken to submit this issue to European attention.

}, keywords = {Certification, European Union, Italy, Occupational Medicine}, issn = {1120-9135}, doi = {10.7416/ai.2017.2147}, author = {Cegolon, L and Heymann, W C and Xodo, C and Lange, J H} } @article {10570, title = {Whole-body MRI reveals high incidence of osteonecrosis in children treated for Hodgkin lymphoma.}, journal = {Br J Haematol}, volume = {176}, year = {2017}, month = {2017 02}, pages = {637-642}, abstract = {

Osteonecrosis is a well-recognized complication in patients treated with corticosteroids. The incidence of osteonecrosis in children treated for Hodgkin lymphoma is unknown because prospective whole-body magnetic resonance imaging (MRI) studies are lacking in this patient population. Paediatric patients with newly diagnosed Hodgkin lymphoma who were treated according to a uniform paediatric Hodgkin protocol were eligible for inclusion in this prospective study. Whole-body MRI was performed in all 24 included patients (mean age 15{\textperiodcentered}1~years, 12 girls) both before treatment and after 2 cycles of chemotherapy, and in 16 patients after completion of chemotherapy. Osteonecrosis was identified in 10 patients (41{\textperiodcentered}7\%, 95\% confidence interval: 22{\textperiodcentered}0-61{\textperiodcentered}4\%), with a total of 56 osteonecrotic sites. Osteonecrosis was detected in 8 patients after 2 cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin), and in 2 additional patients after completion of chemotherapy. Epiphyseal involvement of long bones was seen in 4 of 10 children. None of the patients with osteonecrosis had any signs of bone collapse at the times of scanning. Whole-body MRI demonstrates osteonecrosis to be a common finding occurring during therapy response assessment of paediatric Hodgkin lymphoma. Detection of early epiphyseal osteonecrosis could allow for treatment before bone collapse and joint damage may occur.

}, keywords = {Adolescent, Antineoplastic Combined Chemotherapy Protocols, Child, Doxorubicin, Epiphyses, Etoposide, Female, Hodgkin Disease, Humans, Incidence, Magnetic Resonance Imaging, Male, Osteonecrosis, Prednisone, Prospective Studies, Vincristine}, issn = {1365-2141}, doi = {10.1111/bjh.14452}, author = {Littooij, Annemieke S and Kwee, Thomas C and Enr{\'\i}quez, Goya and Verbeke, Jonathan I M L and Granata, Claudio and Beishuizen, Auke and de Lange, Charlotte and Zennaro, Floriana and Bruin, Marrie C A and Nievelstein, Rutger A J} } @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 {8355, title = {Action of methotrexate and tofacitinib on directly stimulated and bystander-activated lymphocytes.}, journal = {Mol Med Rep}, volume = {14}, year = {2016}, month = {2016 Jul}, pages = {574-82}, abstract = {

Chronic inflammation associated with autoimmune activation is characteristic of rheumatic diseases from childhood to adulthood. In recent decades, significant improvements in the treatment of these types of disease have been achieved using disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) and, more recently, using biologic inhibitors. The recent introduction of kinase inhibitors (for example, tofacitinib; Tofa) further increases the available ARDs. However, there are patients that do not respond to any treatment strategies, for whom combination therapies are proposed. The data regarding the combined action of different drugs is lacking and the knowledge of the mechanisms of ARDs and their actions upon pathogenic lymphocytes, which are hypothesized to sustain disease, is poor. An in~vitro model of inflammation was developed in the current study, in which stimulated and unstimulated lymphocytes were cultured together, but tracked separately, to investigate the action of MTX and Tofa on the two populations. By analysing lymphocyte proliferation and activation, and cytokine secretion in the culture supernatants, it was established that, due to the presence of activated cells, unstimulated cells underwent a bystander activation that was modulated by the ARDs. Additionally, varying administration schedules were demonstrated to affect lymphocytes differently in~vitro, either directly or via bystander activation. Furthermore, MTX and Tofa exerted different effects; while MTX showed an antiproliferative effect, Tofa marginally effected activation, although only a slight antiproliferative action, which could be potentiated by sequential treatment with MTX. Thus, it was hypothesized that these differences may be exploited in sequential therapeutic strategies, to maximize the anti-rheumatic effect. These findings are notable and must be accounted for, as bystander-activated cells in~vivo could contribute to the spread of autoimmune activation and disease progression.

}, issn = {1791-3004}, doi = {10.3892/mmr.2016.5263}, author = {Piscianz, Elisa and Candilera, Vanessa and Valencic, Erica and Loganes, Claudia and Paron, Greta and De Iudicibus, Sara and Decorti, Giuliana and Tommasini, Alberto} } @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 {8310, title = {Association between p21 Ser31Arg polymorphism and the development of cervical lesion in women infected with high risk HPV.}, journal = {Tumour Biol}, volume = {37}, year = {2016}, month = {2016 Aug}, pages = {10935-41}, abstract = {

Infection by high-risk human papillomavirus (HR-HPV) and single nucleotide polymorphism (SNP) in genes involved in cell cycle control, as p21 and p27, are important factors in the development of different types of human cancers. This study aims at investigating whether both the p21 Ser31Arg and p27 V109G polymorphisms are associated with susceptibility to the development of cervical lesions in women HR-HPV positive. We analyzed 132 women HPV positive and with cervical lesions or CC and 154 healthy control (HPV negative and without cervical lesions). p21 Ser31Arg and p27 V109G polymorphisms were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and sequencing. The p21 31Arg allele was associated with susceptibility for the development of cervical lesions (P* = 0.0009), while p27 V109G polymorphism showed no significant differences for this association (P* = 0.89). However, the combined effect of the polymorphisms showed that the presence of the CC genotype (SNP p21 Ser31Arg) conferred protection for the development of cervical lesions (OR = 0.39). p21 Ser31Arg and p27 V109G polymorphisms were not associated with the grade of cervical lesions (CINI, CINII, and CINIII) or CC (P* > 0.05). The HR-HPV more frequent in this study were of 16 (57.6~\%) and 18 (37.1~\%) types; however, no association was observed when both polymorphisms and risk factors analyzed were compared (P* > 0.05). Our findings suggest a possible association between p21 Ser31tabArg polymorphism and susceptibility to the development of cervical lesions in women from Pernambuco. Brazil.

}, issn = {1423-0380}, doi = {10.1007/s13277-016-4979-0}, author = {Lima, G{\'e}ssica and Santos, Erinaldo and Angelo, Hildson and Oliveira, Micheline and Her{\'a}clio, Sandra and Leite, Fernanda and de Melo, Celso and Crovella, Sergio and Maia, Maria and Souza, Paulo} } @article {8291, title = {Association of the HLA-G 3{\textquoteright}UTR polymorphisms with colorectal cancer in Italy: a first insight.}, journal = {Int J Immunogenet}, volume = {43}, year = {2016}, month = {2016 Feb}, pages = {32-9}, abstract = {

This study aimed to explore functional and regulatory polymorphisms and haplotypes at the HLA-G 3{\textquoteright}UTR region in colorectal cancer development. The presence of nonpolymorphic variants was also evaluated. Three-hundred and eight patients with colorectal cancer and 294 healthy controls were analysed at the germinal level. We found an association with increased risk of colorectal cancer for +2960 14-bp INDEL, +3196 C>G SNPs and UTR-2 haplotype, and a {\textquoteright}protective{\textquoteright} role for +3003 T>C, +3010 C>G polymorphisms and UTR-4 haplotype. We detected in 3 distinct patients, a novel nucleotide change (+3037 C>A) and 2 already described rare variants, +3032 G/C (EUR MAF~=~0.1\%) and +3092~G/T (EUR MAF~=~0\%). This is the first study showing associations between different polymorphisms in the HLA-G 3{\textquoteright}UTR and colorectal cancer susceptibility.

}, issn = {1744-313X}, doi = {10.1111/iji.12243}, author = {Garziera, M and Catamo, E and Crovella, S and Montico, M and Cecchin, E and Lonardi, S and Mini, E and Nobili, S and Romanato, L and Toffoli, G} } @article {8302, title = {C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016}, pages = {10346}, abstract = {

Complement C1q is the activator of the classical pathway. However, it is now recognized that C1q can exert functions unrelated to complement activation. Here we show that C1q, but not C4, is expressed in the stroma and vascular endothelium of several human malignant tumours. Compared with wild-type (WT) or C3- or C5-deficient mice, C1q-deficient (C1qa(-/-)) mice bearing a syngeneic B16 melanoma exhibit a slower tumour growth and prolonged survival. This effect is not attributable to differences in the tumour-infiltrating immune cells. Tumours developing in WT mice display early deposition of C1q, higher vascular density and an increase in the number of lung metastases compared with C1qa(-/-) mice. Bone marrow (BM) chimeras between C1qa(-/-) and WT mice identify non-BM-derived cells as the main local source of C1q that can promote cancer cell adhesion, migration and proliferation. Together these findings support a role for locally synthesized C1q in promoting tumour growth.

}, keywords = {Animals, Apoptosis, Cell Line, Tumor, Cell Movement, Cell Proliferation, Complement Activation, Complement C1q, Complement C3, Complement C5, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasms}, issn = {2041-1723}, doi = {10.1038/ncomms10346}, author = {Bulla, Roberta and Tripodo, Claudio and Rami, Damiano and Ling, Guang Sheng and Agostinis, Chiara and Guarnotta, Carla and Zorzet, Sonia and Durigutto, Paolo and Botto, Marina and Tedesco, Francesco} } @article {8512, title = {Carbamazepine-induced thrombocytopenic purpura in a child: Insights from a genomic analysis.}, journal = {Blood Cells Mol Dis}, volume = {59}, year = {2016}, month = {2016 Jul}, pages = {97-9}, issn = {1096-0961}, doi = {10.1016/j.bcmd.2016.05.001}, author = {Abate, Maria Valentina and Stocco, Gabriele and Devescovi, Raffaella and Carrozzi, Marco and Pierobon, Chiara and Valencic, Erica and Lucaf{\`o}, Marianna and Di Silvestre, Alessia and d{\textquoteright}Adamo, Pio and Tommasini, Alberto and Decorti, Giuliana and Ventura, Alessandro} } @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 {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 {8331, title = {Clinical Characteristics of Patients Carrying the Q703K Variant of the NLRP3 Gene: A 10-year Multicentric National Study.}, journal = {J Rheumatol}, volume = {43}, year = {2016}, month = {2016 Jun}, pages = {1093-100}, abstract = {

OBJECTIVE: The aim of our study was to analyze the clinical and functional effect of the p.Q703K (p. Q705K, c. 2107C>A) variant of the NLRP3 gene in a population of patients screened for suspected cryopyrin-associated periodic syndrome (CAPS).

METHODS: Since 2002, 580 patients underwent molecular analysis for NLRP3. Data on clinical presentation, response to treatment, and longterm followup were collected using a uniform questionnaire. The pattern of cytokine secretion after lipopolysaccharide stimulation from isolated monocytes was analyzed in 3 patients carrying the p.Q703K variant and 1 patient with a chronic infantile neurologic, cutaneous, articular syndrome phenotype carrying both the p.M406I and p.Q703K, and compared with 7 patients with CAPS with sure pathogenic variants and 6 healthy controls.

RESULTS: The p.Q703K variant was found in 57 screened patients with an overall allelic frequency of 5\%. The frequency in normal controls was 5.5\%. Clinical data at the moment of molecular analysis and at followup were available in 36 patients. Two patients displayed additional mutations of NLRP3. The mean followup was 2.5 years. Thirteen patients (39\%) had a final diagnosis different from the original suspicion of CAPS. The remaining 21 patients displayed a mild phenotype mainly characterized by recurrent episodes of urticarial rash and arthralgia. Only 8 patients were treated with anti-interleukin (IL)-1 treatment, with a complete response in 5 patients. The pattern of secretion of IL-1β and other cytokines (IL-6 and IL-1 receptor antagonist) in patients did not display the aberrancies observed in patients with CAPS and was similar to that observed in healthy controls.

CONCLUSION: The present study confirms the weak clinical and functional effect of the p.Q703K variant.

}, issn = {0315-162X}, doi = {10.3899/jrheum.150962}, author = {Naselli, Aldo and Penco, Federica and Cantarini, Luca and Insalaco, Antonella and Alessio, Mariolina and Tommasini, Alberto and Maggio, Cristina and Obici, Laura and Gallizi, Romina and Cimmino, Marco and Signa, Sara and Lucherini, Orso Maria and Carta, Sonia and Caroli, Francesco and Martini, Alberto and Rubartelli, Anna and Ceccherini, Isabella and Gattorno, Marco} } @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 {8505, title = {Cross-sectional study of coeliac autoimmunity in a population of Vietnamese children.}, journal = {BMJ Open}, volume = {6}, year = {2016}, month = {2016}, pages = {e011173}, abstract = {

OBJECTIVE: The prevalence of coeliac disease (CD) in Vietnam is unknown. To fill this void, we assessed the prevalence of serological markers of CD autoimmunity in a population of children in Hanoi.

SETTING: The outpatient blood drawing laboratory of the largest paediatric hospital in North Vietnam was used for the study, which was part of an international project of collaboration between Italy and Vietnam.

PARTICIPANTS: Children having blood drawn for any reason were included. Exclusion criteria were age younger than 2 years, acquired or congenital immune deficiency and inadequate sample. A total of 1961 children (96\%) were enrolled (838 females, 1123 males, median age 5.3 years).

OUTCOMES: Primary outcome was the prevalence of positive autoimmunity to both IgA antitransglutaminase antibodies (anti-tTG) assessed with an ELISA test and antiendomysial antibodies (EMA). Secondary outcome was the prevalence of CD predisposing human leucocyte antigens (HLA) (HLA DQ2/8) in the positive children and in a random group of samples negative for IgA anti-tTG.

RESULTS: The IgA anti-tTG test was positive in 21/1961 (1\%; 95\% CI 0.61\% to 1.53\%); however, EMA antibodies were negative in all. HLA DQ2/8 was present in 7/21 (33\%; 95\% CI 14.5\% to 56.9\%) of the anti-tTG-positive children and in 72/275 (26\%; 95\% CI 21\% to 32\%) of those who were negative.

CONCLUSIONS: Coeliac autoimmunity is rare in Vietnam, although prevalence of HLA DQ2/8 is similar to that of other countries. We hypothesise that the scarce exposure to gluten could be responsible for these findings.

}, issn = {2044-6055}, doi = {10.1136/bmjopen-2016-011173}, author = {Zanella, Sara and De Leo, Luigina and Nguyen-Ngoc-Quynh, Le and Nguyen-Duy, Bo and Not, Tarcisio and Tran-Thi-Chi, Mai and Phung-Duc, Son and Le-Thanh, Hai and Malaventura, Cristina and Vatta, Serena and Ziberna, Fabiana and Mazzocco, Martina and Volpato, Stefano and Phung-Tuyet, Lan and Le-Thi-Minh, Huong and Borgna-Pignatti, Caterina} } @article {8523, title = {Decline in Lung Function in Childhood Asthma.}, journal = {N Engl J Med}, volume = {375}, year = {2016}, month = {2016 Aug 18}, pages = {e13}, keywords = {Anti-Inflammatory Agents, Asthma, Female, Humans, Lung, Male}, issn = {1533-4406}, doi = {10.1056/NEJMc1608228$\#$SA2}, author = {Bibalo, Cristina and Longo, Giorgio and Ventura, Alessandro} } @article {8329, title = {Differential expression of GAS5 in rapamycin-induced reversion of glucocorticoid resistance.}, journal = {Clin Exp Pharmacol Physiol}, volume = {43}, year = {2016}, month = {2016 Jun}, pages = {602-5}, abstract = {

This study evaluates the association between the long noncoding RNA GAS5 levels and the anti-proliferative effect of the glucocorticoid (GC) methylprednisolone (MP) alone and in combination with rapamycin in peripheral blood mononuclear cells (PBMCs) obtained from healthy donors. The effect of MP, rapamycin, and MP plus rapamycin was determined in 17 healthy donors by labelling metabolically active cells with [methyl-3H] thymidine and the expression levels of GAS5 gene were evaluated by real-time RT-PCR TaqMan analysis. We confirmed a role for GAS5 in modulating GC response: poor responders presented higher levels of GAS5 in comparison with good responders. Interestingly, when PBMCs were treated with the combination of rapamycin plus MP, the high levels of GAS5 observed for each drug in the MP poor responders group decreased in comparison with rapamycin (P value~=~0.0134) or MP alone (P value~=~0.0193). GAS5 is involved in GC resistance and co-treatment of rapamycin with GCs restores GC effectiveness in poor responders through the downregulation of the long noncoding RNA. GAS5 could be considered a biomarker to personalize therapy and a novel therapeutic target useful for the development of new pharmacological approaches to restore GC sensitivity.

}, issn = {1440-1681}, doi = {10.1111/1440-1681.12572}, author = {Lucaf{\`o}, Marianna and Bravin, Vanessa and Tommasini, Alberto and Martelossi, Stefano and Rabach, Ingrid and Ventura, Alessandro and Decorti, Giuliana and De Iudicibus, Sara} } @article {8491, title = {Dyslipidemia, Diet, and Physical Exercise in Children on Treatment with Anti-Retroviral Medication in El Salvador: A Cross-Sectional Study.}, journal = {Pediatr Infect Dis J}, year = {2016}, month = {2016 May 31}, abstract = {

BACKGROUND: Dyslipidemias are common in HIV-infected children, especially if treated with protease-inhibitors, but there are few data on how to treat dyslipidemias in this population. We estimated the dislypidemia prevalence and its association with treatment, diet, and physical exercise in children on anti-retroviral treatment at the El Salvador reference center for pediatric HIV care (CENID).

METHODS: Information was gathered regarding socio-demographic characteristics, treatment, diet, and physical activity of 173 children aged 5-18 years and receiving anti-retroviral therapy.Triglycerides, total cholesterol, low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), viral load, and CD4 T-lymphocytes were measured. Abnormal concentrations were defined as triglycerides >=130 mg/dl in 10- to 18-year-olds and >=100 mg/dl in <10 year-olds; total cholesterol >=200 mg/dl; LDL-C >=130 mg/dl; and HDL-C <=35 mg/dl.We adjusted four different multivariate models to assess the independent association of each type of dyslipidemia with protease-inhibitors, diet, and physical exercise.

RESULTS: Of the 173 children, 83 (48\%) had hypertriglyceridemia and 25 (14.5\%) hypercholesterolemia. High LDL-C concentrations were observed in 17 children (9.8\%) and low HDL-C in 38 (22\%). Treatment with protease-inhibitors was significantly associated with hypertriglyceridemia (Prevalence Ratio (PR) 2.8; 95\%CI 2.0-3.8) and hypercholesterolemia (PR 9.0; 95\%CI 3.6-22.2).Higher adherence to a "high fat/sugar diet" was associated with hypercholesterolemia (PR 1.6; 95\%CI 1.1-2.3) and high LDL-C (PR 1.7; 95\%CI 1.0-2.9).Compared with those exercising <3 times/week, children exercising >=7 times were less likely to have low HDL-C (PR=0.4; 95\%CI 0.2-0.7).

CONCLUSIONS: These results suggest that a healthy diet and exercise habits can contribute to controlling some aspects of the lipid profile in this population.

}, issn = {1532-0987}, doi = {10.1097/INF.0000000000001244}, author = {Sonego, Michela and Sagrado, Maria Jos{\'e} and Escobar, Gustavo and Lazzerini, Marzia and Rivas, Estefanie and Mart{\'\i}n-Ca{\~n}avate, Rocio and de L{\'o}pez, Elsy P{\'e}rez and Ayala, Sandra and Castaneda, Luis and Aparicio, Pilar and Custodio, Estefan{\'\i}a} } @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 {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 {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 {8323, title = {Geranylgeraniol and Neurological Impairment: Involvement of Apoptosis and Mitochondrial Morphology.}, journal = {Int J Mol Sci}, volume = {17}, year = {2016}, month = {2016}, pages = {365}, abstract = {

Deregulation of the cholesterol pathway is an anomaly observed in human diseases, many of which have in common neurological involvement and unknown pathogenesis. In this study we have used Mevalonate Kinase Deficiency (MKD) as a disease-model in order to investigate the link between the deregulation of the mevalonate pathway and the consequent neurodegeneration. The blocking of the mevalonate pathway in a neuronal cell line (Daoy), using statins or mevalonate, induced an increase in the expression of the inflammasome gene (NLRP3) and programmed cell death related to mitochondrial dysfunction. The morphology of the mitochondria changed, clearly showing the damage induced by oxidative stress and the decreased membrane potential associated with the alterations of the mitochondrial function. The co-administration of geranylgeraniol (GGOH) reduced the inflammatory marker and the damage of the mitochondria, maintaining its shape and components. Our data allow us to speculate about the mechanism by which isoprenoids are able to rescue the inflammatory marker in neuronal cells, independently from the block of the mevalonate pathway, and about the fact that cell death is mitochondria-related.

}, issn = {1422-0067}, doi = {10.3390/ijms17030365}, author = {Marcuzzi, Annalisa and Piscianz, Elisa and Zweyer, Marina and Bortul, Roberta and Loganes, Claudia and Girardelli, Martina and Baj, Gabriele and Monasta, Lorenzo and Celeghini, Claudio} } @article {8351, title = {Global diversity in the TAS2R38 bitter taste receptor: revisiting a classic evolutionary PROPosal.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016}, pages = {25506}, abstract = {

The ability to taste phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) is a polymorphic trait mediated by the TAS2R38 bitter taste receptor gene. It has long been hypothesized that global genetic diversity at this locus evolved under pervasive pressures from balancing natural selection. However, recent high-resolution population genetic studies of TAS2Rs suggest that demographic events have played a critical role in the evolution of these genes. We here utilized the largest TAS2R38 database yet analyzed, consisting of 5,589 individuals from 105 populations, to examine natural selection, haplotype frequencies and linkage disequilibrium to estimate the effects of both selection and demography on contemporary patterns of variation at this locus. We found signs of an ancient balancing selection acting on this gene but no post Out-Of-Africa departures from neutrality, implying that the current observed patterns of variation can be predominantly explained by demographic, rather than selective events. In addition, we found signatures of ancient selective forces acting on different African TAS2R38 haplotypes. Collectively our results provide evidence for a relaxation of recent selective forces acting on this gene and a revised hypothesis for the origins of the present-day worldwide distribution of TAS2R38 haplotypes.

}, issn = {2045-2322}, doi = {10.1038/srep25506}, author = {Risso, Davide S and Mezzavilla, Massimo and Pagani, Luca and Robino, Antonietta and Morini, Gabriella and Tofanelli, Sergio and Carrai, Maura and Campa, Daniele and Barale, Roberto and Caradonna, Fabio and Gasparini, Paolo and Luiselli, Donata and Wooding, Stephen and Drayna, Dennis} } @article {8347, title = {Hand-held computers can help to distract children undergoing painful venipuncture procedures.}, journal = {Acta Paediatr}, volume = {105}, year = {2016}, month = {2016 Aug}, pages = {930-4}, abstract = {

AIM: Needle-related procedures can be painful for children, and distraction provides ideal pain relief in blood-drawing centres. This study assessed the effectiveness of playing a computer game during venipuncture, compared with low-tech distraction by a nurse.

METHODS: We conducted this prospective, randomised controlled trial at the blood-drawing centre of a tertiary-level children{\textquoteright}s hospital in Italy. Half of the 200 children played Angry Birds on a hand-held computer while the other half were distracted by a second, specifically trained nurse who sang to them, read a book, blew bubbles or played with puppets. Pain was measured using a faces pain scale for children aged 4-7 years and a numeric scale for children aged 8-13 years.

RESULTS: The 200 children had a median age of eight years. Children reported significant pain in 16 cases (16\%) in the hand-held computer distraction group and in 15 cases (15\%) in the nurse-led low-tech distraction group (p = 0.85). The procedural success rate at the first attempt was not different in the two groups.

CONCLUSION: Playing a game on a hand-held computer meant that only one in six children reported pain during venipuncture, but it was not superior to being distracted by nurses.

}, issn = {1651-2227}, doi = {10.1111/apa.13454}, author = {Crevatin, Franca and Cozzi, Giorgio and Braido, Elena and Bertossa, Gabriella and Rizzitelli, Patrizia and Lionetti, Daniela and Matassi, Daniela and Calusa, Dorotea and Ronfani, Luca and Barbi, Egidio} } @article {8312, title = {Histopathological data of iron and calcium in the mouse lung after asbestos exposure.}, journal = {Data Brief}, volume = {6}, year = {2016}, month = {2016 Mar}, pages = {769-75}, abstract = {

This data article contains data related to the research article entitled, "Synchrotron X-ray microscopy reveals early calcium and iron interaction with crocidolite fibers in the lung of exposed mice" [1]. Asbestos fibers disrupt iron homeostasis in the human and mouse lung, leading to the deposition of iron (Fe) onto longer asbestos fibers which forms asbestos bodies (AB) [2]. Similar to Fe, calcium (Ca) is also deposited in the coats of the AB. This article presents data on iron and calcium in the mouse lung after asbestos exposure detected by histochemical evaluation.

}, issn = {2352-3409}, doi = {10.1016/j.dib.2016.01.026}, author = {Trevisan, Elisa and Zabucchi, Giuliano and Pascolo, Lorella and Pascotto, Ernesto and Casarsa, Claudia and Lucattelli, Monica and Lungarella, Giuseppe and Cavarra, Eleonora and Bartalesi, Barbara and Zweyer, Marina and Borelli, Violetta} } @article {8335, title = {Improving regional universal newborn hearing screening programmes in Italy.}, journal = {Acta Otorhinolaryngol Ital}, volume = {36}, year = {2016}, month = {2016 Feb}, pages = {10-4}, abstract = {

The Universal Newborn Hearing Screening (UNHS) programme aims at achieving early detection of hearing impairment. Subsequent diagnosis and intervention should follow promptly. 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", the limitations and strengths of current UNHS programs in Italy have been analysed by a group of professionals working in tertiary centres involved in regional UNHS programmes, using SWOT analysis and a subsequent TOWS matrix. Coverage and lost-to-follow up rates are issues related to UNHS programmes. Recommendations to improve the effectiveness of the UNHS programme have been identified. The need for homogeneous policies, high-quality information and dissemination of knowledge for operators and families of hearing-impaired children emerged from the discussion.

}, issn = {1827-675X}, doi = {10.14639/0392-100X-1072}, author = {Molini, E and Cristi, M C and Lapenna, R and Calzolaro, L and Muzzi, E and Ciciriello, E and Della Volpe, A and Orzan, E and Ricci, G} } @article {8285, title = {Mortality and its risk factors in Malawian children admitted to hospital with clinical pneumonia, 2001-12: a retrospective observational study.}, journal = {Lancet Glob Health}, volume = {4}, year = {2016}, month = {2016 Jan}, pages = {e57-68}, abstract = {

BACKGROUND: Few studies have reported long-term data on mortality rates for children admitted to hospital with pneumonia in Africa. We examined trends in case fatality rates for all-cause clinical pneumonia and its risk factors in Malawian children between 2001 and 2012.

METHODS: Individual patient data for children (<5 years) with clinical pneumonia who were admitted to hospitals participating in Malawi{\textquoteright}s Child Lung Health Programme between 2001 and 2012 were recorded prospectively on a standardised medical form. We analysed trends in pneumonia mortality and children{\textquoteright}s clinical characteristics, and we estimated the association of risk factors with case fatality for children younger than 2 months, 2-11 months of age, and 12-59 months of age using separate multivariable mixed effects logistic regression models.

FINDINGS: Between November, 2012, and May, 2013, we retrospectively collected all available hard copies of yellow forms from 40 of 41 participating hospitals. We examined 113 154 pneumonia cases, 104 932 (92{\textperiodcentered}7\%) of whom had mortality data and 6903 of whom died, and calculated an overall case fatality rate of 6{\textperiodcentered}6\% (95\% CI 6{\textperiodcentered}4-6{\textperiodcentered}7). The case fatality rate significantly decreased between 2001 (15{\textperiodcentered}2\% [13{\textperiodcentered}4-17{\textperiodcentered}1]) and 2012 (4{\textperiodcentered}5\% [4{\textperiodcentered}1-4{\textperiodcentered}9]; ptrend<0{\textperiodcentered}0001). Univariable analyses indicated that the decrease in case fatality rate was consistent across most subgroups. In multivariable analyses, the risk factors significantly associated with increased odds of mortality were female sex, young age, very severe pneumonia, clinically suspected Pneumocystis jirovecii infection, moderate or severe underweight, severe acute malnutrition, disease duration of more than 21 days, and referral from a health centre. Increasing year between 2001 and 2012 and increasing age (in months) were associated with reduced odds of mortality. Fast breathing was associated with reduced odds of mortality in children 2-11 months of age. However, case fatality rate in 2012 remained high for children with very severe pneumonia (11{\textperiodcentered}8\%), severe undernutrition (15{\textperiodcentered}4\%), severe acute malnutrition (34{\textperiodcentered}8\%), and symptom duration of more than 21 days (9{\textperiodcentered}0\%).

INTERPRETATION: Pneumonia mortality and its risk factors have steadily improved in the past decade in Malawi; however, mortality remains high in specific subgroups. Improvements in hospital care may have reduced case fatality rates though a lack of sufficient data on quality of care indicators and the potential of socioeconomic and other improvements outside the hospital precludes adequate assessment of why case-fatality rates fell. Results from this study emphasise the importance of effective national systems for data collection. Further work combining this with data on trends in the incidence of pneumonia in the community are needed to estimate trends in the overall risk of mortality from pneumonia in children in Malawi.

FUNDING: Bill \& Melinda Gates Foundation.

}, issn = {2214-109X}, doi = {10.1016/S2214-109X(15)00215-6}, author = {Lazzerini, Marzia and Seward, Nadine and Lufesi, Norman and Banda, Rosina and Sinyeka, Sophie and Masache, Gibson and Nambiar, Bejoy and Makwenda, Charles and Costello, Anthony and McCollum, Eric D and Colbourn, Tim} } @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 {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 {8485, title = {Oral zinc provision in acute diarrhea.}, journal = {Curr Opin Clin Nutr Metab Care}, volume = {19}, year = {2016}, month = {2016 May}, pages = {239-43}, abstract = {

PURPOSE OF REVIEW: The clinical management of acute diarrhea is based on the use of oral rehydration salts and appropriate nutrition. In addition, the WHO and The United Nations Children{\textquoteright}s Fund recommend zinc supplementation for diarrhea in children below 5 years. This article aims at reviewing recent literature on the effects of oral zinc for treating acute diarrhea in children.

RECENT FINDINGS: Recent studies confirm that zinc supplementation has a benefit in children below 5 years with acute diarrhea in countries at medium or high risk of zinc deficiency. A few small trials have reported a benefit of zinc in children at low risk of zinc deficiency, with heterogeneity in results. No recent study has explored the effects of zinc in children younger than 6 months, and in this age group previous research refuted any benefit from zinc.

SUMMARY: Current literature supports the use of oral zinc in treating diarrhea in children older than 6 months, especially if at risk of zinc deficiency, such as children with poor diets exposed to recurrent gastrointestinal infections. More research is needed to confirm findings in children at low risk of zinc deficiency. Currently there is no evidence that zinc benefits children younger than 6 months.

}, issn = {1473-6519}, doi = {10.1097/MCO.0000000000000276}, author = {Lazzerini, Marzia} } @article {8295, title = {Pharmacogenetics driving personalized medicine: analysis of genetic polymorphisms related to breast cancer medications in Italian isolated populations.}, journal = {J Transl Med}, volume = {14}, year = {2016}, month = {2016}, pages = {22}, abstract = {

BACKGROUND: Breast cancer is the most common cancer in women characterized by a high variable clinical outcome among individuals treated with equivalent regimens and novel targeted therapies. In this study, we performed a population based approach intersecting high-throughput genotype data from Friuli Venezia Giulia (FVG) isolated populations with publically available pharmacogenomics information to estimate the frequency of genotypes correlated with responsiveness to breast cancer treatment thus improving the clinical management of this disease in an efficient and cost effective way.

METHODS: A list of 80 variants reported to be related to the efficacy or toxicity of breast cancer drugs was obtained from PharmGKB database. Fourty-one were present in FVG, 1000G European (EUR) and ExAC (Non Finnish European) databases. Their frequency was extracted using PLINK software and the differences tested by Fisher{\textquoteright}s exact test.

RESULTS: Statistical analyses revealed that 13 out of the 41 (32 \%) variants were significantly different in frequency in our sample as compared to the EUR/ExAC cohorts. For nine variants the available level of evidence (LOE) included polymorphisms related to cyclophosphamide, tamoxifen, doxorubicin, fluorpyrimidine and paclitaxel. In particular, for trastuzumab two variants were detected: (1) rs1801274-G within FCGR2A and associated with decreased efficacy (LOE 2B); (2) rs1136201-G located within ERBB2 and associated with increased toxicity (LOE 3). Both these two variants were underrepresented in the FVG population compared to EUR/ExAC population thus suggesting a high therapeutic index of this drug in our population. Moreover, as regards fluoropyrimidines, the frequency of two polymorphisms within the DPYD gene associated with drug toxicity (e.g., rs2297595-C allele and rs3918290-T allele, LOE 2A and 1, respectively) was extremely low in FVG population thus suggesting that a larger number of FVG patients could benefit from full dosage of fluoropyrimidine therapy.

CONCLUSIONS: All these findings increase the overall knowledge on the prevalence of specific variants related with breast cancer treatment responsiveness in FVG population and highlight the importance of assessing gene polymorphisms related with cancer medications in isolated communities.

}, issn = {1479-5876}, doi = {10.1186/s12967-016-0778-z}, author = {Cocca, Massimiliano and Bedognetti, Davide and La Bianca, Martina and Gasparini, Paolo and Girotto, Giorgia} } @article {8317, title = {Pitfalls and promises in FTIR spectromicroscopy analyses to monitor iron-mediated DNA damage in sperm.}, journal = {Reprod Toxicol}, volume = {61}, year = {2016}, month = {2016 Jun}, pages = {39-46}, abstract = {

Many drugs, chemicals, and environmental factors can impair sperm functionality by inducing DNA damage, one of the important causes of reduced fertility potential. The use of vibrational spectromicroscopy represents a promising approach for monitoring DNA integrity in sperm, although some limitations exist, depending from the experimental conditions. Here, we report that when using FTIR spectromicroscopy to reveal oxidative stress mediated by Fenton{\textquoteright}s reaction on hydrated sperm samples, DNA damage interpretation is partially compromised by unexpected cell surface precipitates. The precipitates give a broad band in the 1150-1000cm(-1) infrared region, which partially covers one of the signatures of DNA (phosphate stretching bands), and are detected as iron and oxygen containing material when using XRF spectroscopy. On the other hand, the analyses further support the potential of FTIR spectromicroscopy to reveal cellular oxidative damage events such as lipid peroxidation, protein misfolding and aggregations, as well as DNA strain breaks.

}, issn = {1873-1708}, doi = {10.1016/j.reprotox.2016.02.011}, author = {Pascolo, Lorella and Bedolla, Diana E and Vaccari, Lisa and Venturin, Irene and Cammisuli, Francesca and Gianoncelli, Alessandra and Mitri, Elisa and Giolo, Elena and Luppi, Stefania and Martinelli, Monica and Zweyer, Marina and Ricci, Giuseppe} } @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 {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 {8487, title = {Role of inflammasome genetics in susceptibility to HPV infection and cervical cancer development.}, journal = {J Med Virol}, volume = {88}, year = {2016}, month = {2016 Sep}, pages = {1646-51}, abstract = {

PROBLEM: Only a small proportion of HPV+ women develop virus-associated lesions and cervical cancer, suggesting that other factors are involved in HPV+ keratinocyte transformation. Immune response plays an important role in clearing HPV infection, and host genetic variants resulting in defective immune response have been associated with virus persistence and/or cervical cancer. Considering that genetic variations in inflammasome genes were previously associated with viral infection and cancer development, the present study investigates selected single nucleotide polymorphisms (SNPs) in inflammasome genes as a possible risk factor for HPV infection susceptibility and/or for progression to cervical cancer.

PATIENTS AND METHODS: 12 SNPs in seven inflammasome-related genes (NLRP1, NLRP3, NLRP6, CARD8, IL1B, IL18, TNFAIP3) were genotyped in a Brazilian HPV+ case/control cohort (n = 246/310). Multivariate analysis was performed in case/control as well as in HPV+ women stratified by the presence or severity of histologic lesion, HPV persistence, and type of virus.

RESULTS: IL1B rs1143643 was associated with protection against HPV infection in case/control analysis. NLRP1 rs11651270 plays a protection role against HPV persistence and/or oncogenesis. NLRP3 rs10754558 and IL18 rs1834481 exert a beneficial role against HPV persistence. NLRP3 rs10754558 variant resulted significantly associated with a lower risk to be infected with a high-risk HPV.

CONCLUSION: Our findings for the first time demonstrated that inflammasome genetics could affect HPV/host interaction in terms of virus susceptibility as well as of virus/persistence and cervical cancer progression. J. Med. Virol. 88:1646-1651, 2016. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, issn = {1096-9071}, doi = {10.1002/jmv.24514}, author = {Pontillo, A and Bricher, P and Leal, V N C and Lima, S and Souza, P R E and Crovella, S} } @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 {8085, title = {Synchrotron X-ray microscopy reveals early calcium and iron interaction with crocidolite fibers in the lung of exposed mice.}, journal = {Toxicol Lett}, volume = {241}, year = {2016}, month = {2016 Jan 22}, pages = {111-20}, abstract = {

Human exposure to asbestos can cause a wide variety of lung diseases that are still a current major health concern, even if asbestos has been banned in many countries. It has been shown in many studies that asbestos fibers, ingested by alveolar macrophages, disrupt lung iron homeostasis by sequestering iron. Calcium can also be deposited on the fibers. The pathways along which iron and above all calcium interact with fibers are still unknown. Our aim was that of investigating if the iron accumulation induced by the inhaled asbestos fibers also involves calcium ions accumulation. Lung sections of asbestos-exposed mice were analyzed using an extremely sensitive procedure available at the synchrotron facilities, that provides morphological and chemical information based on X-ray fluorescence microspectroscopy (μ-XRF). In this study we show that (1) where conventional histochemical procedures revealed only weak deposits of iron and calcium, μ-XRF analysis is able to detect significant deposits of both iron and calcium on the inhaled asbestos fibers; (2) the extent of the deposition of these ions is proportionally directly related and (3) iron and calcium deposition on inhaled asbestos fibers is concomitant with the appearance of inflammatory and hyperplastic reactions.

}, issn = {1879-3169}, doi = {10.1016/j.toxlet.2015.11.016}, author = {Pascolo, Lorella and Zabucchi, Giuliano and Gianoncelli, Alessandra and Kourousias, George and Trevisan, Elisa and Pascotto, Ernesto and Casarsa, Claudia and Ryan, Chris and Lucattelli, Monica and Lungarella, Giuseppe and Cavarra, Eleonora and Bartalesi, Barbara and Zweyer, Marina and Cammisuli, Francesca and Melato, Mauro and Borelli, Violetta} } @article {8494, title = {Thalidomide for inflammatory bowel disease: Systematic review.}, journal = {Medicine (Baltimore)}, volume = {95}, year = {2016}, month = {2016 Jul}, pages = {e4239}, abstract = {

BACKGROUND: Thalidomide is an immunomodulatory drug used in the experimental treatment of refractory Crohn disease and ulcerative colitis. We aimed to review the existing evidence on the efficacy and safety of thalidomide in the treatment of inflammatory bowel diseases.

METHODS: CENTRAL, MEDLINE, LILACS, POPLINE, CINHAL, and Web of Science were searched in March 2016. Manual search included conference and reference lists. All types of studies, except single case reports, were included. Outcomes evaluated were: induction of remission; maintenance of remission; steroid reduction; effect on penetrating Crohn disease; endoscopic remission; adverse events.

RESULTS: The research strategies retrieved 722 papers. Two randomized controlled trials and 29 uncontrolled studies for a total of 489 patients matched the inclusion criteria. Thalidomide induced a clinical response in 296/427 (69.3\%) patients. Clinical remission was achieved in 220/427 (51.5\%) cases. Maintenance of remission was reported in 128/160 (80.0\%) patients at 6 months and in 96/133 (72.2\%) at 12 months. Reduction in steroid dosage was reported in 109/152 (71.7\%) patients. Fistulas improved in 49/81 (60.5\%) cases and closed in 28/81 (34.6\%). Endoscopic improvement was observed in 46/66 (69.7\%) and complete mucosal healing in 35/66 (53.0\%) patients. Cumulative incidence of total adverse events and of those leading to drug suspension was 75.6 and 19.7/1000 patient-months, respectively. Neurological disturbances accounted for 341/530 (64.3\%) adverse events and were the most frequent cause of drug withdrawal.

CONCLUSION: Existing evidence suggests that thalidomide may be a valid treatment option for patients with inflammatory bowel diseases refractory to other first- and second-line treatments.

}, issn = {1536-5964}, doi = {10.1097/MD.0000000000004239}, author = {Bramuzzo, Matteo and Ventura, Alessandro and Martelossi, Stefano and Lazzerini, Marzia} } @article {8319, title = {Thiopurine Biotransformation and Pharmacological Effects: Contribution of Oxidative Stress.}, journal = {Curr Drug Metab}, volume = {17}, year = {2016}, month = {2016}, pages = {542-9}, abstract = {

BACKGROUND: Thiopurine antimetabolites are important agents for the treatment of severe diseases, such as acute lymphoblastic leukemia and inflammatory bowel disease. Their pharmacological actions depend on biotransformation into active thioguanine-nucleotides; intracellular metabolism is mediated by enzymes of the salvage pathway of nucleotide synthesis and relies on polymorphic enzymes involved in thiopurines{\textquoteright} catabolism such as thiopurine-S-methyl transferase. Given the enzymes involved in thiopurines{\textquoteright} metabolism, it is reasonable to hypothesize that these drugs are able to induce significant oxidative stress conditions, possibly altering their pharmacological activity.

METHODS: A systemic search of peer-reviewed scientific literature in bibliographic databases has been carried out. Both clinical and preclinical studies as well as mechanistic studies have been included to shed light on the role of oxidative stress in thiopurines{\textquoteright} pharmacological effects.

RESULTS: Sixty-nine papers were included in our review, allowing us to review the contribution of oxidative stress in the pharmacological action of thiopurines. Thiopurines are catabolized in the liver by xanthine oxidase, with potential production of reactive oxidative species and azathioprine is converted into mercaptopurine by a reaction with reduced glutathione, that, in some tissues, may be facilitated by glutathione- S-transferase (GST). A clear role of GSTM1 in modulating azathioprine cytotoxicity, with a close dependency on superoxide anion production, has been recently demonstrated. Interestingly, recent genome-wide association studies have shown that, for both azathioprine in inflammatory bowel disease and mercaptopurine in acute lymphoblastic leukemia, treatment effects on patients{\textquoteright} white blood cells are related to variants of a gene, NUDT15, involved in biotransformation of oxidated nucleotides.

CONCLUSIONS: Basing on previous evidences published in literature, oxidative stress may contribute to thiopurine effects in significant ways that, however, are still not completely elucidated.

}, issn = {1875-5453}, author = {Pelin, Marco and De Iudicibus, Sara and Londero, Margherita and Spizzo, Riccardo and Dei Rossi, Sveva and Martelossi, Stefano and Ventura, Alessandro and Decorti, Giuliana and Stocco, Gabriele} } @article {8495, title = {TRIM32 ubiquitin E3 ligase, one enzyme for several pathologies: From muscular dystrophy to tumours.}, journal = {Int J Biochem Cell Biol}, year = {2016}, month = {2016 Jul 22}, abstract = {

TRIM32 is a member of the TRIpartite Motif family characterised by the presence of an N-terminal three-domain-module that includes a RING domain, which confers E3 ubiquitin ligase activity, one or two B-box domains and a Coiled-Coil region that mediates oligomerisation. Several TRIM32 substrates were identified including muscular proteins and proteins involved in cell cycle regulation and cell motility. As ubiquitination is a versatile post-translational modification that can affect target turnover, sub-cellular localisation or activity, it is likely that diverse substrates may be differentially affected by TRIM32-mediated ubiquitination, reflecting its multi-faceted roles in muscle physiology, cancer and immunity. With particular relevance for muscle physiology, mutations in TRIM32 are associated with autosomal recessive Limb-Girdle Muscular Dystrophy 2H, a muscle-wasting disease with variable clinical spectrum ranging from almost asymptomatic to wheelchair-bound patients. In this review, we will focus on the ability of TRIM32 to mark specific substrates for proteasomal degradation discussing how the TRIM32-proteasome axis may (i) be important for muscle homeostasis and for the pathogenesis of muscular dystrophy; and (ii) define either an oncogenic or tumour suppressive role for TRIM32 in the context of different types of cancer.

}, issn = {1878-5875}, doi = {10.1016/j.biocel.2016.07.023}, author = {Lazzari, Elisa and Meroni, Germana} } @article {8297, title = {Understanding the role of personality and alexithymia in food preferences and PROP taste perception.}, journal = {Physiol Behav}, volume = {157}, year = {2016}, month = {2016 Apr 1}, pages = {72-8}, abstract = {

Taste perception and food preferences are influenced by a variety of factors, including personality characteristics. The aims of this study were to examine the role of personality characteristics, such as alexithymia (a personality construct characterized by inability to identify, describe, and work with one{\textquoteright}s own feelings), in: 1) taste responses to the bitter genetic taste-marker PROP and 2) food liking. We studied 649 healthy subjects residing in six genetically-isolated villages of Northeast Italy. Data on PROP taste responsiveness, food liking, personality characteristics and TAS2R28 genotypes were collected. Results showed that PROP non-tasters had higher alexithymia scores than PROP tasters. Moreover, the presence of alexithymia in heterozygous individuals for the rs1726886 polymorphism of the TAS2R38 gene was associated with a reduction in the perceived intensity of PROP. Finally, higher alexithymia scores were associated with liking of alcohol, sweets and fats/meats whereas lower alexithymia scores were related to liking of vegetables, condiments and strong cheeses, Measures of temperament, character, anxiety and depression were also related to food liking. Our findings suggest that: 1) alexithymia, in addition to the TAS2R38 polymorphism, may play a role in responsiveness to the aversive and bitter taste of PROP; and 2) alexithymia, in combination with other personality traits, may provide important insights for better understanding food liking.

}, issn = {1873-507X}, doi = {10.1016/j.physbeh.2016.01.022}, author = {Robino, Antonietta and Mezzavilla, Massimo and Pirastu, Nicola and La Bianca, Martina and Gasparini, Paolo and Carlino, Davide and Tepper, Beverly J} } @article {8498, title = {When a lymphatic malformation determines a bowel volvulus: Are clinical status and images always reliable?}, journal = {Int J Surg Case Rep}, volume = {25}, year = {2016}, month = {2016}, pages = {192-5}, abstract = {

INTRODUCTION: An acute abdomen in the form of small-bowel volvulus could be a presentation of a lymphatic malformation in childhood.

CASE PRESENTATION: A 5year old male was admitted to our Institute for an acute abdomen. Clinical aspects and radiological images were not specific for a certain diagnosis. Laparotomy revealed a big soft mass, with a milky content, completely involving about 50cm of ileus with a partial volvulus of the intestinal loop. A complete mass excision and also a bowel involved resection were performed. After a histological examination, a lymphatic malformation was diagnosed.

DISCUSSION: The diagnosis of a mesenteric lymphatic malformation could be intraoperative and a complete resection should be the treatment of choice. Sometimes it could be necessary to perform an involved bowel tract resection in the case of volvolus with ischemia.

CONCLUSIONS: Paediatricians and surgeons should bare in mind that an intrabdominal lymphatic malformation may present as a nonspecific an acute abdomen caused by a bowel volvolus and diagnosis may not be so simple preoperatively.

}, issn = {2210-2612}, doi = {10.1016/j.ijscr.2016.06.030}, author = {Guida, Edoardo and Di Grazia, Massimo and Cattaruzzi, Elisabetta and Bussani, Rossana and Rigamonti, Waifro and Lembo, Maria Antonietta} } @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 {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 {7775, title = {Analysis of functional variants reveals new candidate genes associated with alexithymia.}, journal = {Psychiatry Res}, volume = {227}, year = {2015}, month = {2015 Jun 30}, pages = {363-5}, abstract = {

In this study we explored the possible association between 36,915 functional variants and alexithymia, a personality trait characterized by the inability to identify and describe emotions and feelings. From our analysis, variants in the genes ABCB4, TP53AIP1, ARHGAP32 and TMEM88B were identified linked to the alexithymia phenotype.

}, keywords = {Adolescent, Adult, Affective Symptoms, Aged, Case-Control Studies, DNA-Binding Proteins, Emotions, Female, Humans, Male, Membrane Proteins, Middle Aged, P-Glycoproteins, Personality Inventory, Phenotype, Tumor Suppressor Proteins, Young Adult}, issn = {1872-7123}, doi = {10.1016/j.psychres.2015.03.018}, author = {Mezzavilla, Massimo and Ulivi, Sheila and Bianca, Martina La and Carlino, Davide and Gasparini, Paolo and Robino, Antonietta} } @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 {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 {8030, title = {Delayed reactivation of chronic infantile neurologic, cutaneous, articular syndrome (CINCA) in a patient with somatic mosaicism of CIAS1/NLRP3 gene after withdrawal of anti-IL-1 beta therapy.}, journal = {Clin Exp Rheumatol}, volume = {33}, year = {2015}, month = {2015 Sep-Oct}, pages = {766}, keywords = {Antibodies, Monoclonal, Carrier Proteins, Cryopyrin-Associated Periodic Syndromes, Drug Administration Schedule, Female, Genetic Predisposition to Disease, Humans, Immunosuppressive Agents, Interleukin 1 Receptor Antagonist Protein, Interleukin-1beta, Mosaicism, Phenotype, Recurrence, Remission Induction, Time Factors, Treatment Outcome, Young Adult}, issn = {0392-856X}, author = {Paloni, Giulia and Pastore, Serena and Tommasini, Alberto and Lepore, Loredana and Taddio, Andrea} } @article {8088, title = {The diagnostic challenge of very early-onset enterocolitis in an infant with XIAP deficiency.}, journal = {BMC Pediatr}, volume = {15}, year = {2015}, month = {2015}, pages = {208}, abstract = {

BACKGROUND: Aggressive course and resistance to treatments usually characterize very early onset inflammatory bowel disease (VEO-IBD). Some VEO-IBD cases are due to monogenic immune defects and can benefit from hematopoietic stem cell transplantation (HSCT).

CASE PRESENTATION: We describe a Caucasian male baby who presented in the first months of life macrophage activation syndrome, followed by intractable colitis, recurrent episodes of fever and mild splenomegaly. After several immunological, genetic and clinical investigations, subsequently a therapeutic attempt with colectomy, analysis of VEO-IBD-associated genes, revealed a causative mutation in XIAP. The genetic diagnosis of a primary immune deficiency allowed curing the boy with hematopoietic stem cell transplantation.

CONCLUSION: Our report, together with novel findings from recent literature, should contribute to increase awareness of monogenic immune defects as a cause of VEO-IBD. Comprehensive genetic analysis can allow a prompt diagnosis, resulting in the choice of effective treatments and sparing useless and damaging procedures.

}, issn = {1471-2431}, doi = {10.1186/s12887-015-0522-5}, author = {Girardelli, Martina and Arrigo, Serena and Barabino, Arrigo and Loganes, Claudia and Morreale, Giuseppe and Crovella, Sergio and Tommasini, Alberto and Bianco, Anna Monica} } @article {7780, title = {Different presentations of mevalonate kinase deficiency: a case series.}, journal = {Clin Exp Rheumatol}, volume = {33}, year = {2015}, month = {2015 May-Jun}, pages = {437-42}, abstract = {

OBJECTIVES: We aimed to raise awareness among paediatricians and physicians about this often misunderstood condition.

METHODS: We discussed the clinical profiles associated with late or wrong diagnosis of mevalonate kinase deficency (MKD) in a single centre case series.

RESULTS: We analysed the most common challenges and pitfalls that a clinician might face during the diagnostic process. Five main clinical profiles were characterised.

CONCLUSIONS: We propose a new perspective on MKD, suggesting that the presentation of this disease can vary from patient to patient.

}, keywords = {Age Factors, Bacterial Infections, Child, Child, Preschool, Diagnosis, Differential, Diagnostic Errors, Female, Genetic Predisposition to Disease, Humans, Infant, Inflammatory Bowel Diseases, Male, Mevalonate Kinase Deficiency, Phenotype, Predictive Value of Tests, Recurrence, Risk Factors, Sepsis, Vasculitis, Young Adult}, issn = {0392-856X}, author = {De Pieri, Carlo and Taddio, Andrea and Insalaco, Antonella and Barbi, Egidio and Lepore, Loredana and Ventura, Alessandro and Tommasini, Alberto} } @article {7711, title = {Differential protein folding and chemical changes in lung tissues exposed to asbestos or particulates.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015}, pages = {12129}, abstract = {

Environmental and occupational inhalants may induce a large number of pulmonary diseases, with asbestos exposure being the most risky. The mechanisms are clearly related to chemical composition and physical and surface properties of materials. A combination of X-ray fluorescence (μXRF) and Fourier Transform InfraRed (μFTIR) microscopy was used to chemically characterize and compare asbestos bodies versus environmental particulates (anthracosis) in lung tissues from asbestos exposed and control patients. μXRF analyses revealed heterogeneously aggregated particles in the anthracotic structures, containing mainly Si, K, Al and Fe. Both asbestos and particulates alter lung iron homeostasis, with a more marked effect in asbestos exposure. μFTIR analyses revealed abundant proteins on asbestos bodies but not on anthracotic particles. Most importantly, the analyses demonstrated that the asbestos coating proteins contain high levels of β-sheet structures. The occurrence of conformational changes in the proteic component of the asbestos coating provides new insights into long-term asbestos effects.

}, issn = {2045-2322}, doi = {10.1038/srep12129}, author = {Pascolo, Lorella and Borelli, Violetta and Canzonieri, Vincenzo and Gianoncelli, Alessandra and Birarda, Giovanni and Bedolla, Diana E and Salom{\`e}, Murielle and Vaccari, Lisa and Calligaro, Carla and Cotte, Marine and Hesse, Bernhard and Luisi, Fernando and Zabucchi, Giuliano and Melato, Mauro and Rizzardi, Clara} } @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 {3619, title = {Dysplastic bone marrow changes during maintenance therapy for acute leukemia.}, journal = {J Pediatr Hematol Oncol}, volume = {37}, year = {2015}, month = {2015 Mar}, pages = {156-7}, abstract = {

We describe the case of an 8-year-old girl with common precursor B-cell acute lymphoblastic leukemia who presented with severe pancytopenia during maintenance therapy with methotrexate and 6-mercaptopurine. The bone marrow smear showed moderate hypocellularity and trilinear dysplastic changes consistent with a diagnosis of drug toxicity, with no evidence of lymphoblasts. Flow cytometric immunophenotyping was negative for leukemic cells. Blood cell counts normalized after treatment with folinic acid. Maintenance therapy was gradually restarted and she remained well at follow-up visits. Myelotoxicity from methotrexate and 6-mercaptopurine may represent an unpredictable incident during an otherwise uneventful maintenance therapy, and may occur independently of other organ toxicities.

}, keywords = {6-Mercaptopurine, Antineoplastic Combined Chemotherapy Protocols, Bone Marrow Diseases, Child, Disease Management, Female, Follow-Up Studies, Humans, Methotrexate, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Prognosis}, issn = {1536-3678}, doi = {10.1097/MPH.0000000000000295}, author = {Chinello, Matteo and Naviglio, Samuele and Shardlow, Alison and Severino, Alessandro and Ventura, Alessandro and Locasciulli, Anna} } @article {3479, title = {Early onset bilateral anterior uveitis preceding a late manifestation of juvenile idiopathic arthritis: a case report.}, journal = {Ocul Immunol Inflamm}, volume = {23}, year = {2015}, month = {2015 Feb}, pages = {102-5}, keywords = {Adolescent, Arthritis, Juvenile, Female, Humans, Time Factors, Tomography, Optical Coherence, Uveitis, Anterior}, issn = {1744-5078}, doi = {10.3109/09273948.2013.863941}, author = {Parentin, Fulvio and Matarazzo, Lorenza and Lepore, Loredana and Pensiero, Stefano and Ventura, Alessandro} } @article {8049, title = {Effect of seminal leukocytes on in vitro fertilization and intracytoplasmic sperm injection outcomes.}, journal = {Fertil Steril}, volume = {104}, year = {2015}, month = {2015 Jul}, pages = {87-93}, abstract = {

OBJECTIVE: To investigate the influence of seminal leukocytes on conventional IVF and intracytoplasmic sperm injection (ICSI) outcomes, using a flow cytometry method.

DESIGN: Prospective study.

SETTING: Tertiary infertility center and research institute.

PATIENT(S): One hundred sixty-four couples undergoing conventional IVF or ICSI.

INTERVENTION(S): Seminal leukocytes were counted by flow cytometry.

MAIN OUTCOME MEASURE(S): Correlation between seminal leukocytes concentration and reproductive outcomes in IVF and ICSI cycles.

RESULT(S): The median number of oocytes retrieved, the fertilization and cleavage rate, the median number and grade of embryos transferred, the median number of good-quality embryos transferred, and the median percentage of good-quality embryos from total embryos transferred, in leukocytospermic and non-leukocytospermic patients were not statistically different after either IVF or ICSI. Similarly, there were no significant differences between the two groups for implantation rate and clinical pregnancy rate. Multivariate logistic regression analysis showed that the reproductive outcomes were not influenced by adjustment for female age, infertility diagnosis, number of previous attempts, treatment protocol (GnRH agonist or antagonist), assisted reproduction procedure (IVF or ICSI), and leukocytospermia. By profiling the proper Poisson regression models, no leukocytospermia cut-off value was able to identify the subjects at risk for oocyte fertilization or embryo cleavage failure.

CONCLUSION(S): Using a flow cytometry method, we demonstrated that leukocytospermia does not significantly influence IVF or ICSI outcomes. The same results were obtained by using lower or higher cut-off values for leukocytospermia (from 0.2 to 2 {\texttimes} 10(6)/mL).

}, keywords = {Adult, Female, Fertilization in Vitro, Flow Cytometry, Humans, Leukocytes, Male, Pregnancy, Pregnancy Rate, Prospective Studies, Semen, Sperm Injections, Intracytoplasmic}, issn = {1556-5653}, doi = {10.1016/j.fertnstert.2015.04.007}, author = {Ricci, Giuseppe and Granzotto, Marilena and Luppi, Stefania and Giolo, Elena and Martinelli, Monica and Zito, Gabriella and Borelli, Massimo} } @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 {7697, title = {Efficacy of intravenous immunoglobulin therapy in giant cell hepatitis with autoimmune hemolytic anemia: A multicenter study.}, journal = {Clin Res Hepatol Gastroenterol}, year = {2015}, month = {2015 Jun 29}, abstract = {

BACKGROUND AND OBJECTIVE: Giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA) is a rare disease of infancy, of possible autoimmune mechanism with poor prognosis due to its scarce response to immunosuppressive drugs. The aim of this retrospective multicenter study was to evaluate the efficacy and safety of intravenous immunoglobulin (IVIg) treatment in inducing and maintaining remission of the liver disease, in patients with GCH-AHA.

METHODS: Seven children with GCH-AHA, four newly diagnosed, and three in relapse, being treated with different therapies, received one to three IVIg infusions (0.5 to 2g/kg) in association with other immunosuppressive drugs. Subsequently five of them received monthly sequential IVIg infusions (mean 13.4, range 7-24).

RESULTS: IVIg infusions as first-line therapy associated with prednisone and other immunosuppressive drugs significantly (P=0.04) reduced the aminotransferase activity in all patients and normalized prothombin activity in the only patient with severe liver dysfunction. Sequential monthly IVIg infusions determined a steroid-sparing effect and allowed a complete or partial remission in all patients, although with temporary efficacy, since relapse of the hemolytic anemia and/or of liver disease occurred in all patients. IVIg infusions were associated with mild side effects in two patients.

CONCLUSIONS: IVIg infusion can be safely and effectively administered in patients with severe GCH-AHA at diagnosis, or in case of relapse, in association with other immunosuppressive drugs. Repeated IVIg infusions may help maintain remission, however, due to their temporary efficacy, they should not be routinely employed.

}, issn = {2210-741X}, doi = {10.1016/j.clinre.2015.03.009}, author = {Marsalli, Giulia and Nastasio, Silvia and Sciveres, Marco and Calvo, Pier Luigi and Ramenghi, Ugo and Gatti, Simona and Albano, Veronica and Lega, Sara and Ventura, Alessandro and Maggiore, Giuseppe} } @article {7739, title = {Food protein-induced enterocolitis syndrome caused by fish and/or shellfish in Italy.}, journal = {Pediatr Allergy Immunol}, year = {2015}, month = {2015 Aug 19}, abstract = {

BACKGROUND: The study describes the demographic features, culprit foods, clinical features and outcomes for children presenting with acute fish and/or shellfish food protein-induced enterocolitis syndrome (FPIES) in four Italian paediatric allergy centres.

METHODS: A retrospective/prospective study was undertaken. All children diagnosed with fish or shellfish FPIES were enrolled. The diagnosis of FPIES was based on Sicherer{\textquoteright}s or Miceli Sopo clinical criteria. Skin prick tests (SPT) were performed in all patients, at the time of diagnosis and prior to OFC.

RESULTS: Seventy children were enrolled. Mean age at first episode was 14 months (range 6-46 months); mean age at diagnosis was 34 months (range 6-164 months). Sole and cod were the fish most commonly implicated. Fifty-seven of 70 (81\%) children had FPIES exclusively to fish, 37 of 57 (65\%) children had single-fish FPIES, 20 of 57 (35\%) multiple-fish FPIES, nine of 70 (13\%) presented adverse reactions exclusively to shellfish, and four of 70 (6\%) presented adverse reactions to both fish and shellfish. Only four (5.7\%) children presented episodes of acute FPIES with different foods (2 to cow{\textquoteright}s milk, 1 to egg, 1 to beef); in all cases, onset was prior to that of fish or shellfish FPIES. Fifteen of 70 (21\%) children tolerated fish other than the offending fish. Twenty-four of 70 (34\%) children achieved tolerance (age range 24-102 months).

CONCLUSIONS: The chief peculiarities of acute fish and shellfish FPIES, compared to more frequent cow{\textquoteright}s milk or soy FPIES, are (i) later age of onset, (ii) longer persistence and (iii) possibility of tolerating fish other than the offending fish. Adverse reactions with shellfish are possible.

}, issn = {1399-3038}, doi = {10.1111/pai.12461}, author = {Miceli Sopo, Stefano and Monaco, Serena and Badina, Laura and Barni, Simona and Longo, Giorgio and Novembre, Elio and Viola, Serena and Monti, Giovanna} } @article {8055, title = {Functionalized synchrotron in-line phase-contrast computed tomography: a novel approach for simultaneous quantification of structural alterations and localization of barium-labelled alveolar macrophages within mouse lung samples.}, journal = {J Synchrotron Radiat}, volume = {22}, year = {2015}, month = {2015 Jan}, pages = {143-55}, abstract = {

Functionalized computed tomography (CT) in combination with labelled cells is virtually non-existent due to the limited sensitivity of X-ray-absorption-based imaging, but would be highly desirable to realise cell tracking studies in entire organisms. In this study we applied in-line free propagation X-ray phase-contrast CT (XPCT) in an allergic asthma mouse model to assess structural changes as well as the biodistribution of barium-labelled macrophages in lung tissue. Alveolar macrophages that were barium-sulfate-loaded and fluorescent-labelled were instilled intratracheally into asthmatic and control mice. Mice were sacrificed after 24 h, lungs were kept in situ, inflated with air and scanned utilizing XPCT at the SYRMEP beamline (Elettra Synchrotron Light Source, Italy). Single-distance phase retrieval was used to generate data sets with ten times greater contrast-to-noise ratio than absorption-based CT (in our setup), thus allowing to depict and quantify structural hallmarks of asthmatic lungs such as reduced air volume, obstruction of airways and increased soft-tissue content. Furthermore, we found a higher concentration as well as a specific accumulation of the barium-labelled macrophages in asthmatic lung tissue. It is believe that XPCT will be beneficial in preclinical asthma research for both the assessment of therapeutic response as well as the analysis of the role of the recruitment of macrophages to inflammatory sites.

}, keywords = {Algorithms, Allergens, Animals, Asthma, Barium Sulfate, Cell Line, Transformed, Cell Movement, Contrast Media, Disease Models, Animal, Female, Image Processing, Computer-Assisted, Imaging, Three-Dimensional, Lung, Macrophages, Alveolar, Mice, Mice, Inbred BALB C, Microscopy, Fluorescence, Ovalbumin, Synchrotrons, Tomography, X-Ray Computed}, issn = {1600-5775}, doi = {10.1107/S1600577514021730}, author = {Dullin, Christian and dal Monego, Simeone and Larsson, Emanuel and Mohammadi, Sara and Krenkel, Martin and Garrovo, Chiara and Biffi, Stefania and Lorenzon, Andrea and Markus, Andrea and Napp, Joanna and Salditt, Tim and Accardo, Agostino and Alves, Frauke and Tromba, Giuliana} } @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 {7720, title = {Genome-wide association analysis on normal hearing function identifies PCDH20 and SLC28A3 as candidates for hearing function and loss.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Oct 1}, pages = {5655-64}, abstract = {

Hearing loss and individual differences in normal hearing both have a substantial genetic basis. Although many new genes contributing to deafness have been identified, very little is known about genes/variants modulating the normal range of hearing ability. To fill this gap, we performed a two-stage meta-analysis on hearing thresholds (tested at 0.25, 0.5, 1, 2, 4, 8 kHz) and on pure-tone averages (low-, medium- and high-frequency thresholds grouped) in several isolated populations from Italy and Central Asia (total N = 2636). Here, we detected two genome-wide significant loci close to PCDH20 and SLC28A3 (top hits: rs78043697, P = 4.71E-10 and rs7032430, P = 2.39E-09, respectively). For both loci, we sought replication in two independent cohorts: B58C from the UK (N = 5892) and FITSA from Finland (N = 270). Both loci were successfully replicated at a nominal level of significance (P < 0.05). In order to confirm our quantitative findings, we carried out RT-PCR and reported RNA-Seq data, which showed that both genes are expressed in mouse inner ear, especially in hair cells, further suggesting them as good candidates for modulatory genes in the auditory system. Sequencing data revealed no functional variants in the coding region of PCDH20 or SLC28A3, suggesting that variation in regulatory sequences may affect expression. Overall, these results contribute to a better understanding of the complex mechanisms underlying human hearing function.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddv279}, author = {Vuckovic, Dragana and Dawson, Sally and Scheffer, Deborah I and Rantanen, Taina and Morgan, Anna and Di Stazio, Mariateresa and Vozzi, Diego and Nutile, Teresa and Concas, Maria P and Biino, Ginevra and Nolan, Lisa and Bahl, Aileen and Loukola, Anu and Viljanen, Anne and Davis, Adrian and Ciullo, Marina and Corey, David P and Pirastu, Mario and Gasparini, Paolo and Girotto, Giorgia} } @article {7700, title = {Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 May}, pages = {535-8}, abstract = {

Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell-precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotypes identified 2 with ETV6 mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.

}, keywords = {Adult, Child, Preschool, DNA Mutational Analysis, Erythrocytes, Abnormal, Exome, Female, Genetic Association Studies, Genetic Predisposition to Disease, Germ-Line Mutation, HEK293 Cells, Hematologic Diseases, Humans, Male, Mutation, Missense, Pedigree, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogene Proteins c-ets, Repressor Proteins, Thrombocytopenia}, issn = {1546-1718}, doi = {10.1038/ng.3253}, author = {Noetzli, Leila and Lo, Richard W and Lee-Sherick, Alisa B and Callaghan, Michael and Noris, Patrizia and Savoia, Anna and Rajpurkar, Madhvi and Jones, Kenneth and Gowan, Katherine and Balduini, Carlo L and Pecci, Alessandro and Gnan, Chiara and De Rocco, Daniela and Doubek, Michael and Li, Ling and Lu, Lily and Leung, Richard and Landolt-Marticorena, Carolina and Hunger, Stephen and Heller, Paula and Gutierrez-Hartmann, Arthur and Xiayuan, Liang and Pluthero, Fred G and Rowley, Jesse W and Weyrich, Andrew S and Kahr, Walter H A and Porter, Christopher C and Di Paola, Jorge} } @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 {8037, title = {Hypoxaemia as a Mortality Risk Factor in Acute Lower Respiratory Infections in Children in Low and Middle-Income Countries: Systematic Review and Meta-Analysis.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0136166}, abstract = {

OBJECTIVE: To evaluate the association between hypoxaemia and mortality from acute lower respiratory infections (ALRI) in children in low- and middle-income countries (LMIC).

DESIGN: Systematic review and meta-analysis.

STUDY SELECTION: Observational studies reporting on the association between hypoxaemia and death from ALRI in children below five years in LMIC.

DATA SOURCES: Medline, Embase, Global Health Library, Lilacs, and Web of Science to February 2015.

RISK OF BIAS ASSESSMENT: Quality In Prognosis Studies tool with minor adaptations to assess the risk of bias; funnel plots and Egger{\textquoteright}s test to evaluate publication bias.

RESULTS: Out of 11,627 papers retrieved, 18 studies from 13 countries on 20,224 children met the inclusion criteria. Twelve (66.6\%) studies had either low or moderate risk of bias. Hypoxaemia defined as oxygen saturation rate (SpO2) <90\% associated with significantly increased odds of death from ALRI (OR 5.47, 95\% CI 3.93 to 7.63) in 12 studies on 13,936 children. An Sp02 <92\% associated with a similar increased risk of mortality (OR 3.66, 95\% CI 1.42 to 9.47) in 3 studies on 673 children. Sensitivity analyses (excluding studies with high risk of bias and using adjusted OR) and subgroup analyses (by: altitude, definition of ALRI, country income, HIV prevalence) did not affect results. Only one study was performed on children living at high altitude.

CONCLUSIONS: The results of this review support the routine evaluation of SpO2 for identifying children with ALRI at increased risk of death. Both a Sp02 value of 92\% and 90\% equally identify children at increased risk of mortality. More research is needed on children living at high altitude. Policy makers in LMIC should aim at improving the regular use of pulse oximetry and the availability of oxygen in order to decrease mortality from ALRI.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0136166}, author = {Lazzerini, Marzia and Sonego, Michela and Pellegrin, Maria Chiara} } @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 {8029, title = {Interleukin-18, interleukin-12B and interferon-γ gene polymorphisms in Brazilian patients with rheumatoid arthritis: a pilot study.}, journal = {Tissue Antigens}, volume = {86}, year = {2015}, month = {2015 Oct}, pages = {276-8}, abstract = {

Polymorphisms in interleukin (IL)-18, IL-12 and interferon (IFN)-γ genes are associated with different levels of cytokines expression and have been associated with rheumatoid arthritis (RA). IL-18 +105 A/C, IL-12B +1188 A/C and IFN-γ +874 T/A polymorphisms were analyzed by restriction fragment length polymorphism-polymerase chain reaction (PCR) and amplification refractory mutation system PCR from 90 RA patients and 186 healthy individuals. There were significant differences to IL-18 +105 A/C polymorphism between the RA and control groups (odds ratio = 3.77; P < 0.0001). Individual carriers of the variant allele C had a 3.77-fold increased risk of for RA (P = 0.0032). No association was observed for IL-12B and IFN-γ polymorphisms. Our finds suggest a possible role for IL-18 polymorphism in the RA susceptibility in studied population.

}, issn = {1399-0039}, doi = {10.1111/tan.12645}, author = {Angelo, H D and Gomes Silva, I I F and Oliveira, R D R and Louzada-J{\'u}nior, P and Donadi, E A and Crovella, S and Maia, M M D and de Souza, P R E and Sandrin-Garcia, P} } @article {8071, title = {Kinetic Profiles of Inflammatory Mediators in the Conjunctival Sac Fluid of Patients upon Photorefractive Keratectomy.}, journal = {Mediators Inflamm}, volume = {2015}, year = {2015}, month = {2015}, pages = {942948}, abstract = {

Photorefractive keratectomy (PRK) represents a therapeutic option to remodel corneal stroma and to compensate refractive errors, which involves inflammatory and/or regenerative processes. In this context, the modulation of cytokines/chemokines in the conjunctival sac fluid and their role in the maintenance of the corneal microenvironment during the healing process upon refractive procedures has not been deeply investigated. In this study, serial samples of conjunctival sac fluid of patients (n = 25) undergoing PRK were harvested before and at different time points after surgery. The levels of 29 cytokines/chemokines/growth factors involved in inflammatory/immune processes were measured with a multiplex array system. The results have firstly highlighted the different pattern of cytokine expression between the microenvironment at the anterior surface of the eye and the systemic circulation. More importantly, the kinetic of modulation of cytokines/chemokines at the conjunctival level following PRK revealed that while the majority of cytokines/chemokines showed a significant decrease, MCP-1 emerged in light of its pronounced and significant increase soon after PRK and during the follow-up. This methodological approach has highlighted the role of MCP-1 in the healing process following PRK and has shown a potential for the identification of expression/modulation of soluble factors for biomarker profiling in ocular surface diseases.

}, issn = {1466-1861}, doi = {10.1155/2015/942948}, author = {Tisato, Veronica and Perri, Paolo and Rimondi, Erika and Melloni, Elisabetta and Lamberti, Giuseppe and Milani, Daniela and Secchiero, Paola and Zauli, Giorgio} } @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 {7764, title = {Long noncoding RNA GAS5: a novel marker involved in glucocorticoid response.}, journal = {Curr Mol Med}, volume = {15}, year = {2015}, month = {2015}, pages = {94-9}, abstract = {

Glucocorticoids (GCs) exert their effects through regulation of gene expression after activation in the cytoplasm of the glucocorticoid receptor (GR) encoded by NR3C1 gene. A negative feedback mechanism resulting in GR autoregulation has been demonstrated through the binding of the activated receptor to intragenic sequences called GRE-like elements, contained in GR gene. The long noncoding RNA growth arrest-specific transcript 5 (GAS5) interacts with the activated GR suppressing its transcriptional activity. The aim of this study was to evaluate the possible role of GAS5 and NR3C1 gene expression in the antiproliferative effect of methylprednisolone in peripheral blood mononuclear cells and to correlate the expression with individual sensitivity to GCs. Subjects being poor responders to GCs presented higher levels of GAS5 and NR3C1 in comparison with good responders. We suggest that abnormal levels of GAS5 may alter GC effectiveness, probably interfering with the mechanism of GR autoregulation.

}, keywords = {Adult, Cell Proliferation, Female, Gene Expression Regulation, Glucocorticoids, Humans, Leukocytes, Mononuclear, Male, Methylprednisolone, Middle Aged, Receptors, Glucocorticoid, RNA, Long Noncoding, Transcription, Genetic}, issn = {1875-5666}, author = {Lucafo, M and De Iudicibus, S and Di Silvestre, A and Pelin, M and Candussio, L and Martelossi, S and Tommasini, A and Piscianz, E and Ventura, A and Decorti, G} } @article {8068, title = {MID2 can substitute for MID1 and control exocytosis of lytic granules in cytotoxic T cells.}, journal = {APMIS}, volume = {123}, year = {2015}, month = {2015 Aug}, pages = {682-7}, abstract = {

We have recently shown that the E3 ubiquitin ligase midline 1 (MID1) is upregulated in murine cytotoxic lymphocytes (CTL), where it controls exocytosis of lytic granules and the killing capacity. Accordingly, CTL from MID1 knock-out (MID1(-/-)) mice have a 25-30\% reduction in exocytosis of lytic granules and cytotoxicity compared to CTL from wild-type (WT) mice. We wondered why the MID1 gene knock-out did not affect exocytosis and cytotoxicity more severely and speculated whether MID2, a close homologue of MID1, might partially compensate for the loss of MID1 in MID1(-/-) CTL. Here, we showed that MID2, like MID1, is upregulated in activated murine T cells. Furthermore, MID1(-/-) CTL upregulated MID2 two-twenty-fold stronger than CTL from WT mice, suggesting that MID2 might compensate for MID1. In agreement, transfection of MID2 into MID1(-/-) CTL completely rescued exocytosis of lytic granules in MID1(-/-) CTL, and vice versa, knock-down of MID2 inhibited exocytosis of lytic granules in both WT and MID1(-/-) CTL, demonstrating that both MID1 and MID2 play a central role in the regulation of granule exocytosis and that functional redundancy exists between MID1 and MID2 in CTL.

}, keywords = {Animals, Cytoplasmic Granules, Exocytosis, Interferon-gamma, Mice, Mice, Inbred C57BL, Mice, Knockout, Microtubule-Associated Proteins, Proteins, T-Lymphocytes, Cytotoxic, Transcription Factors, Up-Regulation}, issn = {1600-0463}, doi = {10.1111/apm.12402}, author = {Boding, Lasse and Hansen, Ann K and Meroni, Germana and Levring, Trine B and Woetmann, Anders and {\O}dum, Niels and Bonefeld, Charlotte M and Geisler, Carsten} } @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 {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 {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 {8075, title = {Patients{\textquoteright} Induced Pluripotent Stem Cells to Model Drug Induced Adverse Events: A Role in Predicting Thiopurine Induced Pancreatitis?}, journal = {Curr Drug Metab}, volume = {17}, year = {2015}, month = {2015}, pages = {91-8}, abstract = {

Induced pluripotent stem cells (iPSC) can be produced from adult cells by transfecting them with a definite set of pluripotency-associated genes. Under adequate growth conditions and stimulation iPSC can differentiate to almost every somatic lineage in the body. Patients{\textquoteright} derived iPSC are an innovative model to study mechanisms of adverse drug reactions in individual patients and in cell types that cannot be easily obtained from human subjects. Proof-of concept studies with known toxicants have been performed for liver, cardiovascular and central nervous system cells: neurons obtained from iPSC have been used to elucidate the mechanism of chemotherapy-induced peripheral neuropathy by evaluating the effects of neurotoxic drugs such as vincristine. However, no study has been performed yet on pancreatic tissue and drug induced pancreatitis. Thiopurines (azathioprine and mercaptopurine) are immunosuppressive antimetabolite drugs, commonly used to treat Crohn{\textquoteright}s disease. About 5\% of Crohn{\textquoteright}s disease patients treated with thiopurines develop pancreatitis, a severe idiosyncratic adverse event; these patients have to stop thiopurine administration and may require medical treatment, with significant personal and social costs. Molecular mechanism of thiopurine induced pancreatitis (TIP) is currently unknown and no fully validated biomarker is available to assist clinicians in preventing this adverse event. Hence, in this review we have reflected upon the probable research applications of exocrine pancreatic cells generated from patient specific iPS cells. Such pancreatic cells can provide excellent insights into the molecular mechanism of TIP. In particular three hypotheses on the mechanism of TIP could be explored: drug biotransformation, innate immunity and adaptative immunity.

}, issn = {1875-5453}, author = {Stocco, Gabriele and Lanzi, Gaetana and Yue, Fengming and Giliani, Silvia and Sasaki, Katsunori and Tommasini, Alberto and Pelin, Marco and Martelossi, Stefano and Ventura, Alessandro and Decorti, Giuliana} } @article {7715, title = {Persistent viremia and urine shedding of tick-borne encephalitis virus in an infected immunosuppressed patient from a new epidemic cluster in North-Eastern Italy.}, journal = {J Clin Virol}, volume = {69}, year = {2015}, month = {2015 Aug}, pages = {48-51}, abstract = {

A persistent tick-borne encephalitis virus infection in an immune-suppressed patient is presented. Such an unusual clinical case offers the unique chance of detecting persistent viremia associated to the erythrocyte fraction and shedding of the virus in the urine for more than six weeks. The infection occurred in a new area of the Friuli Venezia-Giulia region (North Eastern Italy) where two additional cases are also being reported.

}, issn = {1873-5967}, doi = {10.1016/j.jcv.2015.05.019}, author = {Caracciolo, Ilaria and Bassetti, Matteo and Paladini, Giorgio and Luzzati, Roberto and Santon, Daniela and Merelli, Maria and Sabbata, Giovanni De and Carletti, Tea and Marcello, Alessandro and D{\textquoteright}Agaro, Pierlanfranco} } @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 {8076, title = {PRE- AND POSTNATAL MODIFICATIONS IN PARENTAL MENTAL REPRESENTATIONS IN THREE CASES OF FETAL GASTROSCHISIS DIAGNOSED DURING PREGNANCY.}, journal = {Infant Ment Health J}, year = {2015}, month = {2015 Nov 10}, abstract = {

The aim of this study was to identify possible effects of gastroschisis on parents{\textquoteright} intrapsychic dynamics by applying an observational clinical approach. More specifically, we intend to (a) evaluate the representational style of parents informed about the diagnosis of fetal gastroschisis during pregnancy using the Interview of Maternal Representations During Pregnancy and the Interview of Paternal Representations During Pregnancy (M. Ammaniti, C. Candelori, M. Pola, \& R. Tambelli, ) and (b) observe whether the baby{\textquoteright}s birth influences the parents{\textquoteright} representational styles through the application of the same tools (the Interview of Maternal Representations After the Birth, M. Ammaniti \& R. Tambelli, , and the Interview of Paternal Representations After the Birth, M. Ammaniti \& R. Tambelli, ), adapted to the postnatal period. During the prenatal period, all parents showed a restricted/disinvested style. Three parents-one mother and two fathers-changed their styles from restricted/disinvested to integrated between pregnancy and Month 6 after the birth of their child. Clinical data from the interviews and observations are discussed in an attempt at better defining intrapsychic dynamics of parents after a diagnosis of gastroschisis.

}, issn = {1097-0355}, doi = {10.1002/imhj.21534}, author = {Tripani, Antonella and Pellizzoni, Sandra and Giuliani, Rosella and Bembich, Stefano and Clarici, Andrea and Lonciari, Isabella and Ammaniti, Massimo} } @article {7702, title = {Prevalence of celiac disease in patients with severe food allergy.}, journal = {Allergy}, volume = {70}, year = {2015}, month = {2015 Oct}, pages = {1346-9}, abstract = {

The association between food allergy and celiac disease (CD) is still to be clarified. We screened for CD 319 patients with severe food allergy (IgE~>~85~kU/l against food proteins and a history of severe allergic reactions) who underwent specific food oral immunotherapy (OIT), together with 128 children with mild allergy who recovered without OIT, and compared the prevalence data with our historical data regarding healthy schoolchildren. Sixteen patients (5\%) with severe allergy and one (0.8\%) with mild allergy tested positive for both genetic and serological CD markers, while the prevalence among the schoolchildren was 1\%. Intestinal biopsies were obtained in 13/16 patients with severe allergy and in the one with mild allergy, confirming the diagnosis of CD. Sufferers from severe food allergy seem to be at a fivefold increased risk of CD. Our findings suggest that routine screening for CD should be recommended in patients with severe food allergy.

}, issn = {1398-9995}, doi = {10.1111/all.12692}, author = {Pillon, R and Ziberna, F and Badina, L and Ventura, A and Longo, G and Quaglia, S and De Leo, L and Vatta, S and Martelossi, S and Patano, G and Not, T and Berti, I} } @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 {8026, title = {Recommendations for the use of long-term central venous catheter (CVC) in children with hemato-oncological disorders: management of CVC-related occlusion and CVC-related thrombosis. On behalf of the coagulation defects working group and the supportive the}, journal = {Ann Hematol}, volume = {94}, year = {2015}, month = {2015 Nov}, pages = {1765-76}, abstract = {

Central venous catheters (CVC), used for the management of children with hemato-oncological disorders, are burdened by a significant incidence of mechanical, infective, or thrombotic complications. These complications favor an increasing risk in prolongation of hospitalization, extra costs of care, and sometimes severe life-threatening events. No guidelines for the management of CVC-related occlusion and CVC-related thrombosis are available for children. To this aim, members of the coagulation defects working group and the supportive therapy working group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) reviewed the pediatric and adult literature to propose the first recommendations for the management of CVC-related occlusion and CVC-related thrombosis in children with hemato-oncological disorders.

}, keywords = {Adult, Blood Coagulation Disorders, Catheter Obstruction, Catheterization, Central Venous, Central Venous Catheters, Child, Hematologic Neoplasms, Humans, Risk Factors, Thrombosis}, issn = {1432-0584}, doi = {10.1007/s00277-015-2481-1}, author = {Giordano, Paola and Saracco, Paola and Grassi, Massimo and Luciani, Matteo and Banov, Laura and Carraro, Francesca and Crocoli, Alessandro and Cesaro, Simone and Zanazzo, Giulio Andrea and Molinari, Angelo Claudio} } @article {7687, title = {Reply to Thalidomide Treatment of Pediatric Ulcerative Colitis: A New Use for an Old Drug.}, journal = {Inflamm Bowel Dis}, volume = {21}, year = {2015}, month = {2015 Aug}, pages = {1752-3}, keywords = {Crohn Disease, Female, Humans, Immunosuppressive Agents, Male, Thalidomide}, issn = {1536-4844}, doi = {10.1097/MIB.0000000000000451}, author = {Lazzerini, Marzia and Martelossi, Stefano and Ventura, Alessandro} } @article {8054, title = {Risk factors for mortality from acute lower respiratory infections (ALRI) in children under five years of age in low and middle-income countries: a systematic review and meta-analysis of observational studies.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0116380}, abstract = {

OBJECTIVE: To evaluate risk factors for death from acute lower respiratory infections (ALRI) in children in low- and middle-income countries.

DESIGN: Systematic review and meta-analysis.

STUDY SELECTION: Observational studies reporting on risk factors for death from ALRI in children below five years in low- and middle income countries.

DATA SOURCES: Medline, Embase, Global Health Library, Lilacs, and Web of Science to January 2014.

RISK OF BIAS ASSESSMENT: Quality In Prognosis Studies tool with minor adaptations to assess the risk of bias; funnel plots and Egger{\textquoteright}s test to evaluate publication bias.

RESULTS: Out of 10,655 papers retrieved, 77 studies from 39 countries (198,359 children) met the inclusion criteria. Host and disease characteristics more strongly associated with ALRI mortality were: diagnosis of very severe pneumonia as per WHO definition (odds ratio 9.42, 95\% confidence interval 6.37-13.92); age below two months (5.22, 1.70-16.03); diagnosis of Pneumocystis Carinii (4.79, 2.67-8.61), chronic underlying diseases (4.76, 3.27-6.93); HIV/AIDS (4.68, 3.72-5.90); and severe malnutrition (OR 4.27, 3.47-5.25). Socio-economic and environmental factors significantly associated with increased odds of death from ALRI were: young maternal age (1.84, 1.03-3.31); low maternal education (1.43, 1.13-1.82); low socio-economic status (1.62, 1.32-2.00); second-hand smoke exposure (1.52, 1.20 to 1.93); indoor air pollution (3.02, 2.11-4.31). Immunisation (0.46, 0.36-0.58) and good antenatal practices (0.50, 0.31-0.81) were associated with decreased odds of death.

CONCLUSIONS: Host and disease characteristics as well as socio-economic and environmental determinants affect the risk of death from ALRI in children. Together with the prevention and treatment of chronic diseases, interventions to modify underlying risk factors such as poverty, lack of female education, and poor environmental conditions, should be considered among the strategies to reduce ALRI mortality in children in low- and middle-income countries.

}, keywords = {Child, Preschool, Developing Countries, Environmental Exposure, Humans, Infant, Infant, Newborn, Observational Studies as Topic, Poverty, Respiratory Tract Infections, Risk Factors, Survival Analysis}, issn = {1932-6203}, doi = {10.1371/journal.pone.0116380}, author = {Sonego, Michela and Pellegrin, Maria Chiara and Becker, Genevieve and Lazzerini, Marzia} } @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 {7755, title = {Subcutaneous panniculitis-like T-cell lymphoma presenting with diffuse cutaneous edema in a 2-year-old child.}, journal = {J Pediatr Hematol Oncol}, volume = {37}, year = {2015}, month = {2015 May}, pages = {329-30}, keywords = {Child, Preschool, Edema, Humans, Lymphoma, T-Cell, Male, Panniculitis, Skin Diseases}, issn = {1536-3678}, doi = {10.1097/MPH.0000000000000312}, author = {Chinello, Matteo and Naviglio, Samuele and Remotti, Daniele and Locasciulli, Anna 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 {7725, title = {Targeted tumor imaging of anti-CD20-polymeric nanoparticles developed for the diagnosis of B-cell malignancies.}, journal = {Int J Nanomedicine}, volume = {10}, year = {2015}, month = {2015}, pages = {4099-109}, abstract = {

The expectations of nanoparticle (NP)-based targeted drug delivery systems in cancer, when compared with convectional therapeutic methods, are greater efficacy and reduced drug side effects due to specific cellular-level interactions. However, there are conflicting literature reports on enhanced tumor accumulation of targeted NPs, which is essential for translating their applications as improved drug-delivery systems and contrast agents in cancer imaging. In this study, we characterized biodegradable NPs conjugated with an anti-CD20 antibody for in vivo imaging and drug delivery onto tumor cells. NPs{\textquoteright} binding specificity mediated by anti-CD20 antibody was evaluated on MEC1 cells and chronic lymphocytic leukemia patients{\textquoteright} cells. The whole-body distribution of untargeted NPs and anti-CD20 NPs were compared by time-domain optical imaging in a localized human/mouse model of B-cell malignancy. These studies provided evidence that NPs{\textquoteright} functionalization by an anti-CD20 antibody improves tumor pharmacokinetic profiles in vivo after systemic administration and increases in vivo imaging of tumor mass compared to non-targeted NPs. Together, drug delivery and imaging probe represents a promising theranostics tool for targeting B-cell malignancies.

}, issn = {1178-2013}, doi = {10.2147/IJN.S78995}, author = {Capolla, Sara and Garrovo, Chiara and Zorzet, Sonia and Lorenzon, Andrea and Rampazzo, Enrico and Spretz, Ruben and Pozzato, Gabriele and N{\'u}{\~n}ez, Luis and Tripodo, Claudio and Macor, Paolo and Biffi, Stefania} } @article {7727, title = {TNF-related apoptosis inducing ligand in ocular cancers and ocular diabetic complications.}, journal = {Biomed Res Int}, volume = {2015}, year = {2015}, month = {2015}, pages = {424019}, abstract = {

TNF-related apoptosis inducing ligand (TRAIL) is an intensively studied cytokine, in particular for its anticancer activity. The discovery that conjunctival sac fluid contains extremely high levels of soluble TRAIL as compared to other body fluids suggested important implications in the context of the immunological surveillance of the eye, in particular of the anterior surface. In this review, we discuss the potential physiopathologic and therapeutic role of the TRAIL/TRAIL receptor system in a variety of ocular cancers. Moreover, since an increasing amount of data has indicated the important biological activities of the TRAIL/TRAIL receptor systems also in a completely different pathologic context such as diabetes mellitus, in the second part of this review we summarize the currently available data on the involvement of TRAIL in the ocular complications of diabetes mellitus as modulator of the inflammatory and angiogenic response in the eye.

}, keywords = {Apoptosis, Diabetes Complications, Diabetes Mellitus, Eye Neoplasms, Humans, Receptors, TNF-Related Apoptosis-Inducing Ligand, TNF-Related Apoptosis-Inducing Ligand}, issn = {2314-6141}, doi = {10.1155/2015/424019}, author = {Perri, Paolo and Zauli, Giorgio and Gonelli, Arianna and Milani, Daniela and Celeghini, Claudio and Lamberti, Giuseppe and Secchiero, Paola} } @article {7749, title = {Treatment of asthma based on symptoms.}, journal = {J Pediatr}, volume = {166}, year = {2015}, month = {2015 May}, pages = {1324-5}, keywords = {Asthma, Female, Humans, Male, Spirometry}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2015.01.029}, author = {Bibalo, Cristina and Longo, Giorgio and Ventura, Alessandro} } @article {8053, title = {Ultrastructural Morphology of Sperm from Human Globozoospermia.}, journal = {Biomed Res Int}, volume = {2015}, year = {2015}, month = {2015}, pages = {798754}, abstract = {

Globozoospermia is a rare disorder characterized by the presence of sperm with round head, lacking acrosome. Coiling tail around the nucleus has been reported since early human studies, but no specific significance has conferred it. By contrast, studies on animal models suggest that coiling tail around the nucleus could represent a crucial step of defective spermatogenesis, resulting in round-headed sperm. No observations, so far, support the transfer of this hypothesis to human globozoospermia. The purpose of this work was to compare ultrastructural morphology of human and mouse model globozoospermic sperm. Sperm have been investigated by using scanning and transmission electron microscopy. The images that we obtained show significant similarities to those described in GOPC knockout mice, an animal model of globozoospermia. By using this model as reference, we were able to identify the probable steps of the tail coiling process in human globozoospermia. Although we have no evidence that there is the same pathophysiology in man and knocked-out mouse, the similarities between these ultrastructural observations in human and those in the experimental model are very suggestive. This is the first demonstration of the existence of relevant morphological homologies between the tail coiling in animal model and human globozoospermia.

}, issn = {2314-6141}, doi = {10.1155/2015/798754}, author = {Ricci, Giuseppe and Andolfi, Laura and Zabucchi, Giuliano and Luppi, Stefania and Boscolo, Rita and Martinelli, Monica and Zweyer, Marina and Trevisan, Elisa} } @article {7748, title = {Usher syndrome: an effective sequencing approach to establish a genetic and clinical diagnosis.}, journal = {Hear Res}, volume = {320}, year = {2015}, month = {2015 Feb}, pages = {18-23}, abstract = {

Usher syndrome is an autosomal recessive disorder characterized by retinitis pigmentosa, sensorineural hearing loss and, in some cases, vestibular dysfunction. The disorder is clinically and genetically heterogeneous and, to date, mutations in 11 genes have been described. This finding makes difficult to get a precise molecular diagnosis and offer patients accurate genetic counselling. To overcome this problem and to increase our knowledge of the molecular basis of Usher syndrome, we designed a targeted resequencing custom panel. In a first validation step a series of 16 Italian patients with known molecular diagnosis were analysed and 31 out of 32 alleles were detected (97\% of accuracy). After this step, 31 patients without a molecular diagnosis were enrolled in the study. Three out of them with an uncertain Usher diagnosis were excluded. One causative allele was detected in 24 out 28 patients (86\%) while the presence of both causative alleles characterized 19 patients out 28 (68\%). Sixteen novel and 27 known alleles were found in the following genes: USH2A (50\%), MYO7A (7\%), CDH23 (11\%), PCDH15 (7\%) and USH1G (2\%). Overall, on the 44 patients the protocol was able to characterize 74 alleles out of 88 (84\%). These results suggest that our panel is an effective approach for the genetic diagnosis of Usher syndrome leading to: 1) an accurate molecular diagnosis, 2) better genetic counselling, 3) more precise molecular epidemiology data fundamental for future interventional plans.

}, keywords = {Adult, Alleles, Cadherins, Extracellular Matrix Proteins, Female, Genetic Counseling, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mutation, Myosins, Nerve Tissue Proteins, Usher Syndromes}, issn = {1878-5891}, doi = {10.1016/j.heares.2014.12.006}, author = {Lenarduzzi, S and Vozzi, D and Morgan, A and Rubinato, E and D{\textquoteright}Eustacchio, A and Osland, T M and Rossi, C and Graziano, C and Castorina, P and Ambrosetti, U and Morgutti, M and Girotto, G} } @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 {7777, title = {A young soccer player with sudden pain after kicking the ball.}, journal = {BMJ}, volume = {350}, year = {2015}, month = {2015}, pages = {h1944}, keywords = {Adolescent, Athletic Injuries, Emergency Medicine, Fractures, Bone, Humans, Ilium, Male, Soccer}, issn = {1756-1833}, doi = {10.1136/bmj.h1944}, author = {Lega, Sara and Rabach, Ingrid and Barbi, Egidio and Ventura, Alessandro} } @article {3607, title = {Acute-onset pretibial swelling.}, journal = {Indian Pediatr}, volume = {51}, year = {2014}, month = {2014 Apr}, pages = {334}, keywords = {Bone Marrow Diseases, Child, Preschool, Edema, Female, Granuloma Annulare, Humans, Leg, Tibia}, issn = {0974-7559}, author = {Lega, Sara and Rabusin, Marco and Pederiva, Federica} } @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 {3556, title = {Association between orofacial granulomatosis and Crohn{\textquoteright}s disease in children: systematic review.}, journal = {World J Gastroenterol}, volume = {20}, year = {2014}, month = {2014 Jun 21}, pages = {7497-504}, abstract = {

AIM: To review pediatric cases of orofacial granulomatosis (OFG), report disease characteristics, and explore the association between OFG and Crohn{\textquoteright}s disease.

METHODS: We conducted a systematic review according to the PRISMA guidelines. We searched Medline, LILACS, Virtual Health Library, and Web of Knowledge in September 2013 for cases of OFG in the pediatric age range (< 18 years), with no language limitations. All relevant articles were accessed in full text. The manual search included references of retrieved articles. We extracted data on patients{\textquoteright} characteristics, disease characteristics, association with other diseases, and treatment. We analyzed the data and reported the results in tables and text.

RESULTS: We retrieved 173 reports of OFG in children. Mean age at onset was 11.1 {\textpm} 3.8 years (range: 2.0-18 years). Prevalence in males was significant higher than in females (P < 0.001), with a male:female ratio of 2:1. Gastrointestinal signs or symptoms were present in 26.0\% of children at the time of OFG diagnosis. Overall, 70/173 (40.4\%) children received a concomitant diagnosis of Crohn{\textquoteright}s disease. In about half (51.4\%) of the cases the onset of OFG anticipated the diagnosis of Crohn{\textquoteright}s disease, with a mean time between the two diagnoses of 13.1 {\textpm} 11.6 mo (range: 3-36 mo). Overall, 21/173 (12.1\%) of the children with OFG had perianal disease, while 11/173 (6.4\%) had a family history of Crohn{\textquoteright}s disease. Both perianal disease and a family history of Crohn{\textquoteright}s disease were significantly associated with a higher risk of Crohn{\textquoteright}s disease diagnosis in children with OFG [relative risk (RR) = 3.10, 95\% confidence interval (CI): 2.46-3.90; RR = 2.74, 95\%CI: 2.24-3.36, P < 0.0001 for both). Treatment of OFG included steroids (70.8\% of children) and other immunosuppressive drugs (42.7\%), such as azathioprine, thalidomide and infliximab.

CONCLUSION: High prevalence of Crohn{\textquoteright}s disease in children with OFG suggests that OFG may be a subtype of Crohn{\textquoteright}s disease.

}, keywords = {Adolescent, Age of Onset, Child, Child, Preschool, Crohn Disease, Female, Granulomatosis, Orofacial, Humans, Immunosuppressive Agents, Male, Prevalence, Risk Factors, Steroids, Treatment Outcome}, issn = {2219-2840}, doi = {10.3748/wjg.v20.i23.7497}, author = {Lazzerini, Marzia and Bramuzzo, Matteo and Ventura, Alessandro} } @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 {3561, title = {C1q as a unique player in angiogenesis with therapeutic implication in wound healing.}, journal = {Proc Natl Acad Sci U S A}, volume = {111}, year = {2014}, month = {2014 Mar 18}, pages = {4209-14}, abstract = {

We have previously shown that C1q is expressed on endothelial cells (ECs) of newly formed decidual tissue. Here we demonstrate that C1q is deposited in wound-healing skin in the absence of C4 and C3 and that C1q mRNA is locally expressed as revealed by real-time PCR and in situ hybridization. C1q was found to induce permeability of the EC monolayer, to stimulate EC proliferation and migration, and to promote tube formation and sprouting of new vessels in a rat aortic ring assay. Using a murine model of wound healing we observed that vessel formation was defective in C1qa(-/-) mice and was restored to normal after local application of C1q. The mean vessel density of wound-healing tissue and the healed wound area were significantly increased in C1q-treated rats. On the basis of these results we suggest that C1q may represent a valuable therapeutic agent that can be used to treat chronic ulcers or other pathological conditions in which angiogenesis is impaired, such as myocardial ischemia.

}, keywords = {Animals, Cell Proliferation, Complement C1q, DNA Primers, Endothelial Cells, Enzyme-Linked Immunosorbent Assay, Human Umbilical Vein Endothelial Cells, Humans, Immunoblotting, Immunohistochemistry, In Situ Hybridization, Mice, Mice, Inbred C57BL, Mice, Knockout, Neovascularization, Physiologic, Rats, Rats, Wistar, Real-Time Polymerase Chain Reaction, Wound Healing}, issn = {1091-6490}, doi = {10.1073/pnas.1311968111}, author = {Bossi, Fleur and Tripodo, Claudio and Rizzi, Lucia and Bulla, Roberta and Agostinis, Chiara and Guarnotta, Carla and Munaut, Carine and Baldassarre, Gustavo and Papa, Giovanni and Zorzet, Sonia and Ghebrehiwet, Berhane and Ling, Guang Sheng and Botto, Marina and Tedesco, Francesco} } @article {3601, title = {Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study.}, journal = {Blood}, volume = {123}, year = {2014}, month = {2014 Mar 6}, pages = {1470-8}, abstract = {

The outcome of high-risk (HR) acute lymphoblastic leukemia patients enrolled in the AIEOP-BFM ALL 2000 study in Italy is described. HR criteria were minimal residual disease (MRD) levels >=10(-3) at day 78 (MRD-HR), no complete remission (CR) at day 33, t(4;11) translocation, and prednisone poor response (PPR). Treatment (2 years) included protocol I, 3 polychemotherapy blocks, delayed intensification (protocol IIx2 or IIIx3), cranial radiotherapy, and maintenance. A total of 312 HR patients had a 5-year event-free survival (EFS) of 58.9\% (standard error [SE] = 2.8) and an overall survival of 68.9\% (SE = 2.6). In hierarchical order, EFS was 45.9\% (4.4) in 132 MRD-HR patients, 41.2\% (11.9) in 17 patients with no CR at day 33, 36.4\% (14.5) in 11 patients with t(4;11), and 74.0\% (3.6) in 152 HR patients only for PPR. No statistically significant difference was found for disease-free survival in patients with very HR features [MRD-HR, no CR at day 33, t(4;11) translocation], given hematopoietic stem cell transplantation (HSCT) (n = 66) or chemotherapy only (n = 88), after adjusting for waiting time to HSCT (5.7 months). Patients at HR only for PPR have a favorable outcome. MRD-HR is associated with poor outcome despite intensive treatment and/or HSCT and may qualify for innovative therapies. The study was registered at www.clinicaltrials.gov as $\#$NCT00613457.

}, keywords = {Adolescent, Antineoplastic Combined Chemotherapy Protocols, Child, Child, Preschool, Combined Modality Therapy, Female, Hematopoietic Stem Cell Transplantation, Humans, Infant, Male, Neoplasm, Residual, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Radiotherapy, Remission Induction, Treatment Outcome}, issn = {1528-0020}, doi = {10.1182/blood-2013-10-532598}, author = {Conter, Valentino and Valsecchi, Maria Grazia and Parasole, Rosanna and Putti, Maria Caterina and Locatelli, Franco and Barisone, Elena and Lo Nigro, Luca and Santoro, Nicola and Aric{\`o}, Maurizio and Ziino, Ottavio and Pession, Andrea and Testi, Anna Maria and Micalizzi, Concetta and Casale, Fiorina and Zecca, Marco and Casazza, Gabriella and Tamaro, Paolo and La Barba, Gaetano and Notarangelo, Lucia Dora and Silvestri, Daniela and Colombini, Antonella and Rizzari, Carmelo and Biondi, Andrea and Masera, Giuseppe and Basso, Giuseppe} } @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 {3493, title = {Cow{\textquoteright}s milk allergy in children, from avoidance to tolerance.}, journal = {Endocr Metab Immune Disord Drug Targets}, volume = {14}, year = {2014}, month = {2014 Mar}, pages = {47-53}, abstract = {

Food allergy is the primary cause of anaphylaxis in paediatric age affecting roughly 4\% of children and their families worldwide, and requiring changes in dietary habits. The prognosis for food allergy in children has traditionally been regarded as good for the most frequent allergens, however the prognosis for cow{\textquoteright}s milk allergy in the pediatric age is currently considered to be worse than previously believed. There is now enough evidence that measures of avoidance for children at risk did not have any preventive effect whatsoever, but they still came to be counterproductive by avoiding the physiological interaction between food allergens and gastrointestinal mucosal immune system. Programs of specific oral tolerance induction (SOTI) have obtained interesting results in the treatment of food allergy supporting the idea that antigen exposure through gastrointestinal section is important to allow the development of tolerance. Nevertheless this approach is not yet considered "ready" for community recommendations. In this paper we describe our experience in the field of SOTI in children with cow{\textquoteright}s milk allergy.

}, keywords = {Animals, Cattle, Child, Child, Preschool, Desensitization, Immunologic, Humans, Immune Tolerance, Milk Hypersensitivity, Milk Substitutes, Retrospective Studies}, issn = {2212-3873}, author = {Calligaris, Lorenzo and Longo, Giorgio and Badina, Laura and Berti, Irene and Barbi, Egidio} } @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 {3566, title = {Effects of estroprogestins containing natural estrogen on vaginal flora.}, journal = {Gynecol Endocrinol}, volume = {30}, year = {2014}, month = {2014 Nov}, pages = {830-5}, abstract = {

Estroprogestins with "natural oestrogen" has represented a new option in terms of combined hormonal contraception. So, the aim of this study is to investigate how estroprogestins with natural estrogen may modify the vaginal niche. In literature, very few studies focused on the interaction between hormonal contraception and vaginal milieu. This is a prospective comparative study. We enrolled 60 women from January 2013 to September 2013, 30 of them were administered estradiol valerate dienogest (E2V+DNG - Klaira{\textregistered}) in a quadriphasic regimen, while the other 30 women were administered 17-β estradiol with nomestrol acetate (EV+NOMAC - Zoely{\textregistered}) in a monophasic regimen. After a baseline study of vaginal milieu at recruitment of patients (Gram stain with Nugent score, vaginal pH, vaginal wet mount for the quantification of leukocytes, Lactobacilli and/or presence of Candida), we performed the same follow-up after six months of estroprogestin therapy. Our results showed that the women treated with E2V+DNG had a trend of an improvement of vaginal health in terms of increase of lactobacillar flora and reduction of vaginal pH in place of women treated with EV+NOMAC that showed a reduction of cervical mucus. Finally, our data about the effects on vaginal flora exerted by two estroprogestin pills (EPs) containing a natural estrogen suggest slight, but interesting differences in terms of vaginal ecology. These differences could be related to the type of estrogen, type of progestin, regimen of administration and, after all, to the net balance between estrogenic and progestin component of the EPs.

}, keywords = {Adolescent, Adult, Drug Combinations, Estradiol, Female, Humans, Megestrol, Middle Aged, Nandrolone, Norpregnadienes, Prospective Studies, Vagina, Young Adult}, issn = {1473-0766}, doi = {10.3109/09513590.2014.936847}, author = {De Seta, Francesco and Restaino, Stefano and Banco, Rubina and Conversano, Ester and De Leo, Rossella and Tonon, Maddalena and Maso, Gianpaolo and Barbati, Giulia and Lello, Stefano} } @article {3494, title = {Expression and replication studies to identify new candidate genes involved in normal hearing function.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e85352}, abstract = {

Considerable progress has been made in identifying deafness genes, but still little is known about the genetic basis of normal variation in hearing function. We recently carried out a Genome Wide Association Study (GWAS) of quantitative hearing traits in southern European populations and found several SNPs with suggestive but none with significant association. In the current study, we followed up these SNPs to investigate which of them might show a genuine association with auditory function using alternative approaches. Firstly, we generated a shortlist of 19 genes from the published GWAS results. Secondly, we carried out immunocytochemistry to examine expression of these 19 genes in the mouse inner ear. Twelve of them showed distinctive cochlear expression patterns. Four showed expression restricted to sensory hair cells (Csmd1, Arsg, Slc16a6 and Gabrg3), one only in marginal cells of the stria vascularis (Dclk1) while the others (Ptprd, Grm8, GlyBP, Evi5, Rimbp2, Ank2, Cdh13) in multiple cochlear cell types. In the third step, we tested these 12 genes for replication of association in an independent set of samples from the Caucasus and Central Asia. Nine out of them showed nominally significant association (p<0.05). In particular, 4 were replicated at the same SNP and with the same effect direction while the remaining 5 showed a significant association in a gene-based test. Finally, to look for genotype-phenotype relationship, the audiometric profiles of the three genotypes of the most strongly associated gene variants were analyzed. Seven out of the 9 replicated genes (CDH13, GRM8, ANK2, SLC16A6, ARSG, RIMBP2 and DCLK1) showed an audiometric pattern with differences between different genotypes further supporting their role in hearing function. These data demonstrate the usefulness of this multistep approach in providing new insights into the molecular basis of hearing and may suggest new targets for treatment and prevention of hearing impairment.

}, keywords = {Adult, Animals, DNA Replication, Gene Expression Profiling, Genome-Wide Association Study, Genotype, Hair Cells, Auditory, Hearing, Humans, Mice, Phenotype, Polymorphism, Single Nucleotide, Stria Vascularis}, issn = {1932-6203}, doi = {10.1371/journal.pone.0085352}, author = {Girotto, Giorgia and Vuckovic, Dragana and Buniello, Annalisa and Lorente-C{\'a}novas, Beatriz and Lewis, Morag and Gasparini, Paolo and Steel, Karen P} } @article {3542, title = {The first trimester gravid serum regulates procalcitonin expression in human macrophages skewing their phenotype in vitro.}, journal = {Mediators Inflamm}, volume = {2014}, year = {2014}, month = {2014}, pages = {248963}, abstract = {

Procalcitonin (PCT) is one of the best diagnostic and prognostic markers in clinical practice, widely used to evaluate the evolution of bacterial infections. Although it is mainly produced by thyroid, during sepsis almost all the peripheral tissues are involved in PCT production. Parenchymal cells have been suggested as the main source of PCT expression; however the contribution of macrophages is not clear yet. In response to environmental cues, tissue macrophages acquire distinct functional phenotypes, ranging from proinflammatory (M1) to anti-inflammatory (M2) phenotype. Macrophages at the fetal-maternal interface show immunosuppressive M2-like activities required for the maintenance of immunological homeostasis during pregnancy. This study aims to clarify the ability to synthesise PCT of fully differentiated (M0), polarized (M1/M2) macrophages and those cultured either in the presence of first trimester gravid serum (GS) or pregnancy hormones. We found out that M1 macrophages upregulate PCT expression following LPS stimulation compared to M0 and M2. The GS downregulates PCT expression in macrophages, skewing them towards an M2-like phenotype. This effect seems only partially mediated by the hormonal milieu. Our findings strengthen the key role of macrophages in counteracting inflammatory stimuli during pregnancy, suggesting PCT as a possible new marker of M1-like macrophages.

}, keywords = {Biomarkers, Calcitonin, Cells, Cultured, Chorionic Gonadotropin, Estradiol, Female, Gene Expression Regulation, Homeostasis, Humans, Inflammation, Macrophages, Monocytes, Phenotype, Pregnancy, Pregnancy Trimester, First, Protein Precursors, Serum, Up-Regulation}, issn = {1466-1861}, doi = {10.1155/2014/248963}, author = {Rami, Damiano and La Bianca, Martina and Agostinis, Chiara and Zauli, Giorgio and Radillo, Oriano and Bulla, Roberta} } @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 {3639, title = {Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Aug 15}, pages = {4452-64}, abstract = {

Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants{\textquoteright} relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 {\texttimes} 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 {\texttimes} 10(-5)) and short adult stature (p = 7.5 {\texttimes} 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddu150}, author = {Cousminer, Diana L and Stergiakouli, Evangelia and Berry, Diane J and Ang, Wei and Groen-Blokhuis, Maria M and K{\"o}rner, Antje and Siitonen, Niina and Ntalla, Ioanna and Marinelli, Marcella and Perry, John R B and Kettunen, Johannes and Jansen, Rick and Surakka, Ida and Timpson, Nicholas J and Ring, Susan and McMahon, George and Power, Chris and Wang, Carol and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Lehtim{\"a}ki, Terho and Middeldorp, Christel M and Hulshoff Pol, Hilleke E and Neef, Madlen and Weise, Sebastian and Pahkala, Katja and Niinikoski, Harri and Zeggini, Eleftheria and Panoutsopoulou, Kalliope and Bustamante, Mariona and Penninx, Brenda W J H and Murabito, Joanne and Torrent, Maties and Dedoussis, George V and Kiess, Wieland and Boomsma, Dorret I and Pennell, Craig E and Raitakari, Olli T and Hypp{\"o}nen, Elina and Davey Smith, George and Ripatti, Samuli and McCarthy, Mark I and Widen, Elisabeth} } @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 {3486, title = {Influence of HLA-G polymorphisms in human immunodeficiency virus infection and hepatitis C virus co-infection in Brazilian and Italian individuals.}, journal = {Infect Genet Evol}, volume = {21}, year = {2014}, month = {2014 Jan}, pages = {418-23}, abstract = {

OBJECTIVE: This study aimed to investigate the role of Human Leukocyte Antigen (HLA)-G in the susceptibility to HIV-1 infection through the analysis of the HLA-G 3{\textquoteright} untranslated region (UTR) polymorphisms 14 bp insertion/deletion (rs66554220) and +3142C>G (rs1063320).

DESIGN: We analyzed 582 HIV-1 infected patients and 626 uninfected individuals from Brazil and Italy in a case-control study.

METHODS: HLA-G polymorphisms were genotyped using PCR, PCR-RFLP assays or direct sequencing. All analyses were stratified by ethnicity. Genotypic, allelic and diplotypic frequencies were compared between HIV-1 infected subjects and controls using Chi-square or Fischer exact tests. Also, haplotypic frequencies were estimated using MLocus software.

RESULTS: African-derived HIV-infected individuals presented a higher frequency of the 14 bp insertion allele as compared to non-infected individuals (0.468 versus 0.373, respectively; p(Bonf) = 0.010). A higher frequency of the 14 bp insertion +3142G (insG) haplotype (0.456 versus 0.346, p<0.001) and the insG/insG diplotype (OR=1.88, 95\%CI = 1.08-3.23, p=0.021) was observed among African-derived patients as compared to uninfected controls. Also, we observed a higher frequency of the ins/ins genotype among African-derived HIV patients co-infected with HCV (OR=2.78, 95\%CI = 1.20-6.49, p = 0.008).

CONCLUSIONS: Our data point out to an increased frequency of alleles and genotypes associated with low HLA-G expression among African-derived patients, suggesting a potential role for HLA-G in the susceptibility to HIV-1 infection and HCV co-infection in those individuals.

}, keywords = {3{\textquoteright} Untranslated Regions, Adolescent, Adult, African Continental Ancestry Group, Aged, Brazil, Coinfection, Gene Frequency, Genetic Variation, Haplotypes, Hepatitis C, HIV Infections, HLA-G Antigens, Humans, Italy, Male, Middle Aged, Polymorphism, Single Nucleotide, Young Adult}, issn = {1567-7257}, doi = {10.1016/j.meegid.2013.12.013}, author = {da Silva, G K and Vianna, Priscila and Veit, Tiago Degani and Crovella, Sergio and Catamo, Eulalia and Cordero, Elvira Alicia Aparicio and Mattevi, Vanessa Su{\~n}{\'e} and Lazzaretti, Rosmeri Kuhmmer and Sprinz, Eduardo and Kuhmmer, Regina and Chies, Jos{\'e} Artur Bogo} } @article {3485, title = {Inhibition of mesenchymal stromal cells by pre-activated lymphocytes and their culture media.}, journal = {Stem Cell Res Ther}, volume = {5}, year = {2014}, month = {2014}, pages = {3}, abstract = {

INTRODUCTION: Despite having a proven immunosuppressive potential in vitro, human mesenchymal stromal cells (MSCs) are reported to display variable efficacy in vivo and, in fact, their proven benefit in the clinical practice is still limited and controversial.

METHODS: The interplay between clinical grade MSCs and pre-activated donor lymphocytes or selected lymphocyte subsets was studied in vitro. The kinetics of MSC growth and viability was evaluated by adhesion-dependent changes of culture plate impedance and biochemically by a colorimetric assay. Activation of natural killer (NK) cells was assessed as well, using a flow cytometry assay.

RESULTS: A strong inhibition of MSC growth was rapidly induced by the addition of pre-activated lymphocytes but not of resting lymphocytes. Inhibition seems not to be attributable to a single cell population, as similar results can be obtained by depleting NK cells or by using either selected CD4+ or CD8+ lymphocytes. In addition, conditioned medium (CM) from activated lymphocytes was able to inhibit MSC growth in a dose-dependent manner. Furthermore, licensing with IFN-γ partially protected MSCs from pre-activated lymphocytes but not from their CM. These results suggest an inhibitory role of lymphocyte-activation-derived substances. However, the identification of a single molecule responsible for MSC inhibition remained elusive, even if preliminary experiments showed that ATP and, to a lesser extent, TNF-α might play a role.

CONCLUSIONS: These results suggest that survival of MSCs can be affected by soluble mediators released by activated lymphocytes. Thus it can be hypothesized that MSC immunosuppressive action in vivo could be impaired by ongoing immune activation through the release of inflammatory mediators.

}, keywords = {CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Proliferation, Cell Survival, Cells, Cultured, Coculture Techniques, Culture Media, Conditioned, Cytokines, Humans, Killer Cells, Natural, Lymphocyte Activation, Mesenchymal Stromal Cells}, issn = {1757-6512}, doi = {10.1186/scrt392}, author = {Valencic, Erica and Loganes, Claudia and Cesana, Stefania and Piscianz, Elisa and Gaipa, Giuseppe and Biagi, Ettore and Tommasini, Alberto} } @article {3628, title = {Medical treatments for endometriosis-associated pelvic pain.}, journal = {Biomed Res Int}, volume = {2014}, year = {2014}, month = {2014}, pages = {191967}, abstract = {

The main sequelae of endometriosis are represented by infertility and chronic pelvic pain. Chronic pelvic pain causes disability and distress with a very high economic impact. In the last decades, an impressive amount of pharmacological agents have been tested for the treatment of endometriosis-associated pelvic pain. However, only a few of these have been introduced into clinical practice. Following the results of the controlled studies available, to date, the first-line treatment for endometriosis associated pain is still represented by oral contraceptives used continuously. Progestins represent an acceptable alternative. In women with rectovaginal lesions or colorectal endometriosis, norethisterone acetate at low dosage should be preferred. GnRH analogues may be used as second-line treatment, but significant side effects should be taken into account. Nonsteroidal anti-inflammatory drugs are widely used, but there is inconclusive evidence for their efficacy in relieving endometriosis-associated pelvic pain. Other agents such as GnRH antagonist, aromatase inhibitors, immunomodulators, selective progesterone receptor modulators, and histone deacetylase inhibitors seem to be very promising, but there is not enough evidence to support their introduction into routine clinical practice. Some other agents, such as peroxisome proliferator activated receptors-γ ligands, antiangiogenic agents, and melatonin have been proven to be efficacious in animal studies, but they have not yet been tested in clinical studies.

}, keywords = {Endometriosis, Female, Gonadotropin-Releasing Hormone, Histone Deacetylase Inhibitors, Hormone Antagonists, Humans, Pain Management, Pelvic Pain, Progestins}, issn = {2314-6141}, doi = {10.1155/2014/191967}, author = {Zito, Gabriella and Luppi, Stefania and Giolo, Elena and Martinelli, Monica and Venturin, Irene and Di Lorenzo, Giovanni and Ricci, Giuseppe} } @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 {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 {3624, title = {NLRP3 polymorphism is associated with protection against human T-lymphotropic virus 1 infection.}, journal = {Mem Inst Oswaldo Cruz}, volume = {109}, year = {2014}, month = {2014 Nov}, pages = {960-3}, abstract = {

Inter-individual heterogeneity in the response to human T-lymphotropic virus 1 (HTLV-1) infection has been partially attributed to host genetic background. The antiviral activity of the inflammasome cytoplasmic complex recognises viral molecular patterns and regulates immune responses via the activation of interleukin (IL)-1 family (IL-1, IL-18 and IL-33) members. The association between polymorphisms in the inflammasome receptors NLRP1 and NLRP3 and HTLV-1 infection was evaluated in a northeastern Brazilian population (84 HTLV-1 carriers and 155 healthy controls). NLRP3 rs10754558 G/G was associated with protection against HTLV-1 infection (p = 0.012; odds ratio = 0.37). rs10754558 affects NLRP3 mRNA stability; therefore, our results suggest that higher NLRP3 expression may augment first-line defences, leading to the effective protection against HTLV-1 infection.

}, keywords = {Adult, Brazil, Carrier Proteins, Female, Genetic Predisposition to Disease, HTLV-I Infections, Human T-lymphotropic virus 1, Humans, Inflammasomes, Interleukin-1, Male, Middle Aged, Polymorphism, Single Nucleotide, Protective Factors}, issn = {1678-8060}, author = {Kamada, Anselmo Jiro and Pontillo, Alessandra and Guimar{\~a}es, Rafael Lima and Loureiro, Paula and Crovella, Sergio and Brand{\~a}o, Lucas Andr{\'e} Cavalcanti} } @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 {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 {3546, title = {Pregnancy and postpartum following a prenatal diagnosis of fetal thoracoabdominal malformation: the parental perspective.}, journal = {J Pediatr Surg}, volume = {49}, year = {2014}, month = {2014 Feb}, pages = {353-8}, abstract = {

PURPOSE: The study{\textquoteright}s aim was to evaluate how information related to a prenatal diagnosis of fetal malformation could modify parenthood experience descriptions during pregnancy and after the child{\textquoteright}s birth.

METHODS: A longitudinal case-control clinical study was conducted. Data on parenthood experience descriptions collected using a validated semantic differential technique during pregnancy and after the child{\textquoteright}s birth were compared between seven couples of parents receiving a prenatal diagnosis of fetal malformation and seven couples without any fetal diagnosis.

RESULTS: Our results show that during pregnancy parents in the clinical group describe themselves as more fragile, passive, and timid [p=0.007] than those in the control group. On the other hand, after the child{\textquoteright}s birth, there are no significant differences between groups.

CONCLUSIONS: Data are discussed with reference to better knowledge of the psychological dynamics involved in becoming a parent and to rational planning of support for parents receiving a diagnosis of fetal malformation.

}, keywords = {Adult, Case-Control Studies, Counseling, Cystic Adenomatoid Malformation of Lung, Congenital, Female, Hernia, Diaphragmatic, Hernias, Diaphragmatic, Congenital, Humans, Hydronephrosis, Kidney Diseases, Longitudinal Studies, Male, Musculoskeletal Abnormalities, Parents, Pregnancy, Psychological Tests, Stress, Psychological, Ultrasonography, Prenatal, Urogenital Abnormalities}, issn = {1531-5037}, doi = {10.1016/j.jpedsurg.2013.07.025}, author = {Giuliani, Rosella and Tripani, Antonella and Pellizzoni, Sandra and Clarici, Andrea and Lonciari, Isabella and D{\textquoteright}Ottavio, Giuseppina and Schleef, Jurgen} } @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 {3574, title = {Salt-inducible kinase 3, SIK3, is a new gene associated with hearing.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Dec 1}, pages = {6407-18}, abstract = {

Hearing function is known to be heritable, but few significant and reproducible associations of genetic variants have been identified to date in the adult population. In this study, genome-wide association results of hearing function from the G-EAR consortium and TwinsUK were used for meta-analysis. Hearing ability in eight population samples of Northern and Southern European ancestry (n = 4591) and the Silk Road (n = 348) was measured using pure-tone audiometry and summarized using principal component (PC) analysis. Genome-wide association analyses for PC1-3 were conducted separately in each sample assuming an additive model adjusted for age, sex and relatedness of subjects. Meta-analysis was performed using 2.3 million single-nucleotide polymorphisms (SNPs) tested against each of the three PCs of hearing ability in 4939 individuals. A single SNP lying in intron 6 of the salt-inducible kinase 3 (SIK3) gene was found to be associated with hearing PC2 (P = 3.7{\texttimes}10(-8)) and further supported by whole-genome sequence in a subset. To determine the relevance of this gene in the ear, expression of the Sik3 protein was studied in mouse cochlea of different ages. Sik3 was expressed in murine hair cells during early development and in cells of the spiral ganglion during early development and adulthood. Our results suggest a developmental role of Sik3 in hearing and may be required for the maintenance of adult auditory function.

}, keywords = {Age Factors, Animals, Cochlea, European Continental Ancestry Group, Genome-Wide Association Study, Hearing, Humans, Mice, Inbred C57BL, Polymorphism, Single Nucleotide, Protein Kinases}, issn = {1460-2083}, doi = {10.1093/hmg/ddu346}, author = {Wolber, Lisa E and Girotto, Giorgia and Buniello, Annalisa and Vuckovic, Dragana and Pirastu, Nicola and Lorente-C{\'a}novas, Beatriz and Rudan, Igor and Hayward, Caroline and Polasek, Ozren and Ciullo, Marina and Mangino, Massimo and Steves, Claire and Concas, Maria Pina and Cocca, Massilimiliano and Spector, Tim D and Gasparini, Paolo and Steel, Karen P and Williams, Frances M K} } @article {3577, title = {Serum amyloid protein A concentration in cryopyrin-associated periodic syndromes patients treated with interleukin-1 beta antagonist.}, journal = {Clin Exp Rheumatol}, volume = {32}, year = {2014}, month = {2014 Jul-Aug}, pages = {S63-6}, abstract = {

OBJECTIVES: Cryopyrin-associated periodic syndromes (CAPS) are a group of chronic, relapsing autoinflammatory disorders which may be complicated by systemic AA amyloidosis. The aim of our study was to evaluate serum amyloid protein A (SAA) level in CAPS patients treated with Interleukin-1beta (IL-1β) antagonist and to correlate its level with treatment response.

METHODS: All patients of CAPS Italian Register treated with IL-1β inhibitor were enrolled. SAA levels before starting therapy, and at last visit were evaluated. Patients were then divided in complete responders and partial responders.

RESULTS: Twenty-five patients were enrolled. SAA level before starting therapy was increased (median 118.5 mg/L, IQR 96.4-252.8; normal value <6.4 mg/L), while at last visit SAA was significantly reduced (median 4.3 mg/L, IQR 2.3-12.7) (p<0.001). However 12 patients still presented SAA levels beyond normal range, 10/25 patients (40\%) showed a complete response to treatment. Conversely, 15 patients presented only a partial response, of which 12 for increased SAA value and 3 for increased CRP value. Patients with partial response had SAA values significantly higher than patients with complete response (median 12.6 mg/L; IQR 8.3-20.0 vs. 2.7 mg/L; IQR 1.6-4.1, p<0.001).

CONCLUSIONS: Our results confirm the long term efficacy of anti IL-1β treatment in CAPS and the decrease of SAA levels; however 48\% of patients still presented SAA elevation despite treatment. The real risk of these patients in developing amyloidosis is not clear but the persistent increase of SAA needs a close follow-up.

}, keywords = {Adolescent, Adult, Amyloidosis, Child, Child, Preschool, Cryopyrin-Associated Periodic Syndromes, Drug Monitoring, Female, Humans, Immunosuppressive Agents, Interleukin-1beta, Male, Middle Aged, Serum Amyloid A Protein, Treatment Outcome, Young Adult}, issn = {0392-856X}, author = {Pastore, Serena and Paloni, Giulia and Caorsi, Roberta and Ronfani, Luca and Taddio, Andrea and Lepore, Loredana} } @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 {3519, title = {Severe neonatal hyperbilirubinemia and UGT1A1 promoter polymorphism.}, journal = {J Pediatr}, volume = {165}, year = {2014}, month = {2014 Jul}, pages = {42-5}, abstract = {

OBJECTIVE: To assess whether UGT1A1 promoter polymorphisms associated with Gilbert Syndrome (GS) occur with a greater frequency in neonates with severe hyperbilirubinemia.

STUDY DESIGN: In a case-control study performed at a single hospital center in Italy, 70 case subjects with severe hyperbilirubinemia (defined as bilirubin level >=20~mg/dL or 340~μmol/L) and 70 controls (bilirubin level <12~mg/dL or 210~μmol/L) were enrolled. Both case and control subjects were full term newborns. Polymerase chain reaction analysis on blood spot was performed to determine the frequency of UGTA1A1 promoter polymorphisms in cases and controls.

RESULTS: No statistical difference in the prevalence of UGTA1A1 gene variants was found between cases and controls (P~=~1). Thirteen infants homozygous for (TA)7 polymorphism associated with GS were in the case group (18.6\%) and 14 in the control group (20.0\%). A heterozygous group was also equally distributed between cases (44.3\%) and controls (42.9\%). No (TA)8 repeat was found in the 2 groups.

CONCLUSIONS: In our study population, GS polymorphism alone does not appear to play a major role in severe neonatal hyperbilirubinemia in neonates without signs of hemolysis.

}, keywords = {Case-Control Studies, Female, Genotype, Gilbert Disease, Glucuronosyltransferase, Humans, Hyperbilirubinemia, Neonatal, Infant, Newborn, Male, Polymerase Chain Reaction, Polymorphism, Genetic, Prevalence, Promoter Regions, Genetic}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2014.03.013}, author = {Travan, Laura and Lega, Sara and Crovella, Sergio and Montico, Marcella and Panontin, Elisa and Demarini, Sergio} } @article {3625, title = {Short communication: novel truncating mutations in the CFTR gene causing a severe form of cystic fibrosis in Italian patients.}, journal = {Genet Mol Res}, volume = {13}, year = {2014}, month = {2014}, pages = {9636-41}, abstract = {

Cystic fibrosis (CF) is a common recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. More than 1800 different mutations have been described to date. Here, we report 3 novel mutations in CFTR in 3 Italian CF patients. To detect and identify 36 frequent mutations in Caucasians, we used the INNO-LiPA CFTR19 and INNO-LiPA CFTR17+Tn Update kits (Innogenetics; Ghent, Belgium). Our first analysis did not reveal both of the responsible mutations; thus, direct sequencing of the CFTR gene coding region was performed. The 3 patients were compound heterozygous. In one allele, the F508del (c.1521_1523delCTT, p.PHE508del) mutation in exon 11 was observed in each case. For the second allele, in patient No.1, direct sequencing revealed an 11-base pair deletion (GAGGCGATACT) in exon 14 (c.2236_2246del; pGlu746Alafs*29). In patient No. 2, direct sequencing revealed a nonsense mutation at nucleotide 3892 (c.3892G>T) in exon 24. In patient No. 3, direct sequencing revealed a deletion of cytosine in exon 27 (c.4296delC; p.Asn1432Lysfs*16). These 3 novel mutations indicate the production of a truncated protein, which consequently results in a non-functional polypeptide.

}, keywords = {Alleles, Base Sequence, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, DNA Mutational Analysis, Exons, Female, Heterozygote, Humans, Infant, Infant, Newborn, Italy, Molecular Sequence Data, Mutation, Open Reading Frames, Severity of Illness Index}, issn = {1676-5680}, doi = {10.4238/2014.November.14.8}, author = {Lenarduzzi, S and Morgutti, M and Crovella, S and Coiana, A and Rosatelli, M C} } @article {3527, title = {Soluble TRAIL is present at high concentrations in seminal plasma and promotes spermatozoa survival.}, journal = {Reproduction}, volume = {148}, year = {2014}, month = {2014 Aug}, pages = {191-8}, abstract = {

The expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL(TNFSF10)) and of its receptors (TRAILR1, TRAILR2, TRAILR3, and TRAILR4) have been documented in testis, but the presence of soluble TRAIL in seminal fluid, as well as the potential physiopathological role of the TRAIL/TRAILR system in spermatozoa, has not been previously investigated. Male donors (n=123) among couples presenting for infertility evaluation were consecutively enrolled in this study. The presence of soluble TRAIL was analyzed in seminal samples by ELISA, while the surface expression of TRAIL receptors was investigated by flow cytometry. High levels of soluble TRAIL were detected in seminal plasma (median, 11 621 pg/ml and mean{\textpm}s.d., 13 371{\textpm}8367 pg/ml) and flow cytometric analysis revealed a variable expression of TRAIL receptors in the sperm cellular fraction among different subjects. In addition, the effect of physiologically relevant concentrations of recombinant TRAIL was investigated on survival and motility of spermatozoa. Of interest, the in vitro exposure of capacitated spermatozoa to recombinant TRAIL (10 ng/ml) significantly preserved their overall survival. Therefore, the present study demonstrates for the first time the presence of elevated levels of the anti-inflammatory cytokine TRAIL in seminal fluids. Moreover, the demonstration that recombinant TRAIL promotes spermatozoa survival after capacitation suggests potential therapeutic implications.

}, keywords = {Adult, Apoptosis, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Infertility, Male, Male, Receptors, TNF-Related Apoptosis-Inducing Ligand, Semen, Sperm Capacitation, Sperm Motility, Spermatozoa, TNF-Related Apoptosis-Inducing Ligand}, issn = {1741-7899}, doi = {10.1530/REP-14-0144}, author = {Zauli, Giorgio and Celeghini, Claudio and Monasta, Lorenzo and Martinelli, Monica and Luppi, Stefania and Gonelli, Arianna and Grill, Vittorio and Ricci, Giuseppe and Secchiero, Paola} } @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 {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 {3511, title = {Use of placebo in a trial of thalidomide for pediatric Crohn disease--reply.}, journal = {JAMA}, volume = {311}, year = {2014}, month = {2014 Mar 26}, pages = {1251-2}, keywords = {Crohn Disease, Female, Humans, Immunosuppressive Agents, Male, Thalidomide}, issn = {1538-3598}, doi = {10.1001/jama.2014.1278}, author = {Lazzerini, Marzia and Martelossi, Stefano and Ventura, Alessandro} } @article {1796, title = {Amenorrhea in women treated with thalidomide: report of two cases and literature review.}, journal = {Inflamm Bowel Dis}, volume = {19}, year = {2013}, month = {2013 Jan}, pages = {E10-1}, keywords = {Adolescent, Amenorrhea, Colitis, Ulcerative, Crohn Disease, Female, Humans, Review Literature as Topic, Thalidomide}, issn = {1536-4844}, doi = {10.1002/ibd.22845}, author = {Lazzerini, Marzia and Bramuzzo, Matteo and Martelossi, Stefano and Magazz{\`u}, Giuseppe and Pellegrino, Salvatore and Ventura, Alessandro} } @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 {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 {1974, title = {Under pressure.}, journal = {Eur J Pediatr}, volume = {172}, year = {2013}, month = {2013 Mar}, pages = {417}, abstract = {

Physical urticaria is a rare but challenging subset of chronic urticaria. Wheals of pressure urticaria are typically delayed in appearance. A pressure test can easily be done to confirm the diagnosis.

}, keywords = {Child, Humans, Male, Pressure, Urticaria}, issn = {1432-1076}, doi = {10.1007/s00431-012-1819-0}, author = {De Cunto, Angela and Berti, Irene and Minute, Marta and Longo, Giorgio} } @article {1857, title = {Accuracy of diagnostic antibody tests for coeliac disease in children: summary of an evidence report.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {54}, year = {2012}, month = {2012 Feb}, pages = {229-41}, abstract = {

OBJECTIVE: The aim of this study was to summarise the evidence from 2004 to September 2009 on the performance of laboratory-based serological and point of care (POC) tests for diagnosing coeliac disease (CD) in children using histology as reference standard.

PATIENTS AND METHODS: We searched MEDLINE and EMBASE for studies reporting on children for tests based on IgA and IgG anti-gliadin (AGA), endomysial (EmA), anti-transglutaminase-2 (TG2), and anti-deamidated gliadin peptides (DGP) antibodies or POC tests. For inclusion, histological analysis of duodenal biopsies and sensitivity and specificity for index tests had to be reported. Data were pooled and summary measures calculated for sensitivity, specificity, positive and negative likelihood ratios ("LR+", "LR-"), and diagnostic odds ratios (DOR). In case of elevated statistical heterogeneity, studies reaching 90\% sensitivity or specificity were reported.

RESULTS: A total of 2510 articles were reviewed; 16 entered meta-analysis, reporting on 3110 patients (1876 with CD, 1234 without CD). For IgA-EmA, sensitivity was >=90\% in 7/11 studies and pooled specificity 98.2\%. For IgA-anti-TG2, 11/15 studies yielded sensitivities >=90\% and 13/15 specificities >=90\%. For IgA-DGP, sensitivity ranged between 80.7\% and 95.1\% (specificity 86.3\%-93.1\%); for IgG-DGP between 80.1\% and 98.6\% (specificity 86.0-96.9\%). IgA-EmA had the highest pooled DOR (554) and LR+ (31.8) for a laboratory test, followed by IgA-anti-TG2, IgG-DGP, IgA-DGP and IgA-AGA. POC tests showed a pooled sensitivity of 96.4\% for IgA-TG2 (specificity 97.7\%).

CONCLUSIONS: IgA-EmA and IgA-anti-TG2 tests appear highly accurate to diagnose CD. IgG-anti-DGP tests may help in excluding CD. IgA-AGA and IgA-DGP tests show inferior accuracy. POC tests may achieve high accuracy in the hands of experienced readers, but IgA-anti-TG2/EmA were superior.

}, keywords = {Autoantibodies, Biological Markers, Celiac Disease, Child, Gliadin, GTP-Binding Proteins, Humans, Immunoglobulin A, Immunoglobulin G, Point-of-Care Systems, Sensitivity and Specificity, Transglutaminases}, issn = {1536-4801}, doi = {10.1097/MPG.0b013e318216f2e5}, author = {Giersiepen, Klaus and Lelgemann, Monika and Stuhldreher, Nina and Ronfani, Luca and Husby, Steffen and Koletzko, Sibylle and Korponay-Szab{\'o}, Ilma R} } @article {1793, title = {Adverse effects during specific oral tolerance induction: in home phase.}, journal = {Allergol Immunopathol (Madr)}, volume = {40}, year = {2012}, month = {2012 Jan-Feb}, pages = {41-50}, abstract = {

BACKGROUND: Specific oral tolerance induction (SOTI) is a promising approach for severe food allergies. There are little data in the literature regarding the home-phase of SOTI, not only with regard to type and frequency of adverse reactions but also regarding the most suitable treatment and protocol.

AIMS: To define the incidence and severity of adverse reactions, possible risk factors, and the safety and effectiveness of the home-phase of an original SOTI protocol in a large group of children with severe cow{\textquoteright}s milk (CM) allergy, after the hospital "rush" phase.

METHODS: The study was conducted by recording in-home phase adverse events, success and failure as reported by parents, and calling families. Adverse reactions were treated following the International Guidelines, arbitrarily modified by introducing nebulised epinephrine for respiratory reactions, oral beclomethasone for acute gastric pain and oral cromolyn for recurrent gastric pain.

RESULTS: Out of 140 patients, 132 were contacted; eight were inaccessible (follow-up 2-84 months). The number of adverse reactions was 1 in every 100 doses. The reactions were treated with nebulised epinephrine (221 reactions), IM epinephrine (6 reactions), and other drugs. Patients with high specific IgE levels (greater than 100 kU(A)/L) and lower CM dose (less than 5 ml) at the end of in-hospital phase showed a higher risk both for number of reactions and use of nebulised epinephrine.

CONCLUSIONS: The home phase of SOTI was characterised by a significant number of adverse reactions, mostly managed with an acceptable rate of side effects. Nebulised epinephrine played a pivotal role in respiratory reactions.

}, keywords = {Adolescent, Adult, Age Factors, Allergens, Child, Child, Preschool, Desensitization, Immunologic, Epinephrine, Female, Food Hypersensitivity, Humans, Immune Tolerance, Immunoglobulin E, Male, Milk Hypersensitivity, Nebulizers and Vaporizers}, issn = {1578-1267}, doi = {10.1016/j.aller.2011.05.004}, author = {Barbi, E and Longo, G and Berti, I and Matarazzo, L and Rubert, L and Saccari, A and Lenisa, I and Ronfani, L and Radillo, O and Ventura, A} } @article {1895, title = {Adverse effects during specific oral tolerance induction: in-hospital "rush" phase.}, journal = {Eur Ann Allergy Clin Immunol}, volume = {44}, year = {2012}, month = {2012 Feb}, pages = {18-25}, abstract = {

BACKGROUND: Specific oral tolerance induction (SOTI) is a promising approach in the treatment of severe food allergies. Different protocols have demonstrated its efficacy. Nevertheless, SOTI is still considered an experimental method and should be limited to highly controlled settings.

AIMS: To define the incidence and severity of adverse reactions, possible risk factors, and the safety and effectiveness of nebulized epinephrine as a first-line treatment of respiratory reactions during in-hospital SOTI for cow{\textquoteright}s milk allergy.

MATERIALS AND METHODS: A retrospective study was conducted by reviewing the medical records of patients admitted for SOTI beginning in 2001. Reactions were classified as mild, moderate and severe on a partially modified Clark scale. Adverse reactions were treated following the International Guidelines with the introduction of nebulized epinephrine for level four reactions.

RESULTS: Of 209 patients, 17 were excluded due to the absence of objective reactions. The remaining 192 were classified as follows: Mild Reactions (Clark Scale 1 to 3): 100 patients received either no treatment, oral antihistamines or nebulized steroids; Moderate Reactions (Clark Scale 4): 87 patients treated with nebulized epinephrine and, depending on their symptoms, oral antihistamines, corticosteroids (nebulized, oral or IV) or nebulized beta 2 agonists; Severe Reactions (Clark Scale 5): 5 children, 4 of whom initially underwent one nebulization of epinephrine and eventually required an IM dose. The fifth patient was immediately treated with IM epinephrine due to hypotension.

DISCUSSION: adverse reactions during this in-hospital SOTI protocol were frequent but easily manageable. Nebulized epinephrine can play a relevant role in the treatment of respiratory reactions.

}, keywords = {Administration, Inhalation, Anaphylaxis, Animals, Bronchodilator Agents, Child, Desensitization, Immunologic, Epinephrine, Humans, Milk, Milk Hypersensitivity, Retrospective Studies}, issn = {1764-1489}, author = {Barbi, E and Longo, G and Berti, I and Neri, E and Saccari, A and Rubert, L and Matarazzo, L and Montico, M and Ventura, A} } @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 {1965, title = {Association between the JC polyomavirus infection and male infertility.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e42880}, abstract = {

In recent years the incidence of male infertility has increased. Many risk factors have been taken into consideration, including viral infections. Investigations into viral agents and male infertility have mainly been focused on human papillomaviruses, while no reports have been published on polyomaviruses and male infertility. The aim of this study was to verify whether JC virus and BK virus are associated with male infertility. Matched semen and urine samples from 106 infertile males and 100 fertile males, as controls, were analyzed. Specific PCR analyses were carried out to detect and quantify large T (Tag) coding sequences of JCV and BKV. DNA sequencing, carried out in Tag JCV-positive samples, was addressed to viral protein 1 (VP1) coding sequences. The prevalence of JCV Tag sequences in semen and urine samples from infertile males was 34\% (72/212), whereas the BKV prevalence was 0.94\% (2/212). Specifically, JCV Tag sequences were detected in 24.5\% (26/106) of semen and 43.4\% (46/106) of urine samples from infertile men. In semen and urine samples from controls the prevalence was 11\% and 28\%, respectively. A statistically significant difference (p<0.05) in JCV prevalence was disclosed in semen and urine samples of cases vs. controls. A higher JC viral DNA load was detected in samples from infertile males than in controls. In samples from infertile males the JC virus type 2 strain, subtype 2b, was more prevalent than ubiquitous type 1. JCV type 2 strain infection has been found to be associated with male infertility. These data suggest that the JC virus should be taken into consideration as an infectious agent which is responsible for male infertility.

}, keywords = {Adult, Amino Acid Sequence, Amino Acid Substitution, Base Sequence, BK Virus, Capsid Proteins, DNA, Viral, Humans, Infertility, Male, JC Virus, Male, Molecular Sequence Data, Polyomavirus Infections, Semen, Sequence Analysis, DNA, Tumor Virus Infections}, issn = {1932-6203}, doi = {10.1371/journal.pone.0042880}, author = {Comar, Manola and Zanotta, Nunzia and Croci, Eleonora and Murru, Immacolata and Marci, Roberto and Pancaldi, Cecilia and Dolcet, Ornella and Luppi, Stefania and Martinelli, Monica and Giolo, Elena and Ricci, Giuseppe and Tognon, Mauro} } @article {1880, title = {CD14 polymorphisms correlate with an augmented risk for celiac disease in Italian patients.}, journal = {Genes Immun}, volume = {13}, year = {2012}, month = {2012 Sep}, pages = {489-95}, abstract = {

Celiac disease (CD) is a T-cell-mediated chronic inflammatory disease characterized by autoimmune, immunological and environmental components, where genetic factors in addition to the main known risk factors (gliadin and human leukocyte antigen (HLA)-DQ haplotypes) are supposed to be involved. CD14 is a multifunctional receptor involved in the bacterial lipopolysaccharides-dependent signal transduction. The CD14 gene maps on the long arm of chromosome 5 (5q22-q32), a {\textquoteright}hotbed{\textquoteright} region for CD; promoter polymorphisms are known to influence its expression. In this study we analyzed three CD14 promoter polymorphisms (c.-1359G>T, c.-1145A>G and c.-159C>T, ) in 938 CD Italian patients and 533 healthy controls, with known HLA-DQ haplotypes, with the aim of evaluating their possible association with the disease. The c.-1145A>G G and c.-159C>T T alleles (as well as the combination of the two alleles in the GT haplotype), were identified as susceptibility factors for CD development, being significantly more frequent in CD patients than in healthy controls. This association was also confirmed when the analysis was restricted to only those subjects characterized by HLA-DQ risk haplotypes. Our results indicate the involvement of CD14 gene polymorphisms in the susceptibility to CD.

}, keywords = {Adolescent, Adult, Aged, Antigens, CD14, Case-Control Studies, Celiac Disease, Child, Child, Preschool, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Haplotypes, HLA Antigens, Humans, Infant, Italy, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Young Adult}, issn = {1476-5470}, doi = {10.1038/gene.2012.23}, author = {Catamo, E and Segat, L and Lenarduzzi, S and Petix, V and Morgutti, M and Crovella, S} } @article {1922, title = {Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIbα (Bolzano mutation).}, journal = {Haematologica}, volume = {97}, year = {2012}, month = {2012 Jan}, pages = {82-8}, abstract = {

BACKGROUND: Bernard-Soulier syndrome is a very rare form of inherited thrombocytopenia that derives from mutations in GPIbα, GPIbβ, or GPIX and is typically inherited as a recessive disease. However, some years ago it was shown that the monoallelic c.515C>T transition in the GPIBA gene (Bolzano mutation) was responsible for macrothrombocytopenia in a few Italian patients.

DESIGN AND METHODS: Over the past 10 years, we have searched for the Bolzano mutation in all subjects referred to our institutions because of an autosomal, dominant form of thrombocytopenia of unknown origin.

RESULTS: We identified 42 new Italian families (103 cases) with a thrombocytopenia induced by monoallelic Bolzano mutation. Analyses of the geographic origin of affected pedigrees and haplotypes indicated that this mutation originated in southern Italy. Although the clinical expression was variable, patients with this mutation typically had a mild form of Bernard-Soulier syndrome with mild thrombocytopenia and bleeding tendency. The most indicative laboratory findings were enlarged platelets and reduced GPIb/IX/V platelet expression; in vitro platelet aggregation was normal in nearly all of the cases.

CONCLUSIONS: Our study indicates that monoallelic Bolzano mutation is the most frequent cause of inherited thrombocytopenia in Italy, affecting 20\% of patients recruited at our institutions during the last 10 years. Because many people from southern Italy have emigrated during the last century, this mutation may have spread to other countries.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Bernard-Soulier Syndrome, Child, Child, Preschool, Family Health, Female, Heterozygote, Humans, Infant, Italy, Male, Membrane Glycoproteins, Middle Aged, Mutation, Missense, Platelet Aggregation, Platelet Count, Platelet Glycoprotein GPIb-IX Complex, Polymorphism, Genetic, Thrombocytopenia, Thrombopoietin, Tubulin, Young Adult}, issn = {1592-8721}, doi = {10.3324/haematol.2011.050682}, author = {Noris, Patrizia and Perrotta, Silverio and Bottega, Roberta and Pecci, Alessandro and Melazzini, Federica and Civaschi, Elisa and Russo, Sabina and Magrin, Silvana and Loffredo, Giuseppe and Di Salvo, Veronica and Russo, Giovanna and Casale, Maddalena and De Rocco, Daniela and Grignani, Claudio and Cattaneo, Marco and Baronci, Carlo and Dragani, Alfredo and Albano, Veronica and Jankovic, Momcilo and Scianguetta, Saverio and Savoia, Anna and Balduini, Carlo L} } @article {1861, title = {Dealing with abdominal pain in children affected by systemic lupus erythematosus.}, journal = {Semin Arthritis Rheum}, volume = {41}, year = {2012}, month = {2012 Feb}, pages = {e3-4}, keywords = {Abdominal Pain, Female, Humans, Lupus Erythematosus, Systemic, Male}, issn = {1532-866X}, doi = {10.1016/j.semarthrit.2011.05.002}, author = {Taddio, Andrea and Ros{\'e}, Carlos and Lepore, Loredana and Ventura, Alessandro} } @article {1947, title = {Diagnosed child, treated child: food challenge as the first step toward tolerance induction in cow{\textquoteright}s milk protein allergy.}, journal = {Eur Ann Allergy Clin Immunol}, volume = {44}, year = {2012}, month = {2012 Apr}, pages = {54-60}, abstract = {

BACKGROUND: Food challenge is required to assess tolerance in cow milk (CM) allergy. A positive challenge contraindicates the reintroduction of CM. Specific oral tolerance induction (SOTI) is a promising treatment.

METHODS: All children admitted for a challenge were prospectively enrolled. To those tolerating between 2 and 150 ml a SOTI protocol was offered. Outcome, adverse reactions, parents{\textquoteright} satisfaction were recorded.

RESULTS: Out of 245 challenged patients, 175 reacted 122 out of 125, able to tolerate a minimum dose of 2 ml, underwent SOTI. After one year 75.4\% were in an unrestricted diet, 16.1\% tolerated between 5 and 150 ml, 8.5\% stopped SOTI. Side effects were mild, parents{\textquoteright} satisfaction was very high.

CONCLUSIONS: The majority of children tolerating limited amounts of CM at the challenge acquires tolerance with SOTI without relevant side effects. Maintaining on an exclusion diet partially tolerant children should be considered debatable.

}, keywords = {Administration, Oral, Adolescent, Animals, Cattle, Child, Child, Preschool, Humans, Immune Tolerance, Infant, Milk Hypersensitivity, Milk Proteins, Self Administration}, issn = {1764-1489}, author = {Longo, G and Berti, I and Barbi, E and Calligaris, L and Matarazzo, L and Radillo, O and Ronfani, L and Ventura, A} } @article {1935, title = {The dietary paradox in food allergy: yesterday{\textquoteright}s mistakes, today{\textquoteright}s evidence and lessons for tomorrow.}, journal = {Curr Pharm Des}, volume = {18}, year = {2012}, month = {2012}, pages = {5782-7}, abstract = {

During the last decades the prevalence of food allergy has significantly increased among children and antigen avoidance still remains the standard care for the management of this condition. Most reactions are IgE-mediated with a high risk of anaphylaxis requiring emergency medications in case of inadvertent ingestion. Recent studies showed that continuous administration of the offending food, rather than an elimination diet, could promote the development and maintenance of oral tolerance. Indeed, intestinal transit of food proteins and their interaction with gut-associated lymphoid tissue (GALT) is the essential prerequisite for oral tolerance. On the contrary, low-dose cutaneous exposure to environmental foods in children with atopic dermatitis and altered skin barrier facilitates allergic sensitization. The timing and the amount of cutaneous and oral exposure determine whether a child will have allergy or tolerance. Furthermore, previous preventive strategies such as the elimination diet during pregnancy and breastfeeding, prolonged exclusive breastfeeding and delayed weaning to solid foods did not succeed in preventing the development of food allergy. On the other hand, there could be an early narrow window of immunological opportunity to expose children to allergenic foods and induce natural tolerance. Finally, the gradual exposure to the offending food through special protocols of specific oral tolerance induction (SOTI) may be a promising approach to a proactive treatment of food allergy.

}, keywords = {Anaphylaxis, Antigens, Breast Feeding, Child, Dermatitis, Atopic, Female, Food Hypersensitivity, Humans, Immunoglobulin E, Pregnancy, Time Factors}, issn = {1873-4286}, author = {Badina, Laura and Barbi, Egidio and Berti, Irene and Radillo, Oriano and Matarazzo, Lorenza and Ventura, Alessandro and Longo, Giorgio} } @article {1924, title = {Efficacy of rifaximin vaginal tablets in treatment of bacterial vaginosis: a molecular characterization of the vaginal microbiota.}, journal = {Antimicrob Agents Chemother}, volume = {56}, year = {2012}, month = {2012 Aug}, pages = {4062-70}, abstract = {

Bacterial vaginosis (BV) is a common vaginal disorder characterized by an alteration of the vaginal bacterial morphotypes, associated with sexually transmitted infections and adverse pregnancy outcomes. The purpose of the present study was to evaluate the impact of different doses of rifaximin vaginal tablets (100 mg/day for 5 days, 25 mg/day for 5 days, and 100 mg/day for 2 days) on the vaginal microbiota of 102 European patients with BV enrolled in a multicenter, double-blind, randomized, placebo-controlled study. An integrated molecular approach based on quantitative PCR (qPCR) and PCR-denaturing gradient gel electrophoresis (PCR-DGGE) was used to investigate the effects of vaginal tablets containing the antibiotic. An increase in members of the genus Lactobacillus and a decrease in the BV-related bacterial groups after the antibiotic treatment were demonstrated by qPCR. PCR-DGGE profiles confirmed the capability of rifaximin to modulate the composition of the vaginal microbial communities and to reduce their complexity. This molecular analysis supported the clinical observation that rifaximin at 25 mg/day for 5 days represents an effective treatment to be used in future pivotal studies for the treatment of BV.

}, keywords = {Adolescent, Adult, Anti-Bacterial Agents, Double-Blind Method, Female, Humans, Lactobacillus, Metagenome, Middle Aged, Rifamycins, RNA, Ribosomal, 16S, Vagina, Vaginal Creams, Foams, and Jellies, Vaginosis, Bacterial, Young Adult}, issn = {1098-6596}, doi = {10.1128/AAC.00061-12}, author = {Cruciani, Federica and Brigidi, Patrizia and Calanni, Fiorella and Lauro, Vittoria and Tacchi, Raffaella and Donders, Gilbert and Peters, Klaus and Guaschino, Secondo and Vitali, Beatrice} } @article {1944, title = {Endoscopic treatment of primary vesicoureteral reflux.}, journal = {N Engl J Med}, volume = {367}, year = {2012}, month = {2012 Jul 5}, pages = {88; author reply 89}, keywords = {Female, Humans, Ureteroscopy, Vesico-Ureteral Reflux}, issn = {1533-4406}, doi = {10.1056/NEJMc1204964$\#$SA1}, author = {Pennesi, Marco and L{\textquoteright}erario, Ines and Barbi, Egidio} } @article {1843, title = {European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {54}, year = {2012}, month = {2012 Jan}, pages = {136-60}, abstract = {

OBJECTIVE: Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved.

METHODS: A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing.

RESULTS: In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative.

CONCLUSIONS: The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively.

}, keywords = {Adolescent, Celiac Disease, Child, Duodenum, HLA-DQ Antigens, Humans, Immunoglobulin A, Transglutaminases}, issn = {1536-4801}, doi = {10.1097/MPG.0b013e31821a23d0}, author = {Husby, S and Koletzko, S and Korponay-Szab{\'o}, I R and Mearin, M L and Phillips, A and Shamir, R and Troncone, R and Giersiepen, K and Branski, D and Catassi, C and Lelgeman, M and M{\"a}ki, M and Ribes-Koninckx, C and Ventura, A and Zimmer, K P} } @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 {1810, title = {Exhaled nitric oxide as a guide to management of asthma in pregnancy.}, journal = {Lancet}, volume = {379}, year = {2012}, month = {2012 Feb 25}, pages = {708; author reply 708-9}, keywords = {Asthma, Breath Tests, Female, Glucocorticoids, Humans, Nitric Oxide, Pregnancy, Pregnancy Complications}, issn = {1474-547X}, doi = {10.1016/S0140-6736(12)60300-6}, author = {Bibalo, Chiara and Badina, Laura and Longo, Giorgio and Ventura, Alessandro} } @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 {1960, title = {Genetics of food preferences: a first view from silk road populations.}, journal = {J Food Sci}, volume = {77}, year = {2012}, month = {2012 Dec}, pages = {S413-8}, abstract = {

Food preferences are the main factor driving food intake and choice. There are good reasons to suspect some genetic influence on food acceptance, not least because genetic factors are implicated in a number of factors that are likely to be related to food choice. In addition, some food dislikes show themselves early in life, before there is any evidence for aversive experiences. Although taste has been widely studied in regards of pure tastes such as bitter or sweet perception, the relationship between taste-related genes and food preferences has seldom been explored. In this work we investigated relationship of 37 taste-related genes with food preferences. The study was carried out during a scientific expedition through Caucasus and Central Asia (Silk Road) analyzing more than 400 samples from 5 different countries. A food preference questionnaire was administered to each participant and a DNA sample was obtained. Other information, such as age, sex, life style and anthropometrical measures, were also collected. We found significant associations with variants of: (1) TAS1R2 [Correction added after initial online publication on 27 Aug 2012. TAS1R3 was changed to TAS1R2.] gene and liking of Vodka (P= 1.6 {\texttimes} 10(-3)), white wine (P= 4.0 {\texttimes} 10(-4)) and lamb meat (P= 1.6 {\texttimes} 10(-3)); (2) PCLB2 gene and preference for Hot Tea (P= 8.0 {\texttimes} 10(-4)); (3) TPRV1 gene and beet liking (P= 3.8 {\texttimes} 10(-5)); and (4) ITPR3 gene and liking of both lamb meat (5.8 {\texttimes} 10(-4)) and sheep cheese (8.9{\texttimes}10(-4)). These findings give a new insight on a better understanding, of genetic factors influencing food preferences which is critical to the development of effective dietary interventions, especially for people that may be genetically not predisposed for liking specific nutrients.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Azerbaijan, Child, Choice Behavior, Cohort Studies, Female, Food Habits, Food Preferences, Gene Frequency, Genotype, Georgia, Humans, Kazakhstan, Linear Models, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Questionnaires, Tajikistan, Taste, Uzbekistan, Young Adult}, issn = {1750-3841}, doi = {10.1111/j.1750-3841.2012.02852.x}, author = {Pirastu, Nicola and Robino, Antonietta and Lanzara, Carmela and Athanasakis, Emmanouil and Esposito, Laura and Tepper, Beverly J and Gasparini, Paolo} } @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 {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 {1819, title = {How the newly introduced compression, airway, and breathing sequence affects the training in pediatric cardiopulmonary resuscitation.}, journal = {Am J Emerg Med}, volume = {30}, year = {2012}, month = {2012 Feb}, pages = {371-2}, keywords = {Cardiopulmonary Resuscitation, Clinical Competence, Feedback, Female, Heart Massage, Humans, Inservice Training, Male}, issn = {1532-8171}, doi = {10.1016/j.ajem.2011.08.006}, author = {Lubrano, Riccardo and Messi, Gianni and Elli, Marco} } @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 {1853, title = {Managing children under 36 months of age with febrile urinary tract infection: a new approach.}, journal = {Pediatr Nephrol}, volume = {27}, year = {2012}, month = {2012 Apr}, pages = {611-5}, abstract = {

BACKGROUND: Recent guidelines on urinary tract infection (UTI) agree on reducing the number of invasive procedures. None of these has been validated by a long-term study. We describe our 11-years experience in the application of a diagnostic protocol that uses a reduced number of invasive procedures.

METHODS: We reviewed retrospectively the records of 406 children aged between 1 and 36 months at their first UTI. All patients underwent renal ultrasound (RUS). Children with abnormal RUS and those with UTI recurrences underwent voiding cystourethrography (VCUG) and dimercaptosuccinic acid (DMSA) renal scans.

RESULTS: RUS after the first UTI was pathological in 7.4\% children; 4.4 \% had a second UTI. We performed 48 VCUG: 14 patients (29\%) had vesicoureteral reflux (VUR), 12 of which showed an abnormal RUS while 2 had recurrent UTI. After DMSA renal scan renal damage appeared in only 6 of them (12.5\%); all these children showed grade IV VUR.

CONCLUSIONS: The application of our guidelines leads to a decrease in invasive examinations without missing any useful diagnoses or compromising the child{\textquoteright}s health.

}, keywords = {Anti-Bacterial Agents, Child, Preschool, Female, Humans, Infant, Male, Pediatrics, Recurrence, Retrospective Studies, Urinary Tract Infections}, issn = {1432-198X}, doi = {10.1007/s00467-011-2087-3}, author = {Pennesi, Marco and L{\textquoteright}erario, Ines and Travan, Laura and Ventura, Alessandro} } @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 {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 {1925, title = {Oral zinc for treating diarrhoea in children.}, journal = {Cochrane Database Syst Rev}, volume = {6}, year = {2012}, month = {2012}, pages = {CD005436}, abstract = {

BACKGROUND: In developing countries, diarrhoea causes around two million child deaths annually. Zinc supplementation during acute diarrhoea is currently recommended by the World Health Organization and UNICEF.

OBJECTIVES: To evaluate oral zinc supplementation for treating children with acute or persistent diarrhoea.

SEARCH METHODS: In February 2012, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2011, Issue 11), MEDLINE, EMBASE, LILACS, CINAHL, mRCT, and reference lists. We also contacted researchers.

SELECTION CRITERIA: Randomized controlled trials comparing oral zinc supplementation with placebo in children aged one month to five years with acute or persistent diarrhoea, including dysentery.

DATA COLLECTION AND ANALYSIS: Both authors assessed trial eligibility and risk of bias, extracted and analysed data, and drafted the review. Diarrhoea duration and severity were the primary outcomes. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD) with 95\% confidence intervals (CI). Where appropriate, we combined data in meta-analyses (using the fixed- or random-effects model) and assessed heterogeneity.The quality of evidence has been assessed using the GRADE methods

MAIN RESULTS: Twenty-four trials, enrolling 9128 children, met our inclusion criteria. The majority of the data is from Asia, from countries at high risk of zinc deficiency, and may not be applicable elsewhere.Acute diarrhoeaThere is currently not enough evidence from well conducted randomized controlled trials to be able to say whether zinc supplementation during acute diarrhoea reduces death or hospitalization (very low quality evidence).In children aged greater than six months with acute diarrhoea, zinc supplementation may shorten the duration of diarrhoea by around 10 hours (MD -10.44 hours, 95\% CI -21.13 to 0.25; 2091 children, five trials, low quality evidence), and probably reduces the number of children whose diarrhoea persists until day seven (RR 0.73, 95\% CI 0.61 to 0.88; 3865 children, six trials, moderate quality evidence). In children with signs of moderate malnutrition the effect appears greater, reducing the duration of diarrhoea by around 27 hours (MD -26.98 hours, 95\% CI -14.62 to -39.34; 336 children, three trials, high quality evidence).Conversely, In children aged less than six months, the available evidence suggests zinc supplementation may have no effect on mean diarrhoea duration (MD 5.23 hours, 95\% CI -4.00 to 14.45; 1334 children, two trials, low quality evidence), and may even increase the proportion of children whose diarrhoea persists until day seven (RR 1.24, 95\% CI 0.99 to 1.54; 1074 children, one trial, moderate quality evidence).No trials reported serious adverse events, but zinc supplementation during acute diarrhoea causes vomiting in both age groups (RR 1.59, 95\% 1.27 to 1.99; 5189 children, 10 trials, high quality evidence).Persistent diarrhoeaIn children with persistent diarrhoea, zinc supplementation probably shortens the duration of diarrhoea by around 16 hours (MD -15.84 hours, 95\% CI -25.43 to -6.24; 529 children, five trials, moderate quality evidence).

AUTHORS{\textquoteright} CONCLUSIONS: In areas where the prevalence of zinc deficiency or the prevalence of moderate malnutrition is high, zinc may be of benefit in children aged six months or more.The current evidence does not support the use of zinc supplementation in children below six months of age.

}, keywords = {Acute Disease, Age Factors, Child, Child, Preschool, Diarrhea, Humans, Infant, Randomized Controlled Trials as Topic, Time Factors, Trace Elements, Zinc}, issn = {1469-493X}, doi = {10.1002/14651858.CD005436.pub3}, author = {Lazzerini, Marzia and Ronfani, Luca} } @article {1882, title = {Review of the scientific literature on the health of the Roma and Sinti in Italy.}, journal = {Ethn Dis}, volume = {22}, year = {2012}, month = {2012 Summer}, pages = {367-71}, abstract = {

BACKGROUND: Roma and Sinti in Italy are excluded from the rest of society, often live in precarious housing conditions and have poor access to health services. In Italy, the Roma and Sinti minority (.3\% of the overall population) is scarcely represented if compared with other European countries.

METHODS: To establish what is known and how Roma and Sinti health is studied in Italy, we conducted a review of the scientific literature, including articles published between 2000 and 2010, found in Medline, Embase and Web of Science.

RESULTS: We analyzed 15 relevant articles out of 32 references. Four papers describe rare autosomal recessive disorders. Four illustrate outbreaks of measles. The remaining papers describe health conditions suffered by this minority. All but two, however, are based on data collected at health services.

CONCLUSIONS: The lack of prevalence data and analysis of determinants is a detriment to the health of the Roma and Sinti populations in Italy. Participatory research and evidence-based interventions are needed to improve health outcomes and living conditions of the Roma and Sinti people.

}, keywords = {Gypsies, Health Services Accessibility, Health Status, Housing, Humans, Italy, Minority Groups, Prejudice}, issn = {1049-510X}, author = {Monasta, Lorenzo and Erenbourg, Anna and Restaino, Stefano and Lutje, Vittoria and Ronfani, Luca} } @article {1818, title = {Should cardiac involvement be included in the criteria for diagnosis of Churg Strauss syndrome?}, journal = {J Pediatr}, volume = {160}, year = {2012}, month = {2012 Apr}, pages = {707}, keywords = {Adolescent, Churg-Strauss Syndrome, Heart Diseases, Humans, Male}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2011.09.057}, author = {Amaddeo, Alessandro and Ventura, Alessandro and Marchetti, Federico and Benettoni, Alessandra and Londero, Margherita} } @article {1926, title = {The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status.}, journal = {Haematologica}, volume = {97}, year = {2012}, month = {2012 Nov}, pages = {1722-30}, abstract = {

BACKGROUND: Both the multi-kinase inhibitor sorafenib and the small molecule inhibitor of the MDM2/p53 interaction, nutlin-3, used alone, have shown promising anti-leukemic activity in acute myeloid leukemia cells. Thus, in this study we investigated the effect of the combination of sorafenib plus nutlin-3 in acute myeloid leukemia.

DESIGN AND METHODS: Primary acute myeloid leukemia blasts (n=13) and FLT3(wild-type)/p53(wild-type) (OCI-AML3), FLT3(mutated)/p53(wild-type) (MOLM), FLT3(mutated)/p53(mutated) (MV4-11), FLT3(wild-type)/p53(deleted) (HL60) or FLT3(wild-type)/p53(mutated) (NB4) acute myeloid cell lines were exposed to sorafenib, used alone or in association with nutlin-3 at a 1:1 ratio, in a range of clinically achievable concentrations (1-10 μM). Induction of apoptosis and autophagy was evaluated by transmission electron microscopy and by specific flow cytometry analyses. The levels of Mcl-1, p53 and Bak proteins were analyzed by western blotting. Knock-down of Bax and Bak gene expression was performed in transfection experiments with specific short interfering RNA.

RESULTS: The sorafenib+nutlin-3 drug combination exhibits synergistic cytotoxicity in primary acute myeloid leukemia blasts and in acute myeloid leukemia cell lines with maximal cytotoxicity in FLT3(mutated) MV4-11 and MOLM, followed by the FLT3(wild-type) OCI-AML3, HL60 and NB4 cell lines. The cytotoxic activity of sorafenib+nutlin-3 was characterized by an increase of both apoptosis and autophagy. Moreover, Bax and Bak showed prominent roles in mediating the decrease of cell viability in response to the drug combination in p53(wild-type) OCI-AML3 and p53(deleted) HL-60 cells, respectively, as demonstrated in transfection experiments performed with specific short interfering RNA.

CONCLUSIONS: Our data demonstrate that acute myeloid leukemia cells show a variable but overall good susceptibility to the innovative therapeutic combination of sorafenib+nutlin-3, which differentially involves the pro-apoptotic Bcl-2 family members Bax and Bak in p53(wild-type) and p53(deleted) cells.

}, keywords = {Antineoplastic Agents, Drug Synergism, Female, fms-Like Tyrosine Kinase 3, HL-60 Cells, Humans, Imidazoles, Leukemia, Myeloid, Acute, Male, Niacinamide, Phenylurea Compounds, Piperazines, Tumor Suppressor Protein p53}, issn = {1592-8721}, doi = {10.3324/haematol.2012.062083}, author = {Zauli, Giorgio and Celeghini, Claudio and Melloni, Elisabetta and Voltan, Rebecca and Ongari, Manuele and Tiribelli, Mario and di Iasio, Maria Grazia and Lanza, Francesco and Secchiero, Paola} } @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 {1872, title = {Thoracoscopic removal of a bulky cystic mediastinal mature teratoma in a 4-year-old child: report of one case and few surgical tricks.}, journal = {Eur J Pediatr Surg}, volume = {22}, year = {2012}, month = {2012 Aug}, pages = {318-20}, keywords = {Child, Preschool, Female, Humans, Mediastinal Neoplasms, Teratoma, Thoracoscopy, Tomography, X-Ray Computed}, issn = {1439-359X}, doi = {10.1055/s-0032-1308697}, author = {Codrich, Daniela and Lembo, Maria Antonietta and Schleef, Jurgen} } @article {1910, title = {Treatment with pamidronate for osteoporosis complicating long-term intestinal failure.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {55}, year = {2012}, month = {2012 Nov}, pages = {615-8}, abstract = {

Long-term home parenteral nutrition (PN) is a potential risk for developing osteoporosis. Various attempts have been made to treat bone disease both by modifying the composition of PN and by administering hormones, such as calcitonin, parathyroid hormone, and sexual hormones. Bisphosphonates are recognized as a medication useful for the treatment of several bone disorders associated with excessive reabsorption. Nevertheless, there have been no paediatric studies on bisphosphonates use for intestinal failure-associated bone disease. Our study includes 6 paediatric patients receiving extremely long-term home PN (at least 3 years) who showed radiological and clinical signs of osteoporosis. Diagnosis of bone disease was made after a median period of 127.5 PN months. Treatment consisted in 2 cycles of intravenous pamidronate, 30 mg/m once per month for 6 months consecutively. They all showed a significant improvement in bone mineral density, evaluated after 6 and 12 months of pamidronate treatment. In our sample anthropometrical variables (weight, height, and body mass index) are not related with the z-score trend. Our patients had normal levels of calcium, phosphorus, and vitamin D, and proper nutrient intake. At the last follow-up, dual-energy x-ray absorptiometry scan showed that no patients had a z-score lower than -2.5; moreover, nobody developed bone fractures during the 108-month follow-up. The patients did not have any prominent adverse effect. Finally, in our experience, pamidronate is effective for improving bone mineral density and safe in patients with intestinal failure-associated bone disease.

}, keywords = {Absorptiometry, Photon, Adolescent, Bone Density, Bone Density Conservation Agents, Child, Child, Preschool, Diphosphonates, Female, Humans, Intestinal Diseases, Male, Osteoporosis, Parenteral Nutrition, Home}, issn = {1536-4801}, doi = {10.1097/MPG.0b013e31825f1c7d}, author = {Pastore, S and Londero, M and Barbieri, F and Di Leo, G and Paparazzo, R and Ventura, A} } @article {1770, title = {Acute cardiac valvular involvement in Kawasaki Disease.}, journal = {Clin Exp Rheumatol}, volume = {29}, year = {2011}, month = {2011 Jan-Feb}, pages = {S140}, keywords = {Adrenal Cortex Hormones, Child, Preschool, Female, Heart Valve Diseases, Humans, Immunoglobulins, Intravenous, Immunosuppressive Agents, Infant, Male, Mucocutaneous Lymph Node Syndrome, Treatment Outcome}, issn = {0392-856X}, author = {Pellegrin, Maria Chiara and Taddio, Andrea and Lepore, Loredana} } @article {1771, title = {Antibiotics in severely malnourished children: systematic review of efficacy, safety and pharmacokinetics.}, journal = {Bull World Health Organ}, volume = {89}, year = {2011}, month = {2011 Aug 1}, pages = {594-607}, abstract = {

OBJECTIVE: To systemically review the evidence in support of World Health Organization guidelines recommending broad-spectrum antibiotics for children with severe acute malnutrition (SAM).

METHODS: CENTRAL, MEDLINE, EMBASE, LILACS, POPLINE, CAB Abstracts and ongoing trials registers were searched. Experts were contacted. Conference proceedings and reference lists were manually searched. All study types, except single case reports, were included.

FINDINGS: Two randomized controlled trials (RCTs), one before-and-after study and two retrospective reports on clinical efficacy and safety were retrieved, together with 18 pharmacokinetic studies. Trial quality was generally poor and results could not be pooled due to heterogeneity. Oral amoxicillin for 5~days was as effective as intramuscular ceftriaxone for 2~days (1 RCT). For uncomplicated SAM, amoxicillin showed no benefit over placebo (1 retrospective study). The introduction of a standardized regimen using ampicillin and gentamicin significantly reduced mortality in hospitalized children (odds ratio, OR: 4.0; 95\% confidence interval, CI: 1.7-9.8; 1~before-and-after study). Oral chloramphenicol was as effective as trimethoprim-sulfamethoxazole in children with pneumonia (1 RCT). Pharmacokinetic data suggest that normal doses of penicillins, cotrimoxazole and gentamicin are safe in malnourished children, while the dose or frequency of chloramphenicol requires adjustment. Existing evidence is not strong enough to further clarify recommendations for antibiotic treatment in children with SAM.

CONCLUSION: Large RCTs are needed to define optimal antibiotic treatment in children with SAM with and without complications. Further research into gentamicin and chloramphenicol toxicity and into the pharmacokinetics of ceftriaxone and ciprofloxacin is also required.

}, keywords = {Anti-Bacterial Agents, Child, Child Nutrition Disorders, Child, Preschool, Humans, Severity of Illness Index, Treatment Outcome}, issn = {1564-0604}, doi = {10.2471/BLT.10.084715}, author = {Lazzerini, Marzia and Tickell, David} } @article {1797, title = {Anti-α-enolase Antibodies in Serum from Pediatric Patients Affected by Inflammatory Diseases: Diagnostic and Pathogenetic Insights.}, journal = {Int J Rheumatol}, volume = {2011}, year = {2011}, month = {2011}, pages = {870214}, abstract = {

Human glycolytic enzyme α-enolase was associated with human diseases and with inflammation. An ELISA test was developed to measure anti-α-enolase AAE IgG and AAE IgA in the serum from patients affected by inflammatory diseases with the purpose to evaluate it as a novel diagnostic marker. 80 healthy blood donors and 194 paediatric patients affected by Juvenile idiopathic arthritis (JIA), celiac disease (CD), Crohn{\textquoteright}s Disease (CrD), hereditary periodic fever (HPF), and PFAPA syndrome were included in the study. HPF patients showed high levels of AAE antibodies, whereas JIA, CD, and CrD presented only partial results. Benign fevers such as PFAPA were almost negative for AAE Abs. These findings suggested that the genetic dysfunction of inflammasome associated with HPF could lead to the formation of AAE Abs that could be used for an early and easy diagnosis.

}, issn = {1687-9279}, doi = {10.1155/2011/870214}, author = {Pontillo, Alessandra and Di Toro, Nicola and Edomi, Paolo and Shadlow, A and Ammadeo, A and Gattorno, M and Not, T and Lepore, L and Crovella, S} } @article {1703, title = {Association of a variant in the CHRNA5-A3-B4 gene cluster region to heavy smoking in the Italian population.}, journal = {Eur J Hum Genet}, volume = {19}, year = {2011}, month = {2011 May}, pages = {593-6}, abstract = {

Large-scale population studies have established that genetic factors contribute to individual differences in smoking behavior. Linkage and genome-wide association studies have shown many chromosomal regions and genes associated with different smoking behaviors. One study was the association of single-nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 gene cluster to nicotine addiction. Here, we report a replication of this association in the Italian population represented by three genetically isolated populations. One, the Val Borbera, is a genetic isolate from North-Western Italy; the Cilento population, is located in South-Western Italy; and the Carlantino village is located in South-Eastern Italy. Owing to their position and their isolation, the three populations have a different environment, different history and genetic structure. The variant A of the rs1051730 SNP was significantly associated with smoking quantity in two populations, Val Borbera and Cilento, no association was found in Carlantino population probably because difference in LD pattern in the variant region.

}, keywords = {Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Italy, Multigene Family, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Receptors, Nicotinic, Smoking, Tobacco Use Disorder}, issn = {1476-5438}, doi = {10.1038/ejhg.2010.240}, author = {Sorice, Rossella and Bione, Silvia and Sansanelli, Serena and Ulivi, Sheila and Athanasakis, Emmanouil and Lanzara, Carmela and Nutile, Teresa and Sala, Cinzia and Camaschella, Clara and d{\textquoteright}Adamo, Pio and Gasparini, Paolo and Ciullo, Marina and Toniolo, Daniela} } @article {1772, title = {Atlanto-axial joint involvement as exclusive manifestation of juvenile idiopathic arthritis (JIA).}, journal = {Clin Exp Rheumatol}, volume = {29}, year = {2011}, month = {2011 Jul-Aug}, pages = {755}, keywords = {Antirheumatic Agents, Arthritis, Juvenile, Atlanto-Axial Joint, Child, Dislocations, Female, Glucocorticoids, Humans, Magnetic Resonance Imaging, Pulse Therapy, Drug, Torticollis, Treatment Outcome, Uveitis}, issn = {0392-856X}, author = {Taddio, A and Pellegrin, M C and Gregori, M and Wientroub, S and Padeh, S and Lepore, L} } @article {1613, title = {Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome.}, journal = {Clin Immunol}, volume = {139}, year = {2011}, month = {2011 Apr}, pages = {6-11}, abstract = {

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive organ-specific autoimmune disorder that is characterized by a variable combination of (i) chronic mucocutaneous candidiasis, (ii) polyendocrinopathy and/or hepatitis and (iii) dystrophy of the dental enamel and nails. We analyzed the AIRE (autoimmune regulator) gene in subjects who presented any symptom that has been associated with APECED, including candidiasis and autoimmune endocrinopathy. We observed that 83.3\% of patients presented at least two of the three typical manifestations of APECED, while the remaining 16.7\% of patients showed other signs of the disease. Analysis of the genetic diagnosis of these subjects revealed that a considerable delay occurs in the majority of patients between the appearance of symptoms and the diagnosis. Overall, the mean diagnostic delay in our patients was 10.2 years. These results suggest that molecular analysis of AIRE should be performed in patients with relapsing mucocutaneous candidiasis for early identification of APECED.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Heterozygote, Homozygote, Humans, Middle Aged, Mutation, Polyendocrinopathies, Autoimmune, Time Factors, Young Adult}, issn = {1521-7035}, doi = {10.1016/j.clim.2010.12.021}, author = {Mazza, Cinzia and Buzi, Fabio and Ortolani, Federica and Vitali, Alberto and Notarangelo, Lucia D and Weber, Giovanna and Bacchetta, Rosa and Soresina, Annarosa and Lougaris, Vassilios and Greggio, Nella A and Taddio, Andrea and Pasic, Srdjan and de Vroede, Monique and Pac, Malgorzata and Kilic, Sara Sebnem and Ozden, Sanal and Rusconi, Roberto and Martino, Silvana and Capalbo, Donatella and Salerno, Mariacarolina and Pignata, Claudio and Radetti, Giorgio and Maggiore, Giuseppe and Plebani, Alessandro and Notarangelo, Luigi D and Badolato, Raffaele} } @article {1803, title = {Decreased levels of soluble TNF-related apoptosis-inducing ligand (TRAIL) in the conjunctival sac fluid of patients with diabetes affected by proliferative retinopathy.}, journal = {Diabet Med}, volume = {28}, year = {2011}, month = {2011 Oct}, pages = {1277-8}, keywords = {Apoptosis Regulatory Proteins, Body Fluids, Conjunctiva, Diabetic Retinopathy, Female, Humans, Male, Middle Aged, Receptors, TNF-Related Apoptosis-Inducing Ligand, TNF-Related Apoptosis-Inducing Ligand}, issn = {1464-5491}, doi = {10.1111/j.1464-5491.2010.03202.x}, author = {Secchiero, P and Perri, P and Melloni, E and Martini, A and Lamberti, G and Sebastiani, A and Zauli, G} } @article {1858, title = {ESPGHAN{\textquoteright}s 2008 recommendation for early introduction of complementary foods: how good is the evidence?}, journal = {Matern Child Nutr}, volume = {7}, year = {2011}, month = {2011 Oct}, pages = {335-43}, abstract = {

Since 2002, the World Health Organization and many governments and professional associations have recommended exclusive breastfeeding for 6 months followed by complementary feeding (giving solid foods alongside breast milk) as optimal infant feeding practice. Several articles have been published challenging this recommendation. Arguably, the most influential has been the 2008 commentary of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition, which recommended that complementary foods should be introduced to all infants between 17 and 26 weeks. We challenge the validity of ESPGHAN{\textquoteright}s position, questioning the adequacy of the literature search, the interpretation and evidence used to reach their conclusions and the balance of an approach that focuses on disease prevention, with scant consideration of growth and neuromotor development. We contend that ESPGHAN{\textquoteright}s position should be understood as an expert opinion that may be influenced by conflicts of interest. In our view, the ESPGHAN position paper is not evidence based and does not justify a change of the current public health recommendation for 6 months of exclusive breastfeeding. At an individual level, health professionals should understand that developmental readiness for starting solid foods has an age range like other developmental milestones; that fewer infants will probably be ready to start complementary feeding before, rather than after, 6 months; and that their role is to equip parents with the confidence and skills to recognise the signs of developmental readiness. This empowerment process for infants and parents should be preferred over the prescriptive ESPGHAN approach.

}, keywords = {Breast Feeding, Evidence-Based Practice, Humans, Infant, Infant Food, Infant Nutritional Physiological Phenomena, Milk, Human, Nutritional Status, Public Health, Reproducibility of Results, World Health Organization}, issn = {1740-8709}, doi = {10.1111/j.1740-8709.2011.00363.x}, author = {Cattaneo, Adriano and Williams, Carol and Pall{\'a}s-Alonso, Carmen Rosa and Hern{\'a}ndez-Aguilar, Maria Teresa and Lasarte-Velillas, Juan Jos{\'e} and Landa-Rivera, Leonardo and Rouw, Elien and Pina, M{\'o}nica and Volta, Alessandro and Oudesluys-Murphy, Anne Marie} } @article {1652, title = {Genetic predictors of glucocorticoid response in pediatric patients with inflammatory bowel diseases.}, journal = {J Clin Gastroenterol}, volume = {45}, year = {2011}, month = {2011 Jan}, pages = {e1-7}, abstract = {

BACKGROUND: Glucocorticoids (GCs) are used in moderate-to-severe inflammatory bowel diseases (IBD) but their effect is often unpredictable.

AIM: To determine the influence of 4 polymorphisms in the GC receptor [nuclear receptor subfamily 3, group C, member 1 (NR3C1)], interleukin-1β (IL-1β), and NACHT leucine-rich-repeat protein 1 (NALP1) genes, on the clinical response to steroids in pediatric patients with IBD.

METHODS: One hundred fifty-four young IBD patients treated with GCs for at least 30 days and with a minimum follow-up of 1 year were genotyped. The polymorphisms considered are the BclI in the NR3C1 gene, C-511T in IL-1β gene, and Leu155His and rs2670660/C in NALP1 gene. Patients were grouped as responder, dependant, and resistant to GCs. The relation between GC response and the genetic polymorphisms considered was examined using univariate, multivariate, and Classification and Regression Tree (CART) analysis.

RESULTS: Univariate analysis showed that BclI polymorphism was more frequent in responders compared with dependant patients (P=0.03) and with the combined dependant and resistant groups (P=0.02). Moreover, the NALP1 Leu155His polymorphism was less frequent in the GC responsive group compared with resistant (P=0.0059) and nonresponder (P=0.02) groups. Multivariate analysis comparing responders and nonresponders confirmed an association between BclI mutated genotype and steroid response (P=0.030), and between NALP1 Leu155His mutant variant and nonresponders (P=0.033). An association between steroid response and male sex was also observed (P=0.034). In addition, Leu155His mutated genotype was associated with steroid resistance (P=0.034). Two CART analyses supported these findings by showing that BclI and Leu155His polymorphisms had the greatest effect on steroid response (permutation P value=0.046). The second CART analysis also identified age of disease onset and male sex as important variables affecting response.

CONCLUSIONS: These results confirm that genetic and demographic factors may affect the response to GCs in young patients with IBD and strengthen the importance of studying high-order interactions for predicting response.

}, keywords = {Adolescent, Child, Drug Resistance, Female, Follow-Up Studies, Genotype, Glucocorticoids, Humans, Inflammatory Bowel Diseases, Male, Multivariate Analysis, Polymorphism, Genetic, Receptors, Glucocorticoid, Regression Analysis, Retrospective Studies, Sex Factors, Treatment Outcome}, issn = {1539-2031}, doi = {10.1097/MCG.0b013e3181e8ae93}, author = {De Iudicibus, Sara and Stocco, Gabriele and Martelossi, Stefano and Londero, Margherita and Ebner, Egle and Pontillo, Alessandra and Lionetti, Paolo and Barabino, Arrigo and Bartoli, Fiora and Ventura, Alessandro and Decorti, Giuliana} } @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 {1781, title = {In vivo distribution of β2 glycoprotein I under various pathophysiologic conditions.}, journal = {Blood}, volume = {118}, year = {2011}, month = {2011 Oct 13}, pages = {4231-8}, abstract = {

In vitro studies have documented β2 glycoprotein I (β2GPI) binding to endothelial cells (ECs) and trophoblast using antiphospholipid antibodies. The in vivo binding of β2GPI to these cells and the conditions that favor their interaction have not been investigated. We analyzed the in vivo distribution of cyanine 5.5-labeled β2GPI in mice and evaluated the effect of pregnancy and circulating antibodies on its tissue localization. The signal was detected in the liver by whole body scan and ex vivo analysis. The β2GPI failed to bind to the vascular endothelium and reacted only with the ECs of uterine vessels. In pregnant mice the protein was localized on ECs and trophoblast at the embryo implantation sites. Immunized mice showed a similar β2GPI biodistribution to naive mice but the immunized pregnant animals exhibited a significant increase in fetal loss associated with C3 and C9 deposition at the implantation sites. Treatment of mice with LPS after β2GPI-Cy5.5 injection promoted protein localization on gut and brain ECs associated with IgG, C1q, and C9 deposition in immunized mice. These findings indicate that β2GPI binding to EC requires priming with pro-inflammatory factors which is not needed for uterine and placental localization probably dependent on hormonal changes.

}, keywords = {Animals, beta 2-Glycoprotein I, Complement C1q, Complement C3, Complement C9, Endothelial Cells, Endothelium, Vascular, Female, Fetal Death, Humans, Mice, Mice, Inbred BALB C, Pregnancy, Trophoblasts, Uterus}, issn = {1528-0020}, doi = {10.1182/blood-2011-01-333617}, author = {Agostinis, Chiara and Biffi, Stefania and Garrovo, Chiara and Durigutto, Paolo and Lorenzon, Andrea and Bek, Alpan and Bulla, Roberta and Grossi, Claudia and Borghi, Maria O and Meroni, Pierluigi and Tedesco, Francesco} } @article {1676, title = {Interventions for the prevention of overweight and obesity in preschool children: a systematic review of randomized controlled trials.}, journal = {Obes Rev}, volume = {12}, year = {2011}, month = {2011 May}, pages = {e107-18}, abstract = {

The objective of this study was to analyse interventions for the prevention of overweight and obesity in children under 5 years of age. We carried out a systematic review focusing exclusively on randomized controlled trials (RCTs). Data sources include Medline, Cochrane Library, EMBASE, CINHAL, PsychInfo and Web of Science. Data were extracted from seventeen articles describing seven RCTs identified through electronic search, screening of references in systematic reviews, own files and contact with authors. RCTs were assessed with the Jadad scale. Four trials were carried out in preschool settings, one with an exclusive educational component, two with an exclusive physical activity component and one with both. Two trials were family-based, with education and counselling for parents and children. The remaining trial was carried out in maternity hospitals, with a training intervention on breastfeeding. None of the interventions had an effect in preventing overweight and obesity. The failure to show an effect may be due to the choice of outcomes, the quality of the RCTs, the suboptimal implementation of the interventions, the lack of focus on social and environmental determinants. More rigorous research is needed on interventions and on social and environmental factors that could impact on lifestyle.

}, keywords = {Child Nutrition Sciences, Child Nutritional Physiological Phenomena, Child, Preschool, Exercise, Female, Health Promotion, Humans, Life Style, Male, Obesity, Overweight, Randomized Controlled Trials as Topic}, issn = {1467-789X}, doi = {10.1111/j.1467-789X.2010.00774.x}, author = {Monasta, L and Batty, G D and Macaluso, A and Ronfani, L and Lutje, V and Bavcar, A and van Lenthe, F J and Brug, J and Cattaneo, A} } @article {1619, title = {Mannose-binding lectin gene (MBL-2) polymorphism in oral lichen planus.}, journal = {Clin Oral Investig}, volume = {15}, year = {2011}, month = {2011 Oct}, pages = {699-704}, abstract = {

TNF-α may be associated with the etiopathogenesis of oral lichen planus (OLP), and it has been suggested that polymorphism of mannose-binding lectin (MBL) increases the in vitro production of TNF- α. The aim of the present study was to assess the relevance of genetic diversity of MBL in OLP. The study sample comprised 90 individuals, 45 OLP patients and 45 healthy volunteers. MBL-2 gene was amplified using real-time PCR. Frequency of A/A genotype was 55.6\% in OLP and 53.3\% in healthy volunteers. Likewise, A/0 heterozygote genotype was found in 42.2\% and 35.6\%; 2.2\% and 11.1\%, had the recessive 0/0 genotype respectively. Frequencies of the "A" and "0" alleles were 77\% and 23\% in the OLP group and 71.2\% in control group. There were no statistically significant differences regarding genotype frequency (p = 0.546) or allele frequency (p = 0.497). In conclusion, no significant association was found between polymorphism of MBL-2 gene and OLP.

}, keywords = {Adolescent, Adult, Aged, Female, Gene Expression Regulation, Gene Frequency, Genes, Recessive, Genetic Variation, Genotype, Heterozygote, Homozygote, Humans, Lichen Planus, Oral, Male, Mannose-Binding Lectin, Middle Aged, Mutation, Polymorphism, Genetic, Real-Time Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, Young Adult}, issn = {1436-3771}, doi = {10.1007/s00784-010-0428-4}, author = {Barkokebas, Andreza and de Albuquerque T Carvalho, Alessandra and de Souza, Paulo Roberto Eleut{\'e}rio and Gomez, Ricardo Santiago and Xavier, Guilherme Machado and Ribeiro, Camila Maria Beder and Crovella, Sergio and Porter, Stephen Ross and Le{\~a}o, Jair Carneiro} } @article {1847, title = {Marriage and parenthood among childhood cancer survivors: a report from the Italian AIEOP Off-Therapy Registry.}, journal = {Haematologica}, volume = {96}, year = {2011}, month = {2011 May}, pages = {744-51}, abstract = {

BACKGROUND: The aim of this study was to describe the patterns of marriage and parenthood in a cohort of childhood cancer survivors included in the Off-Therapy Registry maintained by the Italian Association of Pediatric Hematology and Oncology.

DESIGN AND METHODS: We analyzed a cohort of 6,044 patients diagnosed with cancer between 1960 and 1998, while aged 0 to 14 years and who were 18 years old or older by December 2003. They were followed up through the regional vital statistics registers until death or the end of follow up (October 30, 2006), whichever occurred first, and their marital status and date of birth of their children were recorded. The cumulative probabilities of being married and having a first child were computed by gender and compared by tumor type within the cohort. Marriage and fertility rates (the latter defined as the number of live births per woman-year) were compared with those of the Italian population of the same age, gender, area of residence and calendar period by means of the observed to expected (O/E) ratios.

RESULTS: During the follow-up period, 4,633 (77\%) subjects had not married. The marriage O/E ratios were 0.56 (95\% CI: 0.51-0.61) and 0.70 (95\% CI: 0.65-0.76) among men and women, respectively. Overall, 263 men had 367 liveborn children, and 473 women had 697 liveborn children. The female fertility O/E ratio was 0.57 (95\% CI: 0.53-0.62) overall, and 1.08 (95\% CI: 0.99-1.17) when analyses were restricted to married/cohabiting women

CONCLUSIONS: Childhood cancer survivors are less likely to marry and to have children than the general population, confirming the life-long impact of their previous disease on their social behavior and choices. The inclusion of counseling in the strategies of management and long-term surveillance of childhood cancer patients could be beneficial to survivors as they approach adulthood.

}, keywords = {Adult, Child, Child, Preschool, Cohort Studies, Female, Follow-Up Studies, Hematologic Neoplasms, Humans, Infant, Infant, Newborn, Italy, Male, Marriage, Middle Aged, Parents, Registries, Survivors}, issn = {1592-8721}, doi = {10.3324/haematol.2010.036129}, author = {Pivetta, Emanuele and Maule, Milena M and Pisani, Paola and Zugna, Daniela and Haupt, Riccardo and Jankovic, Momcilo and Aric{\`o}, Maurizio and Casale, Fiorina and Clerico, Anna and Cordero di Montezemolo, Luca and Kiren, Valentina and Locatelli, Franco and Palumbo, Giovanna and Pession, Andrea and Pillon, Marta and Santoro, Nicola and Terenziani, Monica and Valsecchi, Maria Grazia and Dama, Elisa and Magnani, Corrado and Merletti, Franco and Pastore, Guido} } @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 {1736, title = {Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families.}, journal = {Blood}, volume = {117}, year = {2011}, month = {2011 Jun 16}, pages = {6673-80}, abstract = {

Until recently, thrombocytopenia 2 (THC2) was considered an exceedingly rare form of autosomal dominant thrombocytopenia and only 2 families were known. However, we recently identified mutations in the 5{\textquoteright}-untranslated region of the ANKRD26 gene in 9 THC2 families. Here we report on 12 additional pedigrees with ANKRD26 mutations, 6 of which are new. Because THC2 affected 21 of the 210 families in our database, it has to be considered one of the less rare forms of inherited thrombocytopenia. Analysis of all 21 families with ANKRD26 mutations identified to date revealed that thrombocytopenia and bleeding tendency were usually mild. Nearly all patients had no platelet macrocytosis, and this characteristic distinguishes THC2 from most other forms of inherited thrombocytopenia. In the majority of cases, platelets were deficient in glycoprotein Ia and α-granules, whereas in vitro platelet aggregation was normal. Bone marrow examination and serum thrombopoietin levels suggested that thrombocytopenia was derived from dysmegakaryopoiesis. Unexplained high values of hemoglobin and leukocytes were observed in a few cases. An unexpected finding that warrants further investigation was a high incidence of acute leukemia. Given the scarcity of distinctive characteristics, the ANKRD26-related thrombocytopenia has to be taken into consideration in the differential diagnosis of isolated thrombocytopenias.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Ankyrin Repeat, Child, Cohort Studies, Family, Female, Gene Frequency, Humans, Inheritance Patterns, Male, Middle Aged, Mutation, Pedigree, Thrombocytopenia, Transcription Factors, Young Adult}, issn = {1528-0020}, doi = {10.1182/blood-2011-02-336537}, author = {Noris, Patrizia and Perrotta, Silverio and Seri, Marco and Pecci, Alessandro and Gnan, Chiara and Loffredo, Giuseppe and Pujol-Moix, N{\'u}ria and Zecca, Marco and Scognamiglio, Francesca and De Rocco, Daniela and Punzo, Francesca and Melazzini, Federica and Scianguetta, Saverio and Casale, Maddalena and Marconi, Caterina and Pippucci, Tommaso and Amendola, Giovanni and Notarangelo, Lucia D and Klersy, Catherine and Civaschi, Elisa and Balduini, Carlo L and Savoia, Anna} } @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 {1751, title = {Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Mar}, pages = {259-63}, abstract = {

Although mutations in CYTB (cytochrome b) or BCS1L have been reported in isolated defects of mitochondrial respiratory chain complex III (cIII), most cIII-defective individuals remain genetically undefined. We identified a homozygous nonsense mutation in the gene encoding tetratricopeptide 19 (TTC19) in individuals from two families affected by progressive encephalopathy associated with profound cIII deficiency and accumulation of cIII-specific assembly intermediates. We later found a second homozygous nonsense mutation in a fourth affected individual. We demonstrated that TTC19 is embedded in the inner mitochondrial membrane as part of two high-molecular-weight complexes, one of which coincides with cIII. We then showed a physical interaction between TTC19 and cIII by coimmunoprecipitation. We also investigated a Drosophila melanogaster knockout model for TTC19 that showed low fertility, adult-onset locomotor impairment and bang sensitivity, associated with cIII deficiency. TTC19 is a putative cIII assembly factor whose disruption is associated with severe neurological abnormalities in humans and flies.

}, keywords = {Adult, Animals, Brain, Codon, Nonsense, Drosophila melanogaster, Electron Transport Complex III, Female, Gene Knockdown Techniques, Humans, Male, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Nervous System Diseases}, issn = {1546-1718}, doi = {10.1038/ng.761}, author = {Ghezzi, Daniele and Arzuffi, Paola and Zordan, Mauro and Da Re, Caterina and Lamperti, Costanza and Benna, Clara and d{\textquoteright}Adamo, Pio and Diodato, Daria and Costa, Rodolfo and Mariotti, Caterina and Uziel, Graziella and Smiderle, Cristina and Zeviani, Massimo} } @article {1730, title = {Paediatric Beh{\c c}et{\textquoteright}s disease presenting with recurrent papillitis and episcleritis: a case report.}, journal = {J Med Case Rep}, volume = {5}, year = {2011}, month = {2011}, pages = {81}, abstract = {

INTRODUCTION: Beh{\c c}et{\textquoteright}s disease is a chronic multisystem vasculitis characterized by mucocutaneous, articular, neurological, gastrointestinal and ophthalmological lesions. Ocular involvement is mainly represented by recurrent uveitis, especially posterior uveitis; however, iridocyclitis, retinal and choroidal vasculitis, optic neuritis and retinal vascular occlusion can also occur.

CASE PRESENTATION: A 12-year-old Caucasian boy with a history of recurrent buccal aphthosis and nonspecific gastrointestinal symptoms was admitted to our hospital with blurred vision associated with acute episcleritis and papillitis. The patient{\textquoteright}s pathergy test was positive, suggesting a diagnosis of Beh{\c c}et{\textquoteright}s disease. Corticosteroid and cyclosporine therapy was started, but further episodes were noted in both eyes. The patient was then switched to intravenous infliximab, with complete resolution of the inflammation after the second infusion.

CONCLUSION: Episcleritis and papillitis should be added to the list of uncommon manifestations of pediatric Beh{\c c}et{\textquoteright}s disease. Infliximab is an effective, new therapeutic approach for Beh{\c c}et{\textquoteright}s disease that is refractory to the conventional corticosteroid and immunosuppressive therapy.

}, issn = {1752-1947}, doi = {10.1186/1752-1947-5-81}, author = {Parentin, Fulvio and Lepore, Loredana and Rabach, Ingrid and Pensiero, Stefano} } @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 {1733, title = {Phospholipase C-β3 is a key modulator of IL-8 expression in cystic fibrosis bronchial epithelial cells.}, journal = {J Immunol}, volume = {186}, year = {2011}, month = {2011 Apr 15}, pages = {4946-58}, abstract = {

Respiratory insufficiency is the major cause of morbidity and mortality in patients affected by cystic fibrosis (CF). An excessive neutrophilic inflammation, mainly orchestrated by the release of IL-8 from bronchial epithelial cells and amplified by chronic bacterial infection with Pseudomonas aeruginosa, leads to progressive tissue destruction. The anti-inflammatory drugs presently used in CF patients have several limitations, indicating the need for identifying novel molecular targets. To address this issue, we preliminarily studied the association of 721 single nucleotide polymorphisms from 135 genes potentially involved in signal transduction implicated in neutrophil recruitment in a cohort of F508del homozygous CF patients with either severe or mild progression of lung disease. The top ranking association was found for a nonsynonymous polymorphism of the phospholipase C-β3 (PLCB3) gene. Studies in bronchial epithelial cells exposed to P. aeruginosa revealed that PLCB3 is implicated in extracellular nucleotide-dependent intracellular calcium signaling, leading to activation of the protein kinase Cα and Cβ and of the nuclear transcription factor NF-κB p65. The proinflammatory pathway regulated by PLCB3 acts by potentiating the Toll-like Receptors{\textquoteright} signaling cascade and represents an interesting molecular target to attenuate the excessive recruitment of neutrophils without completely abolishing the inflammatory response.

}, keywords = {Adenosine Triphosphate, Calcium, Cell Line, Transformed, Cystic Fibrosis, Enzyme Activation, Epithelial Cells, Gene Expression, Gene Frequency, Genotype, Green Fluorescent Proteins, Host-Pathogen Interactions, Humans, Interleukin-8, Isoenzymes, Lung Diseases, Microscopy, Fluorescence, Phospholipase C beta, Polymorphism, Single Nucleotide, Protein Kinase C, Protein Kinase C beta, Pseudomonas aeruginosa, RNA Interference, Toll-Like Receptors, Transcription Factor RelA}, issn = {1550-6606}, doi = {10.4049/jimmunol.1003535}, author = {Bezzerri, Valentino and d{\textquoteright}Adamo, Pio and Rimessi, Alessandro and Lanzara, Carmen and Crovella, Sergio and Nicolis, Elena and Tamanini, Anna and Athanasakis, Emmanouil and Tebon, Maela and Bisoffi, Giulia and Drumm, Mitchell L and Knowles, Michael R and Pinton, Paolo and Gasparini, Paolo and Berton, Giorgio and Cabrini, Giulio} } @article {1644, title = {A polymorphism in the 5{\textquoteright} UTR of the DEFB1 gene is associated with the lung phenotype in F508del homozygous Italian cystic fibrosis patients.}, journal = {Clin Chem Lab Med}, volume = {49}, year = {2011}, month = {2011 Jan}, pages = {49-54}, abstract = {

BACKGROUND: The identification of cystic fibrosis (CF) patients who are at greater risk of lung damage could be clinically valuable. Thus, we attempted to replicate previous findings and verify the possible association between three single nucleotide polymorphisms (SNPs c.-52G>A, c.-44C>G and c.-20G>A) in the 5{\textquoteright} untranslated region (5{\textquoteright} UTR) of the β defensin 1 (DEFB1) gene and the CF pulmonary phenotype.

METHODS: Genomic DNA from 92 Italian CF patients enrolled in different regional CF centres was extracted from peripheral blood and genotyped for DEFB1 SNPs using TaqMan({\textregistered}) allele specific probes. In order to avoid genetic confounding causes that can account for CF phenotype variability, all patients were homozygous for the F508del CFTR mutation, and were then classified on the basis of clinical and functional data as mild lung phenotype (Mp, n=50) or severe lung phenotype patients (Sp, n=42).

RESULTS: For the c.-20G>A SNP, the frequency of the A allele, as well as the AA genotype, were significantly more frequent in Mp than in Sp patients, and thus this was associated with a protective effect against severe pulmonary disease (OR=0.48 and 0.28, respectively). The effect of the c.-20G>A A allele is consistent with a recessive model, and the protective effect against Sp is exerted only when it is present in homozygosis. For the other two SNPs, no differences were observed as allelic and genotypic frequency in the two subgroups of CF patients.

CONCLUSIONS: Our results, although necessary to be confirmed in larger and multiethnic populations, reinforce DEFB1 as a candidate modifier gene of the CF pulmonary phenotype.

}, keywords = {5{\textquoteright} Untranslated Regions, Adult, beta-Defensins, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Female, Genotype, Homozygote, Humans, Italy, Male, Mutation, Phenotype, Polymorphism, Genetic, Young Adult}, issn = {1437-4331}, doi = {10.1515/CCLM.2011.023}, author = {Crovella, Sergio and Segat, Ludovica and Amato, Annalisa and Athanasakis, Emmanouil and Bezzerri, Valentino and Braggion, Cesare and Casciaro, Rosaria and Castaldo, Giuseppe and Colombo, Carla and Covone, Angela Elvira and De Rose, Virginia and Gagliardini, Rolando and Lanzara, Carmen and Minicucci, Laura and Morgutti, Marcello and Nicolis, Elena and Pardo, Francesca and Quattrucci, Serena and Raia, Valeria and Ravazzolo, Roberto and Seia, Manuela and Stanzial, Valentino and Termini, Lisa and Zazzeron, Laura and Cabrini, Giulio and Gasparini, Paolo} } @article {1727, title = {Prevalence of anaemia in children with thromboembolism in IBD.}, journal = {Arch Dis Child}, volume = {96}, year = {2011}, month = {2011 Aug}, pages = {783}, keywords = {Anemia, Iron-Deficiency, Female, Humans, Male, Stroke}, issn = {1468-2044}, doi = {10.1136/adc.2011.211409}, author = {Bramuzzo, Matteo and Lazzerini, Marzia} } @article {1685, title = {Refractory iron-deficiency anaemia in a child with portal cavernoma.}, journal = {Gut}, volume = {60}, year = {2011}, month = {2011 Mar}, pages = {317, 377}, keywords = {Anemia, Iron-Deficiency, Antihypertensive Agents, Child, Hemangioma, Cavernous, Humans, Hypertension, Portal, Ileal Diseases, Male, Propranolol, Vascular Neoplasms}, issn = {1468-3288}, doi = {10.1136/gut.2009.184697}, author = {Pastore, Serena and Londero, Margherita and Cont, Gabriele and Di Leo, Grazia and Ventura, Alessandro} } @article {1684, title = {The resurgence of rheumatic fever in a developed country area: the role of echocardiography.}, journal = {Rheumatology (Oxford)}, volume = {50}, year = {2011}, month = {2011 Feb}, pages = {396-400}, abstract = {

OBJECTIVES: The annual incidence of ARF ranges from 5 to 51/100, 000 population worldwide in the 5- to 15-year age group. In the past, there was a decline in the incidence of ARF; however, focal outbreaks have been reported. This study evaluated the incidence of ARF in 2007-08 in a region of a developed country compared with the previous decade.

METHODS: A retrospective review of all admission records for ARF in Trieste between January 2007 and December 2008 was undertaken. The diagnosis of ARF was established by the Jones criteria according to the 1992 revision.

RESULTS: Between January 2007 and December 2008: 13 cases of ARF were recorded, 11 females and 2 males. The estimated incidence was 23 and 27/100, 000 population new cases each year, respectively, in the 5- to 15-year age group. Migratory polyarthritis occurred in 6/13, chorea in 7/13 and clinical carditis in 5/13 cases. Five out of 13 patients had only echocardiographic abnormalities, with no clinical cardiac manifestations. Another two patients did not fulfil diagnostic criteria for ARF, presenting with only three minor criteria, but they revealed silent carditis at echocardiography evaluation. During the follow-up, in one case the carditis receded and in the other it significantly improved.

CONCLUSIONS: Our experience underlines that ARF has not yet disappeared in industrialized countries. We observed a high incidence of chorea, always associated with mild carditis. Echocardiographic assessment should be routinely performed in all patients with suspected ARF in order to identify those subclinical cases of valvulitis that would otherwise pass undiagnosed without receiving proper prophylaxis.

}, keywords = {Adolescent, Child, Child, Preschool, Chorea, Developed Countries, Diagnosis, Differential, Echocardiography, Female, Humans, Italy, Male, Myocarditis, Retrospective Studies, Rheumatic Fever}, issn = {1462-0332}, doi = {10.1093/rheumatology/keq290}, author = {Pastore, Serena and De Cunto, Angela and Benettoni, Alessandra and Berton, Emanuela and Taddio, Andrea and Lepore, Loredana} } @article {1749, title = {The role of mannose-binding lectin gene polymorphisms in susceptibility to HIV-1 infection in Southern Brazilian patients.}, journal = {AIDS}, volume = {25}, year = {2011}, month = {2011 Feb 20}, pages = {411-8}, abstract = {

OBJECTIVE: This study investigates the role of mannose-binding lectin (MBL) in the susceptibility to HIV-1 infection analyzing polymorphisms located at the MBL2 promoter and exon 1 regions.

MATERIALS AND METHODS: The prevalence of MBL2 variant alleles was investigated in 410 HIV-1-infected patients from the South Brazilian HIV cohort and in 345 unexposed uninfected healthy individuals. The promoter variants were genotyped using polymerase chain reaction with sequence-specific primers (PCR-SSP) and exon 1 variants were analyzed by real-time PCR using a melting temperature assay and were confirmed by PCR-restriction fragment length polymorphism (RFLP). MBL2 genotypic and allelic frequencies were compared between HIV-1-infected patients and controls using the chi-squared tests.

RESULTS: The analyses were performed subdividing the individuals according to their ethnic origin. Among Euro-derived individuals a higher frequency of the LX/LX genotype was observed in patients when compared to controls (P < 0.001). The haplotypic analysis also showed a higher frequency of the haplotypes associated with lower MBL levels among HIV-1-infected patients (P = 0.0001). Among Afro-derived individuals the frequencies of LY/LY and HY/HY genotypes were higher in patients when compared to controls (P = 0.009 and P = 0.02).

CONCLUSIONS: An increased frequency of MBL2 genotypes associated with low MBL levels was observed in Euro-derived patients, suggesting a potential role for MBL in the susceptibility to HIV-1 infection in Euro-derived individuals.

}, keywords = {Adult, Aged, Brazil, Female, Genetic Predisposition to Disease, HIV Infections, HIV-1, Humans, Lectins, C-Type, Male, Mannose-Binding Lectin, Mannose-Binding Lectins, Middle Aged, Polymorphism, Genetic, Promoter Regions, Genetic, Receptors, Cell Surface, Young Adult}, issn = {1473-5571}, doi = {10.1097/QAD.0b013e328342fef1}, author = {da Silva, Gabriela Kniphoff and Guimar{\~a}es, Rafael and Mattevi, Vanessa Su{\~n}{\'e} and Lazzaretti, Rosmeri Kuhmmer and Sprinz, Eduardo and Kuhmmer, Regina and Brand{\~a}o, Lucas and Crovella, Sergio and Chies, Jos{\'e} Artur Bogo} } @article {1792, title = {A singular case of congenital self-healing histiocytosis with skin, liver and atypical eye involvement.}, journal = {Ocul Immunol Inflamm}, volume = {19}, year = {2011}, month = {2011 Oct}, pages = {337-9}, abstract = {

PURPOSE: To describe a rare case of congenital self-healing Langerhans cell histiocytosis (CSHLCH) presenting with atypical eye involvement.

DESIGN: Case report.

METHODS: A female newborn presented with purpuric lesions over the trunk, limbs, and face. Liver ultrasonography revealed hypoechogenic lesions with blurred borders. Biomicroscopy showed right posterior synechiae with fibrinoid deposits on the lens. At 7 months she presented with right acute glaucoma.

RESULTS: Biomicroscopy showed the presence of inflammatory pseudo-membrane covering the anterior surface of the lens, iris, and iridocorneal angle. Ab externo trabeculotomy was performed; access to the anterior chamber with capsulorrhexis forceps permitted a peeling of the pseudo-membrane with normalization of the intraocular pressure. Histologic examination of the membrane revealed an inflammatory tissue with CD1a and S-100 positive histiocytic cells.

CONCLUSIONS: This is the first case of CSHLCH describing acute glaucoma secondary to a pseudo-inflammatory membrane with typical histiocytic cells, occluding the iridocorneal angle.

}, keywords = {Antigens, CD1, Convalescence, Female, Glaucoma, Histiocytosis, Langerhans-Cell, Humans, Infant, Intraocular Pressure, Iridocorneal Endothelial Syndrome, Liver Diseases, S100 Proteins, Skin Diseases, Trabeculectomy}, issn = {1744-5078}, doi = {10.3109/09273948.2010.605538}, author = {Parentin, Fulvio and Ventura, Giovanna and Pastore, Serena and Kiren, Valentina and Bibalo, Chiara and Pensiero, Stefano and Lepore, Loredana} } @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 {1816, title = {Thromboembolism in pediatric inflammatory bowel disease: systematic review.}, journal = {Inflamm Bowel Dis}, volume = {17}, year = {2011}, month = {2011 Oct}, pages = {2174-83}, abstract = {

BACKGROUND: Several studies suggest an increased risk of venous and arterial thromboembolism (TE) in adults with inflammatory bowel disease (IBD) compared to the general population. We performed a systematic review of studies on incidence and characteristic of TE in children with IBD.

METHODS: We searched Medline, LILACS, EMBASE, POPLINE, CINHAL, and reference lists of identified articles, without language restrictions, in August 2010.

RESULTS: Population studies suggest that there is an increased risk of TE in children with IBD compared to controls. TE occurred in children with IBD in all age ranges, mostly (82.8\%) during active disease, and more frequently in children with ulcerative colitis (odds ratio [OR] 3.7, 95\% confidence interval [CI] 1.8-7.6). At least one specific risk factor for TE was recognized in 50\% of cases; two risk factors were present in 24\%. Out of 92 published cases of TE in children with IBD, 54.3\% occurred in cerebral site, 26\% in the limbs, 13\% in the abdominal vessels, and the remaining in the retina and lungs. After a first episode of TE, an early recurrence was observed in 11.4\% of children, a late recurrence in 10\%. A number of different therapeutic schemes were used. Overall mortality was 5.7\% and was mostly associated with cerebral TE.

CONCLUSIONS: Population studies are needed to clarify the risk of TE in children with IBD, the relative weight of other risk factors, the characteristics of the events, and to define guidelines of therapy and prophylaxis.

}, keywords = {Adult, Child, Humans, Inflammatory Bowel Diseases, Risk Factors, Thromboembolism}, issn = {1536-4844}, doi = {10.1002/ibd.21563}, author = {Lazzerini, Marzia and Bramuzzo, Matteo and Maschio, Massimo and Martelossi, Stefano and Ventura, Alessandro} } @article {1764, title = {Usefulness of wireless capsule endoscopy for detecting inflammatory bowel disease in children presenting with arthropathy.}, journal = {Eur J Pediatr}, volume = {170}, year = {2011}, month = {2011 Oct}, pages = {1343-7}, abstract = {

Inflammatory bowel disease (IBD) is a cause of chronic intestinal inflammation in children. In a subset of patients affected by IBD, arthropathy may be the leading presenting sign. In the past years, remarkable advances in gastrointestinal endoscopy techniques have been achieved; recently, the development of capsule endoscopy (CE) provided a non-invasive method for the complete endoscopic evaluation, including small bowel assessment. We report three children suffering from IBD but presenting with articular complaints in whom CE was a useful tool for detecting gut inflammation. Patients were investigated with the wireless CE: PillCam SB2 (Given Imaging, Yoqneam, Israel) capsule, the second-generation capsule, was used in our paediatric patients. Three patients were initially evaluated for arthropathy. Enteropathic arthritis was suspected for gastrointestinal symptoms and/or persistence of inflammatory markers elevation. In one of these children, conventional endoscopy was refused by parents, while in the other two children, CE was proposed as first-line diagnostic tool. In all patients, CE revealed to be safe and provided information that led to diagnosis. Paediatric rheumatologists should consider CE as a valid, non-invasive tool, eventually first level diagnostic approach in order to evaluate the presence of IBD in children presenting with chronic articular complaints.

}, keywords = {Adolescent, Arthritis, Juvenile, Capsule Endoscopy, Child, Colitis, Ulcerative, Colon, Crohn Disease, Diagnosis, Differential, Follow-Up Studies, Humans, Inflammatory Bowel Diseases, Intestine, Small, Male, Predictive Value of Tests, Sensitivity and Specificity, Severity of Illness Index, Treatment Outcome}, issn = {1432-1076}, doi = {10.1007/s00431-011-1505-7}, author = {Taddio, Andrea and Simonini, Gabriele and Lionetti, Paolo and Lepore, Loredana and Martelossi, Stefano and Ventura, Alessandro and Cimaz, Rolando} } @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 {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 {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 {1671, title = {A child with pain after mild trauma.}, journal = {J Pediatr}, volume = {157}, year = {2010}, month = {2010 Oct}, pages = {693}, keywords = {Antigens, CD, Antigens, CD31, Antigens, CD34, Antigens, Differentiation, Myelomonocytic, Biopsy, Child, Factor VIII, Fingers, Hand Injuries, Hemangioendothelioma, Humans, Immunohistochemistry, Injury Severity Score, Male, Osteolysis, Pain, Pain Measurement, S100 Proteins, Vascular Neoplasms}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2010.04.028}, author = {Londero, Margherita and Pastore, Serena and Zanazzo, Giulio A and Bruno, Irene and Ventura, Alessandro} } @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 {1670, title = {Follow-up and quality of life of patients with cryopyrin-associated periodic syndromes treated with Anakinra.}, journal = {J Pediatr}, volume = {157}, year = {2010}, month = {2010 Aug}, pages = {310-315.e1}, abstract = {

OBJECTIVE: To evaluate the quality of life and long-term follow-up of patients enrolled in the Italian registry of cryopyrin-associated periodic syndromes (CAPS).

STUDY DESIGN: Since 2004, 20 patients with CAPS were enrolled in a common registry from different Italian Centers of Pediatric Rheumatology; 14 patients were treated with Anakinra in an open fashion. Both treated and untreated patients were routinely followed according to standard of care. The Child Health Questionnaire (CHQ-PF 50) was used to assess the health-related quality of life.

RESULTS: The mean duration of follow-up was 37.5 months. In all treated patients, a complete and persistent control of the inflammatory manifestations was observed with no further progression of the disease. At enrollment in the registry, patients showed a poorer health-related quality of life than healthy children in both physical and the psychosocial summary scores. Treatment was associated with a dramatic and sustained amelioration of a variety of measures of poor quality of life, particularly in those concerning the global health perception, bodily pain-discomfort, and other physical domains.

CONCLUSIONS: Long-term IL-1 blockade produces a significant and persistent improvement in the clinical manifestations associated with the disease and on the overall quality of life.

}, keywords = {Adolescent, Adult, Case-Control Studies, Child, Child, Preschool, Cryopyrin-Associated Periodic Syndromes, Female, Follow-Up Studies, Humans, Inflammation, Interleukin 1 Receptor Antagonist Protein, Interleukin-1, Male, Phenotype, Quality of Health Care, Quality of Life, Questionnaires, Syndrome, Treatment Outcome}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2010.02.040}, author = {Lepore, Loredana and Paloni, Giulia and Caorsi, Roberta and Alessio, Maria and Rigante, Donato and Ruperto, Nicola and Cattalini, Marco and Tommasini, Alberto and Zulian, Francesco and Ventura, Alessando and Martini, Alberto and Gattorno, Marco} } @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 {1622, title = {Individual differences in prefrontal cortex activity during perception of bitter taste using fNIRS methodology.}, journal = {Chem Senses}, volume = {35}, year = {2010}, month = {2010 Nov}, pages = {801-12}, abstract = {

Although bitter taste has a crucial role in nutrition by preventing the ingestion of toxic foods, there are few studies on bitter taste neuroimaging. To identify cortical areas involved in bitter taste perception and to determine if individual differences in taste sensitivity to 6-n-propylthiouracil (PROP) are represented in the brain by different cortical activation patterns, we examined 48 healthy volunteers using functional near-infrared spectroscopy. Participants rated the perceived intensity of filter paper disks impregnated with PROP and NaCl during the imaging procedure and were then classified as PROP tasters and nontasters. We monitored cortical activity in both the anterior and posterior regions of the dorsolateral prefrontal cortex (DLPFC) and in the ventrolateral prefrontal cortex (VLPFC). No activity was detected in the anterior DLPFC in any of the participants. However, during the administration of PROP, significant cortical activation was detected in the more posterior regions of the left DLPFC and in the left and right VLPFC but only in PROP tasters. PROP nontasters showed no cortical activity in these areas. These data suggest that the prefrontal cortex is involved in the conscious perception of the bitter taste of PROP and that the pattern of activity is consistent with individual differences in the ability to taste this compound. Thus, the PROP phenotype is associated with fundamental differences in cortical taste processing.

}, keywords = {Adult, Eating, Female, Food Preferences, Humans, Individuality, Male, Perception, Phenotype, Prefrontal Cortex, Propylthiouracil, Sodium Chloride, Spectroscopy, Near-Infrared, Taste, Taste Threshold, Young Adult}, issn = {1464-3553}, doi = {10.1093/chemse/bjq080}, author = {Bembich, Stefano and Lanzara, Carmela and Clarici, Andrea and Demarini, Sergio and Tepper, Beverly J and Gasparini, Paolo and Grasso, Domenico L} } @article {1624, title = {Insights into the binding of Phenyltiocarbamide (PTC) agonist to its target human TAS2R38 bitter receptor.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010}, pages = {e12394}, abstract = {

Humans{\textquoteright} bitter taste perception is mediated by the hTAS2R subfamily of the G protein-coupled membrane receptors (GPCRs). Structural information on these receptors is currently limited. Here we identify residues involved in the binding of phenylthiocarbamide (PTC) and in receptor activation in one of the most widely studied hTAS2Rs (hTAS2R38) by means of structural bioinformatics and molecular docking. The predictions are validated by site-directed mutagenesis experiments that involve specific residues located in the putative binding site and trans-membrane (TM) helices 6 and 7 putatively involved in receptor activation. Based on our measurements, we suggest that (i) residue N103 participates actively in PTC binding, in line with previous computational studies. (ii) W99, M100 and S259 contribute to define the size and shape of the binding cavity. (iii) W99 and M100, along with F255 and V296, play a key role for receptor activation, providing insights on bitter taste receptor activation not emerging from the previously reported computational models.

}, keywords = {Amino Acid Sequence, Calcium, Cell Line, Computational Biology, Dose-Response Relationship, Drug, Humans, Intracellular Space, Ligands, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Phenylthiourea, Protein Binding, Protein Structure, Secondary, Receptors, G-Protein-Coupled}, issn = {1932-6203}, doi = {10.1371/journal.pone.0012394}, author = {Biarn{\'e}s, Xevi and Marchiori, Alessandro and Giorgetti, Alejandro and Lanzara, Carmela and Gasparini, Paolo and Carloni, Paolo and Born, Stephan and Brockhoff, Anne and Behrens, Maik and Meyerhof, Wolfgang} } @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 {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 {1668, title = {Prepregnancy BMI influences maternal and fetal outcomes in women with isolated gestational hyperglycaemia: a multicentre study.}, journal = {Diabetes Metab}, volume = {36}, year = {2010}, month = {2010 Sep}, pages = {265-70}, abstract = {

AIM: This multicentre study analyzed the maternal and fetal outcomes of women who had one elevated 3-h oral glucose tolerance test (isolated gestational hyperglycaemia [IGH]).

METHODS: From 1999 to 2003, data were collected for 606 IGH women from 31 Italian obstetric or diabetic centres, including time and mode of delivery, gestational hypertension, preeclampsia, eclampsia, congenital malformations, and neonatal mortality and morbidity, to compare them with the general pregnant Italian population. A prognostic model for the outcome of pregnancy was constructed, and the concurrence of certain specified conditions was considered a positive outcome, whereas pregnancies that failed to meet one or more of the stated conditions were classified as "complicated".

RESULTS: Macrosomia was significantly more frequent in women with IGH than in the normal pregnant population (10.7 vs 7.4\%, respectively; P=0.003). Stillbirth and neonatal mortality rates did not differ from those in normal pregnancies, while a slight rise in the frequency of major malformations was not statistically significant (1.48 vs 0.89\%, respectively; P<0.11). Multivariate logistic analyses confirmed that the prepregnancy body mass index (BMI) was an independent predictor of a complicated pregnancy. As for fetal growth, multivariate logistic analyses according to BMI showed that being overweight or obese were strong predictors of macrosomia.

CONCLUSION: These findings in a large cohort of Italian women with IGH confirm the detrimental effect of even minimally altered glucose tolerance on fetal outcome. Also, prepregnancy obesity plays an important role in raising the risk of adverse perinatal outcomes in such patients.

}, keywords = {Adult, Blood Glucose, Body Mass Index, Female, Fetal Macrosomia, Glucose Tolerance Test, Humans, Hyperglycemia, Italy, Models, Statistical, Obesity, Pregnancy, Pregnancy Complications, Pregnancy Outcome, Prognosis, Retrospective Studies, Risk Factors, Time Factors}, issn = {1878-1780}, doi = {10.1016/j.diabet.2010.01.008}, author = {Lapolla, A and Bonomo, M and Dalfr{\`a}, M G and Parretti, E and Mannino, D and Mello, G and Di Cianni, G} } @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 {1666, title = {Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor.}, journal = {Am J Hum Genet}, volume = {86}, year = {2010}, month = {2010 Apr 9}, pages = {639-49}, abstract = {

We investigated two male infant patients who were given a diagnosis of progressive mitochondrial encephalomyopathy on the basis of clinical, biochemical, and morphological features. These patients were born from monozygotic twin sisters and unrelated fathers, suggesting an X-linked trait. Fibroblasts from both showed reduction of respiratory chain (RC) cIII and cIV, but not of cI activities. We found a disease-segregating mutation in the X-linked AIFM1 gene, encoding the Apoptosis-Inducing Factor (AIF) mitochondrion-associated 1 precursor that deletes arginine 201 (R201 del). Under normal conditions, mature AIF is a FAD-dependent NADH oxidase of unknown function and is targeted to the mitochondrial intermembrane space (this form is called AIF(mit)). Upon apoptogenic stimuli, a soluble form (AIF(sol)) is released by proteolytic cleavage and migrates to the nucleus, where it induces "parthanatos," i.e., caspase-independent fragmentation of chromosomal DNA. In vitro, the AIF(R201 del) mutation decreases stability of both AIF(mit) and AIF(sol) and increases the AIF(sol) DNA binding affinity, a prerequisite for nuclear apoptosis. In AIF(R201 del) fibroblasts, staurosporine-induced parthanatos was markedly increased, whereas re-expression of AIF(wt) induced recovery of RC activities. Numerous TUNEL-positive, caspase 3-negative nuclei were visualized in patient $\#$1{\textquoteright}s muscle, again indicating markedly increased parthanatos in the AIF(R201 del) critical tissues. We conclude that AIF(R201 del) is an unstable mutant variant associated with increased parthanatos-linked cell death. Our data suggest a role for AIF in RC integrity and mtDNA maintenance, at least in some tissues. Interestingly, riboflavin supplementation was associated with prolonged improvement of patient $\#$1{\textquoteright}s neurological conditions, as well as correction of RC defects in mutant fibroblasts, suggesting that stabilization of the FAD binding in AIF(mit) is beneficial.

}, keywords = {Apoptosis, Apoptosis Inducing Factor, Caspase 3, Computer Simulation, Dietary Supplements, DNA Primers, DNA, Mitochondrial, Electron Transport, Female, Fibroblasts, Flavin-Adenine Dinucleotide, Genes, X-Linked, Humans, In Situ Nick-End Labeling, Infant, Newborn, Magnetic Resonance Imaging, Male, Mitochondrial Encephalomyopathies, Muscle, Skeletal, Mutation, Nervous System Diseases, Pedigree, Poly(ADP-ribose) Polymerases, Protein Conformation, Riboflavin, Staurosporine, Twins, Monozygotic}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2010.03.002}, author = {Ghezzi, Daniele and Sevrioukova, Irina and Invernizzi, Federica and Lamperti, Costanza and Mora, Marina and d{\textquoteright}Adamo, Pio and Novara, Francesca and Zuffardi, Orsetta and Uziel, Graziella and Zeviani, Massimo} } @article {1894, title = {State of the art and recommendations. Kangaroo mother care: application in a high-tech environment.}, journal = {Breastfeed Rev}, volume = {18}, year = {2010}, month = {2010 Nov}, pages = {21-8}, abstract = {

UNLABELLED: Since Kangaroo Mother Care (KMC) was developed in Colombia in the 1970s, two trends in clinical application emerged. In low-income settings, the original KMC modelis implemented. This consists of continuous (24 h/day; 7 days/week) and prolonged mother/parent-infant skin-to-skin contact; early discharge with the infant in the kangaroo position; (ideally) exclusive breastfeeding and, adequate follow up. In affluent settings, intermittent KMC with sessions of one or a few hours skin-to-skin contact for a limited period is common. As a result of the increasing evidence of the benefits of KMC for both infants and families in all intensive care settings, KMC in a high-tech environment was chosen as the topic for the first European Conference on KMC, and the clinical implementation of the KMC modelin all types of settings was discussed at the 7th International Workshop on KMC Kangaroo Mother Care protocols in high-tech Neonatal Intensive Care Units (NICU) should specify criteria for initiation, kangaroo position, transfer to/from KMC, transport in kangaroo position, kangaroo nutrition, parents{\textquoteright}role, modification of the NICU environment, performance of care in KMC, and KMCin case of infant instability.

CONCLUSION: Implementation of the original KMC method, with continuous skin-to-skin contact whenever possible, is recommended for application in high-tech environments, although scientific evaluation should continue.

}, issn = {0729-2759}, author = {Nyqvist, K H and Anderson, G C and Bergman, N and Cattaneo, A and Charpak, N and Davanzo, R and Ewald, U and Ludington-Hoe, S and Mendoza, S and Pall{\'a}s-Allonso, C and Pel{\'a}ez, J G and Sizun, J and Wistr{\"o}m, A M} } @article {1679, title = {State of the art and recommendations. Kangaroo mother care: application in a high-tech environment.}, journal = {Acta Paediatr}, volume = {99}, year = {2010}, month = {2010 Jun}, pages = {812-9}, abstract = {

UNLABELLED: Since Kangaroo Mother Care (KMC) was developed in Colombia in the 1970s, two trends in clinical application emerged. In low income settings, the original KMC model is implemented. This consists of continuous (24 h/day, 7 days/week) and prolonged mother/parent-infant skin-to-skin contact; early discharge with the infant in the kangaroo position; (ideally) exclusive breastfeeding; and, adequate follow-up. In affluent settings, intermittent KMC with sessions of one or a few hours skin-to-skin contact for a limited period is common. As a result of the increasing evidence of the benefits of KMC for both infants and families in all intensive care settings, KMC in a high-tech environment was chosen as the topic for the first European Conference on KMC, and the clinical implementation of the KMC model in all types of settings was discussed at the 7th International Workshop on KMC. Kangaroo Mother Care protocols in high-tech Neonatal Intensive Care Units (NICU) should specify criteria for initiation, kangaroo position, transfer to/from KMC, transport in kangaroo position, kangaroo nutrition, parents{\textquoteright} role, modification of the NICU environment, performance of care in KMC, and KMC in case of infant instability.

CONCLUSION: Implementation of the original KMC method, with continuous skin-to-skin contact whenever possible, is recommended for application in high-tech environments, although scientific evaluation should continue.

}, keywords = {Attitude of Health Personnel, Female, Humans, Infant Care, Infant, Newborn, Intensive Care Units, Neonatal, Male, Parent-Child Relations, Practice Guidelines as Topic, Professional-Patient Relations, Role, Skin, Visitors to Patients}, issn = {1651-2227}, doi = {10.1111/j.1651-2227.2010.01794.x}, author = {Nyqvist, K H and Anderson, G C and Bergman, N and Cattaneo, A and Charpak, N and Davanzo, R and Ewald, U and Ludington-Hoe, S and Mendoza, S and Pall{\'a}s-Allonso, C and Pel{\'a}ez, J G and Sizun, J and Widstr{\"o}m, A-M} } @article {1704, title = {[Strategies for cardiovascular prevention in children].}, journal = {G Ital Cardiol (Rome)}, volume = {11}, year = {2010}, month = {2010 May}, pages = {87S-89S}, keywords = {Body Mass Index, Cardiovascular Diseases, Child, Diet, Mediterranean, Food Habits, Humans, Life Style, Motor Activity, Obesity, Overweight, Patient Education as Topic, Population Surveillance, Questionnaires, Risk Factors}, issn = {1827-6806}, author = {Spinelli, Angela and Nardone, Paola and Lamberti, Anna and Baglio, Giovanni} } @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 {1707, title = {Toward a consensus on guiding principles for health systems strengthening.}, journal = {PLoS Med}, volume = {7}, year = {2010}, month = {2010}, pages = {e1000385}, keywords = {Global Health, Humans, Public Health}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1000385}, author = {Swanson, Robert C and Bongiovanni, Annette and Bradley, Elizabeth and Murugan, Varnee and Sundewall, Jesper and Betigeri, Arvind and Nyonator, Frank and Cattaneo, Adriano and Harless, Brandi and Ostrovsky, Andrey and Labont{\'e}, Ronald} } @article {1678, title = {Towards universal Kangaroo Mother Care: recommendations and report from the First European conference and Seventh International Workshop on Kangaroo Mother Care.}, journal = {Acta Paediatr}, volume = {99}, year = {2010}, month = {2010 Jun}, pages = {820-6}, abstract = {

UNLABELLED: The hallmark of Kangaroo Mother Care (KMC) is the kangaroo position: the infant is cared for skin-to-skin vertically between the mother{\textquoteright}s breasts and below her clothes, 24 h/day, with father/substitute(s) participating as KMC providers. Intermittent KMC (for short periods once or a few times per day, for a variable number of days) is commonly employed in high-tech neonatal intensive care units. These two modalities should be regarded as a progressive adaptation of the mother-infant dyad, ideally towards continuous KMC, starting gradually and progressively with intermittent KMC. The other components in KMC are exclusive breastfeeding (ideally) and early discharge in kangaroo position with strict follow-up. Current evidence allows the following general statements about KMC in affluent and low-income settings: KMC enhances bonding and attachment; reduces maternal postpartum depression symptoms; enhances infant physiologic stability and reduces pain, increases parental sensitivity to infant cues; contributes to the establishment and longer duration of breastfeeding and has positive effects on infant development and infant/parent interaction. Therefore, intrapartum and postnatal care in all types of settings should adhere to a paradigm of nonseparation of infants and their mothers/families. Preterm/low-birth-weight infants should be regarded as extero-gestational foetuses needing skin-to-skin contact to promote maturation.

CONCLUSION: Kangaroo Mother Care should begin as soon as possible after birth, be applied as continuous skin-to-skin contact to the extent that this is possible and appropriate and continue for as long as appropriate.

}, keywords = {Congresses as Topic, Female, Global Health, Humans, Infant Care, Infant, Newborn, Male, Parent-Child Relations, Practice Guidelines as Topic, Randomized Controlled Trials as Topic, Skin}, issn = {1651-2227}, doi = {10.1111/j.1651-2227.2010.01787.x}, author = {Nyqvist, K H and Anderson, G C and Bergman, N and Cattaneo, A and Charpak, N and Davanzo, R and Ewald, U and Ibe, O and Ludington-Hoe, S and Mendoza, S and Pall{\'a}s-Allonso, C and Ruiz Pel{\'a}ez, J G and Sizun, J and Widstr{\"o}m, A-M} } @article {1706, title = {Usefulness of the measurement of azathioprine metabolites in the assessment of non-adherence.}, journal = {J Crohns Colitis}, volume = {4}, year = {2010}, month = {2010 Nov}, pages = {599-602}, abstract = {

Azathioprine is a thiopurine immunosuppressive antimetabolite used to chronically treat inflammatory bowel disease and autoimmune hepatitis. Azathioprine treatment is a long-term therapy and therefore it is at risk for non-adherence, which is considered an important determinant of treatment inefficacy. Measurement of 6-thioguanine and 6-methylmercaptopurine nucleotides has been recently suggested as a screener for non-adherence detection. We describe four young patients in which non-adherence to azathioprine therapy was detected only through the measurement of drug metabolite concentrations, and the criterion for non-adherence was undetectable metabolite levels. After the identification of non-adherence, patients and their families were approached and the importance of a correct drug administration was thoroughly enlightened and discussed; this allowed obtaining a full remission in all subjects. Our observations support the use of undetectable metabolite levels as indicators of non-adherence to therapy in azathioprine treated patients. The additional level of medical supervision given by this assay allows getting a better adherence to medical treatment, which results in an improvement in the response to therapy; these benefits may justify the costs associated with the assay.

}, keywords = {6-Mercaptopurine, Adolescent, Azathioprine, Child, Child, Preschool, Female, Guanine Nucleotides, Hepatitis, Autoimmune, Humans, Immunosuppressive Agents, Inflammatory Bowel Diseases, Male, Medication Adherence, Thionucleotides, Young Adult}, issn = {1876-4479}, doi = {10.1016/j.crohns.2010.04.003}, author = {Stocco, Gabriele and Londero, Margherita and Campanozzi, Angelo and Martelossi, Stefano and Marino, Sara and Malus{\`a}, Noelia and Bartoli, Fiora and Decorti, Giuliana and Ventura, Alessandro} }