Administering analgesia sublingually is a suitable option for children with acute abdominal pain in the emergency department. - Cozzi, Giorgio; Zanchi, Chiara; Chiaretti, Antonio; Tipo, Vincenzo; Cernich, Marta; D'Anna, Carolina; Fantacci, Claudia; Conversano, Ester; Zanon, Davide; Ronfani, Luca; Barbi, Egidio (Acta Paediatr, 2019)
AIM: Acute abdominal pain is a frequent complaint in children attending emergency departments. The aim of this study was to investigate the pain score reductions when children with acute abdominal pain received medication sublingually. METHODS: We carried out a multicentre randomised controlled trial in three children's hospitals in Italy between March 2015 and June 2017. Children from four to 18 years of age with acute abdominal pain were recruited if their self-reported pain was at least six on a scale from 0-10. The children were randomised to receive ketorolac 0.5 mg/kg (n = 70) or tramadol 2 mg/kg (n = 70) sublingually or a melt in the mouth powder of 20 mg/kg paracetamol (n = 70). The main study outcome was the pain scores for the three drugs after two hours. RESULTS: The 210 children (58.6% girls) had a median age of 12 years with an interquartile range of 9-14.3. The median pain scores at two hours were not significantly different between ketorolac 2.0 (interquartile ranges, IQR 0.0-4.3) and tramadol 3.0 (IQR 1.0-5.0) vs paracetamol 3.0 (IQR 0.8-5.0). The median pain reductions were all 5.0 points. CONCLUSION: Delivering analgesia sublingually was a suitable option for pain relief in children with acute abdominal pain in the emergency department.

Adolescent with painful vesicular otitis and vertigo. - Conversano, Ester; Cozzi, Giorgio; Poropat, Federico; Di Mascio, Alberto; Salis, Simona; Grasso, Domenico Leonardo; Barbi, Egidio (Arch Dis Child Educ Pract Ed, 2019)

Antibodies reacting to mimotopes of Simian virus 40 large T antigen, the viral oncoprotein, in sera from children. - Mazzoni, Elisa; Frontini, Francesca; Rotondo, John Charles; Zanotta, Nunzia; Fioravanti, Arianna; Minelli, Francesca; Torreggiani, Elena; Campisciano, Giuseppina; Marcuzzi, Annalisa; Guerra, Giovanni; Tommasini, Alberto; Touzé, Antoine; et al. (J Cell Physiol, 2019)
Recent data indicate that the Simian virus 40 (SV40) infection appears to be transmitted in humans independently from early SV40-contaminated antipolio vaccines. Serum antibodies against SV40 large T antigen (Tag) were analyzed in children/adolescents and young adults. To investigate antibodies reacting to SV40 Tag antigens, serum samples ( n = 812) from children and young adults were analyzed by indirect ELISAs using specific SV40 Tag mimotopes. Mimotopes were synthetic peptides corresponding to SV40 Tag epitopes. In sera ( n = 412) from healthy children up to 17 years old, IgG antibodies against SV40 Tag mimotopes reached an overall prevalence of 15%. IgM antibodies against SV40 Tag were detected in sera of children 6-8 months old confirming and extending the knowledge that SV40 seroconversion occurs early in life. In children/adolescents affected by different diseases ( n = 180) SV40 Tag had a prevalence of 18%, being the difference no significant compared to healthy subjects ( n = 220; 16%) of the same age. Our immunological data indicate that SV40 circulates in children and young adults, both in healthy conditions and affected by distinct diseases. The IgM detection in sera from healthy children suggests that the SV40 infection/seroconversion occurs early in life (>6 months). Our immunological data support the hypothesis that SV40, or a closely related still unknown polyomavirus, infects humans. The SV40 seroprevalence is lower than common polyomaviruses, such as BKPyV and JCPyV, and other new human polyomaviruses. In addition, our immunological surveillance indicates a lack of association between different diseases, considered herein, and SV40.

Causes of Treatment Failure in Children With Inflammatory Bowel Disease Treated With Infliximab: A Pharmacokinetic Study. - Naviglio, Samuele; Lacorte, Doriana; Lucafò, Marianna; Cifù, Adriana; Favretto, Diego; Cuzzoni, Eva; Silvestri, Tania; Pozzi Mucelli, Martina; Radillo, Oriano; Decorti, Giuliana; Fabris, Martina; Bramuzzo, Matteo; et al. (J Pediatr Gastroenterol Nutr, 2019)
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'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.

Cervico-vaginal secretion cytokine profile: A non-invasive approach to study the endometrial receptivity in IVF cycles. - Zanotta, Nunzia; Monasta, Lorenzo; Skerk, Kristina; Luppi, Stefania; Martinelli, Monica; Ricci, Giuseppe; Comar, Manola (Am J Reprod Immunol, 2019)
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.

Changing Epidemiology of Liver Involvement in Children With Celiac Disease. - Benelli, Elisa; Naviglio, Samuele; De Leo, Luigina; Stera, Giacomo; Giangreco, Manuela; Ronfani, Luca; Villanacci, Vincenzo; Martelossi, Stefano; Ventura, Alessandro; Not, Tarcisio (J Pediatr Gastroenterol Nutr, 2019)
OBJECTIVES: Available data indicate that liver involvement is present in a significant proportion of children with celiac disease (CD) at the diagnosis (elevated transaminases 15%-57%, autoimmune liver disease 1%-2%). We sought to evaluate prevalence, clinical course, and risk factors for liver involvement in a large cohort of children with CD. METHODS: Children (age 0-18 years) diagnosed with CD from March 2010 to April 2016 were enrolled. Liver involvement was considered to be present when alanine transaminase (ALT) levels were >40 U/L (hypertransaminasemia [HTS]). Patients with HTS were re-evaluated after at least 12 months of a gluten-free diet. RESULTS: CD was diagnosed in 806 patients during the study period; of these, ALT levels were available for 700 patients (86.9%), and were elevated in 27 (3.9%, HTS group); median ALT and aspartate transaminase levels in the HTS group were 57 U/L (interquartile range 49-80 U/L) and 67 U/L (interquartile range 53-85 U/L), respectively. Younger age, malabsorption symptoms, and low hemoglobin or ferritin were significantly more common in the HTS group at univariate analysis. At multivariate analysis, only age ≤4.27 years correlated with risk of liver involvement (odds ratio 3.73; 95% confidence interval: 1.61-8.66). When retested on a gluten-free diet, all but 3 patients normalized ALT levels; of these, 1 was diagnosed with sclerosing cholangitis. CONCLUSIONS: Liver involvement in celiac children is now less frequent than previously reported, possibly due to changing CD epidemiology. Younger age is the only risk factor. Associated autoimmune liver disease is rare.

An evaluation of the Movement ABC-2 Test for use in Italy: A comparison of data from Italy and the UK. - Zoia, Stefania; Biancotto, Marina; Guicciardi, Marco; Lecis, Romina; Lucidi, Fabio; Pelamatti, Giovanna M; Carrozzi, Marco; Skabar, Aldo; Sugden, David A; Barnett, Anna L; Henderson, Sheila E (Res Dev Disabil, 2019)
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.

Evidence-based mixture containing Lactobacillus strains and lactoferrin to prevent recurrent bacterial vaginosis: a double blind, placebo controlled, randomised clinical trial. - Russo, R; Karadja, E; De Seta, F (Benef Microbes, 2019)
Bacterial vaginosis (BV) is the most common cause of vaginal discomfort in women. It is characterised by abnormal vaginal microbiota with a depletion of lactobacilli and predominance of anaerobic microorganisms, mainly Gardnerella vaginalis and Atopobium vaginae. Although antibiotics represent an effective therapeutic option in the short-term, recurrent infections still remain a serious problem. Nowadays, evidence exists about the efficacy of probiotics for the management of BV. The aim of the current double blind, randomised clinical trial was to assess the efficacy of a probiotic mixture, including Lactobacillus acidophilus GLA-14 and Lactobacillus rhamnosus HN001, in combination with bovine lactoferrin, as adjuvant therapy to metronidazole in women with recurrent BV. In particular, normalisation of Nugent score, remission of symptoms and recurrences during a six-months follow-up were assessed. 48 adult women received metronidazole (500 mg twice daily) for 7 days and randomly assigned to take simultaneously either probiotics plus lactoferrin or placebo (2 capsules/day for 5 days followed by 1 capsule/day for 10 consecutive days; induction phase). The verum or placebo administration (1 capsule/day for 10 consecutive days) was repeated each month (maintenance phase) during the six months of follow-up starting the first day of menstrual cycle since the menstrual blood increases the vaginal pH and contributes to increase the risk of recurrences. The results showed that symptoms (vaginal discharge and itching), Nugent score and recurrence rate were significantly improved by probiotics mixture in association with lactoferrin. This alternative approach may represent a safe and effective remedy for the restoration of healthy vaginal microbiota in preventing recurrent BV.

Facing somatic symptom disorder in the emergency department. - Cozzi, Giorgio; Barbi, Egidio (J Paediatr Child Health, 2019)
Somatic symptom disorder is a condition in which a patient's subjective report of physical symptoms is associated with distress; disruption of day-to-day functioning; or disproportionate thoughts, feelings and behaviours regarding the symptoms, whether or not they are associated with an identified medical condition. While somatic symptom disorder affects a considerable proportion of children and adolescents presenting to the emergency department (ED), it has not been well investigated in the ED literature, nor is there much formal training in, or guidelines for, how to care for affected patients in the ED. The aim of this paper is to highlight the historical clues commonly reported by these patients in order to try to help the emergency physicians recognise patients affected by a somatic symptom disorder. Adolescent age, the presence of daily subjective symptoms presenting daily for weeks or months, a long medical history record, an extensive diagnostic workup and, most of all, disproportionate functional impairment related to the symptoms are all features strongly suggestive of this disorder. Emergency physicians should become used to taking advantage of these clues to formulate a positive diagnosis of somatic symptom disorder according to the most recent diagnostic criteria. Emergency physicians have the unique opportunity to contribute to the correct diagnosis and treatment of these patients and to have a positive impact on their prognosis.

First urinary tract infections in children: the role of the risk factors proposed by the Italian recommendations. - Alberici, I; La Manna, A; Pennesi, M; Starc, M; Scozzola, F; Nicolini, G; Toffolo, A; Marra, G; Chimenz, R; Sica, F; Maringhini, S; Monasta, L; et al. (Acta Paediatr, 2019)
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.

Four-miRNA Signature to Identify Asbestos-Related Lung Malignancies. - Santarelli, Lory; Gaetani, Simona; Monaco, Federica; Bracci, Massimo; Valentino, Matteo; Amati, Monica; Rubini, Corrado; Sabbatini, Armando; Pasquini, Ernesto; Zanotta, Nunzia; Comar, Manola; Neuzil, Jiri; et al. (Cancer Epidemiol Biomarkers Prev, 2019)
BACKGROUND: Altered miRNA expression is an early event upon exposure to occupational/environmental carcinogens; thus, identification of a novel asbestos-related profile of miRNAs able to distinguish asbestos-induced cancer from cancer with different etiology can be useful for diagnosis. We therefore performed a study to identify miRNAs associated with asbestos-induced malignancies. METHODS: Four groups of patients were included in the study, including patients with asbestos-related (NSCLC) and asbestos-unrelated non-small cell lung cancer (NSCLC) or with malignant pleural mesothelioma (MPM), and disease-free subjects (CTRL). The selected miRNAs were evaluated in asbestos-exposed population. RESULTS: Four serum miRNAs, that is miR-126, miR-205, miR-222, and miR-520g, were found to be implicated in asbestos-related malignant diseases. Notably, increased expression of miR-126 and miR-222 were found in asbestos-exposed subjects, and both miRNAs are involved in major pathways linked to cancer development. Epigenetic changes and cancer-stroma cross-talk could induce repression of miR-126 to facilitate tumor formation, angiogenesis, and invasion. CONCLUSIONS: This study indicates that miRNAs are potentially involved in asbestos-related malignancies, and their expression outlines mechanism(s) whereby miRNAs may be involved in an asbestos-induced pathogenesis. IMPACT: The discovery of a miRNA panel for asbestos-related malignancies would impact on occupational compensation and may be utilized for screening asbestos-exposed populations.

Gadolinium tissue deposition in the periodontal ligament of mice with reduced renal function exposed to Gd-based contrast agents. - Delfino, Riccarda; Biasotto, Matteo; Candido, Riccardo; Altissimo, Matteo; Stebel, Marco; Salomè, Murielle; van Elteren, Johannes T; Vogel Mikuš, Katarina; Zennaro, Cristina; Šala, Martin; Addobbati, Riccardo; Tromba, Giuliana; et al. (Toxicol Lett, 2019)
Gadolinium deposition in tissue is linked to nephrogenic systemic fibrosis (NSF): a rare disorder occurring in patients with severe chronic kidney disease and associated with administration of Gd-based contrast agents (GBCAs) for Magnetic Resonance Imaging (MRI). It is suggested that the GBCAs prolonged permanence in blood in these patients may result in a Gd precipitation in peripheral or central organs, where it initiates a fibrotic process. In this study we investigated new sites of retention/precipitation of Gd in a mouse model of renal disease (5/6 nephrectomy) receiving two doses (closely after each other) of a linear GBCA. Two commercial GBCAs (Omniscan® and Magnevist®) were administered at doses slightly higher than those used in clinical practice (0.7 mmol/kg body weight, each). The animals were sacrificed one month after the last administration and the explanted organs (kidney, liver, femur, dorsal skin, teeth) were analysed by X-ray fluorescence (XRF) at two synchrotron facilities. The XRF analysis with a millimetre-sized beam at the SYRMEP beamline (Elettra, Italy) produced no detectable levels of Gd in the examined tissues, with the notable exception of the incisors of the nephrectomised mice. The XRF analyses at sub-micron resolution performed at ID21 (ESRF, France) allowed to clearly localize Gd in the periodontal ligaments of teeth both from Omniscan® and Magnevist® treated nephrectomised mice. The latter results were further confirmed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The study prompts that prolonged permanence of GBCAs in blood may result in Gd retention in this particular muscular tissue, opening possibilities for diagnostic applications at this level when investigating Gd-related toxicities.
Keywords: Animals; Contrast Media; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gadolinium; Gadolinium DTPA; Magnetic Resonance Imaging; Mice; Nephrogenic Fibrosing Dermopathy; Periodontal Ligament; Renal Insufficiency; Tissue Distribution

Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. (Lancet Neurol, 2019)
BACKGROUND: Traumatic brain injury (TBI) and spinal cord injury (SCI) are increasingly recognised as global health priorities in view of the preventability of most injuries and the complex and expensive medical care they necessitate. We aimed to measure the incidence, prevalence, and years of life lived with disability (YLDs) for TBI and SCI from all causes of injury in every country, to describe how these measures have changed between 1990 and 2016, and to estimate the proportion of TBI and SCI cases caused by different types of injury. METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016 to measure the global, regional, and national burden of TBI and SCI by age and sex. We measured the incidence and prevalence of all causes of injury requiring medical care in inpatient and outpatient records, literature studies, and survey data. By use of clinical record data, we estimated the proportion of each cause of injury that required medical care that would result in TBI or SCI being considered as the nature of injury. We used literature studies to establish standardised mortality ratios and applied differential equations to convert incidence to prevalence of long-term disability. Finally, we applied GBD disability weights to calculate YLDs. We used a Bayesian meta-regression tool for epidemiological modelling, used cause-specific mortality rates for non-fatal estimation, and adjusted our results for disability experienced with comorbid conditions. We also analysed results on the basis of the Socio-demographic Index, a compound measure of income per capita, education, and fertility. FINDINGS: In 2016, there were 27·08 million (95% uncertainty interval [UI] 24·30-30·30 million) new cases of TBI and 0·93 million (0·78-1·16 million) new cases of SCI, with age-standardised incidence rates of 369 (331-412) per 100 000 population for TBI and 13 (11-16) per 100 000 for SCI. In 2016, the number of prevalent cases of TBI was 55·50 million (53·40-57·62 million) and of SCI was 27·04 million (24·98-30·15 million). From 1990 to 2016, the age-standardised prevalence of TBI increased by 8·4% (95% UI 7·7 to 9·2), whereas that of SCI did not change significantly (-0·2% [-2·1 to 2·7]). Age-standardised incidence rates increased by 3·6% (1·8 to 5·5) for TBI, but did not change significantly for SCI (-3·6% [-7·4 to 4·0]). TBI caused 8·1 million (95% UI 6·0-10·4 million) YLDs and SCI caused 9·5 million (6·7-12·4 million) YLDs in 2016, corresponding to age-standardised rates of 111 (82-141) per 100 000 for TBI and 130 (90-170) per 100 000 for SCI. Falls and road injuries were the leading causes of new cases of TBI and SCI in most regions. INTERPRETATION: TBI and SCI constitute a considerable portion of the global injury burden and are caused primarily by falls and road injuries. The increase in incidence of TBI over time might continue in view of increases in population density, population ageing, and increasing use of motor vehicles, motorcycles, and bicycles. The number of individuals living with SCI is expected to increase in view of population growth, which is concerning because of the specialised care that people with SCI can require. Our study was limited by data sparsity in some regions, and it will be important to invest greater resources in collection of data for TBI and SCI to improve the accuracy of future assessments. FUNDING: Bill & Melinda Gates Foundation.

Idiopathic neutropenia of infancy: Data from the Italian Neutropenia Registry. - Farruggia, Piero; Fioredda, Francesca; Puccio, Giuseppe; Onofrillo, Daniela; Russo, Giovanna; Barone, Angelica; Bonanomi, Sonia; Boscarol, Gianluca; Finocchi, Andrea; Ghilardi, Roberta; Giordano, Paola; Ladogana, Saverio; et al. (Am J Hematol, 2019)
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).

Loss-of-function mutations in cause a new form of inherited thrombocytopenia. - Marconi, Caterina; Di Buduo, Christian A; LeVine, Kellie; Barozzi, Serena; Faleschini, Michela; Bozzi, Valeria; Palombo, Flavia; McKinstry, Spencer; Lassandro, Giuseppe; Giordano, Paola; Noris, Patrizia; Balduini, Carlo L; et al. (Blood, 2019)
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' 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.

Management of endometrial, ovarian and cervical cancer in the elderly: current approach to a challenging condition. - Vitale, Salvatore Giovanni; Capriglione, Stella; Zito, Gabriella; Lopez, Salvatore; Gulino, Ferdinando Antonio; Di Guardo, Federica; Vitagliano, Amerigo; Noventa, Marco; La Rosa, Valentina Lucia; Sapia, Fabrizio; Valenti, Gaetano; Rapisarda, Agnese Maria Chiara; et al. (Arch Gynecol Obstet, 2019)
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 'elderly', 'cancer', 'clinical trial' and 'geriatric assessment'. 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.

Menstruation-related disseminated intravascular coagulation in an adenomyosis patient: case report and review of the literature. - Cernogoraz, Alice; Schiraldi, Luigi; Bonazza, Deborah; Ricci, Giuseppe (Gynecol Endocrinol, 2019)
Disseminated intravascular coagulation (DIC) is a high mortality coagulopathy that leads to simultaneous thrombotic and bleeding problems. It occurs as a complication in different disease as malignancies, obstetrical catastrophes, bacterial sepsis and traumas. We report on an extremely rare case of acute DIC in a patient with misdiagnosed adenomyosis and massive methrorragia which led to acute kidney failure. The patient was successfully treated with hysterectomy and blood product transfusions; however, a slight reduction of renal function persisted. We were able to confirm the cause-consequence link between adenomyosis and consumptive DIC since we saw the thrombi in the adenomyotic uterus from early hysterectomy specimen. Moreover, this is the first case, for the best of our knowledge, in which systemic consequences persist in an adenomyosis patient who developed a DIC. Early diagnose and treatment of acute DIC is essential for patient's survival and to prevent severe complications: adenomyosis should be kept in mind as a possible cause of DIC when a patient shows up with massive bleeding.

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. - Zaninetti, Carlo; De Rocco, Daniela; Giangregorio, Tania; Bozzi, Valeria; Demeter, Judit; Leoni, Pietro; Noris, Patrizia; Ryhänen, Samppa; Barozzi, Serena; Pecci, Alessandro; Savoia, Anna (Hamostaseologie, 2019)
-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.

Next-generation sequencing identified SPATC1L as a possible candidate gene for both early-onset and age-related hearing loss. - Morgan, Anna; Vuckovic, Dragana; Krishnamoorthy, Navaneethakrishnan; Rubinato, Elisa; Ambrosetti, Umberto; Castorina, Pierangela; Franzè, Annamaria; Vozzi, Diego; La Bianca, Martina; Cappellani, Stefania; Di Stazio, Mariateresa; Gasparini, Paolo; et al. (Eur J Hum Genet, 2019)
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.

Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy. - Mancini, C; Giorgio, E; Rubegni, A; Pradotto, L; Bagnoli, S; Rubino, E; Prontera, P; Cavalieri, S; Di Gregorio, E; Ferrero, M; Pozzi, E; Riberi, E; et al. (Eur J Neurol, 2019)
BACKGROUND AND PURPOSE: Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant. METHODS: We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing. RESULTS: We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (~80% of patients), urinary urgency (~30%) and pyramidal signs (~70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes. CONCLUSIONS: The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.

Retrospective study showed that palpitations with tachycardia on admission to a paediatric emergency department were related to cardiac arrhythmias. - Bobbo, Marco; Amoroso, Stefano; Tamaro, Gianluca; Gesuete, Valentina; D'agata Mottolese, Biancamaria; Barbi, Egidio; Ventura, Alessandro (Acta Paediatr, 2019)
AIM: This retrospective study reviewed the prevalence and long-term prognosis of children aged 0-18 with palpitations who were admitted to the emergency department (ED) of an Italian paediatric hospital. METHODS: We examined all admissions to the ED of the IRCCS Burlo Garofolo between January 2009 and December 2015 by selecting triage diagnoses of palpitations. The hospital discharge cards were reviewed to assess vital parameters, physical examinations, diagnostic tests, cardiology consultations and final diagnoses. RESULTS: Of the 142 803 patients who attended our ED for any reason, 96 (0.07%) complained of palpitations. Despite this low prevalence, it was noteworthy that 13.5% had a real underlying arrhythmic cause and needed medical assistance. Over half (52.1%) were women and the mean age was 12.7 years. At the long-term follow-up, at a mean of 47 ± 23 months, 53.8% of patients with a cardiac arrhythmia had received medical therapy and 46.1% had undergone trans-catheter ablation for supraventricular tachycardia. A heart rate above 146 beats per minute or palpitations for more than an hour was statistically related to a cardiac arrhythmia. CONCLUSION: Palpitations were an infrequent cause of admission to our ED, but 13.5% who displayed them had an underlying cardiac arrhythmia.

When Long-Lasting Food Selectivity Leads to an Unusual Genetic Diagnosis: A Case Report. - Da Lozzo, Prisca; Magnolato, Andrea; Del Rizzo, Irene; Sirchia, Fabio; Bruno, Irene; Barbi, Egidio (J Adolesc Health, 2019)
Hereditary fructose intolerance is an autosomal recessive disorder of fructose metabolism caused by catalytic deficiency of aldolase B enzyme [1]. The disease is typically expressed when fructose- and sucrose-containing foods are first introduced in the diet; acute manifestations include nausea, vomiting, abdominal distress, and symptomatic hypoglycemia [1,2]. Chronic fructose ingestion eventually leads to poor feeding, growth retardation and gradual liver and/or renal failure [3,4]. Some patients may remain undiagnosed until adulthood because of a self-protective avoidance of sweet tasting food that prevents the development of acute toxicity from fructose containing food; however, these subjects may suffer intermittent symptoms throughout life, leading to potentially serious misdiagnosis [4]. We report the case of a patient with unrecognized hereditary fructose intolerance in which chronic gastrointestinal complaints, low body weight, and unexplained food avoidance were addressed as manifestations of an eating disorder during adolescence.

Activation of hepatic stem cells compartment during hepatocarcinogenesis in a HBsAg HBV-transgenic mouse model. - Anfuso, Beatrice; El-Khobar, Korri E; Ie, Susan I; Avellini, Claudio; Radillo, Oriano; Raseni, Alan; Tiribelli, Claudio; Sukowati, Caecilia H C (Sci Rep, 2018)
Chronic infection of Hepatitis B Virus (HBV) is one of the highest risk factors of hepatocellular carcinoma (HCC). The accumulation of HBV surface antigen (HBsAg) into hepatocytes induces inflammation and oxidative stress, impairing their replicative ability and allowing the activation of the hepatic stem cells (SC) compartment. This study aimed to understand the involvement of SC during hepatocarcinogenesis in HBsAg-related liver damage, from early injury until HCC. HBsAg-transgenic (TG) and wild type (WT) mouse were followed at several stages of the liver damage: inflammation, early hepatocytes damage, dysplasia, and HCC. Serum transaminases, liver histology, and diagnostic data were collected. The expressions of SC and cancer stem cells (CSC) markers was analyzed by RT-qPCR, immunohistochemistry and Western blot. Starting from 3 months, TG animals showed a progressive liver damage characterized by transaminases increase. The up-regulations of SCs markers Cd34 and Sca-1 started from the beginning of the inflammatory stage while progressive increase of Krt19 and Sox9 and CSCs markers Epcam and Cd133 from early hepatic injury. The expressions of Cd133, Cd34, and Afp were significantly higher in HCC compared to paired non-HCC tissue, in contrast to Epcam and Krt19. Western blot and IHC confirmed the positivity of Cd34 and Cd133 in small cells subpopulation.

ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia. - Faleschini, Michela; Melazzini, Federica; Marconi, Caterina; Giangregorio, Tania; Pippucci, Tommaso; Cigalini, Elena; Pecci, Alessandro; Bottega, Roberta; Ramenghi, Ugo; Siitonen, Timo; Seri, Marco; Pastore, Annalisa; et al. (Br J Haematol, 2018)
The inherited thrombocytopenias (IT) are a heterogeneous group of diseases resulting from mutations in more than 30 different genes. Among them, ACTN1-related thrombocytopenia (ACTN1-RT; Online Mendelian Inheritance in Man: 615193) is one of the most recently identified forms. It has been described as a mild autosomal dominant macrothrombocytopenia caused by mutations in ACTN1, a gene encoding for one of the two non-muscle isoforms of α-actinin. We recently identified seven new unrelated families with ACTN1-RT caused by different mutations. Two of them are novel missense variants (p.Trp128Cys and p.Pro233Leu), whose pathogenic role has been confirmed by in vitro studies. Together with the 10 families we have previously described, our cohort of ACTN1-RT now consists of 49 individuals carrying ACTN1 mutations. This is the largest case series ever collected and enabled a critical evaluation of the clinical aspects of the disease. We concluded that ACTN1-RT is the fourth most frequent form of IT worldwide and it is characterized by platelet macrocytosis in all affected subjects and mild thrombocytopenia in less than 80% of cases. The risk of bleeding, either spontaneous or upon haemostatic challenge, is negligible and there are no other associated defects, either congenital or acquired. Therefore, ACTN1-RT is a benign form of IT, whose diagnosis provides affected individuals and their families with a good prognosis.

Acute small bowel obstruction in a child with a strict raw vegan diet. - Amoroso, Stefano; Scarpa, Maria-Grazia; Poropat, Federico; Giorgi, Rita; Murru, Flora Maria; Barbi, Egidio (Arch Dis Child, 2018)

Adenomyomatosis of the Gallbladder as a Cause of Recurrent Abdominal Pain. - Agrusti, Anna; Gregori, Massimo; Salviato, Tiziana; Codrich, Daniela; Barbi, Egidio (J Pediatr, 2018)
Keywords: Abdominal Pain; Adenomyoma; Adolescent; Biopsy, Needle; Cholecystectomy; Diagnosis, Differential; Female; Gallbladder; Gallbladder Neoplasms; Humans; Immunohistochemistry; Recurrence; Risk Assessment; Severity of Illness Index; Ultrasonography, Doppler

Adolescent with intermittent haematuria. - Pillon, Roberto; Pennesi, Marco; Rabach, Ingrid; Barbi, Egidio (Arch Dis Child Educ Pract Ed, 2018)

Afebrile seizures in infants: Never forget magnesium! - Minute, Marta; Ventura, Giovanna; Giorgi, Rita; Faletra, Flavio; Costa, Paola; Cozzi, Giorgio (J Paediatr Child Health, 2018)

Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. (Lancet, 2018)
BACKGROUND: Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older. METHODS: Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health. FINDINGS: Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2·2% (95% uncertainty interval [UI] 1·5-3·0) of age-standardised female deaths and 6·8% (5·8-8·0) of age-standardised male deaths. Among the population aged 15-49 years, alcohol use was the leading risk factor globally in 2016, with 3·8% (95% UI 3·2-4·3) of female deaths and 12·2% (10·8-13·6) of male deaths attributable to alcohol use. For the population aged 15-49 years, female attributable DALYs were 2·3% (95% UI 2·0-2·6) and male attributable DALYs were 8·9% (7·8-9·9). The three leading causes of attributable deaths in this age group were tuberculosis (1·4% [95% UI 1·0-1·7] of total deaths), road injuries (1·2% [0·7-1·9]), and self-harm (1·1% [0·6-1·5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27·1% (95% UI 21·2-33·3) of total alcohol-attributable female deaths and 18·9% (15·3-22·6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0·0-0·8) standard drinks per week. INTERPRETATION: Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption. FUNDING: Bill & Melinda Gates Foundation.
Keywords: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Alcohol Drinking; Cause of Death; Commerce; Female; Global Burden of Disease; Global Health; Humans; Male; Middle Aged; Observational Studies as Topic; Population Surveillance; Prevalence; Prospective Studies; Quality-Adjusted Life Years; Retrospective Studies; Risk Assessment; Risk Factors; Sex Distribution; Young Adult

Alendronate treatment induces IL-1B expression and apoptosis in glioblastoma cell line. - Tricarico, Paola Maura; Epate, Angeladine; Celsi, Fulvio; Crovella, Sergio (Inflammopharmacology, 2018)
Alendronate (ALD), one among the nitrogen-containing bisphosphonates (NBPs), is currently used for the treatment of many pathological conditions. Unfortunately, although generally tolerated, NBPs treatment has been associated with central nervous system (CNS) adverse outcomes, such as amnesia, hallucinations and visual disturbances. So, we analyzed the effect of ALD treatment in glial cells, the main sources of cholesterol for neurons and principal cells involved in the immunological defense of the brain. We treated a glial cell line (U87-MG) with increasing doses of ALD (0.1, 1, 10, 25, 50 μM) for 48 h, aimed at evaluating the influence of this drug treatment on IL-1B expression, NLRP3 and CASP1 expression, mitochondrial activity and apoptotic cell death. We observed that ALD treatment, at the higher concentrations, induced a significant increase of IL-1B, NLRP3, CASP1 expression, provoked apoptosis and also mitochondrial damage in U87-MG. Considering the reported CNS adverse outcomes of NBPs treatment, our results confirm ALD side-effects on glial cell model.
Keywords: Alendronate; Apoptosis; Brain; Cell Line, Tumor; Diphosphonates; Glioblastoma; Humans; Interleukin-1beta; Neuroglia

Anaphylaxis in atypical cold urticaria: case report and review of literature. - Benelli, Elisa; Longo, Giorgio; Barbi, Egidio; Berti, Irene (Ital J Pediatr, 2018)
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'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

Antibody response to polyomavirus primary infection: high seroprevalence of Merkel cell polyomavirus and lymphoid tissue involvement. - Cason, Carolina; Monasta, Lorenzo; Zanotta, Nunzia; Campisciano, Giuseppina; Maestri, Iva; Tommasino, Massimo; Pawlita, Michael; Villani, Sonia; Comar, Manola; Delbue, Serena (J Neurovirol, 2018)
Human polyomaviruses (HPyVs) asymptomatically infect the human population establishing latency in the host, and their seroprevalence can reach 90% in healthy adults. Few studies have focused on the pediatric population, and there are no reports regarding the seroprevalence of all the newly isolated HPyVs among Italian children. Therefore, we investigated the frequency of serum antibodies against 12 PyVs in 182 immunocompetent children from Northeast Italy, by means of a multiplex antibody detection system. Additionally, secondary lymphoid tissues were collected to analyze the presence of HPyV DNA sequences using a specific real-time PCRs or PCRs. Almost 100% of subjects were seropositive for at least one PyV. Seropositivity ranged from 3% for antibodies against simian virus 40 (SV40) in children from 0 to 3 years, to 91% for antibodies against WU polyomavirus (WUPyV) and HPyV10 in children from 8 to 17 years. The mean number of PyV for which children were seropositive increased with the increasing of age: 4 standard deviations (SD) 1.8 in the 0-3-year group, 5 (SD 1.9) in the 4-7-year group, and 6 (SD 2.2) in the 8-17-year group. JC polyomavirus (JCPyV) DNA was detected in 1% of the adenoids, WUPyV in 12% of the tonsils, and 28% of the adenoids, and Merkel cell polyomavirus (MCPyV) was present in 6 and 2% of the tonsils and adenoids, respectively. Our study gives new insights on the serological evidence of exposure to PyVs during childhood, and on their possible respiratory route of transmission.

Anti-transglutaminase 6 Antibody Development in Children With Celiac Disease Correlates With Duration of Gluten Exposure. - De Leo, Luigina; Aeschlimann, Daniel; Hadjivassiliou, Marios; Aeschlimann, Pascale; Salce, Nicola; Vatta, Serena; Ziberna, Fabiana; Cozzi, Giorgio; Martelossi, Stefano; Ventura, Alessandro; Not, Tarcisio (J Pediatr Gastroenterol Nutr, 2018)
OBJECTIVES: Antibodies against transglutaminase 6 (anti-TG6) have been implicated in neurological manifestations in adult patients with genetic gluten intolerance, and it is unclear whether autoimmunity to TG6 develops following prolonged gluten exposure. We measured the anti-TG6 in children with celiac disease (CD) at the diagnosis time to establish a correlation between these autoantibodies and the duration of gluten exposure. We investigated a correlation between anti-TG6 and the presence of neurological disorders. METHODS: Anti-TG6 (IgA/IgG) were measured by ELISA in sera of children with biopsy-proven CD and of children experiencing gastrointestinal disorders. CD patients positive for anti-TG6 were retested after 2 years of gluten-free diet (GFD). RESULTS: We analyzed the sera of 274 CD children and of 121 controls. Anti-TG6 were detected in 68/274 (25%) CD patients and in 19/121 (16%) controls, with significant difference between the 2 groups (P = 0.04). None of the CD patients and of the controls testing positive for anti-TG6 were experiencing neurological disorders. Eleven of 18 (61%) CD patients with other autoimmune diseases were positive for anti-TG6. In CD patients, a significant correlation between the gluten exposure before the CD diagnosis and anti-TG6 concentration was found (P = 0.006 for IgA; P < 0.0001 for IgG). After GFD anti-TG6 concentrations were significantly reduced (P < 0.001). No significant correlation was observed between anti-TG6 and anti-TG2 serum concentrations. CONCLUSIONS: Anti-TG6 are more prevalent in children with untreated CD in the absence of overt neurological disorders. The synthesis of the anti-TG6 is related to a longer exposure to gluten before the CD diagnosis, and the autoimmunity against TG6 is gluten dependent and disappeared during GFD.

Are aortic coarctation and rheumatoid arthritis different models of aortic stiffness? Data from an echocardiographic study. - Faganello, Giorgio; Cioffi, Giovanni; Rossini, Maurizio; Ognibeni, Federica; Giollo, Alessandro; Fisicaro, Maurizio; Russo, Giulia; Di Nora, Concetta; Doimo, Sara; Tarantini, Luigi; Mazzone, Carmine; Cherubini, Antonella; et al. (Cardiovasc Ultrasound, 2018)
BACKGROUND: Patients who underwent a successful repair of the aortic coarctation (CoA) show high risk for cardiovascular (CV) events. Mechanical and structural abnormalities in the ascending aorta (Ao) might have a role in the prognosis of CoA patients. We analyzed the elastic properties of Ao measured as aortic stiffness index (AoSI) in CoA patients in the long-term period and we compared AoSI with a cohort of 38 patients with rheumatoid arthritis (RA) and 38 non-RA matched controls. METHODS: Data from 19 CoA patients were analyzed 28 ± 13 years after surgery. Abnormally high AoSI was diagnosed if AoSI > 6.07% (95th percentile of the AoSI detected in our reference healthy population). AoSI was assessed at the level of the aortic root by two-dimensional guided M-mode evaluation. RESULTS: CoA patients showed more than two-fold higher AoSI compared to RA and controls (9.8 ± 12.6 vs 4.8 ± 2.5% and 3.1 ± 2.0%, respectively; all p < 0.05 and in 5 of 19 patients with CoA (26%) AoSI was exceptionally high. The 5 patients with abnormally high AoSI were older with higher BP, LV mass and prevalence of LV diastolic dysfunction. Multiple linear regression analysis revealed that AoSI was independently related to the presence of LV hypertrophy and higher LV relative wall thickness. CONCLUSIONS: CoA patients have higher AoSI levels than RA patients and non-RA matched controls. AoSI levels are abnormally high in a small sub-group of CoA patients who show a very high-risk clinical profile for adverse CV events.
Keywords: Aorta; Aortic Coarctation; Arthritis, Rheumatoid; Humans; Prognosis; Vascular Stiffness

Bariatric surgery drives major rearrangements of the intestinal microbiota including the biofilm composition. - Campisciano, Giuseppina; Cason, Carolina; Palmisano, Silvia; Giuricin, Michela; Rizzardi, Alessia; Croce, Lory Saveria; De Manzini, Nicolo; Comar, Manola (Front Biosci (Elite Ed), 2018)
The intestinal microbiota disequilibrium has been associated with obesity, while the role of the gut mucosal biofilms in this pathology is still unknown. We analysed the changes in the intestinal microbiota of obese patients after bariatric surgery with the aim of disclosing the rearrangement of the biofilm configuration. Although the bariatric surgery drives major rearrangements of the gut microbiota, obese patients maintain the enterotype before and after surgery, as shown by normal weight patients, with an increase of and . The enterotype guarantees the strong ability to form a biofilm which allows a more efficient digestion of polysaccharides than planktonic communities and leads to the production of acetate which is a key player to inhibit enteropathogens. Additionally, the laparoscopic gastric bypass induces an increase of , a facultative anaerobic bacterium involved in intestinal and inflammatory disorders. Bariatric surgery influences the microbial composition of gut biofilm. Further studies are needed to elucidate the impact of this variation on recovery after surgery and on weight loss.
Keywords: Biofilms; Case-Control Studies; Gastric Bypass; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Obesity; Prospective Studies

Benign hereditary chorea and deletions outside NKX2-1: What's the role of MBIP? - Invernizzi, Federica; Zorzi, Giovanna; Legati, Andrea; Coppola, Giovanni; d'Adamo, Pio; Nardocci, Nardo; Garavaglia, Barbara; Ghezzi, Daniele (Eur J Med Genet, 2018)
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

Boy with fish-mouth meatus. - Cortellazzo Wiel, Luisa; Pederiva, Federica; Castagnetti, Marco; Barbi, Egidio; Pennesi, Marco (Arch Dis Child, 2018)

Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells. - Bellazzo, Arianna; Di Minin, Giulio; Valentino, Elena; Sicari, Daria; Torre, Denis; Marchionni, Luigi; Serpi, Federica; Stadler, Michael B; Taverna, Daniela; Zuccolotto, Gaia; Montagner, Isabella Monia; Rosato, Antonio; et al. (Cell Death Differ, 2018)
The tumor suppressor DAB2IP contributes to modulate the network of information established between cancer cells and tumor microenvironment. Epigenetic and post-transcriptional inactivation of this protein is commonly observed in multiple human malignancies, and can potentially favor progression of tumors driven by a variety of genetic mutations. Performing a high-throughput screening of a large collection of human microRNA mimics, we identified miR-149-3p as a negative post-transcriptional modulator of DAB2IP. By efficiently downregulating DAB2IP, this miRNA enhances cancer cell motility and invasiveness, facilitating activation of NF-kB signaling and promoting expression of pro-inflammatory and pro-angiogenic factors. In addition, we found that miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility, thus potentially remodeling the tumor microenvironment. Finally, we found that inhibition of endogenous miR-149-3p restores DAB2IP activity and efficiently reduces tumor growth and dissemination of malignant cells. These observations suggest that miR-149-3p can promote cancer progression via coordinated inhibition of DAB2IP in tumor cells and in stromal cells.

Cerebrospinal Fluid Cytokine Expression Profile in Multiple Sclerosis and Chronic Inflammatory Demyelinating Polyneuropathy. - Bonin, Serena; Zanotta, Nunzia; Sartori, Arianna; Bratina, Alessio; Manganotti, Paolo; Trevisan, Giusto; Comar, Manola (Immunol Invest, 2018)
BACKGROUND: Cerebrospinal fluid (CSF) analysis in patients with particular neurologic disorders is a powerful tool to evaluate specific central nervous system inflammatory markers for diagnostic needs, because CSF represents the specific immune micro-environment to the central nervous system. METHODS: CSF samples from 49 patients with multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP), and non-inflammatory neurologic disorders (NIND) as controls were submitted to protein expression profiles of 47 inflammatory biomarkers by multiplex Luminex bead assay to investigate possible differences in the inflammatory process for MS and CIDP. RESULTS: Our results showed differences in CSF cytokine levels in MS and CIDP; in particular, IL12 (p40) was significantly highly expressed in MS in comparison with CIDP and NIND, while SDF-1α and SCGF-β were significantly highly expressed in CIDP cohort when compared to MS and NIND. IL-9, IL-13, and IL-17 had higher expression levels in NIND if compared with the other groups. CONCLUSIONS: Our study showed that, despite some common pathogenic mechanisms, central and peripheral nervous system demyelinating diseases, such as MS and CIDP, differ in some specific inflammatory soluble proteins in CSF, underlining differences in the immune response involved in those autoimmune diseases.
Keywords: Adult; Aged; Biomarkers; Central Nervous System; Diagnosis, Differential; Female; Hematopoietic Cell Growth Factors; Humans; Interleukin-12; Lectins, C-Type; Male; Middle Aged; Multiple Sclerosis; Peripheral Nervous System; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Proteins

Cervical-length measurement in mid-gestation to predict spontaneous preterm birth in asymptomatic triplet pregnancy. - Fichera, A; Pagani, G; Stagnati, V; Cascella, S; Faiola, S; Gaini, C; Lanna, M; Pasquini, L; Raffaelli, R; Stampalija, T; Tommasini, A; Prefumo, F (Ultrasound Obstet Gynecol, 2018)
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' 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' 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' gestation in asymptomatic triplet pregnancy. Copyright © 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

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders. - Fontana, L; Bedeschi, M F; Maitz, S; Cereda, A; Faré, C; Motta, S; Seresini, A; D'Ursi, P; Orro, A; Pecile, V; Calvello, M; Selicorni, A; et al. (Epigenetics, 2018)
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

A Child with Diminished Linear Growth and Waddling Gait. - Tamaro, Gianluca; Pederiva, Federica; Dibello, Daniela; Gregori, Massimo; Carbone, Marco; Pantaleoni, Francesca; Dentici, Maria Lisa; Niceta, Marcello; Barbi, Egidio (J Pediatr, 2018)
Keywords: Abnormalities, Multiple; Child; Dwarfism; Female; Gait; Humans; Osteochondrodysplasias; Radiography

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. - Grasso, Antonio G; Granzotto, Marilena; Zanon, Davide; Maestro, Alessandra; Loiacono, Stefano; Maximova, Natalia (Cancers (Basel), 2018)
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/m²), 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.

The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases. - Bernardi, Stella; Marcuzzi, Annalisa; Piscianz, Elisa; Tommasini, Alberto; Fabris, Bruno (Int J Mol Sci, 2018)
Lipids and inflammation regulate each other. Early studies on this topic focused on the systemic effects that the acute inflammatory response-and interleukins-had on lipid metabolism. Today, in the era of the obesity epidemic, whose primary complications are cardio-metabolic diseases, attention has moved to the effects that the nutritional environment and lipid derangements have on peripheral tissues, where lipotoxicity leads to organ damage through an imbalance of chronic inflammatory responses. After an overview of the effects that acute inflammation has on the systemic lipid metabolism, this review will describe the lipid-induced immune responses that take place in peripheral tissues and lead to chronic cardio-metabolic diseases. Moreover, the anti-inflammatory effects of lipid lowering drugs, as well as the possibility of using anti-inflammatory agents against cardio-metabolic diseases, will be discussed.
Keywords: Anti-Inflammatory Agents; Cardiovascular Diseases; Humans; Hypolipidemic Agents; Immune System; Inflammation; Interleukins; Lipid Metabolism; Lipids; Metabolic Diseases

Cooking influence in tolerance acquisition in egg-induced acute food protein enterocolitis syndrome. - Miceli Sopo, S; Romano, A; Bersani, G; Fantacci, C; Badina, L; Longo, G; Monti, G; Viola, S; Tripodi, S; Barilaro, G; Iacono, I D; Caffarelli, C; et al. (Allergol Immunopathol (Madr), 2018)
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.

Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway. - Fetoni, Anna Rita; Zorzi, Veronica; Paciello, Fabiola; Ziraldo, Gaia; Peres, Chiara; Raspa, Marcello; Scavizzi, Ferdinando; Salvatore, Anna Maria; Crispino, Giulia; Tognola, Gabriella; Gentile, Giulia; Spampinato, Antonio Gianmaria; et al. (Redox Biol, 2018)
Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2 mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2 mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2 mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4 × 10) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis.
Keywords: Animals; Apoptosis; Connexin 26; Female; Gene Deletion; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidation-Reduction; Presbycusis; Signal Transduction

Cytokine profiles of women with vulvodynia: Identification of a panel of pro-inflammatory molecular targets. - Zanotta, Nunzia; Campisciano, Giuseppina; Scrimin, Federica; Blendi, Ura; Marcuzzi, Annalisa; Vincenti, Ezio; Crovella, Sergio; Comar, Manola (Eur J Obstet Gynecol Reprod Biol, 2018)
OBJECTIVE: The vulvar pain syndrome (VPS) is a multifactorial disease severely influencing the lifestyle of affected women. Among possible etiological factors, local injury, peripheral and/or central sensitization of the nervous system, and a chronic inflammatory status have been positively associated with the development of VPS. The identification of a constitutive altered local inflammatory profile in VPS women may represent an important point in the characterization of patients' phenotype as a useful marker influencing the vulvar micro-environment. The aim of this study was to investigative the possible role of the local cytokines production in women with VPS in comparison to healthy women. STUDY DESIGN: In this study were collected vaginal swabs from 57 healthy women (HC) who never suffered from VPS and from 30 patients diagnosed with vulvodynia (VPS) by at least 3 years and currently symptomatic. All patients included in this study showed the absence of Sexually Transmitted (STD) diseases and Reproductive Tract Infection. Real-time PCR was performed to assess the genomic sequences of ST pathogens. The Luminex Bio-Plex platform was used for the analysis of a panel of 48 immune factors. RESULTS: Eleven molecules, specifically involved in the pro-inflammatory pathway were significantly modulated in VPS patients in comparison to healthy women, suggesting a persistent inflammatory process. CONCLUSIONS: Therefore, these inflammatory factors could be possible biological markers involved in this disease. Nevertheless, other studies are needed to consider this specific immune profile as a valid marker of the vulvodynia.
Keywords: Adult; Aged; Cytokines; Female; Humans; Inflammation; Middle Aged; Vaginal Smears; Vulva; Vulvodynia; Women's Health

De novo unbalanced translocations have a complex history/aetiology. - Bonaglia, Maria Clara; Kurtas, Nehir Edibe; Errichiello, Edoardo; Bertuzzo, Sara; Beri, Silvana; Mehrjouy, Mana M; Provenzano, Aldesia; Vergani, Debora; Pecile, Vanna; Novara, Francesca; Reho, Paolo; Di Giacomo, Marilena Carmela; et al. (Hum Genet, 2018)
We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin. Moreover, the duplicated region was of maternal origin in more than half of the cases, with 25% of them showing two maternal and one paternal haplotype. In all these cases, maternal age was increased. These findings indicate that the primary driver for the occurrence of the de novo unbalanced translocations is a maternal meiotic non-disjunction, followed by partial trisomy rescue of the supernumerary chromosome present in the trisomic zygote. In contrast, asymmetric breakage of a dicentric chromosome, originated either at the meiosis or postzygotically, in which the two resulting chromosomes, one being deleted and the other one inv-dup del, are repaired by telomere capture, appears at the basis of all inv-dup del translocations. Notably, this mechanism also fits with the origin of some simple translocations in which the duplicated region was of paternal origin. In all cases, the signature at the translocation junctions was that of non-homologous end joining (NHEJ) rather than non-allelic homologous recombination (NAHR). Our data imply that there is no risk of recurrence in the following pregnancies for any of the de novo unbalanced translocations we discuss here.
Keywords: DNA End-Joining Repair; Female; Humans; Male; Meiosis; Recombinational DNA Repair; Translocation, Genetic

DEFB1 polymorphisms and HIV-1 mother-to-child transmission in Zambian population. - Zupin, Luisa; Polesello, Vania; Segat, Ludovica; Kamada, Anselmo Jiro; Kuhn, Louise; Crovella, Sergio (J Matern Fetal Neonatal Med, 2018)
INTRODUCTION: Human Beta Defensin-1 (hBD-1) is a component of the innate immune system, the first line of defence against pathogens, already reported as involved in the susceptibility to HIV-1 infection and HIV-1 mother-to-child transmission (MTCT) in different populations. We investigated the role of DEFB1 gene (encoding for hBD-1) functional polymorphisms in the susceptibility to HIV-1 MTCT in a population from Zambia. METHODS: Four selected polymorphisms within DEFB1 gene, three at the 5' untranslated region (UTR), namely -52G > A (rs1799946), -44C > G (rs1800972) and -20G > A (rs11362) and one in the 3'UTR, c.*87A > G (rs1800972), were genotyped in 101 HIV-1 positive mothers (26 transmitters -27% and 75 not transmitters -73%) and 331 infants born to HIV-1 infected mothers (85 HIV-1 positive -26% and 246 exposed but not infected -74%). RESULTS: DEFB1 c.*87-A allele was more frequent among HIV- children with respect to HIV+ (with intrauterine MTCT). Concerning DEFB1 haplotypes, GCGA haplotype resulted more represented in HIV- than HIV+ infants and DEFB1 ACGG haplotype presented increased frequency in HIV- children respect to HIV+ (with intra-partum MTCT) (p = .02, p = .002 and p = .006, respectively). CONCLUSIONS: DEFB1 polymorphisms were significantly associated with decreased risk of HIV-1 infection acquisition in the studied Zambian population suggesting that they may play a role in HIV-1 MTCT.

Does the Application of Heat Gel Pack After Eutectic Mixture of Local Anesthetic Cream Improve Venipuncture or Intravenous Cannulation Success Rate in Children? A Randomized Control Trial. - Schreiber, Silvana; Cozzi, Giorgio; Patti, Giuseppa; Taddio, Andrea; Montico, Marcella; Pierobon, Chiara; Barbi, Egidio (Pediatr Emerg Care, 2018)
OBJECTIVE: Needle-related procedures are the most common sources of pain for children in the hospital setting. The most used topical anesthetic, eutectic mixture of local anesthetic (EMLA) cream, may cause transient vasoconstriction. It has been postulated that this vasoconstriction may decrease vein visualization. The application of heat gel pack after removal of EMLA cream in the site of venipuncture counteracts the vasoconstriction, improving vein visualization. We assessed using a prospective randomized controlled trial whether the application of heat gel pack increases the needle procedure success rate. The primary study outcome was procedural success rate at the first attempt. METHODS: The study enrolled 400 children, 200 of whom applied heat gel pack after removing EMLA (treatment group) and 200 did not (control group). Procedural success rate at the first attempt, vein perception before procedure, procedural pain, and adverse events were recorded in both groups. RESULTS: Eighty-eight percent of the procedures were successful at the first attempt in the treatment group and 89% in the control group (P = 0.876). Vein perception was not significantly different in the 2 groups (P = 0.081). Pain score after the procedure was similar in the 2 groups. CONCLUSIONS: This study shows that the application of heat gel pack after removal of EMLA cream does not improve venipuncture or intravenous cannulation success rate.
Keywords: Anesthetics, Local; Child; Child, Preschool; Female; Hot Temperature; Humans; Lidocaine; Lidocaine, Prilocaine Drug Combination; Male; Pain; Pain Management; Phlebotomy; Prilocaine; Prospective Studies

Dysregulated chaperones associated with cell proliferation and negative apoptosis regulation in the uterine leiomyoma. - Ura, Blendi; Scrimin, Federica; Arrigoni, Giorgio; Aloisio, Michelangelo; Monasta, Lorenzo; Ricci, Giuseppe (Oncol Lett, 2018)
Uterine leiomyomas are benign smooth muscle cell tumors that originate from the myometrium. In this study we focus on dysregulated chaperones associated with cell proliferation and apoptosis. Paired tissue samples of 15 leiomyomas and adjacent myometria were obtained and analyzed by two-dimensional gel electrophoresis (2-DE). Mass spectrometry was used for protein identification and western blotting for 2-DE data validation. The values of 6 chaperones were found to be significantly different in the leiomyoma when compared with the myometrium. A total of 4 proteins were upregulated in the leiomyoma and 2 proteins were downregulated. Calreticulin and 78 kDa glucose-regulated protein were further validated by western blotting because the first is considered a marker of cell proliferation, while the second protects against apoptotic cell death. In addition, we also validated the two downregulated proteins heat shock protein β-1 and heat shock 70 kDa protein 1A. Our study shows the existence of a dysregulation of chaperone proteins associated with leiomyoma development. Functional studies are needed to ascertain the role of these chaperones in the leiomyoma. This may be crucial for the further development of specific inhibitors against the activity of these proteins in order to block the growth of the leiomyoma.

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. - Lazzerini, Marzia; Richardson, Sonia; Ciardelli, Valentina; Erenbourg, Anna (BMJ Open, 2018)
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

Efficacy and Safety of Adalimumab in Pediatric Ulcerative Colitis: A Real-life Experience from the SIGENP-IBD Registry. - Aloi, Marina; Bramuzzo, Matteo; Arrigo, Serena; Romano, Claudio; D'Arcangelo, Giulia; Lacorte, Doriana; Gatti, Simona; Illiceto, Maria T; Zucconi, Francesca; Dilillo, Dario; Zuin, Giovanna; Knafelz, Daniela; et al. (J Pediatr Gastroenterol Nutr, 2018)
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 ± 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.

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. - Bucci, Stefano; Umari, Paolo; Rizzo, Michele; Pavan, Nicola; Liguori, Giovanni; Barbone, Fabio; Trombetta, Carlo (Minerva Urol Nefrol, 2018)
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

Endocrine and psychological aspects of sexual dysfunction in Klinefelter patients. - Ferlin, A; Selice, R; Angelini, S; Di Grazia, M; Caretta, N; Cavalieri, F; Di Mambro, A; Foresta, C (Andrology, 2018)
Klinefelter syndrome is a frequent cause of hypogonadism, but despite hundreds of publications on different aspects of Klinefelter syndrome, only a few studies dealt with sexual dysfunction. In particular, testosterone is critical for various aspects of sexual response, but its role on sexuality in Klinefelter syndrome patients is debatable and no studies have evaluated the efficacy of testosterone treatment on sexual dysfunction in these subjects. Furthermore, the impact of psychological and relational aspects on sexual function of Klinefelter syndrome subjects is poorly defined. In this study, we aimed to determine the presence and type of sexual dysfunctions in Klinefelter syndrome subjects; to correlate them with testosterone levels and psychosexological and relational domains; and to evaluate the effects of testosterone therapy. We studied 62 non-mosaic naïve Klinefelter syndrome patients and 60 age-matched controls by means of medical history, psychosexological history, 15-item International Index of Erectile Function questionnaire, endocrine assessment, and dynamic penile color Doppler ultrasound. Twenty-five hypogonadal Klinefelter syndrome patients were studied after 6 months of testosterone replacement therapy. Klinefelter syndrome subjects have reduced 15-item International Index of Erectile Function scores regarding sexual desire, intercourse satisfaction, and overall satisfaction with respect to controls, and these aspects were significantly associated with testosterone levels. Klinefelter syndrome subjects had also higher prevalence of erectile dysfunction, but no relation with testosterone levels was evident. A high prevalence of a range of psychological disturbances was present in Klinefelter syndrome subjects with erectile dysfunction with respect to those without erectile dysfunction. No statistical difference in the prevalence of premature and delayed ejaculation was observed between Klinefelter syndrome and control subjects. Testosterone replacement therapy improved sexual desire, intercourse satisfaction, and overall satisfaction scores, but had no effect on erectile function. Penile color Doppler ultrasound was normal in all subjects. This study shows that sexual dysfunction in Klinefelter syndrome is multifactorial and related only in part to hypogonadism and largely to psychological disturbances. Evaluation and therapy of sexual dysfunction should include a combined andrological and psychosexological approach.

Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. - Prins, Bram P; Mead, Timothy J; Brody, Jennifer A; Sveinbjornsson, Gardar; Ntalla, Ioanna; Bihlmeyer, Nathan A; van den Berg, Marten; Bork-Jensen, Jette; Cappellani, Stefania; Van Duijvenboden, Stefan; Klena, Nikolai T; Gabriel, George C; et al. (Genome Biol, 2018)
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

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. - Lazzerini, Marzia; Ciuch, Margherita; Rusconi, Silvia; Covi, Benedetta (BMJ Open, 2018)
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'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'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.

Fecal Calprotectin to Detect Inflammatory Bowel Disease in Juvenile Idiopathic Arthritis. - Ferrara, Giovanna; Pastore, Serena; Sancin, Lara; Torelli, Lucio; Radillo, Oriano; Bramuzzo, Matteo; Bibalo, Chiara; Tommasini, Alberto; Ventura, Alessandro; Taddio, Andrea (J Rheumatol, 2018)
OBJECTIVE: This study aimed to test fecal calprotectin (FC) as a screening tool to identify inflammatory bowel disease (IBD) among patients with juvenile idiopathic arthritis (JIA). METHODS: FC level < 100 g/kg was considered normal. Patients with 2 consecutive FC dosage ≥ 100 g/kg underwent endoscopic evaluation. RESULTS: There were 113 patients with JIA enrolled. FC was raised in 7 patients out of 113. All patients had IBD. In 3/7 patients, high FC levels were the only sign consistent with IBD. CONCLUSION: FC is a useful, economical, and noninvasive diagnostic tool to identify JIA patients with underlying IBD.

Ferruginous bodies resolved by synchrotron XRF in a dog with peritoneal malignant mesothelioma. - Pascotto, Ernesto; Gianoncelli, Alessandra; Calligaro, Carla; Marcuzzo, Thomas; Melato, Mauro; Rizzardi, Clara; Pascolo, Lorella (Environ Sci Pollut Res Int, 2018)
Mesothelioma is a malignant tumor mainly correlated to occupational asbestos exposure. Rare reports describe its occurrence also in animals, mainly linked to asbestos in the environment. Asbestos exposure is demonstrated by the appearance of characteristic histological hallmarks: asbestos containing ferruginous bodies that are iron-based structures forming around fibers and also other dust particles. Here we present a clinical case of a suspect of mesothelioma in the peritoneum of a dog with parallel histological observation of ferruginous bodies. To possibly correlate the dog tumor to environmental exposure, we performed X-ray fluorescence (XRF) analyses at two different synchrotrons to resolve the ferruginous bodies' composition. While the histological examination diagnoses a tubulo-papillary mesothelioma, the XRF analyses show that ferruginous bodies contain Si particles, resembling formations of exogenous origin; however, the morphology is unlikely that of asbestos fibers. We speculate that the peritoneal mesothelioma of this dog could be related to environmental exposure to non-asbestos material.
Keywords: Animals; Asbestos; Dogs; Environmental Exposure; Immunohistochemistry; Iron; Lung; Lung Neoplasms; Male; Mesothelioma; Peritoneal Neoplasms; Silicon; Spectrometry, X-Ray Emission; Synchrotrons

Flares After Withdrawal of Biologic Therapies in Juvenile Idiopathic Arthritis: Clinical and Laboratory Correlates of Remission Duration. - Simonini, Gabriele; Ferrara, Giovanna; Pontikaki, Irene; Scoccimarro, Erika; Giani, Teresa; Taddio, Andrea; Meroni, Pier Luigi; Cimaz, Rolando (Arthritis Care Res (Hoboken), 2018)
OBJECTIVE: To assess the time in remission after discontinuing biologic therapy in patients with juvenile idiopathic arthritis (JIA). METHODS: We enrolled 135 patients followed in 3 tertiary-care centers. The primary outcome was to assess, once remission was achieved, the time in remission up to the first flare after discontinuing treatment. Mann-Whitney U test, Wilcoxon's signed rank test for paired samples, chi-square tests, and Fisher's exact test were used to compare data. Pearson's and Spearman's correlation tests were used to determine correlation coefficients for different variables. To identify predictors of outcome, Cox regression model and Kaplan-Meier curves were constructed, each one at the mean of entered covariates. RESULTS: The majority of enrolled patients flared after stopping treatment with biologics (102 of 135, 75.6%) after a median followup time in remission off therapy of 6 months (range 3-109 months). A higher probability of maintaining remission after discontinuing treatment was present in systemic-onset disease compared to the rest of the JIA patients (Mantel-Cox χ = 8.31, P < 0.004). In analysis limited to children with JIA with polyarticular and oligoarticular disease, patients who received biologics >2 years after achieving remission had a higher probability of maintaining such remission off therapy (mean ± SD 18.64 ± 3.3 months versus 11.51 ± 2.7 months [P < 0.009]; Mantel-Cox χ = 9.06, P < 0.002). No other clinical variable was significantly associated with a long-lasting remission. CONCLUSION: Children with oligoarticular and polyarticular JIA who stop treatment before 2 years from remission have a higher chance of relapsing after biologic withdrawal.

Fractional CO laser for genitourinary syndrome of menopause in breast cancer survivors: clinical, immunological, and microbiological aspects. - Becorpi, Angelamaria; Campisciano, Giuseppina; Zanotta, Nunzia; Tredici, Zelinda; Guaschino, Secondo; Petraglia, Felice; Pieralli, Annalisa; Sisti, Giovanni; De Seta, Francesco; Comar, Manola (Lasers Med Sci, 2018)
The composition of vaginal microbiome in menopause and cancer survivor women changes dramatically leading to genitourinary syndrome of menopause (GSM) in up to 70% of patients. Recent reports suggest that laser therapy may be valuable as a not hormonal therapeutic modality. The aim of the present study was to evaluate the effects of fractional CO laser treatment on the vaginal secretory pathway of a large panel of immune mediators, usually implicated in tissue remodeling and inflammation, and on microbiome composition in postmenopausal breast cancer survivors. The Ion Torrent PGM platform and the Luminex Bio-Plex platform were used for microbiome and immune factor analysis. The significant reduction of clinical symptoms and the non-significant changes in vaginal microbiome support the efficacy and safety of laser treatment. Moreover, the high remodeling status in vaginal epithelium is demonstrated by the significant changes in inflammatory and modulatory cytokine patterns. Laser therapy can be used for the treatment of GSM symptoms and does not show any adverse effects. However, further studies will be needed to clarify its long-term efficacy and other effects.
Keywords: Breast Neoplasms; Cancer Survivors; Cytokines; Dyspareunia; Female; Humans; Lasers, Gas; Menopause; Microbiota; Middle Aged; Prospective Studies; Syndrome; Vagina; Vaginal Diseases

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. - Lee, James J; Wedow, Robbee; Okbay, Aysu; Kong, Edward; Maghzian, Omeed; Zacher, Meghan; Nguyen-Viet, Tuan Anh; Bowers, Peter; Sidorenko, Julia; Karlsson Linnér, Richard; Fontana, Mark Alan; Kundu, Tushar; et al. (Nat Genet, 2018)
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.

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. - Evangelou, Evangelos; Warren, Helen R; Mosen-Ansorena, David; Mifsud, Borbala; Pazoki, Raha; Gao, He; Ntritsos, Georgios; Dimou, Niki; Cabrera, Claudia P; Karaman, Ibrahim; Ng, Fu Liang; Evangelou, Marina; et al. (Nat Genet, 2018)
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.

Genetic profile of patients with early onset inflammatory bowel disease. - Girardelli, Martina; Basaldella, Federica; Paolera, Sara Della; Vuch, Josef; Tommasini, Alberto; Martelossi, Stefano; Crovella, Sergio; Bianco, Anna Monica (Gene, 2018)
Inflammatory Bowel disease (IBD) is a widespread pathological condition with clinical heterogeneity and with different levels of severity. Although IBD usually occurs in young adults, onset in childhood and infancy are described in patients within the 10th and second year of age. By genome-wide association studies and meta-analysis, several genetic loci have been identified associated with an increased risk of developing IBD in Western populations with variants that may alter the normal mucosal immunity in the gastrointestinal tract. The clinical complexity and the heterogeneity of the IBD phenotype probably reflect the presence of genetic heterogeneity where different genes or combinations of them may be involved, together with environmental factors. We hypothesized that patients with early onset IBD could have either more severe genetic variants in genes associated with IBD or multiple variants in different genes. Under the multifactorial diseases is crucial to consider the small contribution of a single variant in all not only to other small variations in the same gene but also in different genes belonging to the same pathway. We performed direct gene sequencing looking for 94 variations in NOD2, ATG16L1, IL23R, IL10R, IL10 and XIAP genes previously shown as correlated with IBD both in multifactorial and in Mendelian models. All variants identified are known in literature as being associated with IBD except for three variants in the genes NOD2, IL10 and IL10RB that even though present in online databases have never been involved in association studies on IBD patients. Moreover, we coupled genetic variants identification with an accurate "in silico" analysis to verify their predictive impact on the protein structure and function. The in-silico prediction of these variants results as benign therefore even if they exhibit a very low frequency in control population being benign, they cannot be considered pathogenic as monogenic disease but fall within the multifactorial range. The variants identified in our study partially reflect the association data described in the literature but there are no significant differences with the onset of disease (VEO vs EO-IBD).
Keywords: Age of Onset; Autophagy-Related Proteins; Child; Child, Preschool; Computer Simulation; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Infant; Inflammatory Bowel Diseases; Interleukin-10; Male; Nod2 Signaling Adaptor Protein; Polymorphism, Single Nucleotide; Receptors, Interleukin; Receptors, Interleukin-10; Sequence Analysis, DNA; X-Linked Inhibitor of Apoptosis Protein

A genetic variant of NLRP1 gene is associated with asbestos body burden in patients with malignant pleural mesothelioma. - Crovella, S; Moura, R R; Cappellani, S; Celsi, F; Trevisan, E; Schneider, M; Brollo, A; Nicastro, E M; Vita, F; Finotto, L; Zabucchi, G; Borelli, V (J Toxicol Environ Health A, 2018)
The presence of asbestos bodies (ABs) in lung parenchyma is considered a histopathologic hallmark of past exposure to asbestos fibers, of which there was a population of longer fibers. The mechanisms underlying AB formation are complex, involving inflammatory responses and iron (Fe) metabolism. Thus, the responsiveness to AB formation is variable, with some individuals appearing to be poor AB formers. The aim of this study was to disclose the possible role of genetic variants of genes encoding inflammasome and iron metabolism proteins in the ability to form ABs in a population of 81 individuals from North East Italy, who died after having developed malignant pleural mesothelioma (MPM). This study included 86 genetic variants distributed in 10 genes involved in Fe metabolism and 7 genetic variants in two genes encoding for inflammasome molecules. Genotypes/haplotypes were compared according to the number of lung ABs. Data showed that the NLRP1 rs12150220 missense variant (H155L) was significantly correlated with numbers of ABs in MPM patients. Specifically, a low number of ABs was detected in individuals carrying the NLRP1 rs12150220 A/T genotype. Our findings suggest that the NLRP1 inflammasome might contribute in the development of lung ABs. It is postulated that the NLRP1 missense variant may be considered as one of the possible host genetic factors contributing to individual variability in coating efficiency, which needs to be taken when assessing occupational exposure to asbestos.

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. - Ligthart, Symen; Vaez, Ahmad; Võsa, Urmo; Stathopoulou, Maria G; de Vries, Paul S; Prins, Bram P; van der Most, Peter J; Tanaka, Toshiko; Naderi, Elnaz; Rose, Lynda M; Wu, Ying; Karlsson, Robert; et al. (Am J Hum Genet, 2018)
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 × 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.

Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error. - Tedja, Milly S; Wojciechowski, Robert; Hysi, Pirro G; Eriksson, Nicholas; Furlotte, Nicholas A; Verhoeven, Virginie J M; Iglesias, Adriana I; Meester-Smoor, Magda A; Tompson, Stuart W; Fan, Qiao; Khawaja, Anthony P; Cheng, Ching-Yu; et al. (Nat Genet, 2018)
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.

Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability. - Hysi, Pirro G; Valdes, Ana M; Liu, Fan; Furlotte, Nicholas A; Evans, David M; Bataille, Veronique; Visconti, Alessia; Hemani, Gibran; McMahon, George; Ring, Susan M; Smith, George Davey; Duffy, David L; et al. (Nat Genet, 2018)
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.

A genome-wide association study identifies an association between variants in EFCAB4B gene and periodontal disease in an Italian isolated population. - Bevilacqua, Lorenzo; Navarra, Chiara O; Pirastu, Nicola; Lenarda, Roberto Di; Gasparini, Paolo; Robino, Antonietta (J Periodontal Res, 2018)
BACKGROUND AND OBJECTIVE: Periodontitis in one of the most prevalent dental diseases. Despite numerous studies have investigated its aetiopathogenetic factors, few works have focused on its genetic predisposition and most of them took into account only candidate genes. Therefore, we conducted a Genome Wide Association Study in an Italian isolated population aimed at uncovering genetic variants that predispose to this disorder. METHODS: Diagnosis of chronic periodontitis was made following the criteria of the American Academy of Periodontology. Patients with chronic periodontitis were grouped into different categories: slight, severe, localized and generalized. A control group composed by people without signs of periodontitis or gingivitis was defined. DNA was genotyped using 370k Illumina chips. Linear mixed model regression was used to test the association between each single nucleotide polymorphism (SNP) (independent variable) and the periodontitis status (dependent variable), controlling for confounders sex, age and smoking. The genomic kinship matrix was also used as random effect. RESULTS: Four SNPs on the gene EFCAB4B resulted significantly associated to localized periodontitis (P < 5 × 10 ), with the best hit on the rs242016 SNP (P = 1.5 × 10 ). CONCLUSION: We have identified a novel significant association between the EFCAB4B gene and localized periodontitis. These results open a new perspective in the understanding of genetic factors contributing to this common disorder.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Calcium-Binding Proteins; Chronic Periodontitis; DNA; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Italy; Male; Middle Aged; Polymorphism, Single Nucleotide; Regression Analysis; Young Adult

A genome-wide association study of corneal astigmatism: The CREAM Consortium. - Shah, Rupal L; Li, Qing; Zhao, Wanting; Tedja, Milly S; Tideman, J Willem L; Khawaja, Anthony P; Fan, Qiao; Yazar, Seyhan; Williams, Katie M; Verhoeven, Virginie J M; Xie, Jing; Wang, Ya Xing; et al. (Mol Vis, 2018)
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=5.55×10. 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

A Giant Ovarian Cyst in an Adolescent. - Corrias, Francesca; Pederiva, Federica; Cozzi, Giorgio; Ammar, Lydie; Cattaruzzi, Elisabetta; Lembo, Maria Antonietta; Barbi, Egidio (J Pediatr, 2018)
Keywords: Child; Cystadenoma, Serous; Female; Humans; Ovarian Neoplasms

Girl With Chest Pain. - Scarpa, Maria-Grazia; Rabach, Ingrid; Canuto, Arianna; Sanabor, Daniela; Barbi, Egidio; Schleef, Jurgen (Ann Emerg Med, 2018)

A Girl with Delayed Puberty and Bumpy Lips. - Andrade, Stefanny; Sirchia, Fabio; Faleschini, Elena; Barbi, Egidio (J Pediatr, 2018)
Keywords: Adolescent; Exons; Female; Genes, Dominant; Humans; Lip; Multiple Endocrine Neoplasia Type 2b; Neoplasm Metastasis; Puberty, Delayed; Thyroid Neoplasms; Thyroidectomy; Tongue

Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017. (Lancet, 2018)
BACKGROUND: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. METHODS: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. FINDINGS: Globally, 18·7% (95% uncertainty interval 18·4-19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2-59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5-49·6) to 70·5 years (70·1-70·8) for men and from 52·9 years (51·7-54·0) to 75·6 years (75·3-75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5-51·7) for men in the Central African Republic to 87·6 years (86·9-88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3-238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6-42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2-5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. INTERPRETATION: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing. FUNDING: Bill & Melinda Gates Foundation.
Keywords: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Child; Child, Preschool; Female; Global Burden of Disease; Global Health; Humans; Infant; Infant, Newborn; Life Expectancy; Male; Middle Aged; Mortality; Sex Distribution; Socioeconomic Factors; Young Adult

Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. (Lancet, 2018)
BACKGROUND: Global development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017. METHODS: The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries-Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODEm), to generate cause fractions and cause-specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised. FINDINGS: At the broadest grouping of causes of death (Level 1), non-communicable diseases (NCDs) comprised the greatest fraction of deaths, contributing to 73·4% (95% uncertainty interval [UI] 72·5-74·1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional (CMNN) causes accounted for 18·6% (17·9-19·6), and injuries 8·0% (7·7-8·2). Total numbers of deaths from NCD causes increased from 2007 to 2017 by 22·7% (21·5-23·9), representing an additional 7·61 million (7·20-8·01) deaths estimated in 2017 versus 2007. The death rate from NCDs decreased globally by 7·9% (7·0-8·8). The number of deaths for CMNN causes decreased by 22·2% (20·0-24·0) and the death rate by 31·8% (30·1-33·3). Total deaths from injuries increased by 2·3% (0·5-4·0) between 2007 and 2017, and the death rate from injuries decreased by 13·7% (12·2-15·1) to 57·9 deaths (55·9-59·2) per 100 000 in 2017. Deaths from substance use disorders also increased, rising from 284 000 deaths (268 000-289 000) globally in 2007 to 352 000 (334 000-363 000) in 2017. Between 2007 and 2017, total deaths from conflict and terrorism increased by 118·0% (88·8-148·6). A greater reduction in total deaths and death rates was observed for some CMNN causes among children younger than 5 years than for older adults, such as a 36·4% (32·2-40·6) reduction in deaths from lower respiratory infections for children younger than 5 years compared with a 33·6% (31·2-36·1) increase in adults older than 70 years. Globally, the number of deaths was greater for men than for women at most ages in 2017, except at ages older than 85 years. Trends in global YLLs reflect an epidemiological transition, with decreases in total YLLs from enteric infections, respiratory infections and tuberculosis, and maternal and neonatal disorders between 1990 and 2017; these were generally greater in magnitude at the lowest levels of the Socio-demographic Index (SDI). At the same time, there were large increases in YLLs from neoplasms and cardiovascular diseases. YLL rates decreased across the five leading Level 2 causes in all SDI quintiles. The leading causes of YLLs in 1990-neonatal disorders, lower respiratory infections, and diarrhoeal diseases-were ranked second, fourth, and fifth, in 2017. Meanwhile, estimated YLLs increased for ischaemic heart disease (ranked first in 2017) and stroke (ranked third), even though YLL rates decreased. Population growth contributed to increased total deaths across the 20 leading Level 2 causes of mortality between 2007 and 2017. Decreases in the cause-specific mortality rate reduced the effect of population growth for all but three causes: substance use disorders, neurological disorders, and skin and subcutaneous diseases. INTERPRETATION: Improvements in global health have been unevenly distributed among populations. Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health. For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for NCDs, and the death rate for selected causes has increased in the past decade. FUNDING: Bill & Melinda Gates Foundation.
Keywords: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Cause of Death; Child; Child, Preschool; Female; Global Burden of Disease; Global Health; Humans; Infant; Infant, Newborn; Life Expectancy; Male; Middle Aged; Sex Distribution; Socioeconomic Factors; Young Adult

Global, regional, and national burden of meningitis, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. (Lancet Neurol, 2018)
BACKGROUND: Acute meningitis has a high case-fatality rate and survivors can have severe lifelong disability. We aimed to provide a comprehensive assessment of the levels and trends of global meningitis burden that could help to guide introduction, continuation, and ongoing development of vaccines and treatment programmes. METHODS: The Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2016 study estimated meningitis burden due to one of four types of cause: pneumococcal, meningococcal, Haemophilus influenzae type b, and a residual category of other causes. Cause-specific mortality estimates were generated via cause of death ensemble modelling of vital registration and verbal autopsy data that were subject to standardised data processing algorithms. Deaths were multiplied by the GBD standard life expectancy at age of death to estimate years of life lost, the mortality component of disability-adjusted life-years (DALYs). A systematic analysis of relevant publications and hospital and claims data was used to estimate meningitis incidence via a Bayesian meta-regression tool. Meningitis deaths and cases were split between causes with meta-regressions of aetiological proportions of mortality and incidence, respectively. Probabilities of long-term impairment by cause of meningitis were applied to survivors and used to estimate years of life lived with disability (YLDs). We assessed the relationship between burden metrics and Socio-demographic Index (SDI), a composite measure of development based on fertility, income, and education. FINDINGS: Global meningitis deaths decreased by 21·0% from 1990 to 2016, from 403 012 (95% uncertainty interval [UI] 319 426-458 514) to 318 400 (265 218-408 705). Incident cases globally increased from 2·50 million (95% UI 2·19-2·91) in 1990 to 2·82 million (2·46-3·31) in 2016. Meningitis mortality and incidence were closely related to SDI. The highest mortality rates and incidence rates were found in the peri-Sahelian countries that comprise the African meningitis belt, with six of the ten countries with the largest number of cases and deaths being located within this region. Haemophilus influenzae type b was the most common cause of incident meningitis in 1990, at 780 070 cases (95% UI 613 585-978 219) globally, but decreased the most (-49·1%) to become the least common cause in 2016, with 397 297 cases (291 076-533 662). Meningococcus was the leading cause of meningitis mortality in 1990 (192 833 deaths [95% UI 153 358-221 503] globally), whereas other meningitis was the leading cause for both deaths (136 423 [112 682-178 022]) and incident cases (1·25 million [1·06-1·49]) in 2016. Pneumococcus caused the largest number of YLDs (634 458 [444 787-839 749]) in 2016, owing to its more severe long-term effects on survivors. Globally in 2016, 1·48 million (1·04-1·96) YLDs were due to meningitis compared with 21·87 million (18·20-28·28) DALYs, indicating that the contribution of mortality to meningitis burden is far greater than the contribution of disabling outcomes. INTERPRETATION: Meningitis burden remains high and progress lags substantially behind that of other vaccine-preventable diseases. Particular attention should be given to developing vaccines with broader coverage against the causes of meningitis, making these vaccines affordable in the most affected countries, improving vaccine uptake, improving access to low-cost diagnostics and therapeutics, and improving support for disabled survivors. Substantial uncertainty remains around pathogenic causes and risk factors for meningitis. Ongoing, active cause-specific surveillance of meningitis is crucial to continue and to improve monitoring of meningitis burdens and trends throughout the world. FUNDING: Bill & Melinda Gates Foundation.

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Stu (Lancet, 2018)
BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk-outcome associations. METHODS: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. FINDINGS: In 2017, 34·1 million (95% uncertainty interval [UI] 33·3-35·0) deaths and 1·21 billion (1·14-1·28) DALYs were attributable to GBD risk factors. Globally, 61·0% (59·6-62·4) of deaths and 48·3% (46·3-50·2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10·4 million (9·39-11·5) deaths and 218 million (198-237) DALYs, followed by smoking (7·10 million [6·83-7·37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6·53 million [5·23-8·23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4·72 million [2·99-6·70] deaths and 148 million [98·6-202] DALYs), and short gestation for birthweight (1·43 million [1·36-1·51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4·9% (3·3-6·5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23·5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18·6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. INTERPRETATION: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning. FUNDING: Bill & Melinda Gates Foundation.
Keywords: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Child; Child, Preschool; Disabled Persons; Environmental Exposure; Female; Global Burden of Disease; Global Health; Health Risk Behaviors; Humans; Infant; Infant, Newborn; Life Expectancy; Male; Metabolic Diseases; Middle Aged; Occupational Diseases; Occupational Exposure; Quality-Adjusted Life Years; Risk Assessment; Sex Distribution; Socioeconomic Factors; Young Adult

Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. (Lancet, 2018)
BACKGROUND: How long one lives, how many years of life are spent in good and poor health, and how the population's state of health and leading causes of disability change over time all have implications for policy, planning, and provision of services. We comparatively assessed the patterns and trends of healthy life expectancy (HALE), which quantifies the number of years of life expected to be lived in good health, and the complementary measure of disability-adjusted life-years (DALYs), a composite measure of disease burden capturing both premature mortality and prevalence and severity of ill health, for 359 diseases and injuries for 195 countries and territories over the past 28 years. METHODS: We used data for age-specific mortality rates, years of life lost (YLLs) due to premature mortality, and years lived with disability (YLDs) from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to calculate HALE and DALYs from 1990 to 2017. We calculated HALE using age-specific mortality rates and YLDs per capita for each location, age, sex, and year. We calculated DALYs for 359 causes as the sum of YLLs and YLDs. We assessed how observed HALE and DALYs differed by country and sex from expected trends based on Socio-demographic Index (SDI). We also analysed HALE by decomposing years of life gained into years spent in good health and in poor health, between 1990 and 2017, and extra years lived by females compared with males. FINDINGS: Globally, from 1990 to 2017, life expectancy at birth increased by 7·4 years (95% uncertainty interval 7·1-7·8), from 65·6 years (65·3-65·8) in 1990 to 73·0 years (72·7-73·3) in 2017. The increase in years of life varied from 5·1 years (5·0-5·3) in high SDI countries to 12·0 years (11·3-12·8) in low SDI countries. Of the additional years of life expected at birth, 26·3% (20·1-33·1) were expected to be spent in poor health in high SDI countries compared with 11·7% (8·8-15·1) in low-middle SDI countries. HALE at birth increased by 6·3 years (5·9-6·7), from 57·0 years (54·6-59·1) in 1990 to 63·3 years (60·5-65·7) in 2017. The increase varied from 3·8 years (3·4-4·1) in high SDI countries to 10·5 years (9·8-11·2) in low SDI countries. Even larger variations in HALE than these were observed between countries, ranging from 1·0 year (0·4-1·7) in Saint Vincent and the Grenadines (62·4 years [59·9-64·7] in 1990 to 63·5 years [60·9-65·8] in 2017) to 23·7 years (21·9-25·6) in Eritrea (30·7 years [28·9-32·2] in 1990 to 54·4 years [51·5-57·1] in 2017). In most countries, the increase in HALE was smaller than the increase in overall life expectancy, indicating more years lived in poor health. In 180 of 195 countries and territories, females were expected to live longer than males in 2017, with extra years lived varying from 1·4 years (0·6-2·3) in Algeria to 11·9 years (10·9-12·9) in Ukraine. Of the extra years gained, the proportion spent in poor health varied largely across countries, with less than 20% of additional years spent in poor health in Bosnia and Herzegovina, Burundi, and Slovakia, whereas in Bahrain all the extra years were spent in poor health. In 2017, the highest estimate of HALE at birth was in Singapore for both females (75·8 years [72·4-78·7]) and males (72·6 years [69·8-75·0]) and the lowest estimates were in Central African Republic (47·0 years [43·7-50·2] for females and 42·8 years [40·1-45·6] for males). Globally, in 2017, the five leading causes of DALYs were neonatal disorders, ischaemic heart disease, stroke, lower respiratory infections, and chronic obstructive pulmonary disease. Between 1990 and 2017, age-standardised DALY rates decreased by 41·3% (38·8-43·5) for communicable diseases and by 49·8% (47·9-51·6) for neonatal disorders. For non-communicable diseases, global DALYs increased by 40·1% (36·8-43·0), although age-standardised DALY rates decreased by 18·1% (16·0-20·2). INTERPRETATION: With increasing life expectancy in most countries, the question of whether the additional years of life gained are spent in good health or poor health has been increasingly relevant because of the potential policy implications, such as health-care provisions and extending retirement ages. In some locations, a large proportion of those additional years are spent in poor health. Large inequalities in HALE and disease burden exist across countries in different SDI quintiles and between sexes. The burden of disabling conditions has serious implications for health system planning and health-related expenditures. Despite the progress made in reducing the burden of communicable diseases and neonatal disorders in low SDI countries, the speed of this progress could be increased by scaling up proven interventions. The global trends among non-communicable diseases indicate that more effort is needed to maximise HALE, such as risk prevention and attention to upstream determinants of health. FUNDING: Bill & Melinda Gates Foundation.
Keywords: Aged; Communicable Diseases; Disabled Persons; Female; Global Burden of Disease; Health Status; Healthy Lifestyle; Humans; Life Expectancy; Male; Mortality; Mortality, Premature; Prevalence; Quality-Adjusted Life Years; Risk Factors; Socioeconomic Factors; Wounds and Injuries

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. (Lancet, 2018)
BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. METHODS: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. FINDINGS: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1-4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0-8·4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6-9·2) for males and 6·5% (5·4-7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs s1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]). INTERPRETATION: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury. FUNDING: Bill & Melinda Gates Foundation.
Keywords: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Child; Child, Preschool; Disabled Persons; Female; Global Burden of Disease; Global Health; Humans; Incidence; Infant; Infant, Newborn; Life Expectancy; Male; Middle Aged; Morbidity; Prevalence; Sex Distribution; Socioeconomic Factors; Wounds and Injuries; Young Adult

Gut microbiota characterisation in obese patients before and after bariatric surgery. - Campisciano, G; Palmisano, S; Cason, C; Giuricin, M; Silvestri, M; Guerra, M; Macor, D; De Manzini, N; Crocé, L S; Comar, M (Benef Microbes, 2018)
Intestinal microbiota analysis of obese patients after bariatric surgery showed that Proteobacteria decreased after laparoscopic sleeve gastrectomy (SG), while it increased after laparoscopic gastric bypass (LGB). Comparing to normal weight (NW) patients, obese patients that were selected for SG showed an almost equal amount of Firmicutes and Bacteroidetes and the ratio was not affected by the surgery. Obese patients before LGB showed a predominance of Bacteroidetes, whose amount regained a relative abundance similar to NW patients after surgery. Obese patients before LGB showed the predominance of Bacteroides, which decreased after surgery in favour of Prevotella, a bacterium associated with a healthy diet. The bacteria detected at the highest percentages belonged to biofilm forming species. In conclusion, in this study, we found that the characterization of the gut microbial communities and the modality of mucosal colonisation have a central role as markers for the clinical management of obesity and promote the maintenance of good health and the weight loss.
Keywords: Adult; Bariatric Surgery; Gastrointestinal Microbiome; Humans; Laparoscopy; Microbiota; Middle Aged; Obesity; Young Adult

High-Throughput Sequencing of microRNAs in Glucocorticoid Sensitive Paediatric Inflammatory Bowel Disease Patients. - De Iudicibus, Sara; Lucafò, Marianna; Vitulo, Nicola; Martelossi, Stefano; Zimbello, Rosanna; De Pascale, Fabio; Forcato, Claudio; Naviglio, Samuele; Di Silvestre, Alessia; Gerdol, Marco; Stocco, Gabriele; Valle, Giorgio; et al. (Int J Mol Sci, 2018)
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

How to predict response to anti-tumour necrosis factor agents in inflammatory bowel disease. - Naviglio, Samuele; Giuffrida, Paolo; Stocco, Gabriele; Lenti, Marco Vincenzo; Ventura, Alessandro; Corazza, Gino Roberto; Di Sabatino, Antonio (Expert Rev Gastroenterol Hepatol, 2018)
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 'inflammatory bowel disease,' 'Crohn's disease,' and 'ulcerative colitis,' matched with 'antitumor necrosis factor,' 'biologic therapy,' 'clinical response,' 'predictors,' and 'efficacy,' 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

Human beta defensin-1 is involved in the susceptibility to adeno-tonsillar hypertrophy. - Zupin, Luisa; Celsi, Fulvio; Bresciani, Martina; Orzan, Eva; Grasso, Domenico Leonardo; Crovella, Sergio (Int J Pediatr Otorhinolaryngol, 2018)
INTRODUCTION: Innate immunity molecules are known to play a pivotal role in the homeostasis of the oral mucosa, permitting the presence of commensal microflora and, at the same time, providing a first line of defense against pathogens attempting to invade the oral cavity. Tonsils represent the local immune tissue in oral cavity, being able to provide a non-specific response to pathogens; however, in the presence of microbes or foreign materials present in the mouth tonsils could became infected and develop chronic inflammation, thus leading to hypertrophy. The etiology of the disease is multifactorial depending upon environmental and host factors, the latter including molecules of mucosal innate immunity. METHODS: Ninety-five children with adeno-tonsillar hypertrophy subjected to adeno-tonsillectomy were recruited at the pediatric otorhinolaryngology service of the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste (Italy). The specimen discarded from the surgery were used for genomic DNA extraction and genotyping, for mRNA extraction and gene expression analysis, finally the samples were cut and used to prepare slides to perform immunohistochemistry. RESULTS: Functional polymorphisms within DEFB1 gene, encoding the human beta defensin-1 (hBD-1), were analyzed finding association between DEFB1 rare haplotypes and susceptibility to adeno-tonsillar hypertrophy. DEFB1 mRNA expression was detected in the tonsils and the hBD-1 protein was localized at the epithelia of tonsils mainly in the proximity of the basal lamina. CONCLUSION: Our findings lead us to hypothesize an involvement of hBD-1 mediated innate immunity in the modulation of the susceptibility towards adeno-tonsillar hypertrophy development.
Keywords: Adenoidectomy; Adenoids; Adolescent; beta-Defensins; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Hypertrophy; Immunity, Innate; Immunohistochemistry; Italy; Male; Palatine Tonsil; Tonsillectomy

Hypomorphic FANCA mutations correlate with mild mitochondrial and clinical phenotype in Fanconi anemia. - Bottega, Roberta; Nicchia, Elena; Cappelli, Enrico; Ravera, Silvia; De Rocco, Daniela; Faleschini, Michela; Corsolini, Fabio; Pierri, Filomena; Calvillo, Michaela; Russo, Giovanna; Casazza, Gabriella; Ramenghi, Ugo; et al. (Haematologica, 2018)
Fanconi anemia is a rare disease characterized by congenital malformations, aplastic anemia, and predisposition to cancer. Despite the consolidated role of the Fanconi anemia proteins in DNA repair, their involvement in mitochondrial function is emerging. The purpose of this work was to assess whether the mitochondrial phenotype, independent of genomic integrity, could correlate with patient phenotype. We evaluated mitochondrial and clinical features of 11 affected individuals homozygous or compound heterozygous for p.His913Pro and p.Arg951Gln/Trp, the two residues of FANCA that are more frequently affected in our cohort of patients. Although p.His913Pro and p.Arg951Gln proteins are stably expressed in cytoplasm, they are unable to migrate in the nucleus, preventing cells from repairing DNA. In these cells, the electron transfer between respiring complex I-III is reduced and the ATP/AMP ratio is impaired with defective ATP production and AMP accumulation. These activities are intermediate between those observed in wild-type and FANCA-/- cells, suggesting that the variants at residues His913 and Arg951 are hypomorphic mutations. Consistent with these findings, the clinical phenotype of most of the patients carrying these mutations is mild. These data further support the recent finding that the Fanconi anemia proteins play a role in mitochondria, and open up possibilities for genotype/phenotype studies based on novel mitochondrial criteria.

Imaging and therapy of ovarian cancer: clinical application of nanoparticles and future perspectives. - Di Lorenzo, Giovanni; Ricci, Giuseppe; Severini, Giovanni Maria; Romano, Federico; Biffi, Stefania (Theranostics, 2018)
Despite significant advances in cancer diagnostics and treatment, ovarian cancers (OC) continue to kill more than 150,000 women every year worldwide. Due to the relatively asymptomatic nature and the advanced stage of the disease at the time of diagnosis, OC is the most lethal gynecologic malignancy. The current treatment for advanced OC relies on the synergistic effect of combining surgical cytoreduction and chemotherapy; however, beside the fact that chemotherapy resistance is a major challenge in OC management, new imaging strategies are needed to target microscopic lesions and improve both cytoreductive surgery and patient outcomes. In this context, nanostructured probes are emerging as a new class of medical tool that can simultaneously provide imaging contrast, target tumor cells, and carry a wide range of medicines resulting in better diagnosis and therapeutic precision. Herein we summarize several exemplary efforts in nanomedicine for addressing unmet clinical needs.

Immunohistologic analysis of the duodenal bulb: a new method for celiac disease diagnosis in children. - De Leo, Luigina; Villanacci, Vincenzo; Ziberna, Fabiana; Vatta, Serena; Martelossi, Stefano; Di Leo, Grazia; Zanchi, Chiara; Bramuzzo, Matteo; Giudici, Fabiola; Ventura, Alessandro; Not, Tarcisio (Gastrointest Endosc, 2018)
BACKGROUND AND AIMS: Anti-tissue transglutaminase antibodies (anti-tTG) have simplified celiac disease (CD) diagnosis. However, in atypical forms of CD, intestinal biopsy sampling is still required. This prospective study investigates whether histologic analysis of the duodenal bulb combined with intestinal IgA anti-tTG deposit immunoassay makes CD diagnosis possible in at-risk children with low concentrations of serum anti-tTG. METHODS: Histologic and intestinal IgA anti-tTG deposit immunoassays were used. RESULTS: Two hundred forty-five symptomatic children positive for serum anti-tTG (>7 U/mL) were enrolled and divided into 3 groups: extensive duodenal atrophy (n = 209), with IgA anti-tTG deposits throughout the duodenum and high serum anti-tTG concentrations (157 ± 178 U/mL); bulb duodenal atrophy (n = 22), with widespread IgA anti-tTG deposits in 9 and in the bulb alone in 13 and low serum anti-tTG concentrations (13.9 ± 8.7 U/mL); and normal duodenum (n = 14), with widespread IgA anti-tTG deposits in 8 and in the bulb alone in 6 and low serum anti-tTG concentrations (10.6 ± 6.2 U/mL). All patients in the first 2 groups were diagnosed with CD and 8 from the third group. All improved after 1 year of gluten-free diet. Bulb duodenal analysis led to a 12% (30/245) increase in CD diagnosis. No CD-related lesions were observed in the 30 control subjects. CONCLUSIONS: In children at risk for CD, bulb duodenum biopsy sampling is essential to identify villous atrophy and detect IgA anti-tTG deposits even in absence of intestinal lesions. These mucosal autoantibodies could well represent a new standard for diagnosing CD.
Keywords: Adolescent; Autoantibodies; Celiac Disease; Child; Child, Preschool; Duodenum; Female; Humans; Immunoglobulin A; Immunohistochemistry; Infant; Male; Prospective Studies; Transglutaminases

Impact of near infrared light in pediatric blood drawing Centre on rate of first attempt success and time of procedure. - Conversano, Ester; Cozzi, Giorgio; Pavan, Matteo; Minute, Marta; Gortan, Elena; Montico, Marcella; Vecchi Brumatti, Liza; Ronfani, Luca; Barbi, Egidio (Ital J Pediatr, 2018)
BACKGROUND: Peripheral blood access and venipuncture are a stressful and painful experience in pediatric patients; moreover, it is estimated that more than one attempt is required to achieve the procedure in about one third of children. For this reason, we investigated if Near-infrared light technology routinely used, could give an advantage to venipuncture in a pediatric blood center setting. METHODS: We conducted an open, pseudo-randomized controlled trial with two parallel arms, in the blood-drawing center, with enrolment of 115 patients between 0 and 18 years, in 14 consecutive working days. Fifty-three subjects were enrolled in group 1 (VeinViewer®) and 62 in group 2 (control group). We divided patients into three subgroups considering their age (< 5 years, 6-10 years, > 10 years). The primary study outcome was to assess if the use of VeinViewer® was associated with a reduction of time to perform blood sampling. The secondary outcome was to analyze VienViewer®'s impact on first attempt success rate in blood sampling. RESULTS: No difference was found regarding the duration of blood sampling between the two groups, even after stratifying the patients into the three age subgroups. There was no difference between the two groups in the success at the first attempt in blood sampling. CONCLUSIONS: Routine use of VeinViewer® is not useful to reduce time of the procedure during venipuncture. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov, with number NCT03277092 , on September 8, 2017.
Keywords: Adolescent; Age Factors; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Infrared Rays; Lighting; Male; Phlebotomy; Time Factors

In vivo microbiome and associated immune markers: New insights into the pathogenesis of vaginal dysbiosis. - Campisciano, Giuseppina; Zanotta, Nunzia; Licastro, Danilo; De Seta, Francesco; Comar, Manola (Sci Rep, 2018)
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'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

Inclusion cyst of anterior fontanelle. - Udina, Chiara; Calligaris, Lorenzo; Berti, Irene; Cattaruzzi, Elisabetta; Barbi, Egidio (Arch Dis Child, 2018)

Infant Analgesia With a Combination of Breast Milk, Glucose, or Maternal Holding. - Bembich, Stefano; Cont, Gabriele; Causin, Enrica; Paviotti, Giulia; Marzari, Patrizia; Demarini, Sergio (Pediatrics, 2018)
OBJECTIVES: We studied neonatal cortical brain response to 4 types of nonpharmacological analgesia (oral glucose, expressed breast milk, maternal holding plus oral glucose, breastfeeding). We aimed to assess the differential effect of oral solutions (glucose, breast milk) given alone or combined with the maternal-infant relationship (holding, breastfeeding). METHODS: Eighty healthy term newborns undergoing a heel stick were randomly assigned to 4 parallel groups of 20 infants each: group 1, infants received a glucose solution on a changing table; group 2, infants received expressed breast milk on a changing table; group 3, infants received a glucose solution in their mothers' arms; and group 4, infants were breastfed by their mothers. Cortical activation in parietal, temporal, and frontal cortices was assessed by multichannel near-infrared spectroscopy. Pain expression was also evaluated. RESULTS: Oral glucose alone or combined with maternal holding was associated with no cortical activation during heel stick. Expressed breast milk was associated with localized bilateral activation of somatosensory and motor cortices ( < .01). Breastfeeding was associated with extensive bilateral activation of somatomotor, somatosensory, and right parietal cortices ( < .01). Pain expression was lower with the maternal-infant relationship ( = .007). CONCLUSIONS: Oral glucose, either alone or combined with maternal holding, appears to block or weaken cortical pain processing. Breast milk alone is associated with localized cortical activation. Breastfeeding is associated with extensive activation and may act by extending cortical processing. Maternal relationship, both combined with oral glucose and in breastfeeding, shows the greatest analgesic effect, although the neural patterns involved are distributed differently.

Influence of polymerization time on properties of dual-curing cements in combination with high translucency monolithic zirconia. - Alovisi, Mario; Scotti, Nicola; Comba, Allegra; Manzon, Elena; Farina, Elena; Pasqualini, Damiano; Michelotto Tempesta, Riccardo; Breschi, Lorenzo; Cadenaro, Milena (J Prosthodont Res, 2018)
PURPOSE: The aim of this in vitro study was to assess conversion degree (DC), micro-hardness (MH) and bond strength of two dual-curing resin cements employed under translucent monolithic zirconia irradiated with different time protocols. METHODS: 84 square shaped samples of 1mm thickness were prepared from high translucency zirconia blocks and divided into two groups (n=24) according to the cement employed: (1) Rely-X Ultimate; (2) Panavia SA. Each group was further divided into 3 subgroups (n=8) according to the irradiation time: (a) no light; (b) 20s; (c) 120s. Light curing was performed 60s after the sample was placed on the diamond support of a FT-IR spectrophotometer with a high power multiLED lamp. Final DC% were calculated after 10min. After 24h, Vickers Test on the cement layer was performed. The same protocol was used to lute composite cylinders in order to evaluate microshear bond-strength test. ANOVA and Bonferroni tests were performed to find differences between MH and bond-strength to zirconia, while for DC% the Scheirer-Ray-Hare two-way test was used. RESULTS: The two cements reached higher DC% in subgroup (b) and (c). As concern MH, statistics showed an increase in curing time was able to improve MH significantly. Bond-strength was not affected by irradiation time only for Panavia SA. CONCLUSIONS: The first null hypothesis has to be rejected since DC% and MH of the dual-cements tested were influenced by the curing time. The second null hypothesis is partially rejected since the bond strength was influenced by the curing time only for Rely-X Ultimate.
Keywords: Composite Resins; Dental Bonding; Dental Cements; Hardness; Lansoprazole; Materials Testing; Polymerization; Resins, Synthetic; Spectrophotometry; Time Factors; Zirconium

Interstitial Fluid in Gynecologic Tumors and Its Possible Application in the Clinical Practice. - Ura, Blendi; Di Lorenzo, Giovanni; Romano, Federico; Monasta, Lorenzo; Mirenda, Giuseppe; Scrimin, Federica; Ricci, Giuseppe (Int J Mol Sci, 2018)
Gynecologic cancers are an important cause of worldwide mortality. The interstitium consists of solid and fluid phases, situated between the blood vessels and cells. The interstitial fluid (IF), or fluid phase, is an extracellular fluid bathing and surrounding the tissue cells. The TIF (tumor interstitial fluid) is a dynamic fluid rich in lipids, proteins and enzyme-derived substances. The molecules found in the IF may be associated with pathological changes in tissues leading to cancer growth and metastatization. Proteomic techniques have allowed an extensive study of the composition of the TIF as a source of biomarkers for gynecologic cancers. In our review, we analyze the composition of the TIF, its formation process, the sampling methods, the consequences of its accumulation and the proteomic analyses performed, that make TIF valuable for monitoring different types of cancers.
Keywords: Biomarkers, Tumor; Biophysical Phenomena; Extracellular Fluid; Female; Genital Neoplasms, Female; Humans; Practice Patterns, Physicians'; Tumor Microenvironment

Intranasal dexmedetomidine, as midazolam-sparing drug, for MRI in preterm neonates. - Bua, Jenny; Massaro, Marta; Cossovel, Francesca; Monasta, Lorenzo; Brovedani, Pierpaolo; Cozzi, Giorgio; Barbi, Egidio; Demarini, Sergio; Travan, Laura (Paediatr Anaesth, 2018)

Investigation of the link between PROP taste perception and vegetables consumption using FAOSTAT data. - Mezzavilla, Massimo; Notarangelo, Michela; Concas, Maria Pina; Catamo, Eulalia; Gasparini, Paolo; Grillotti, Maria Gemma; Robino, Antonietta (Int J Food Sci Nutr, 2018)
In this work we investigated, in populations located in Central Asia, the relationship between PROP taste perception and vegetables liking and consumption using FAOSTAT dataset. Collected data were analysed using distance matrices, Mantel test and Pearson correlation. Populations showing similar ability in tasting PROP bitterness are more similar as respect to vegetable consumption (r = 0.63, p-value = .05). Moreover, a significant negative correlation was found between the percentage of Non Taster (NT) in different countries and the percentage of vegetable consumption (r = -0.87, p-value = .02), while a significant positive correlation emerged between the percentage of Super Taster (ST) and the percentage of vegetable liking (r = 0.87, p-value = .02). In our work we showed that differences in bitter perception among populations contributes to differences in vegetable liking and vegetable consumption. More in detail, populations with higher percentage of ST consume more vegetables than population where the majority of individuals are NT.

Irinotecan-induced muscular contractions. - Naviglio, Samuele; Rabusin, Marco (Pediatr Blood Cancer, 2018)

Iron-related toxicity of single-walled carbon nanotubes and crocidolite fibres in human mesothelial cells investigated by Synchrotron XRF microscopy. - Cammisuli, Francesca; Giordani, Silvia; Gianoncelli, Alessandra; Rizzardi, Clara; Radillo, Lucia; Zweyer, Marina; Da Ros, Tatiana; Salomè, Murielle; Melato, Mauro; Pascolo, Lorella (Sci Rep, 2018)
Carbon nanotubes (CNTs) are promising products in industry and medicine, but there are several human health concerns since their fibrous structure resembles asbestos. The presence of transition metals, mainly iron, in the fibres seems also implicated in the pathogenetic mechanisms. To unravel the role of iron at mesothelial level, we compared the chemical changes induced in MeT-5A cells by the exposure to asbestos (crocidolite) or CNTs at different content of iron impurities (raw-SWCNTs, purified- and highly purified-SWCNTs). We applied synchrotron-based X-Ray Fluorescence (XRF) microscopy and soft X-ray imaging (absorption and phase contrast images) to monitor chemical and morphological changes of the exposed cells. In parallel, we performed a ferritin assay. X-ray microscopy imaging and XRF well localize the crocidolite fibres interacting with cells, as well as the damage-related morphological changes. Differently, CNTs presence could be only partially evinced by low energy XRF through carbon distribution and sometimes iron co-localisation. Compared to controls, the cells treated with raw-SWCNTs and crocidolite fibres showed a severe alteration of iron distribution and content, with concomitant stimulation of ferritin production. Interestingly, highly purified nanotubes did not altered iron metabolism. The data provide new insights for possible CNTs effects at mesothelial/pleural level in humans.
Keywords: Asbestos, Crocidolite; Cell Line; Epithelial Cells; Humans; Iron; Microscopy, Fluorescence; Nanotubes, Carbon

Joint Data Analysis in Nutritional Epidemiology: Identification of Observational Studies and Minimal Requirements. - Pinart, Mariona; Nimptsch, Katharina; Bouwman, Jildau; Dragsted, Lars O; Yang, Chen; De Cock, Nathalie; Lachat, Carl; Perozzi, Giuditta; Canali, Raffaella; Lombardo, Rosario; D'Archivio, Massimo; Guillaume, Michèle; et al. (J Nutr, 2018)
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

A Klinefelter boy with congenital adrenal hyperplasia: too much or too little androgens? - Zanella, Giada; Tornese, Gianluca; Mascheroni, Elisabetta; Faleschini, Elena; Ventura, Alessandro; Barbi, Egidio (Ital J Pediatr, 2018)
BACKGROUND: The simultaneous occurrence of Klinefelter Syndrome (KS) and Congenital Adrenal Hyperplasia (CAH) is an exceptional event: there are just three case reports (two children and a 51 years old man) describing males affected by both KS and 21OHD (21-hydroxylase deficiency) CAH, the first causing androgen deficiency, the latter leading to androgen excess. CASE REPORT: We report the 4th case of association of KS and CAH in a young man with CAH with good androgen control and with normal secondary sex characteristics, whose Klinefelter syndrome was diagnosed because of reduced testicular volume. He was the first reported case of association of KS and CAH who started androgen replacement therapy in the pubertal age and whose pubertal development was described and followed up step by step. CONCLUSION: In a boy with CAH and small testicular volume, it's important to consider that hypogonadism may be masked by the adrenal androgens excess and a karyotype should be performed once testicular adrenal rests have been ruled out.
Keywords: Adolescent; Adrenal Hyperplasia, Congenital; Androgens; Follow-Up Studies; Hormone Replacement Therapy; Humans; Klinefelter Syndrome; Male; Rare Diseases; Risk Assessment; Testis

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. - Sung, Yun J; Winkler, Thomas W; de Las Fuentes, Lisa; Bentley, Amy R; Brown, Michael R; Kraja, Aldi T; Schwander, Karen; Ntalla, Ioanna; Guo, Xiuqing; Franceschini, Nora; Lu, Yingchang; Cheng, Ching-Yu; et al. (Am J Hum Genet, 2018)
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 × 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 × 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

Learning curve for the ultrasonographic diagnosis of deep endometriosis using a structured off-line training program. - Guerriero, Stefano; Pascual, M Angela; Ajossa, Silvia; Rodriguez, Ignacio; Zajicek, Michal; Rolla, Martino; Rams, Noelia Llop; Yulzari, Vered; Bardin, Ron; Buonomo, Francesca; Comparetto, Ornella; Perniciano, Maura; et al. (Ultrasound Obstet Gynecol, 2018)
OBJECTIVE: The aim of the present study was to assess the learning curves of trainees during a structured off-line/hands-on training program on the diagnosis of deep infiltrating endometriosis (DIE). METHODS: A two-week training program was conducted. One day was devoted to theoretical issues and guided off-line analysis of 10 volumes of three-dimensional (3D) ultrasound. During the following days, five sessions of real-time sonographic examinations were performed in a DIE referral center Ultrasound unit. In between sessions, the trainees analyzed four off-line sets, containing twenty-five 3D volumes each. At the end of each set, misinterpreted volumes were assessed with the trainer. One trainer and 4 trainees (all post-graduated Ob/Gyn with at least 5 years of experience in ultrasonography in Obstetrics and Gynecology but with no experience in DIE sonographic examinations) participated in the study. Presence or absence of DIE at surgery was considered as gold standard for the trainees. Trainee's results were evaluated by learning curve cumulative summation (LC-CUSUM) and the deviations of the level of trainees' performance at the control stage by CUSUM (standard CUSUM) for different locations of DIE. RESULTS: The trainees reached competence on average after 17 evaluations (range 21-14) for bladder locations, after 39 evaluations (range 60-30) for rectosigmoid locations, after 25 evaluations (range 34-14) for forniceal locations, after 44 evaluations (range 66-25) for utero-sacral locations (USL), after 21 evaluations (range 43-14) for rectovaginal septum (RVS) locations respectively, and kept the process under control with error levels of less than 4.5% until the end of the test. The overall accuracy for each trainee at the different locations ranged from 0.91 to 0.96 for bladder DIE, from 0.80 to 0.94 for recto-sigmoid DIE, from 0.90 to 0.94% for forniceal DIE, from 0.79 to 0.82 for utero-sacral ligaments DIE and from 0.89 to 0.97 for recto-vaginal septum DIE. CONCLUSIONS: The suggested two-weeks learning program based on a mix of off-line and live sessions is feasible and suggests a good performance in training for the diagnosis of DIE. This article is protected by copyright. All rights reserved.

Levels of anxiety in parents in the 24 hr before and after their child's surgery: A descriptive study. - Pomicino, Laura; Maccacari, Elena; Buchini, Sara (J Clin Nurs, 2018)
AIMS AND OBJECTIVES: To (i) investigate pre- and postoperative anxiety levels in parents of surgical patients; (ii) identify factors that affect parental anxiety; and (iii) analyse assistance provided and overall parental satisfaction to assess whether and how this aspect can impact their anxiety level. BACKGROUND: Surgery as an event generates anxiety in children and their parents. Children who are anxious before surgery are likely to develop more postoperative psychological and physiological complications than those who are not. The role parents play in influencing emotional states of their children has been well demonstrated. However, specific national programmes aimed at helping parents develop new models for coping are relatively inexistent in Italy. STUDY DESIGN: Longitudinal study. METHODS: One hundred and one parents of children undergoing surgery at a healthcare facility in Padua, Italy, completed the Italian version of the State-Trait Anxiety Inventory Form Y questionnaire. They also answered questions about their parents' socio-demographic situation, the amount and quality of preoperative information received, assistance provided and their overall satisfaction with this information. RESULTS: The preoperative level of anxiety in parents who were interviewed was higher than Italian normative data, especially in Pediatric Cardiac Surgery and Pediatric Urology departments. Mothers had a significantly higher level of anxiety than fathers. Communicating possible complications of surgical procedures increased anxiety, while providing information about pre- and postsurgery nutrition and pain management and providing local anaesthetic on children decreased parental anxiety. Parents expressed a sufficiently high level of satisfaction although they defined the hospital environment as uncomfortable. CONCLUSIONS: Aspects of care that can make hospitalisation less traumatic for parents are as follows: greater support, involving them in the treatment process, improving hospital department admission procedures and providing thorough preoperative information. RELEVANCE TO CLINICAL PRACTICE: Healthcare professionals are encouraged to pay attention to communication modalities providing detailed information to parents.
Keywords: Adaptation, Psychological; Anxiety; Child; Female; Humans; Italy; Longitudinal Studies; Male; Parents; Perioperative Period; Surgical Procedures, Operative; Surveys and Questionnaires

Light element distribution in fresh and frozen-thawed human ovarian tissues: a preliminary study. - Pascolo, Lorella; Venturin, Irene; Gianoncelli, Alessandra; Bortul, Roberta; Zito, Gabriella; Giolo, Elena; Salomè, Murielle; Bedolla, Diana E; Altissimo, Matteo; Zweyer, Marina; Ricci, Giuseppe (Reprod Biomed Online, 2018)
RESEARCH QUESTION: Does synchrotron X-ray fluorescence (XRF) provide novel chemical information for the evaluation of human ovarian tissue cryopreservation protocols? DESIGN: Tissues from five patients undergoing laparoscopic surgery for benign gynaecological conditions were fixed for microscopic analysis either immediately or after cryopreservation. After fixation, fresh and slowly frozen samples were selected by light microscopy and transmission electron microscopy, and subsequently analysed with synchrotron XRF microscopy at different incident energies. RESULTS: The distributions of elements detected at 7.3 keV (S, P, K, Cl, Fe, and Os) and 1.5 keV (Na and Mg) were related to the changes revealed by light microscopy and transmission electron microscopy analyses. The light elements showed highly informative findings. The S distribution was found to be an indicator of extracellular component changes in the stromal tissues of the freeze-stored samples, further revealed by the transmission electron microscopy analyses. Low-quality follicles, frequent in the freeze-thawed tissues, showed a high Na level in the ooplasm. On the contrary, good-quality follicles were detected by a homogeneous Cl distribution. The occurrence of vacuolated follicles increased after cryopreservation, and the XRF analyses showed that the vacuolar structures contained mainly Cl and Na. CONCLUSIONS: The study demonstrates that elemental imaging techniques, particularly revealing the distribution of light elements, could be useful in establishing new cryopreservation protocols.
Keywords: Cryopreservation; Female; Humans; Microscopy, Electron, Transmission; Organ Preservation; Ovarian Follicle; Ovary

Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications. - De Rose, Domenico Umberto; Giliani, Silvia; Notarangelo, Lucia Dora; Lougaris, Vassilios; Lanfranchi, Arnalda; Moratto, Daniele; Martire, Baldassarre; Specchia, Fernando; Tommasini, Alberto; Plebani, Alessandro; Badolato, Raffaele (Clin Immunol, 2018)
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.

Lopinavir/Ritonavir Treatment Induces Oxidative Stress and Caspaseindependent Apoptosis in Human Glioblastoma U-87 MG Cell Line. - Gratton, Rossella; Tricarico, Paola Maura; Guimarães, Rafael Lima; Celsi, Fulvio; Crovella, Sergio (Curr HIV Res, 2018)
BACKGROUND: Lopinavir and Ritonavir (LPV/r) treatment is widely used to prevent HIV mother-to-child transmission. Nevertheless, studies related to the impact of these compounds on patients, in particular in the foetus and newborns, are strictly required due to the controversial findings reported in the literature concerning possible neurologic side effects following the administration of these drugs. OBJECTIVES: In our study, we evaluated the impact of LPV/r treatment on the human glioblastoma U- 87 MG cell line. METHODS: In order to evaluate the influence of Lopinavir and Ritonavir in terms of oxidative stress (ROS production), mitochondrial morphology and apoptotic cell death, the latter either in the presence or in the absence of caspase-3 and -9 inhibitors, we treated U-87 MG with increasing doses (0.1-1-10-25-50 µM) of Lopinavir and Ritonavir for 24h, either in single formulation or in combination. ROS production was measured by flow cytometry using H2DCFDA dye, mitochondrial morphology was evaluated using MitoRed dye and apoptotic cell death was monitored by flow cytometry using Annexin V-FITC and Propidium Iodide. RESULTS: We observed that co-treatment with Lopinavir and Ritonavir (25 and 50 µM) promoted a significant increase in ROS production, caused mitochondrial network damage and induced apoptosis in a caspase-independent manner. CONCLUSION: Based on our findings, concordant with others reported in the literature, we hypothesize that LPV/r treatment could not be entirely free from side effects, being aware of the need of validation in in vivo models, necessary to confirm our results.

Low-dose sirolimus in two cousins with autoimmune lymphoproliferative syndrome-associated infection. - Nocerino, Agostino; Valencic, Erica; Loganes, Claudia; Pelos, Giorgio; Tommasini, Alberto (Pediatr Int, 2018)
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

Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: a systematic analysis from the Global Burden of Disease Study 2016. (Lancet, 2018)
BACKGROUND: A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. METHODS: Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. FINDINGS: In 2016, HAQ Index performance spanned from a high of 97·1 (95% UI 95·8-98·1) in Iceland, followed by 96·6 (94·9-97·9) in Norway and 96·1 (94·5-97·3) in the Netherlands, to values as low as 18·6 (13·1-24·4) in the Central African Republic, 19·0 (14·3-23·7) in Somalia, and 23·4 (20·2-26·8) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91·5 (89·1-93·6) in Beijing to 48·0 (43·4-53·2) in Tibet (a 43·5-point difference), while India saw a 30·8-point disparity, from 64·8 (59·6-68·8) in Goa to 34·0 (30·3-38·1) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4·8-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20·9-point to 17·0-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17·2-point to 20·4-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. INTERPRETATION: GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle-SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage hinges upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view-and subsequent provision-of quality health care for all populations. FUNDING: Bill & Melinda Gates Foundation.
Keywords: Communicable Diseases; Global Burden of Disease; Health Services Accessibility; Humans; Noncommunicable Diseases; Quality of Health Care; Wounds and Injuries

Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017. (Lancet, 2018)
BACKGROUND: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of "leaving no one behind", it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990-2017, projected indicators to 2030, and analysed global attainment. METHODS: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0-100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. FINDINGS: The global median health-related SDG index in 2017 was 59·4 (IQR 35·4-67·3), ranging from a low of 11·6 (95% uncertainty interval 9·6-14·0) to a high of 84·9 (83·1-86·7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. INTERPRETATION: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains-curative interventions in the case of NCDs-towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions-or inaction-today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030. FUNDING: Bill & Melinda Gates Foundation.
Keywords: Female; Global Burden of Disease; Global Health; Goals; Health Status; Health Status Indicators; Humans; Male; Mortality; Risk Factors; Sex Offenses; Sustainable Development; United Nations

Meconium-stained amniotic fluid: a risk factor for postpartum hemorrhage. - Bouchè, Carlo; Wiesenfeld, Uri; Ronfani, Luca; Simeone, Roberto; Bogatti, Paolo; Skerk, Kristina; Ricci, Giuseppe (Ther Clin Risk Manag, 2018)
Background/aim: Clinical data with respect to the impact of meconium on the risk of maternal hemorrhage are scarce. Therefore, in this study, we aimed to determine whether meconium-stained amniotic fluid (MSAF) represents a risk factor for postpartum hemorrhage (PPH) after vaginal delivery in a large unselected population. Patients and methods: A retrospective cohort study evaluated 78,542 consecutive women who had a vaginal delivery between 24th and 44th weeks of gestation. The women who had undergone cesarean section were excluded to avoid possible bias. Postpartum blood loss was measured with graduated blood sack. Postpartum blood loss between 1,000 and 2,000 mL and >2,000 mL were classified as moderate and severe PPH, respectively. Results: A total of 74,144 patients were available for analysis. According to the color of amniotic fluid (AF), two groups of patients were identified: MSAF (n=10,997) and clear AF (n=63,147). The rates of severe and massive PPH were found to be significantly higher in the MSAF group than that of clear AF group (OR=1.3, 95% CI: 1.2-1.5, <0.001 and OR=2.5, 95% CI: 1.5-4.2, <0.001). Operative vaginal delivery rate was found to be higher in the MSAF group than that of clear AF group, but the difference was only borderline significant (OR=1.5, 95% CI: 1.0-2.2, =0.05). There were no significant differences between the MSAF and the clear AF groups with respect to episiotomies, second- or third-degree perineal tears, vaginal-perineal thrombus, cervical lacerations, vaginal births after cesarean section, twin deliveries, and placental retention rates. Conclusion: To the best of our knowledge, this is the first clinical study that has investigated the role of MSAF as a risk factor for PPH after vaginal delivery in an unselected population. Our results suggest that MSAF is significantly associated with higher risk of moderate and severe PPH than clear AF.

MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study. - Grandone, Anna; Cirillo, Grazia; Sasso, Marcella; Capristo, Carlo; Tornese, Gianluca; Marzuillo, Pierluigi; Luongo, Caterina; Rosaria Umano, Giuseppina; Festa, Adalgisa; Coppola, Ruggero; Miraglia Del Giudice, Emanuele; Perrone, Laura (Endocrine, 2018)
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-Müllerian 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

MKRN3 Levels in Girls with Central Precocious Puberty during GnRHa Treatment: A Longitudinal Study. - Grandone, Anna; Cirillo, Grazia; Sasso, Marcella; Tornese, Gianluca; Luongo, Caterina; Festa, Adalgisa; Marzuillo, Pierluigi; Miraglia Del Giudice, Emanuele (Horm Res Paediatr, 2018)
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 ± 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

Multicenter randomized, double-blind controlled trial to evaluate the efficacy of laser therapy for the treatment of severe oral mucositis induced by chemotherapy in children: laMPO RCT. - Gobbo, Margherita; Verzegnassi, Federico; Ronfani, Luca; Zanon, Davide; Melchionda, Fraia; Bagattoni, Simone; Majorana, Alessandra; Bardellini, Elena; Mura, Rosamaria; Piras, Alessandra; Petris, Maria Grazia; Mariuzzi, Maria Livia; et al. (Pediatr Blood Cancer, 2018)
OBJECTIVES: To demonstrate the efficacy of laser photobiomodulation (PBM) compared to that of placebo on severe oral mucositis (OM) in pediatric oncology patients. The primary objective was the reduction of OM grade (World Health Organization [WHO] scale) 7 days after starting PBM. Secondary objectives were reduction of pain, analgesic consumption, and incidence of side effects. METHODS: One hundred and one children with WHO grade > 2 chemotherapy-induced OM were enrolled in eight Italian hospitals. Patients were randomized to either PBM or sham treatment for four consecutive days (days +1 to +4). On days +4, +7, and +11, OM grade, pain (following a 0-10 numeric pain rating scale, NRS) and need for analgesics were evaluated by an operator blinded to treatment. RESULTS: Fifty-one patients were allocated to the PBM group, and 50 were allocated to the sham group. In total, 93.7% of PBM patients and 72% of sham patients had OM grade < 3 WHO on day +7 (P = 0.01). A significant reduction of pain was registered on day +7 in the PBM versus sham group (NRS 1 [0-3] vs. 2.5 [1-5], P < 0.006). Reduced use of analgesics was reported in the PBM group, although it was not statistically significant. No significant adverse events attributable to treatment were recorded. CONCLUSIONS: PBM is a safe, feasible, and effective treatment for children affected by chemotherapy-induced OM, as it accelerates mucosal recovery and reduces pain.

Multicentre emergency department study found that paracetamol and ibuprofen were inappropriately used in 83% and 63% of paediatric cases. - Benini, Franca; Castagno, Emanuele; Barbi, Egidio; Congedi, Sabrina; Urbino, Antonio; Biban, Paolo; Calistri, Lucia; Mancusi, Rossella Letizia (Acta Paediatr, 2018)
AIM: The Pain Practice in Italian Paediatric Emergency Departments assessed how appropriately analgesic drugs were being used by Italian clinicians, based on national paediatric pain guidelines. METHODS: This was a retrospective study that involved 17 Italian members of the Pain In Pediatric Emergency Rooms group. It comprised patients up to the age of 14 years who came to hospital emergency departments with pain and were treated with paracetamol, ibuprofen or opioids, such as codeine, tramadol and morphine. RESULTS: We studied 1471 patients who were given 1593 doses of analgesics. The median time to administration of analgesia was 25 minutes. Opioids were used in 13.5% of the children, and usage increased with age and with more severe clinical conditions, such as trauma: 1.6% of children under two years, 5.9% aged 3-10 and 8.0% aged 11-14. Inappropriate doses of paracetamol, ibuprofen and opioids were used in 83%, 63% and 33% of cases, respectively. The patient's age was a critical determinant of the correct analgesic dosage; for every one-year increase in the patient's age, the probability of appropriate prescriptions rose 14.8%. CONCLUSION: The appropriate use of paracetamol and ibuprofen for paediatric pain in Italian emergency departments was very poor, but improved with age.

Multiple successful pregnancies in a woman with biliary atresia and native liver. - Matarazzo, Lorenza; Assandro, Paola; Martelossi, Stefano; Maggiore, Giuseppe; Ventura, Alessandro (Eur J Obstet Gynecol Reprod Biol, 2018)

MYH9: Structure, functions and role of non-muscle myosin IIA in human disease. - Pecci, Alessandro; Ma, Xuefei; Savoia, Anna; Adelstein, Robert S (Gene, 2018)
The MYH9 gene encodes the heavy chain of non-muscle myosin IIA, a widely expressed cytoplasmic myosin that participates in a variety of processes requiring the generation of intracellular chemomechanical force and translocation of the actin cytoskeleton. Non-muscle myosin IIA functions are regulated by phosphorylation of its 20 kDa light chain, of the heavy chain, and by interactions with other proteins. Variants of MYH9 cause an autosomal-dominant disorder, termed MYH9-related disease, and may be involved in other conditions, such as chronic kidney disease, non-syndromic deafness, and cancer. This review discusses the structure of the MYH9 gene and its protein, as well as the regulation and physiologic functions of non-muscle myosin IIA with particular reference to embryonic development. Moreover, the review focuses on current knowledge about the role of MYH9 variants in human disease.
Keywords: Animals; Cell Line; Deafness; Hearing Loss, Sensorineural; Humans; Mice; Molecular Motor Proteins; Mutation; Myosin Heavy Chains; Neoplasms; Nonmuscle Myosin Type IIA; Phosphorylation; Renal Insufficiency, Chronic; Thrombocytopenia

Needle-related pain and distress management during needle-related procedures in children with and without intellectual disability. - Pascolo, Paola; Peri, Francesca; Montico, Marcella; Funaro, Mishelle; Parrino, Roberta; Vanadia, Francesca; Rusalen, Francesca; Vecchiato, Luca; Benini, Franca; Congedi, Sabrina; Barbi, Egidio; Cozzi, Giorgio (Eur J Pediatr, 2018)
Children with intellectual disability frequently undergo needle-related procedures for diagnosis or treatment. Nevertheless, only a few studies deal with pain and distress management during the procedure in this population of children. This study aimed to investigate the number of anxiety and pain management techniques performed during needle procedure in children with intellectual disability (cases) compared to a population of children without intellectual disability (controls). This multicenter cohort study was performed from July 2016 to January 2018 in the pediatric ward of four urban hospitals in Italy. Eligible subjects were children with and without intellectual disability, from 4 to 17 years old, who needed venipuncture or intravenous cannulation for diagnosis or treatment. Use of topical anesthesia, distraction techniques, and physical or verbal comfort during procedures were recorded. Pain and anxiety scores were also recorded. Forty-seven cases and 94 controls were recruited. Three pain- and anxiety-relieving techniques were performed during the procedure in 12 (25%) cases and in 10 controls (11%); two techniques were performed in 23 (50%) cases and in 26 (28%) controls; 12 (25%) cases and 52 (55%) controls received only one.Conclusion: In this series, children with intellectual disability received significantly more relieving techniques, but experienced more pain and anxiety when compared to children without intellectual disability. What is Known: • Children with intellectual disability experience more episodes of pain than cognitively healthy ones, and almost 10% of these episodes are due to medical procedures. What is New: • Children with intellectual disability despite receiving more relieving techniques during a needle-related procedure experienced more pain and anxiety when compared to healthy children.
Keywords: Adolescent; Anxiety; Child; Child, Preschool; Cohort Studies; Female; Humans; Intellectual Disability; Italy; Male; Pain Management; Pain Measurement; Pain, Procedural; Phlebotomy

Neuronal Dysfunction Associated with Cholesterol Deregulation. - Marcuzzi, Annalisa; Loganes, Claudia; Valencic, Erica; Piscianz, Elisa; Monasta, Lorenzo; Bilel, Sabrine; Bortul, Roberta; Celeghini, Claudio; Zweyer, Marina; Tommasini, Alberto (Int J Mol Sci, 2018)
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

A new form of inherited thrombocytopenia due to monoallelic loss of function mutation in the thrombopoietin gene. - Noris, Patrizia; Marconi, Caterina; De Rocco, Daniela; Melazzini, Federica; Pippucci, Tommaso; Loffredo, Giuseppe; Giangregorio, Tania; Pecci, Alessandro; Seri, Marco; Savoia, Anna (Br J Haematol, 2018)

Non-invasive biomarkers of fetal brain development reflecting prenatal stress: An integrative multi-scale multi-species perspective on data collection and analysis. - Frasch, Martin G; Lobmaier, Silvia M; Stampalija, Tamara; Desplats, Paula; Pallarés, María Eugenia; Pastor, Verónica; Brocco, Marcela A; Wu, Hau-Tieng; Schulkin, Jay; Herry, Christophe L; Seely, Andrew J E; Metz, Gerlinde A S; et al. (Neurosci Biobehav Rev, 2018)
Prenatal stress (PS) impacts early postnatal behavioural and cognitive development. This process of 'fetal programming' 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.

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. - Feitosa, Mary F; Kraja, Aldi T; Chasman, Daniel I; Sung, Yun J; Winkler, Thomas W; Ntalla, Ioanna; Guo, Xiuqing; Franceschini, Nora; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; et al. (PLoS One, 2018)
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

Nutrient intakes in an Italian population of infants during the complementary feeding period. - Concina, Federica; Pani, Paola; Bravo, Giulia; Barbone, Fabio; Carletti, Claudia V; Knowles, Alessandra; Ronfani, Luca; Parpinel, Maria (Public Health Nutr, 2018)
OBJECTIVE: To describe the nutrient intakes of an Italian cohort of infants at 6, 9 and 12 months of age. DESIGN: Dietary data were collected using a food diary at three follow-ups (6, 9 and 12 months of age of infants). The infants' dietary data were used to estimate nutrient intakes using the Italian food composition database integrated with data from nutritional labels and the literature. The mean and standard deviation, median and interquartile range, minimum and maximum, and 5th, 25th, 75th and 95th percentiles were calculated for the daily intake of twenty-eight nutrients, with sex differences evaluated using parametric/non-parametric statistical methods. SETTING: A prospective population-based birth cohort.SubjectInfants (n 400) living in the urban area of Trieste (Italy). RESULTS: The sex distribution was fairly balanced at each follow-up. The mean daily intakes of energy and the other twenty-seven nutrients considered were greater in males at all follow-ups. In particular, a significant statistical difference was observed in higher male consumption of cholesterol at 9 months and in energy and carbohydrate intakes at 12 months (P < 0·05). The mean daily intake of proteins was greater than that recommended by the Italian Dietary Reference Values at all follow-ups. CONCLUSIONS: These preliminary results provide a useful basis for understanding the nutrient intake patterns of infants in this area of Italy during the first year of life.

Ocular Manifestations of Paediatric Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. - Ottaviano, Giorgio; Salvatore, Silvia; Salvatoni, Alessandro; Martelossi, Stefano; Ventura, Alessandro; Naviglio, Samuele (J Crohns Colitis, 2018)
Background and Aims: Ocular extraintestinal manifestations [O-EIMs] are known complications of Crohn's disease [CD], ulcerative colitis [UC], and inflammatory bowel disease unclassified [IBD-U]. However, data on their prevalence in children are scarce and there are no clear recommendations on what follow-up should be offered. We aimed to review available data on O-EIMs in children. Methods: In January 2018, we performed a systematic review of published English literature using PubMed and EMBASE databases and disease-specific queries. Results: Fifteen studies [7467 patients] reported data on O-EIMs prevalence in children. Overall prevalence of O-EIMs was 0.62-1.82%. Uveitis was the most common O-EIM. Meta-analysis showed that children with CD are at increased risk of O-EIMs as compared with children with UC and IBD-U (odds ratio [OR] 2.70, 95% confidence interval [CI] 1.51-4.83). Five studies [357 patients] reported data on ophthalmological screening in asymptomatic children: mild asymptomatic uveitis was identified in a variable proportion of patients [1.06-23.1%], more frequently in male patients with CD and colonic involvement. No evidence of ocular complications from untreated uveitis was detected. A total of 23 case reports [24 patients] were identified. Conclusions: Data on O-EIMs in children are scarce. Prevalence of O-EIMs is lower than in adults but may be underestimated because of the possibility of asymptomatic uveitis; however, the long-term significance of this condition is unknown. Children with CD may be at increased risk of O-EIMs. No recommendations on routine ophthalmological examination can be made, but a low threshold for ophthalmological referral should be maintained. Larger studies in paediatric IBD populations are needed.
Keywords: Adolescent; Cataract; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Eye Diseases; Humans; Prevalence; Uveitis

Off-label drugs use in pediatric palliative care. - De Zen, Lucia; Marchetti, Federico; Barbi, Egidio; Benini, Franca (Ital J Pediatr, 2018)
BACKGROUND: Paediatric palliative care (PPC) aim to ensure the control of symptoms and the best possible quality of life for patients whose underlying disease, characterized by an unstoppable evolution and negative prognosis, no longer responds to specific treatments. The scientific evidence in this context are very deficient and, in order to obtain welfare objectives consistent with the situation, in the overwhelming majority of cases the prescription of drugs is off-label for indication of use and/or for age and/or for way of administration and/or formulation. The Agenzia Italiana del Farmaco - AIFA and the Italian Society of Palliative Care (Società Italiana di Cure Palliative - SICP), under a dedicated working group, wrote a document that collects the scientific evidence available to support the off-label use of medicines more frequently used in PPC. The goal is to certify the consolidated off-label use of these drugs and propose their use under the Law 648/96, in the absence of data from its pivotal clinical trials. Aim of the commentary is to report the conditions for this important work and to present the 10 drugs, usually used off-label in PPC and in pain therapy, now included in Law 648/96. CONCLUSION: This work is deemed essential to resolve, at least in part, the lack of availability of medicines researched and approved.

Orthopaedic challenges for mucopolysaccharidoses. - Borgo, Andrea; Cossio, Andrea; Gallone, Denise; Vittoria, Francesca; Carbone, Marco (Ital J Pediatr, 2018)
Mucopolysaccharidoses (MPS) are a group of diseases characterized by abnormal accumulation of glycosaminoglycans (GAGs). Although there are differences among the various disease types, the osteoarticular system is always involved. The aim of the present study was to establish a framework for MPS-related orthopaedic manifestations and for their treatment. The authors, affiliated to three different Italian Orthopaedic Centres, report data taken from the literature reviewed in light of their accumulated professional experience. Bone alterations make up what is known as dysostosis multiplex, involving the trunk and limbs and with typical radiological findings. Joints are affected by pathological tissue infiltrations. The cervical spinal cord is involved, with stenosis and cervical and occipitocervical instability. In MPS there is a much higher incidence of scoliosis compared with healthy subjects without any particular distinctive feature. Kyphosis of the spine is more frequent and also more severe because of its possible neurological complications, and it is localized at the thoracolumbar level with a malformed vertebra at the top of the deformity. Evolving forms, and those associated with neurological damage, require anteroposterior spine fusion. The hip is invariably involved, with dysplasia affecting the femoral neck (coxa valga), the femoral epiphysis (loss of sphericity, osteonecrosis), and the femoral acetabulum which is flared. All these features explain the tendency to progressive hip migration. Genu valgum is often found (a deviation of the physiological axis with an obtuse angle opening laterally). This deformity is often localized at the proximal tibial metaphysis; it causes functional limitations and leads to an irregular erosion of the articular cartilage. In young patients who still have the growth plate, it is possible to execute a medial hemiepiphysiodesis, a temporary inhibition of cartilage growth, with progressive axis correction. In this paper, the characterisation of clinical features and the review of treatments are divided into separate sections based on the part of the body involved. The conclusions of each section are presented as a summary. One section discusses the high risk of anaesthesia-related complications requiring the collaboration of specifically trained personnel.
Keywords: Bone Diseases; Humans; Mucopolysaccharidoses; Orthopedic Procedures

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). - Lezo, Antonella; Capriati, Teresa; Spagnuolo, Maria Immacolata; Lacitignola, Laura; Goreva, Irina; Di Leo, Grazia; Cecchi, Nicola; Gandullia, Paolo; Amarri, Sergio; Forchielli, Maria Luisa; Dipasquale, Valeria; Parma, Barbara; et al. (Nutrients, 2018)
Home Artificial Nutrition (HAN) is a safe and efficacious technique that insures children'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'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' 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

Pain Intensity and Risk of Bone Fracture in Children With Minor Extremity Injuries. - Zanchi, Chiara; Giangreco, Manuela; Ronfani, Luca; Germani, Claudio; Giorgi, Rita; Calligaris, Lorenzo; Norbedo, Stefania; Liccari, Giulio; Cozzi, Giorgio; Barbi, Egidio (Pediatr Emerg Care, 2018)
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'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'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.

Pancreatic ductal adenocarcinoma can be detected by analysis of volatile organic compounds (VOCs) in alveolar air. - Princivalle, Andrea; Monasta, Lorenzo; Butturini, Giovanni; Bassi, Claudio; Perbellini, Luigi (BMC Cancer, 2018)
BACKGROUND: In the last decade many studies showed that the exhaled breath of subjects suffering from several pathological conditions has a peculiar volatile organic compound (VOC) profile. The objective of the present work was to analyse the VOCs in alveolar air to build a diagnostic tool able to identify the presence of pancreatic ductal adenocarcinoma in patients with histologically confirmed disease. METHODS: The concentration of 92 compounds was measured in the end-tidal breath of 65 cases and 102 controls. VOCs were measured with an ion-molecule reaction mass spectrometry. To distinguish between subjects with pancreatic adenocarcinomas and controls, an iterated Least Absolute Shrinkage and Selection Operator multivariate Logistic Regression model was elaborated. RESULTS: The final predictive model, based on 10 VOCs, significantly and independently associated with the outcome had a sensitivity and specificity of 100 and 84% respectively, and an area under the ROC curve of 0.99. For further validation, the model was run on 50 other subjects: 24 cases and 26 controls; 23 patients with histological diagnosis of pancreatic adenocarcinomas and 25 controls were correctly identified by the model. CONCLUSIONS: Pancreatic cancer is able to alter the concentration of some molecules in the blood and hence of VOCs in the alveolar air in equilibrium. The detection and statistical rendering of alveolar VOC composition can be useful for the clinical diagnostic approach of pancreatic neoplasms with excellent sensitivity and specificity.

Pathological Significance and Prognostic Value of Surfactant Protein D in Cancer. - Mangogna, Alessandro; Belmonte, Beatrice; Agostinis, Chiara; Ricci, Giuseppe; Gulino, Alessandro; Ferrara, Ines; Zanconati, Fabrizio; Tripodo, Claudio; Romano, Federico; Kishore, Uday; Bulla, Roberta (Front Immunol, 2018)
Surfactant protein D (SP-D) is a pattern recognition molecule belonging to the Collectin (collagen-containing C-type lectin) family that has pulmonary as well as extra-pulmonary existence. In the lungs, it is a well-established opsonin that can agglutinate a range of microbes, and enhance their clearance phagocytosis and super-oxidative burst. It can interfere with allergen-IgE interaction and suppress basophil and mast cell activation. However, it is now becoming evident that SP-D is likely to be an innate immune surveillance molecule against tumor development. SP-D has been shown to induce apoptosis in sensitized eosinophils derived from allergic patients and a leukemic cell line p53 pathway. Recently, SP-D has been shown to suppress lung cancer progression interference with the epidermal growth factor signaling. In addition, a truncated form of recombinant human SP-D has been reported to induce apoptosis in pancreatic adenocarcinoma Fas-mediated pathway in a p53-independent manner. To further establish a correlation between SP-D presence/levels and normal and cancer tissues, we performed a bioinformatics analysis, using Oncomine dataset and the survival analysis platforms Kaplan-Meier plotter, to assess if SP-D can serve as a potential prognostic marker for human lung cancer, in addition to human gastric, breast, and ovarian cancers. We also analyzed immunohistochemically the presence of SP-D in normal and tumor human tissues. We conclude that (1) in the lung, gastric, and breast cancers, there is a lower expression of SP-D than normal tissues; (2) in ovarian cancer, there is a higher expression of SP-D than normal tissue; and (3) in lung cancer, the presence of SP-D could be associated with a favorable prognosis. On the contrary, at non-pulmonary sites such as gastric, breast, and ovarian cancers, the presence of SP-D could be associated with unfavorable prognosis. Correlation between the levels of SP-D and overall survival requires further investigation. Our analysis involves a large number of dataset; therefore, any trend observed is reliable. Despite apparent complexity within the results, it is evident that cancer tissues that produce less levels of SP-D compared to their normal tissue counterparts are probably less susceptible to SP-D-mediated immune surveillance mechanisms infiltrating immune cells.

Pharmacogenetics of treatments for inflammatory bowel disease. - Lucafò, Marianna; Franca, Raffaella; Selvestrel, Davide; Curci, Debora; Pugnetti, Letizia; Decorti, Giuliana; Stocco, Gabriele (Expert Opin Drug Metab Toxicol, 2018)
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

Photobiomodulation at Multiple Wavelengths Differentially Modulates Oxidative Stress and . - Rupel, Katia; Zupin, Luisa; Colliva, Andrea; Kamada, Anselmo; Poropat, Augusto; Ottaviani, Giulia; Gobbo, Margherita; Fanfoni, Lidia; Gratton, Rossella; Santoro, Massimo; Di Lenarda, Roberto; Biasotto, Matteo; et al. (Oxid Med Cell Longev, 2018)
Photobiomodulation (PBM) is emerging as an effective strategy for the management of multiple inflammatory conditions, including oral mucositis (OM) in cancer patients who receive chemotherapy or radiotherapy. Still, the poor understanding of the mechanisms by which the light interacts with biological tissues and the heterogeneity of light sources and protocols employed worldwide significantly limits its applicability. Reactive oxygen species (ROS) are massively generated during the early phases of OM and play a major role in the pathogenesis of inflammation in general. Here, we report the results of a clinical and experimental study, aimed at evaluating the effect of laser light at different wavelengths on oxidative stress in oncologic patients suffering from OM and in two cell types abundantly present within the inflamed oral mucosa, neutrophil polymorphonuclear (PMN) granulocytes, and keratinocytes. In addition to standard ROS detection methods, we exploited a roGFP2-Orp1 genetically encoded sensor, allowing specific, quantitative, and dynamic imaging of redox events in living cells in response to oxidative stress and PBM. We found that the various wavelengths differentially modulate ROS production. In particular, the 660 nm laser light increases ROS production when applied either before or after an oxidative stimulus. In contrast, the 970 nm laser light exerted a moderate antioxidant activity both in the saliva of OM patients and in both cell types. The most marked reduction in the levels of ROS was detected in cells exposed either to the 800 nm laser light or to the combination of the three wavelengths. Overall, our study demonstrates that PBM exerts different effects on the redox state of both PMNs and keratinocytes depending on the used wavelength and prompts the validation of a multiwavelength protocol in the clinical settings.
Keywords: Adult; Aged; Aged, 80 and over; Female; Humans; Keratinocytes; Lasers, Semiconductor; Low-Level Light Therapy; Male; Middle Aged; Neutrophils; Oxidation-Reduction; Oxidative Stress; Stomatitis

Population and fertility by age and sex for 195 countries and territories, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017. (Lancet, 2018)
BACKGROUND: Population estimates underpin demographic and epidemiological research and are used to track progress on numerous international indicators of health and development. To date, internationally available estimates of population and fertility, although useful, have not been produced with transparent and replicable methods and do not use standardised estimates of mortality. We present single-calendar year and single-year of age estimates of fertility and population by sex with standardised and replicable methods. METHODS: We estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods. We based the estimates on the demographic balancing equation, with inputs of fertility, mortality, population, and migration data. Fertility data came from 7817 location-years of vital registration data, 429 surveys reporting complete birth histories, and 977 surveys and censuses reporting summary birth histories. We estimated age-specific fertility rates (ASFRs; the annual number of livebirths to women of a specified age group per 1000 women in that age group) by use of spatiotemporal Gaussian process regression and used the ASFRs to estimate total fertility rates (TFRs; the average number of children a woman would bear if she survived through the end of the reproductive age span [age 10-54 years] and experienced at each age a particular set of ASFRs observed in the year of interest). Because of sparse data, fertility at ages 10-14 years and 50-54 years was estimated from data on fertility in women aged 15-19 years and 45-49 years, through use of linear regression. Age-specific mortality data came from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 estimates. Data on population came from 1257 censuses and 761 population registry location-years and were adjusted for underenumeration and age misreporting with standard demographic methods. Migration was estimated with the GBD Bayesian demographic balancing model, after incorporating information about refugee migration into the model prior. Final population estimates used the cohort-component method of population projection, with inputs of fertility, mortality, and migration data. Population uncertainty was estimated by use of out-of-sample predictive validity testing. With these data, we estimated the trends in population by age and sex and in fertility by age between 1950 and 2017 in 195 countries and territories. FINDINGS: From 1950 to 2017, TFRs decreased by 49·4% (95% uncertainty interval [UI] 46·4-52·0). The TFR decreased from 4·7 livebirths (4·5-4·9) to 2·4 livebirths (2·2-2·5), and the ASFR of mothers aged 10-19 years decreased from 37 livebirths (34-40) to 22 livebirths (19-24) per 1000 women. Despite reductions in the TFR, the global population has been increasing by an average of 83·8 million people per year since 1985. The global population increased by 197·2% (193·3-200·8) since 1950, from 2·6 billion (2·5-2·6) to 7·6 billion (7·4-7·9) people in 2017; much of this increase was in the proportion of the global population in south Asia and sub-Saharan Africa. The global annual rate of population growth increased between 1950 and 1964, when it peaked at 2·0%; this rate then remained nearly constant until 1970 and then decreased to 1·1% in 2017. Population growth rates in the southeast Asia, east Asia, and Oceania GBD super-region decreased from 2·5% in 1963 to 0·7% in 2017, whereas in sub-Saharan Africa, population growth rates were almost at the highest reported levels ever in 2017, when they were at 2·7%. The global average age increased from 26·6 years in 1950 to 32·1 years in 2017, and the proportion of the population that is of working age (age 15-64 years) increased from 59·9% to 65·3%. At the national level, the TFR decreased in all countries and territories between 1950 and 2017; in 2017, TFRs ranged from a low of 1·0 livebirths (95% UI 0·9-1·2) in Cyprus to a high of 7·1 livebirths (6·8-7·4) in Niger. The TFR under age 25 years (TFU25; number of livebirths expected by age 25 years for a hypothetical woman who survived the age group and was exposed to current ASFRs) in 2017 ranged from 0·08 livebirths (0·07-0·09) in South Korea to 2·4 livebirths (2·2-2·6) in Niger, and the TFR over age 30 years (TFO30; number of livebirths expected for a hypothetical woman ageing from 30 to 54 years who survived the age group and was exposed to current ASFRs) ranged from a low of 0·3 livebirths (0·3-0·4) in Puerto Rico to a high of 3·1 livebirths (3·0-3·2) in Niger. TFO30 was higher than TFU25 in 145 countries and territories in 2017. 33 countries had a negative population growth rate from 2010 to 2017, most of which were located in central, eastern, and western Europe, whereas population growth rates of more than 2·0% were seen in 33 of 46 countries in sub-Saharan Africa. In 2017, less than 65% of the national population was of working age in 12 of 34 high-income countries, and less than 50% of the national population was of working age in Mali, Chad, and Niger. INTERPRETATION: Population trends create demographic dividends and headwinds (ie, economic benefits and detriments) that affect national economies and determine national planning needs. Although TFRs are decreasing, the global population continues to grow as mortality declines, with diverse patterns at the national level and across age groups. To our knowledge, this is the first study to provide transparent and replicable estimates of population and fertility, which can be used to inform decision making and to monitor progress. FUNDING: Bill & Melinda Gates Foundation.
Keywords: Adolescent; Adult; Aged; Birth Rate; Child; Child, Preschool; Female; Global Burden of Disease; Global Health; Humans; Infant; Infant, Newborn; Male; Maternal Age; Middle Aged; Mortality; Population Density; Population Growth; Young Adult

Potential use of MCR-ALS for the identification of coeliac-related biochemical changes in hyperspectral Raman maps from pediatric intestinal biopsies. - Fornasaro, Stefano; Vicario, Annalisa; De Leo, Luigina; Bonifacio, Alois; Not, Tarcisio; Sergo, Valter (Integr Biol (Camb), 2018)
Raman hyperspectral imaging is an emerging practice in biological and biomedical research for label free analysis of tissues and cells. Using this method, both spatial distribution and spectral information of analyzed samples can be obtained. The current study reports the first Raman microspectroscopic characterisation of colon tissues from patients with Coeliac Disease (CD). The aim was to assess if Raman imaging coupled with hyperspectral multivariate image analysis is capable of detecting the alterations in the biochemical composition of intestinal tissues associated with CD. The analytical approach was based on a multi-step methodology: duodenal biopsies from healthy and coeliac patients were measured and processed with Multivariate Curve Resolution Alternating Least Squares (MCR-ALS). Based on the distribution maps and the pure spectra of the image constituents obtained from MCR-ALS, interesting biochemical differences between healthy and coeliac patients has been derived. Noticeably, a reduced distribution of complex lipids in the pericryptic space, and a different distribution and abundance of proteins rich in beta-sheet structures was found in CD patients. The output of the MCR-ALS analysis was then used as a starting point for two clustering algorithms (k-means clustering and hierarchical clustering methods). Both methods converged with similar results providing precise segmentation over multiple Raman images of studied tissues.

PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. - van Setten, Jessica; Brody, Jennifer A; Jamshidi, Yalda; Swenson, Brenton R; Butler, Anne M; Campbell, Harry; Del Greco, Fabiola M; Evans, Daniel S; Gibson, Quince; Gudbjartsson, Daniel F; Kerr, Kathleen F; Krijthe, Bouwe P; et al. (Nat Commun, 2018)
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

Predictive value of the number of adverse reaction episodes for the IgE-mediated food allergy diagnosis. - Miceli Sopo, S; Gurnari, G; Monaco, S; Romano, A; Liotti, L; Cuomo, B; Dello Iacono, I; Badina, L; Longo, G; Calvani, M; Giannone, A; Calabrò, C; et al. (Allergol Immunopathol (Madr), 2018)
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.

Pre-eclampsia affects procalcitonin production in placental tissue. - Agostinis, Chiara; Rami, Damiano; Zacchi, Paola; Bossi, Fleur; Stampalija, Tamara; Mangogna, Alessandro; Amadio, Leonardo; Vidergar, Romana; Vecchi Brumatti, Liza; Ricci, Giuseppe; Celeghini, Claudio; Radillo, Oriano; et al. (Am J Reprod Immunol, 2018)
PROBLEM: Procalcitonin (PCT) is the prohormone of calcitonin which is usually released from neuroendocrine cells of the thyroid gland (parafollicular) and the lungs (K cells). PCT is synthesized by almost all cell types and tissues, including monocytes and parenchymal tissue, upon LPS stimulation. To date, there is no evidence for PCT expression in the placenta both in physiological and pathological conditions. METHOD: Circulating and placental PCT levels were analysed in pre-eclamptic (PE) and control patients. Placental cells and macrophages (PBDM), stimulated with PE sera, were analysed for PCT expression. The effect of anti-TNF-α antibody was analysed. RESULTS: Higher PCT levels were detected in PE sera and in PE placentae compared to healthy women. PE trophoblasts showed increased PCT expression compared to those isolated from healthy placentae. PE sera induced an upregulation of PCT production in macrophages and placental cells. The treatment of PBDM with PE sera in the presence of anti-TNF-α completely abrogated the effect induced by pathologic sera. CONCLUSION: Trophoblast cells are the main producer of PCT in PE placentae. TNF-α, in association with other circulating factors present in PE sera, upregulates PCT production in macrophages and normal placental cells, thus contributing to the observed increased in circulating PCT in PE sera.
Keywords: Adult; Calcitonin; Cohort Studies; Female; Humans; Macrophages; Placenta; Pre-Eclampsia; Pregnancy; Trophoblasts; Tumor Necrosis Factor-alpha; Up-Regulation; Young Adult

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. - Wanzira, Humphrey; Muyinda, Richard; Lochoro, Peter; Putoto, Giovanni; Segafredo, Giulia; Wamani, Henry; Lazzerini, Marzia (BMC Health Serv Res, 2018)
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

Red Flags in Torticollis: A Historical Cohort Study. - Starc, Meta; Norbedo, Stefania; Tubaro, Martina; Ronfani, Luca; Bassanese, Giulia; Barbi, Egidio (Pediatr Emerg Care, 2018)
OBJECTIVE: This study aimed to assess the spectrum of pathologies responsible for torticollis in children presenting to the emergency department and to evaluate the associated symptoms to determine clinical red flags for hospitalization. METHODS: This was a historical retrospective cohort study. Medical records of children evaluated in our emergency department for torticollis from 2008 to 2013 were reviewed. RESULTS: Among 392 identified patients, 61% had postural torticollis,19.4% infection related, 16.3% traumatic, and 3.5% other. Twenty-five patients (6.4%) were hospitalized. Four variables were strongly and independently related to the severe outcome: fever, sore throat, headache, and age. CONCLUSIONS: The association of 2 or 3 of these 4 features carried a risk of 32% and 58%, respectively, of having a severe illness.
Keywords: Adolescent; Child; Child, Preschool; Cohort Studies; Emergency Service, Hospital; Female; Hospitalization; Humans; Male; Retrospective Studies; Torticollis

Report on an international workshop on kangaroo mother care: lessons learned and a vision for the future. - Cattaneo, Adriano; Amani, Adidja; Charpak, Nathalie; De Leon-Mendoza, Socorro; Moxon, Sarah; Nimbalkar, Somashekhar; Tamburlini, Giorgio; Villegas, Julieta; Bergh, Anne-Marie (BMC Pregnancy Childbirth, 2018)
BACKGROUND: Globally, complications of prematurity are the leading cause of death in children under five. Preterm infants who survive their first month of life are at greater risk for various diseases and impairments in infancy, childhood and later life, representing a heavy social and economic burden for families, communities and health and social systems. Kangaroo mother care (KMC) is recommended as a beneficial and effective intervention for improving short- and long-term preterm birth outcomes in low- and high-income settings. Nevertheless, KMC is not as widely used as it should be. The International Network on KMC runs biennial workshops and congresses to help improve the coverage and quality of KMC worldwide. This paper reports the results of the two-day workshop held in November 2016, where 92 participants from 33 countries shared experiences in a series of round tables, group work sessions and plenaries. FINDINGS: Barriers to and enablers of KMC are discussed with regard to parents, health workers and the health system. Key factors for effective implementation and uptake relate to appropriate training for health staff, adherence to protocols and the creation of a welcoming environment for families. Recommendations for planning for national programmes are made according to a six-stage change model. Resources and the cost of making progress are discussed in terms of investment, maintenance, and acceleration and scaling-up costs. KMC training requirements are presented according to three levels of care. To ensure quality KMC, key requisites are proposed for the different KMC components and for sensitive communication with caregivers. The group attending to the monitoring and evaluation of KMC at a national and subnational level highlight the lack of standard indicator definitions. Key priorities for investment include health services research, harmonisation of indicators, development of a costing tool, programming and scaling up, and the follow-up of preterm infants. CONCLUSION: It is hoped that this report will help to further scale-up and sustain KMC through a systematic approach that includes raising commitment, identifying key strategies to address the main barriers and using existing facilitators, ensuring training and quality, agreeing on indicators for monitoring and evaluation, and advancing implementation research.
Keywords: Education; Education, Nonprofessional; Female; Government Programs; Health Plan Implementation; Humans; Infant; Infant Mortality; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; International Cooperation; Kangaroo-Mother Care Method; Male

Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice. - Marcuzzi, Annalisa; Loganes, Claudia; Celeghini, Claudio; Kleiner, Giulio (Curr Med Chem, 2018)
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' 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

The Role of Oxidative Stress and Membrane Transport Systems during Endometriosis: A Fresh Look at a Busy Corner. - Vitale, Salvatore Giovanni; Capriglione, Stella; Peterlunger, Isabel; La Rosa, Valentina Lucia; Vitagliano, Amerigo; Noventa, Marco; Valenti, Gaetano; Sapia, Fabrizio; Angioli, Roberto; Lopez, Salvatore; Sarpietro, Giuseppe; Rossetti, Diego; et al. (Oxid Med Cell Longev, 2018)
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

Role of the Long Non-Coding RNA Growth Arrest-Specific 5 in Glucocorticoid Response in Children with Inflammatory Bowel Disease. - Lucafò, Marianna; Di Silvestre, Alessia; Romano, Maurizio; Avian, Alice; Antonelli, Roberta; Martelossi, Stefano; Naviglio, Samuele; Tommasini, Alberto; Stocco, Gabriele; Ventura, Alessandro; Decorti, Giuliana; De Iudicibus, Sara (Basic Clin Pharmacol Toxicol, 2018)
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

Rothmund-Thomson Syndrome: Insights from New Patients on the Genetic Variability Underpinning Clinical Presentation and Cancer Outcome. - Colombo, Elisa A; Locatelli, Andrea; Cubells Sánchez, Laura; Romeo, Sara; Elcioglu, Nursel H; Maystadt, Isabelle; Esteve Martínez, Altea; Sironi, Alessandra; Fontana, Laura; Finelli, Palma; Gervasini, Cristina; Pecile, Vanna; et al. (Int J Mol Sci, 2018)
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

Secondary prevention of early-onset sepsis: a less invasive Italian approach for managing neonates at risk. - Berardi, Alberto; Tzialla, Chryssoula; Travan, Laura; Bua, Jenny; Santori, Daniele; Azzalli, Milena; Spada, Caterina; Lucaccioni, Laura (Ital J Pediatr, 2018)
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.

Serum Stem Cell Growth Factor Beta for the Prediction of Therapy Response in Hepatocellular Carcinoma. - Sukowati, Caecilia H C; Patti, Riccardo; Pascut, Devis; Ladju, Rusdina B; Tarchi, Paola; Zanotta, Nunzia; Comar, Manola; Tiribelli, Claudio; Crocè, Lory S (Biomed Res Int, 2018)
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

Teaching pain recognition through art: the Ramsay-Caravaggio sedation scale. - Poropat, Federico; Cozzi, Giorgio; Magnolato, Andrea; Monasta, Lorenzo; Borrometi, Fabio; Krauss, Baruch; Ventura, Alessandro; Barbi, Egidio (Ital J Pediatr, 2018)
BACKGROUND: Clinical observation is a key component of medical ability, enabling immediate evaluation of the patient's emotional state and contributing to a clinical clue that leads to final decision making. In medical schools, the art of learning to look can be taught using medical humanities and especially visual arts. By presenting a Ramsay sedation score (RSS) integrated with Caravaggio's paintings during a procedural sedation conference for pediatric residents, we want to test the effectiveness of this approach to improve the quality of learning. METHODS: In this preliminary study, we presented videos showing sedated pediatric patients in the setting of a procedural sedation lesson to two randomized groups of residents, one attending a lesson on RSS explained through the masterpieces of Caravaggio, the other without artistic support. A week later we tested their learning with ten multi-choice questions focused on theoretical questions about sedation monitoring and ten more questions focused on recognizing the appropriate RSS viewing the videos. The primary outcome was the comparison of the total number of RSS layers properly recognized in both groups. We also evaluated the appreciation of the residents of the use of works of art integrated with the lesson. RESULTS: Eleven students were randomized to each group. Two residents in the standard lesson did not attend the test. The percentage of correct answers on the theoretical part was similar, 82% in the art group and 89% in the other (p > 0.05). No difference was found in the video recognition part of the RSS recognition test. Residents exposed to paintings shown great appreciation for the integration of the lesson with the Caravaggio's masterpieces. CONCLUSIONS: Adding artwork to a standard medical conference does not improve the performance of student tests, although this approach has been greatly appreciated by residents.
Keywords: Clinical Competence; Conscious Sedation; Deep Sedation; Education, Medical, Graduate; Female; Hospitals, University; Humans; Internship and Residency; Italy; Male; Medicine in the Arts; Monitoring, Physiologic; Pain Measurement; Paintings; Pediatrics; Video Recording

Theophylline as a precision therapy in a young girl with PIK3R1 immunodeficiency. - Valencic, Erica; Grasso, Antonio Giacomo; Conversano, Ester; Lucafò, Marianna; Piscianz, Elisa; Gregori, Massimo; Conti, Francesca; Cancrini, Caterina; Tommasini, Alberto (J Allergy Clin Immunol Pract, 2018)

Total body irradiation and iron chelation treatment are associated with pancreatic injury following pediatric hematopoietic stem cell transplantation. - Maximova, Natalia; Gregori, Massimo; Simeone, Roberto; Sonzogni, Aurelio; Zanon, Davide; Boz, Giulia; D'Antiga, Lorenzo (Oncotarget, 2018)
Whereas many studies have addressed the risk of organ dysfunction following hematopoietic stem cell transplantation (HSCT), little is known about pancreatic susceptibility in this setting. We aimed to investigate the effect of iron overload (IO) and total body irradiation (TBI) on pancreatic function of children undergoing HSCT. We retrospectively evaluated children admitted between 2012-2016 fulfilling the following criteria: normal pancreatic iron concentration (PIC), regular pancreatic function before HSCT, availability of abdominal magnetic resonance imaging with gradient-recalled-echo sequences and a full set of biochemical markers of IO and pancreatic function performed before HSCT and at discharge. We divided the patients according to the use of TBI or myeloablative chemotherapy (MCHT) in the conditioning regimen. All patients with severe IO or moderate IO with a high risk of engraftment delay or transplantation-related complications underwent chelation therapy with deferoxamine (DFO) from the first day of conditioning to discharge. 63 patients had a HSCT in the study period, 13 did not fulfill the inclusion criteria; 50 (25 in each group) are included in the analysis, and did not show differences at baseline evaluation. At follow up testing the TBI group showed a significantly higher PIC (107,8±100,3 μmol/g vs 28,4±37,9 in MCHT group, p<0,0001). In the TBI group the patients who had DFO treatment had higher PIC (223,2±48,8 μmol/g vs 55,7±10,5 without DFO treatment, p<0,0001), and all patients having PIC >100 μmol/g at follow up had DFO-based chelation therapy, versus 26% of those with lower PIC (p<0,0001). The number of patients presenting exocrine pancreatic dysfunctions one month after transplantation was significantly higher in the TBI group (48% vs 4%; p<0.0001). The mean pancreatic volume reduction was significantly greater in the TBI group (39,1% vs 0,9% in the MCHT group; p<0,05), and was significantly worse on those who received DFO therapy. Based on our data, we suggest that TBI is detrimental for pancreatic functions, and speculate that DFO may contribute to the rapid pancreatic IO observed in these patients.

A transcriptomics study of hereditary angioedema attacks. - Castellano, Giuseppe; Divella, Chiara; Sallustio, Fabio; Montinaro, Vincenzo; Curci, Claudia; Zanichelli, Andrea; Bonanni, Erika; Suffritti, Chiara; Caccia, Sonia; Bossi, Fleur; Gallone, Anna; Schena, Francesco Paolo; et al. (J Allergy Clin Immunol, 2018)
BACKGROUND: Hereditary angioedema (HAE) caused by C1-inhibitor deficiency is a lifelong illness characterized by recurrent acute attacks of localized skin or mucosal edema. Activation of the kallikrein/bradykinin pathway at the endothelial cell level has a relevant pathogenetic role in acute HAE attacks. Moreover, other pathways are involved given the variable clinical expression of the disease in different patients. OBJECTIVE: We sought to explore the involvement of other putative genes in edema formation. METHODS: We performed a PBMC microarray gene expression analysis on RNA isolated from patients with HAE during an acute attack and compared them with the transcriptomic profile of the same patients in the remission phase. RESULTS: Gene expression analysis identified 23 genes significantly modulated during acute attacks that are involved primarily in the natural killer cell signaling and leukocyte extravasation signaling pathways. Gene set enrichment analysis showed a significant activation of relevant biological processes, such as response to external stimuli and protein processing (q < 0.05), suggesting involvement of PBMCs during acute HAE attacks. Upregulation of 2 genes, those encoding adrenomedullin and cellular receptor for urokinase plasminogen activator (uPAR), which occurs during an acute attack, was confirmed in PBMCs of 20 additional patients with HAE by using real-time PCR. Finally, in vitro studies demonstrated the involvement of uPAR in the generation of bradykinin and endothelial leakage. CONCLUSIONS: Our study demonstrates the increase in levels of adrenomedullin and uPAR in PBMCs during an acute HAE attack. Activation of these genes usually involved in regulation of vascular tone and in inflammatory response might have a pathogenic role by amplifying bradykinin production and edema formation in patients with HAE.

Ultrasound-guided genitofemoral nerve block for inguinal hernia repair in the male adult: a randomized controlled pilot study. - Frassanito, Luciano; Zanfini, Bruno A; Pitoni, Sara; Germini, Paolo; Del Vicario, Miryam; Draisci, Gaetano (Minerva Anestesiol, 2018)
BACKGROUND: Ultrasound-guided (USG) ilioinguinal/iliohypogastric nerve (II/IHN) block is a widely validated anesthetic technique for inguinal herniorrhaphy. As the spermatic cord, scrotum, and adjacent thigh receive sensory innervation from the genital branch of genitofemoral nerve (GFN), the addition of GFN block has been suggested to improve the quality of perioperative anesthesia and analgesia. The aim of this study is to compare GFN block plus II/IHN block with II/IHN block alone for intraoperative anesthesia and post-operative pain management. METHODS: We enrolled 80, ASA I-III, male adults scheduled for elective open herniorrhaphy. Patients were randomized to receive either USG II/IHN plus GFN block (Case Group) or USG II/IHN block alone (Control Group). The outcome measures were the assessment of postoperative VAS scores on coughing and the adequacy of anesthesia, measured with intraoperative requirement for extra local anesthetic (LA) infiltration and number of patients needing systemic sedation. RESULTS: The requirement of intraoperative additional doses of LA was significantly lower in the Case Group (median LA volume administered by the surgeon: 13.8±5.6 mL vs. 20.7±9.1 mL, P<0.05). Two patients in the Control Group needed systemic sedation. VAS scores at 15 minutes, 30 minutes, 1 hour, 2 hours, pre-discharge, and 24 hours were significantly lower in the Case Group (P<0.005). Four cases of femoral nerve block were reported, three in the Control Group, one in the Case Group (2.2% vs. 7.7%, P>0.05). CONCLUSIONS: The combination of GFN block and II/IHN block is associated with lower postoperative VAS scores and lower doses of intraoperative additional LA.

An unusual unilateral breast enlargement in a prepubertal girl. - Pavan, Matteo; Faleschini, Elena; Tornese, Gianluca; Zandonà, Lorenzo; Ventura, Alessandro (Arch Dis Child, 2018)

Vaginal microbiota dysmicrobism and role of biofilm-forming bacteria. - Campisciano, Giuseppina; Zanotta, Nunzia; Petix, Vincenzo; Corich, Lucia; De Seta, Francesco; Comar, Manola (Front Biosci (Elite Ed), 2018)
Bacterial vaginosis involves the presence of a polymicrobial biofilm on the vaginal epithelium, guaranteeing immune escape and spread of antibiotic resistance. To spot known biofilm-forming bacteria, we profiled the vaginal microbiome of sixty-four symptomatic women suffering from a different grade of vaginal disorders and sixty asymptomatic healthy women. Specific microbial profiles distinguished symptomatic from asymptomatic women and characterized the grade of dysmicrobism within the symptomatic group. Lactobacillus crispatus and iners predominated on the healthy vaginal mucosa, while Lactobacillus gasseri predominated in the intermediate dysmicrobism. Furthermore, the intermediate grade of dysmicrobism was characterized by other lactic acid-producers species than Lactobacilli, able to rescue the microbial imbalance, and Ureaplasma parvum-serovar 3. The vaginosis group exhibited the overgrowth of Prevotella bivia, which is known to enhance the biofilm formation by Gardnerella vaginalis, and the presence of Streptococcus anginosus, which is emerging as a new cooperating player of the vaginal biofilm. Identifying specific microorganisms promoting or preventing the biofilm formation could increase the accuracy for a better definition of the vaginal dysmicrobism concept and therapeutic intervention.
Keywords: Adult; Biofilms; Female; Humans; Microbiota; Vagina; Vaginosis, Bacterial

Vanishing Bile Ducts in the Long Term after Pediatric Hematopoietic Stem Cell Transplantation. - Maximova, Natalia; Sonzogni, Aurelio; Matarazzo, Lorenza; Ghirardi, Arianna; D'Antiga, Lorenzo (Biol Blood Marrow Transplant, 2018)
There are no structured studies on liver histology after hematopoietic stem cell transplantation (HSCT). We aimed to prospectively describe the clinicopathologic features of liver disease in the long term after HSCT in an observational, longitudinal study of liver histology in a consecutive cohort of children undergoing allogeneic HSCT. First liver biopsy was performed in presence of abnormal liver function tests and repeated per protocol thereafter. A previously reported semiquantitative score evaluating inflammation, cholestasis, and ductopenia (bile ducts-to-portal tracts ratio ≤ .5) was adopted. Graft-versus-host disease (GVHD) was diagnosed according to standard criteria. We evaluated 131 biopsies taken in 50 HSCTs performed in 47 children (mean age, 9.7 ± 5.2 years). Pre-HSCT chemotherapy was administered in 36 of 50 (72%). GVHD was diagnosed in 17 of 50 (34%). Over time the overall score decreased from a mean of 6 ± 2.7 to 3.25 ± .96 (P < .01), inflammation from 1.22 ± 1.19 to 1 ± 0 (not significant), and cholestasis from 3.9 ± 2.08 to 1.5 ± .58 (P < .01). Ductopenia, found in 113 of 131 biopsies (93%), worsened from .63 ± .35 to .16 ± .14 (P < .01). On multivariate analysis severe ductopenia (ratio ≤ .2) was associated with previous chemotherapy (P = .04), in particular with thiotepa, but not with history of GVHD. Vanishing bile duct syndrome after HSCT may be due to drug-induced liver disease. Longer follow-up will reveal whether these patients are prone to late liver-related morbidity and mortality.

What is known about deferasirox chelation therapy in pediatric HSCT recipients: two case reports of metabolic acidosis. - Fucile, Carmen; Mattioli, Francesca; Marini, Valeria; Gregori, Massimo; Sonzogni, Aurelio; Martelli, Antonietta; Maximova, Natalia (Ther Clin Risk Manag, 2018)
To date, in pediatric field, various hematological malignancies are increasingly treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Iron overload and systemic siderosis often occur in this particular cohort of patients and are associated with poor prognosis. We describe herein the case of two allo-HSCT patients, on treatment with deferasirox; they showed histopathological elements compatible with venoocclusive disease or vanishing bile duct syndrome in ductopenic evolution before deferasirox started. The first patient developed drug-induced liver damage with metabolic acidosis and the second one a liver impairment with Fanconi syndrome. After withdrawing deferasirox treatment, both patients showed improvement. Measurements of drug plasma concentrations were performed by HPLC assay. The reduction and consequent disappearance of symptoms after the suspension of deferasirox substantiate its role in inducing hepatic damage, probably enabling the diagnosis of drug-induced liver damage. But the difficulties in diagnosing drug-related toxicity must be underlined, especially in compromised subjects. For these reasons, in patients requiring iron-chelating therapy, close and careful drug therapeutic monitoring is strongly recommended.

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. - Bacci, Alberta; Hodorogea, Stelian; Khachatryan, Henrik; Babojonova, Shohida; Irsa, Signe; Jansone, Maira; Dondiuc, Iurie; Matarazde, George; Lazdane, Gunta; Lazzerini, Marzia (BMJ Open, 2018)
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 'inclusion of users' views' (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'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

Young Child in Respiratory Distress. - Cozzi, Giorgio; Conversano, Ester; Cattaruzzi, Elisabetta; Barbi, Egidio (Ann Emerg Med, 2018)
Keywords: Acute Disease; Child, Preschool; Female; Humans; Pulmonary Atelectasis; Radiography, Thoracic; Respiratory Insufficiency

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function. - Gorski, Mathias; van der Most, Peter J; Teumer, Alexander; Chu, Audrey Y; Li, Man; Mijatovic, Vladan; Nolte, Ilja M; Cocca, Massimiliano; Taliun, Daniel; Gomez, Felicia; Li, Yong; Tayo, Bamidele; et al. (Sci Rep, 2017)
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 × 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

46,XY ovotesticular disorders of sex development: A therapeutic challenge. - Scarpa, Maria-Grazia; Grazia, Massimo Di; Tornese, Gianluca (Pediatr Rep, 2017)

Acute Abdominal Pain: Recognition and Management of Constipation in the Emergency Department. - Norbedo, Stefania; Bassanese, Giulia; Barbieri, Francesca; Barbi, Egidio (Pediatr Emerg Care, 2017)
OBJECTIVE: The main aim of the study was to investigate the incidence and the clinically relevant features of functional constipation in patients evaluated for acute abdominal pain in a tertiary care pediatric emergency department. METHODS: This is a retrospective study. We analyzed 4394 medical records and recorded the information (demographics, triage code, symptoms, medical history, physical evaluation, laboratory tests, radiological studies, procedures, and treatments) of all patients admitted for acute abdominal pain to the emergency department of the IRCCS Burlo Garofolo, Trieste, during 2010 to 2013. RESULTS: In this study, a quarter of patients (1020) presenting in the emergency department with acute abdominal pain were affected by functional constipation. Acute pain associated with functional constipation is generally rated from moderate to severe, and the location of the pain on physical evaluation was not a sufficient criterion to guide diagnosis. Isolated vomiting may be present in a minority of cases. Digital rectal exploration was never performed; the majority of patients were treated by means of an enema with prompt relief. Six percent of patients with constipation underwent radiological studies. CONCLUSIONS: This study confirms that the medical history provides a pivotal role in the diagnosis of functional constipation. Digital rectal exploration and x-rays should be avoided in this setting, whereas an enema plays a useful diagnostic and therapeutic role in our study patients.
Keywords: Abdominal Pain; Acute Pain; Adolescent; Child; Child, Preschool; Constipation; Emergency Service, Hospital; Enema; Female; Humans; Incidence; Infant; Male; Retrospective Studies

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. - Caorsi, Roberta; Penco, Federica; Grossi, Alice; Insalaco, Antonella; Omenetti, Alessia; Alessio, Maria; Conti, Giovanni; Marchetti, Federico; Picco, Paolo; Tommasini, Alberto; Martino, Silvana; Malattia, Clara; et al. (Ann Rheum Dis, 2017)
OBJECTIVES: To analyse the prevalence of mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study. METHODS: Direct sequencing of was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor. RESULTS: Biallelic homozygous or compound heterozygous mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect. CONCLUSIONS: DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.
Keywords: Adenosine Deaminase; Adolescent; Age of Onset; Case-Control Studies; Child; Child, Preschool; DNA Mutational Analysis; Female; Heterozygote; Homozygote; Humans; Immunoglobulins; Immunosuppressive Agents; Infant; Intercellular Signaling Peptides and Proteins; Italy; Livedo Reticularis; Male; Pedigree; Polyarteritis Nodosa; Stroke; Thalidomide; Tumor Necrosis Factor-alpha; Young Adult

Adolescent Admissions to Emergency Departments for Self-Injurious Thoughts and Behaviors. - Zanus, Caterina; Battistutta, Sara; Aliverti, Renata; Montico, Marcella; Cremaschi, Silvana; Ronfani, Luca; Monasta, Lorenzo; Carrozzi, Marco (PLoS One, 2017)
The objective of the present study was to describe the incidence and the characteristics of Self-Injurious Thoughts and Behaviors (SITBs), among adolescents aged 11-18 admitted, over a two year period, to all the Emergency Departments of a Region of North-eastern Italy through a comprehensive analysis of medical records. A two-step search was performed in the regional ED electronic database. First, we identified the cases that had been clearly diagnosed as SITBs by an Emergency Department physician. Secondly, suspect cases were detected through a keyword search of the database, and the medical records of these cases were hand screened to identify SITBs. The mean annual incidence rate of SITBs was 90 per 100,000 adolescents aged 11-18 years. Events were more frequent in females. Drug poisoning was the most frequently adopted method (54%). In 42% of cases a diagnosis of SITB was not explicitly reported by the physician. In 65% of cases adolescents were discharged within hours of admission. Only 9% of patients started a psychiatric assessment and treatment program during hospital stay. This research confirms the high incidence of SITBs among adolescents and highlights the difficulty in their proper diagnosis and management. Such difficulty is confirmed by the fact that only a few patients, even among those with a clear diagnosis, were sent for psychiatric assessment. Correct identification and management of SITB patients needs to be improved, since SITBs are an important public health problem in adolescence and one of the main risk factors for suicide.
Keywords: Adolescent; Child; Female; Humans; Incidence; Italy; Male; Medical Records; Patient Admission; Retrospective Studies; Self-Injurious Behavior; Sex Factors; Suicidal Ideation; Suicide, Attempted

Alternative functions of the complement protein C1q at embryo implantation site. - Agostinis, Chiara; Tedesco, Francesco; Bulla, Roberta (J Reprod Immunol, 2017)
Complement component C1q is one of the recognition molecules of the complement system which can serve several functions unrelated to complement activation. This molecule is produced at foeto-maternal interface by macrophages as wells as by decidual endothelial cells and invading trophoblast. Foetal trophoblast cells migrating through the decidua in the early stages of pregnancy synthesize and express C1q on their surface, which is actively involved in promoting trophoblast endovascular and interstitial invasion of the decidua. These functions are mediated by two cell surface receptors, gC1qR and α4β1 integrin, which promote trophoblast adhesion and migration through the activation of ERK1/2 MAPKs. C1q mice manifest increased frequency of foetal resorption, reduced foetal weight, and smaller litter size when compared to their wild-type counterparts, suggesting that defective local production of C1q may be involved in pregnancy disorders, such as pre-eclampsia. C1q acts also as a strong angiogenic factor and promotes neovascularization. These studies suggest novel and unexpected roles of this complement component in physiological and pathological pregnancies.
Keywords: Animals; Complement C1q; Decidua; Embryo Implantation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Integrin alpha4beta1; Mice; Mice, Knockout; Neovascularization, Physiologic; Pre-Eclampsia; Pregnancy; Trophoblasts; Vascular Remodeling

Amniocentesis and chorionic villus sampling in HIV-infected pregnant women: a multicentre case series. - Floridia, M; Masuelli, G; Meloni, A; Cetin, I; Tamburrini, E; Cavaliere, A F; Dalzero, S; Sansone, M; Alberico, S; Guerra, B; Spinillo, A; Chiadò Fiorio Tin, M; et al. (BJOG, 2017)
OBJECTIVES: To assess in pregnant women with HIV the rates of amniocentesis and chorionic villus sampling (CVS), and the outcomes associated with such procedures. DESIGN: Observational study. Data from the Italian National Program on Surveillance on Antiretroviral Treatment in Pregnancy were used. SETTING: University and hospital clinics. POPULATION: Pregnant women with HIV. METHODS: Temporal trends were analysed by analysis of variance and by the Chi-square test for trend. Quantitative variables were compared by Student's t-test and categorical data by the Chi-square test, with odds ratios and 95% confidence intervals calculated. MAIN OUTCOME MEASURES: Rate of invasive testing, intrauterine death, HIV transmission. RESULTS: Between 2001 and 2015, among 2065 pregnancies in women with HIV, 113 (5.5%) had invasive tests performed. The procedures were conducted under antiretroviral treatment in 99 cases (87.6%), with a significant increase over time in the proportion of tests performed under highly active antiretroviral therapy (HAART) (100% in 2011-2015). Three intrauterine deaths were observed (2.6%), and 14 pregnancies were terminated because of fetal anomalies. Among 96 live newborns, eight had no information available on HIV status. Among the remaining 88 cases with either amniocentesis (n = 75), CVS (n = 12), or both (n = 1), two HIV transmissions occurred (2.3%). No HIV transmission occurred among the women who were on HAART at the time of invasive testing, and none after 2005. CONCLUSIONS: The findings reinforce the assumption that invasive prenatal testing does not increase the risk of HIV vertical transmission among pregnant women under suppressive antiretroviral treatment. TWEETABLE ABSTRACT: No HIV transmission occurred among women who underwent amniocentesis or CVS under effective anti-HIV regimens.
Keywords: Adult; Amniocentesis; Analysis of Variance; Anti-Retroviral Agents; Chi-Square Distribution; Chorionic Villi Sampling; Female; Fetal Death; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Odds Ratio; Pregnancy; Pregnancy Complications, Infectious

ANCA-associated vasculitis in childhood: recent advances. - Calatroni, Marta; Oliva, Elena; Gianfreda, Davide; Gregorini, Gina; Allinovi, Marco; Ramirez, Giuseppe A; Bozzolo, Enrica P; Monti, Sara; Bracaglia, Claudia; Marucci, Giulia; Bodria, Monica; Sinico, Renato A; et al. (Ital J Pediatr, 2017)
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are rare systemic diseases that usually occur in adulthood. They comprise granulomatosis with polyangiitis (GPA, Wegener's), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). Their clinical presentation is often heterogeneous, with frequent involvement of the respiratory tract, the kidney, the skin and the joints. ANCA-associated vasculitis is rare in childhood but North-American and European cohort studies performed during the last decade have clarified their phenotype, patterns of renal involvement and their prognostic implications, and outcome. Herein, we review the main clinical and therapeutic aspects of childhood-onset ANCA-associated vasculitis, and provide preliminary data on demographic characteristics and organ manifestations of an Italian multicentre cohort.
Keywords: Age Distribution; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Child; Child, Preschool; Churg-Strauss Syndrome; Female; Granulomatosis with Polyangiitis; Humans; Incidence; Male; Microscopic Polyangiitis; Rare Diseases; Risk Assessment; Severity of Illness Index; Sex Distribution; Survival Rate

and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. - Li, Man; Li, Yong; Weeks, Olivia; Mijatovic, Vladan; Teumer, Alexander; Huffman, Jennifer E; Tromp, Gerard; Fuchsberger, Christian; Gorski, Mathias; Lyytikäinen, Leo-Pekka; Nutile, Teresa; Sedaghat, Sanaz; et al. (J Am Soc Nephrol, 2017)
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 ; <3.7×10), 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, (=5.4×10 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

Antibiotic Prophylaxis for Urinary Tract Infection-Related Renal Scarring: A Systematic Review. - Hewitt, Ian K; Pennesi, Marco; Morello, William; Ronfani, Luca; Montini, Giovanni (Pediatrics, 2017)
CONTEXT: Acute pyelonephritis may result in renal scarring. Recent prospective studies have shown a small benefit of antibiotic prophylaxis in preventing symptomatic and febrile urinary tract infections (UTIs), while being underpowered to detect any influence in prevention of renal damage. OBJECTIVES: Review of the literature and a meta-analysis to evaluate the effect of antibiotic prophylaxis on UTI-related renal scarring. DATA SOURCES: Medline, Embase, and Cochrane Controlled Trials Register electronic databases were searched for studies published in any language and bibliographies of identified prospective randomized controlled trials (RCTs) performed and published between 1946 and August 2016. STUDY SELECTION: Subjects 18 years of age or younger with symptomatic or febrile UTIs, enrolled in prospective RCTs of antibiotic prophylaxis where Tc dimercaptosuccinic acid scans were performed at entry into the study and at late follow-up to detect new scar formation. DATA EXTRACTION: The literature search, study characteristics, inclusion and exclusion criteria, and risk of bias assessment were independently evaluated by 2 authors. RESULTS: Seven RCTs (1427 subjects) were included in the meta-analysis. Our results show no influence of antibiotic prophylaxis in preventing renal scarring (pooled risk ratio, 0.83; 95% confidence interval, 0.55-1.26) as did a subanalysis restricted to those subjects with vesicoureteral reflux (pooled risk ratio, 0.79; 95% confidence interval, 0.51-1.24). LIMITATIONS: Limitations include the small number of studies, short duration of follow-up, and insufficient children with high-grade dilating reflux and/or renal dysplasia enrolled in the studies. CONCLUSIONS: Antibiotic prophylaxis is not indicated for the prevention of renal scarring after a first or second symptomatic or febrile UTI in otherwise healthy children.
Keywords: Acute Disease; Antibiotic Prophylaxis; Child; Cicatrix; Humans; Kidney; Pyelonephritis; Urinary Tract Infections

Antiretroviral Treatment in HIV-1-Positive Mothers: Neurological Implications in Virus-Free Children. - Coelho, Antônio Victor Campos; Tricarico, Paola Maura; Celsi, Fulvio; Crovella, Sergio (Int J Mol Sci, 2017)
Since the worldwide introduction of antiretroviral therapy (ART) in human immunodeficiency virus type 1, HIV-1-positive mothers, together with HIV-1 testing prior to pregnancy, caesarian birth and breastfeeding cessation with replacement feeding, a reduction of HIV-1 mother-to-child transmission (MTCT) has been observed in the last few years. As such, an increasing number of children are being exposed in utero to ART. Several questions have arisen concerning the neurological effects of ART exposure in utero, considering the potential effect of antiretroviral drugs on the central nervous system, a structure which is in continuous development in the fetus and characterized by great plasticity. This review aims at discussing the possible neurological impairment of children exposed to ART in utero, focusing attention on the drugs commonly used for HIV-1 MTCT prevention, clinical reports of ART neurotoxicity in children born to HIV-1-positive mothers, and neurologic effects of protease inhibitors (PIs), especially ritonavir-"boosted" lopinavir (LPV/r) in cell and animal central nervous system models evaluating the potential neurotoxic effect of ART. Finally, we present the findings of a meta-analysis to assess the effects on the neurodevelopment of children exposed to ART in utero.
Keywords: Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Disease Management; Disease Models, Animal; Epigenesis, Genetic; Female; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Maternal Exposure; Meta-Analysis as Topic; Mothers; Neurodevelopmental Disorders; Pregnancy; Prenatal Exposure Delayed Effects

Association between thyroid hormones and TRAIL. - Bernardi, Stella; Bossi, Fleur; Toffoli, Barbara; Giudici, Fabiola; Bramante, Alessandra; Furlanis, Giulia; Stenner, Elisabetta; Secchiero, Paola; Zauli, Giorgio; Carretta, Renzo; Fabris, Bruno (Clin Biochem, 2017)
INTRODUCTION: Recent studies suggest that a circulating protein called TRAIL (TNF-related apoptosis-inducing ligand) might have a role in the regulation of body weight and metabolism. Interestingly, thyroid hormones seem to increase TRAIL tissue expression. This study aimed at evaluating whether overt thyroid disorders affected circulating TRAIL levels. METHODS: TRAIL circulating levels were measured in euthyroid, hyperthyroid, and hypothyroid patients before and after thyroid function normalization. Univariate and multivariate analyses were performed to evaluate the correlation between thyroid hormones and TRAIL. Then, the stimulatory effect of both triiodothyronine (T3) and thyroxine (T4) on TRAIL was evaluated in vitro on peripheral blood mononuclear cells. RESULTS: Circulating levels of TRAIL significantly increased in hyperthyroid and decreased in hypothyroid patients as compared to controls. Once thyroid function was restored, TRAIL levels normalized. There was an independent association between TRAIL and both fT3 and fT4. Consistent with these findings, T3 and T4 stimulated TRAIL release in vitro. CONCLUSION: Here we show that thyroid hormones are associated with TRAIL expression in vivo and stimulate TRAIL expression in vitro. Given the overlap between the metabolic effects of thyroid hormones and TRAIL, this work sheds light on the possibility that TRAIL might be one of the molecules mediating thyroid hormones peripheral effects.
Keywords: Aged; Female; Gene Expression Regulation; Humans; Hyperthyroidism; Hypothyroidism; Leukocytes, Mononuclear; Male; Middle Aged; Thyroxine; TNF-Related Apoptosis-Inducing Ligand; Triiodothyronine

Authors' Reply to M.S. Raghuraman: "Intranasal Dexmedetomidine for Procedural Sedation in Children, a Suitable Alternative to Chloral Hydrate". - Cozzi, Giorgio; Norbedo, Stefania; Barbi, Egidio (Paediatr Drugs, 2017)
Keywords: Administration, Intranasal; Child; Chloral Hydrate; Dexmedetomidine; Humans; Hypnotics and Sedatives; Infant

Autoimmune neutropenia of childhood secondary to other autoimmune disorders: Data from the Italian neutropenia registry. - Farruggia, Piero; Puccio, Giuseppe; Fioredda, Francesca; Lanza, Tiziana; Porretti, Laura; Ramenghi, Ugo; Barone, Angelica; Bonanomi, Sonia; Finocchi, Andrea; Ghilardi, Roberta; Ladogana, Saverio; Marra, Nicoletta; et al. (Am J Hematol, 2017)
Keywords: Autoimmune Diseases; Child; Disease Susceptibility; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Italy; Male; Neutropenia; Prevalence; Registries

Avoiding Ethanol Presence in DNA Samples Enhances the Performance of Ultraviolet Resonance Raman Spectroscopy Analysis. - Cammisuli, Francesca; Pascolo, Lorella; Morgutti, Marcello; Gessini, Alessandro; Masciovecchio, Claudio; D'Amico, Francesco (Appl Spectrosc, 2017)
Ethanol is an essential chemical reagent in DNA preparation as its use increases the yield of extraction. All methodologies for DNA isolation involve the use of ethanol in order to prevent DNA dissolution in water and to optimize the binding of DNA to chromatographic membranes. In this note, we show how the presence of ethanol traces in DNA aqueous solution affects ultraviolet Raman spectra, leading to possible misinterpretations. We report a simple method to remove the ethanol Raman features from the spectra, based on heating the DNA sample at 80 ℃, followed by a slow cooling procedure.
Keywords: DNA; Ethanol; Female; Humans; Placenta; Pregnancy; Spectrophotometry, Ultraviolet; Spectrum Analysis, Raman

Bilateral Finger Swelling in an Adolescent. - Naviglio, Samuele; Mazzolai, Michele; Ventura, Alessandro (J Pediatr, 2017)

Bipolar Disorder With Psychotic Features and Ocular Toxoplasmosis: A Possible Pathogenetic Role of the Parasite? - Del Grande, Claudia; Contini, Carlo; Schiavi, Elisa; Rutigliano, Grazia; Maritati, Martina; Seraceni, Silva; Pinto, Barbara; Dell'Osso, Liliana; Bruschi, Fabrizio (J Nerv Ment Dis, 2017)
Recent evidence suggests the involvement of Toxoplasma gondii infection in the emergence of psychotic and affective disorders. In this report, we describe the case of a young Brazilian woman affected by recurrent ocular toxoplasmosis and presenting with a manic episode with psychotic features in the context of a diagnosis of Bipolar Disorder (BD), type I. We observed a relationship between ocular manifestations and the clinical course of bipolar illness, confirmed by molecular analyses (nested-PCR), as well as by the high level of T. gondii specific IgG. This case report is the first showing the presence of circulating parasite DNA at the time of occurrence of psychiatric symptoms, thus providing further support for a possible role of the parasite in the pathogenesis of some cases of BD.
Keywords: Adult; Bipolar Disorder; Brazil; Female; Humans; Toxoplasmosis, Ocular; Young Adult

Bolus feeding has no effect on cerebral hemodynamics, irrespective of gestational age. - Bembich, Stefano; Cont, Gabriele; Bua, Jenny; Orlando, Chiara; Di Benedetto, Donatella; Demarini, Sergio (J Matern Fetal Neonatal Med, 2017)
OBJECTIVE: By multichannel near-infrared spectroscopy, we studied if gestational age has any influence on preterm cerebral hemodynamics, during bolus feeding. METHODS: Oxy-haemoglobin (HbO), as cerebral blood flow estimate, and the ratio between HbO and total haemoglobin (HbO/HbTot), as cerebral oxygenation estimate, were assessed in 40 stable premature infants, during a 10 min bolus feeding. RESULTS: We found no effect of any of the gestational ages studied (25-34 weeks) either on cerebral blood flow or on oxygenation, during a bolus feeding procedure. CONCLUSIONS: Bolus feeding appears not to affect cerebral hemodynamics of uncritically preterm infants, irrespective of gestational age.
Keywords: Cerebrovascular Circulation; Enteral Nutrition; Female; Gestational Age; Heart Rate; Humans; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Male; Oxygen; Oxyhemoglobins; Spectroscopy, Near-Infrared

A boy with fever and arthralgia. - Poropat, Federico; Pastore, Serena; Gesuete, Valentina; Barbi, Egidio (BMJ, 2017)
Keywords: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Bacterial; Aortic Valve Insufficiency; Arthralgia; Child; Echocardiography; Echocardiography, Doppler, Color; Fever; Humans; Male; Mitral Valve Insufficiency; Rheumatic Fever; Rheumatic Heart Disease; Streptolysins

Cardiac output decreases and systemic vascular resistance increases in newborns placed in the left-lateral position. - Paviotti, G; Todero, S; Demarini, S (J Perinatol, 2017)
OBJECTIVE: The objective of the study was to study the effect of short-term left-lateral position on cardiovascular parameters in hemodynamically stable newborns. STUDY DESIGN: Cardiac output (CO), stroke volume (SV), systemic vascular resistance index (SVRI) and heart rate (HR) were measured by electric velocimetry in hemodynamically stable newborns without respiratory support in the supine, left-lateral and back-to-supine positions, each kept for 10 min. RESULTS: Thirty-two newborns were enrolled, birth weight 2134 (1818 to 2460) g, gestational age 34.5±2.4 weeks. CO and SV decreased significantly from supine to left-lateral position (CO supine: 193.4 (168.0 to 229.6) ml kgmin; CO left-lateral: 172.0 (154.9 to 201.6) ml kgmin, P<0.0001; SV supine: 3.0 (2.7 to 4.0) ml; SV left-lateral: 2.7 (2.4 to 3.2) ml, P<0.0004). Conversely, SVRI increased in left-lateral position: SVRI supine: 18865±9244 dyns cm m; SVRI left-lateral: 21203±10059 dyns cm m, P<0.0001). All variables returned to the initial value when infants were back in the supine position. HR and blood pressure did not change. CONCLUSION: In stable infants, CO and SV decrease and SVRI increases, in left-lateral position.
Keywords: Blood Pressure; Cardiac Output; Female; Gestational Age; Heart Rate; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Italy; Male; Posture; Stroke Volume; Vascular Resistance

CCR5Δ32 and the genetic susceptibility to rheumatoid arthritis in admixed populations: a multicentre study. - Toson, Bruno; Dos Santos, Eduardo José; Adelino, José Eduardo; Sandrin-Garcia, Paula; Crovella, Sergio; Louzada-Júnior, Paulo; Oliveira, Renê Donizete Ribeiro; Pedroza, Larysse Santa Rosa Aquino; de Fátima Lobato Cunha Sauma, Maria; de Lima, Clayton Pereira Silva; Barbosa, Fabiola Brasil; Brenol, Claiton Viegas; et al. (Rheumatology (Oxford), 2017)
Keywords: Arthritis, Rheumatoid; Brazil; Case-Control Studies; Consanguinity; Gene Frequency; Genetic Predisposition to Disease; Humans; Polymorphism, Single Nucleotide; Receptors, CCR5

Cervical stitch (cerclage) for preventing preterm birth in singleton pregnancy. - Alfirevic, Zarko; Stampalija, Tamara; Medley, Nancy (Cochrane Database Syst Rev, 2017)
BACKGROUND: Cervical cerclage is a well-known surgical procedure carried out during pregnancy. It involves positioning of a suture (stitch) around the neck of the womb (cervix), aiming to give mechanical support to the cervix and thereby reduce risk of preterm birth. The effectiveness and safety of this procedure remains controversial. This is an update of a review last published in 2012. OBJECTIVES: To assess whether the use of cervical stitch in singleton pregnancy at high risk of pregnancy loss based on woman's history and/or ultrasound finding of 'short cervix' and/or physical exam improves subsequent obstetric care and fetal outcome. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (30 June 2016) and reference lists of identified studies. SELECTION CRITERIA: We included all randomised trials of cervical suturing in singleton pregnancies. Cervical stitch was carried out when the pregnancy was considered to be of sufficiently high risk due to a woman's history, a finding of short cervix on ultrasound or other indication determined by physical exam. We included any study that compared cerclage with either no treatment or any alternative intervention. We planned to include cluster-randomised studies but not cross-over trials. We excluded quasi-randomised studies. We included studies reported in abstract form only. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion. Two review authors independently assessed risk of bias and extracted data. We resolved discrepancies by discussion. Data were checked for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: This updated review includes a total of 15 trials (3490 women); three trials were added for this update (152 women). Cerclage versus no cerclageOverall, cerclage probably leads to a reduced risk of perinatal death when compared with no cerclage, although the confidence interval (CI) crosses the line of no effect (RR 0.82, 95% CI 0.65 to 1.04; 10 studies, 2927 women; moderate quality evidence). Considering stillbirths and neonatal deaths separately reduced the numbers of events and sample size. Although the relative effect of cerclage is similar, estimates were less reliable with fewer data and assessed as of low quality (stillbirths RR 0.89, 95% CI 0.45 to 1.75; 5 studies, 1803 women; low quality evidence; neonatal deaths before discharge RR 0.85, 95% CI 0.53 to 1.39; 6 studies, 1714 women; low quality evidence). Serious neonatal morbidity was similar with and without cerclage (RR 0.80, 95% CI 0.55 to 1.18; 6 studies, 883 women; low-quality evidence). Pregnant women with and without cerclage were equally likely to have a baby discharged home healthy (RR 1.02, 95% CI 0.97 to 1.06; 4 studies, 657 women; moderate quality evidence).Pregnant women with cerclage were less likely to have preterm births compared to controls before 37, 34 (average RR 0.77, 95% CI 0.66 to 0.89; 9 studies, 2415 women; high quality evidence) and 28 completed weeks of gestation.Five subgroups based on clinical indication provided data for analysis (history-indicated; short cervix based on one-off ultrasound in high risk women; short cervix found by serial scans in high risk women; physical exam-indicated; and short cervix found on scan in low risk or mixed populations). There were too few trials in these clinical subgroups to make meaningful conclusions and no evidence of differential effects. Cerclage versus progesteroneTwo trials (129 women) compared cerclage to prevention with vaginal progesterone in high risk women with short cervix on ultrasound; these trials were too small to detect reliable, clinically important differences for any review outcome. One included trial compared cerclage with intramuscular progesterone (75 women) which lacked power to detect group differences. History indicated cerclage versus ultrasound indicated cerclageEvidence from two trials (344 women) was too limited to establish differences for clinically important outcomes. AUTHORS' CONCLUSIONS: Cervical cerclage reduces the risk of preterm birth in women at high-risk of preterm birth and probably reduces risk of perinatal deaths. There was no evidence of any differential effect of cerclage based on previous obstetric history or short cervix indications, but data were limited for all clinical groups. The question of whether cerclage is more or less effective than other preventative treatments, particularly vaginal progesterone, remains unanswered.
Keywords: Administration, Intravaginal; Cerclage, Cervical; Cesarean Section; Female; Humans; Injections, Intramuscular; Perinatal Death; Pregnancy; Premature Birth; Progesterone; Randomized Controlled Trials as Topic; Stillbirth; Suture Techniques

Child and Adolescent Health From 1990 to 2015: Findings From the Global Burden of Diseases, Injuries, and Risk Factors 2015 Study. - Kassebaum, Nicholas; Kyu, Hmwe Hmwe; Zoeckler, Leo; Olsen, Helen Elizabeth; Thomas, Katie; Pinho, Christine; Bhutta, Zulfiqar A; Dandona, Lalit; Ferrari, Alize; Ghiwot, Tsegaye Tewelde; Hay, Simon I; Kinfu, Yohannes; et al. (JAMA Pediatr, 2017)
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

Children with cancer: a survey on the experience of Italian primary care pediatricians. - Minute, Marta; Cozzi, Giorgio; Plotti, Chiara; Montanari, Giuseppe; Pecile, Paolo; Zanazzo, Giulio Andrea; Ventura, Alessandro; Barbi, Egidio (Ital J Pediatr, 2017)
BACKGROUND: Cancer is the second cause of death in children and its diagnosis can be difficult, due to the presence of vague and non-specific symptoms. The primary care pediatrician is often involved in the diagnostic process, but no longer in child care once the treatment started. Care models involving both primary care pediatricians and oncologic referral centre highlighted a higher family satisfaction when they worked together. We conducted a survey on primary care pediatricians involved in childhood cancer in order to describe the actual situation. METHODS: We conducted a retrospective survey enrolling primary care pediatricians from a north-eastern area of Italy. They received a questionnaire that consisted in two parts: the first one aimed to assess the physician's seniority and experience and the second one pertained to each case of cancer and explored the relationship between the pediatrician, the family and the referral centre, and pediatricians degree of satisfaction and emotional impact. RESULTS: We obtained data from 79 pediatricians who described 150 cancer cases. In 99 cases the primary care pediatrician had visited the child at the onset of symptoms and had referred him to the hospital. In 89 cases, he understood the severity of the disease. In 53.3% of cases the pediatrician was informed by the referral centre. The relationship between the pediatrician and child's family improved in 38% of cases and this was related with their participation to the multidisciplinary meetings on child health. CONCLUSIONS: Primary pediatricians' sharing in the management of their patients with cancer was not satisfactory. Development of specific protocols targeted to an integrated care is needed to increase primary pediatricians' involvement and families' satisfactions.
Keywords: Child; Child, Preschool; Cross-Sectional Studies; Disease-Free Survival; Female; Humans; Italy; Male; Needs Assessment; Neoplasms; Outcome Assessment (Health Care); Pediatricians; Practice Patterns, Physicians'; Prevalence; Primary Health Care; Retrospective Studies; Risk Assessment; Survival Analysis

Circulating osteoprotegerin is associated with chronic kidney disease in hypertensive patients. - Bernardi, Stella; Toffoli, Barbara; Bossi, Fleur; Candido, Riccardo; Stenner, Elisabetta; Carretta, Renzo; Barbone, Fabio; Fabris, Bruno (BMC Nephrol, 2017)
BACKGROUND: Osteoprotegerin (OPG) is a glycoprotein that plays an important regulatory role in the skeletal, vascular, and immune system. It has been shown that OPG predicts chronic kidney disease (CKD) in diabetic patients. We hypothesized that OPG could be a risk marker of CKD development also in non-diabetic hypertensive patients. METHODS: A case-control study was carried out to measure circulating OPG levels in 42 hypertensive patients with CKD and in 141 hypertensive patients without CKD. A potential relationship between OPG and the presence of CKD was investigated and a receiver-operating characteristic (ROC) curve was designed thereafter to identify a cut-off value of OPG that best explained the presence of CKD. Secondly, to evaluate whether OPG increase could affect the kidney, 18 C57BL/6J mice were randomized to be treated with saline or recombinant OPG every 3 weeks for 12 weeks. RESULTS: Circulating OPG levels were significantly higher in hypertensive patients with CKD, and there was a significant inverse association between OPG and renal function, that was independent from other variables. ROC analysis showed that OPG levels had a high statistically predictive value on CKD in hypertensive patients, which was greater than that of hypertension. The OPG best cut-off value associated with CKD was 1109.19 ng/L. In the experimental study, OPG delivery significantly increased the gene expression of pro-inflammatory and pro-fibrotic mediators, as well as the glomerular nitrosylation of proteins. CONCLUSIONS: This study shows that OPG is associated with CKD in hypertensive patients, where it might have a higher predictive value than that of hypertension for CKD development. Secondly, we found that OPG delivery significantly increased the expression of molecular pathways involved in kidney damage. Further longitudinal studies are needed not only to evaluate whether OPG predicts CKD development but also to clarify whether OPG should be considered a risk factor for CKD.
Keywords: Aged; Animals; Biomarkers; Case-Control Studies; Female; Follow-Up Studies; Humans; Hypertension; Male; Mice; Mice, Inbred C57BL; Middle Aged; Osteoprotegerin; Random Allocation; Renal Insufficiency, Chronic

Climate change, emerging infections and blood donations. - Cegolon, L; Heymann, W C; Lange, J H (J Travel Med, 2017)
Keywords: Blood Transfusion; Climate Change; Communicable Diseases, Emerging; Global Health; Humans; Travel

[Clinical and molecular study in a family with autosomal dominant hypohidrotic ectodermal dysplasia]. - Callea, Michele; Cammarata-Scalisi, Francisco; Willoughby, Colin E; Giglio, Sabrina R; Sani, Ilaria; Bargiacchi, Sara; Traficante, Giovanna; Bellacchio, Emanuele; Tadini, Gianluca; Yavuz, Izzet; Galeotti, Angela; Clarich, Gabriella (Arch Argent Pediatr, 2017)
Hypohidrotic ectodermal dysplasia (HED) is a rare disease characterized by deficiency in development of structure derived from the ectoderm and is caused by mutations in the genes EDA, EDAR, or EDARADD. Phenotypes caused by mutations in these three may exhibit similar clinical features, explained by a common signaling pathway. Mutations in EDA gene cause X linked HED, which is the most common form. Mutations in EDAR and EDARADD genes cause autosomal dominant and recessive form of HED. The most striking clinical findings in HED are hypodontia, hypotrichosis and hypohidrosis that can lead to episodes of hyperthermia. We report on clinical findings in a child with HED with autosomal dominant inheritance pattern with a heterozygous mutation c.1072C>T (p.Arg358X) in the EDAR gene. A review of the literature with regard to other cases presenting the same mutation has been carried out and discussed.
Keywords: Child, Preschool; Ectodermal Dysplasia 1, Anhidrotic; Edar Receptor; Humans; Male; Mutation; Pedigree

Combined use of AFM and soft X-ray microscopy to reveal fibres' internalization in mesothelial cells. - Gianoncelli, Alessandra; Kourousias, George; Cammisuli, Francesca; Cassese, Damiano; Rizzardi, Clara; Radillo, Oriano; Lazzarino, Marco; Pascolo, Lorella (Analyst, 2017)
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

Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine. - Corre, Tanguy; Olinger, Eric; Harris, Sarah E; Traglia, Michela; Ulivi, Sheila; Lenarduzzi, Stefania; Belge, Hendrica; Youhanna, Sonia; Tokonami, Natsuko; Bonny, Olivier; Houillier, Pascal; Polasek, Ozren; et al. (Pflugers Arch, 2017)
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 × 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

Comparison of Efficacy and Safety of Caspofungin Versus Micafungin in Pediatric Allogeneic Stem Cell Transplant Recipients: A Retrospective Analysis. - Maximova, Natalia; Schillani, Giulia; Simeone, Roberto; Maestro, Alessandra; Zanon, Davide (Adv Ther, 2017)
INTRODUCTION: The high morbidity and mortality associated with invasive fungal infections (IFIs) provide the rationale for antifungal prophylaxis in immuno-compromised pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Caspofungin and micafungin are antifungal agents of interest for prophylaxis of IFIs because of their potency against Candida and minimal toxicity or interactions with other drugs. Few studies have demonstrated the safety and efficacy of such echinocandins as prophylaxis for IFIs in patients undergoing HSCT. METHODS: This retrospective cohort study compared caspofungin and micafungin for prevention of IFIs in 93 pediatric patients undergoing HSCT for oncological or non-oncological disease. The observation began with the first dose of antifungal agent and ended 3 months after transplantation. RESULTS: Patients in the micafungin group had a higher overall treatment success rate of 87.2 versus 84.8% in the caspofungin group, but the difference was not significant. There were no statistically significant differences in the incidence or type of proven/probable IFIs between the 2 groups. The low incidence of death did not differ statistically between the groups. Patients in the caspofungin group presented more frequently with fever, during and after neutropenia. In both groups, we observed an expected worsening of blood chemistry parameters. There were no adverse events definitely attributable to the two antifungal agents. CONCLUSION: These results demonstrate good efficacy and tolerability for caspofungin and micafungin. However, better results with respect to the incidence and resolution of fever in the micafungin group may suggest its use in preference to that of caspofungin.
Keywords: Adolescent; Antifungal Agents; Caspofungin; Child; Child, Preschool; Cohort Studies; Echinocandins; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Lipopeptides; Male; Micafungin; Mycoses; Neutropenia; Retrospective Studies

Complement Protein C1q Binds to Hyaluronic Acid in the Malignant Pleural Mesothelioma Microenvironment and Promotes Tumor Growth. - Agostinis, Chiara; Vidergar, Romana; Belmonte, Beatrice; Mangogna, Alessandro; Amadio, Leonardo; Geri, Pietro; Borelli, Violetta; Zanconati, Fabrizio; Tedesco, Francesco; Confalonieri, Marco; Tripodo, Claudio; Kishore, Uday; et al. (Front Immunol, 2017)
C1q is the first recognition subcomponent of the complement classical pathway, which acts toward the clearance of pathogens and apoptotic cells. C1q is also known to modulate a range of functions of immune and non-immune cells, and has been shown to be involved in placental development and sensorial synaptic pruning. We have recently shown that C1q can promote tumor by encouraging their adhesion, migration, and proliferation in addition to angiogenesis and metastasis. In this study, we have examined the role of human C1q in the microenvironment of malignant pleural mesothelioma (MPM), a rare form of cancer commonly associated with exposure to asbestos. We found that C1q was highly expressed in all MPM histotypes, particularly in epithelioid rather than in sarcomatoid histotype. C1q avidly bound high and low molecular weight hyaluronic acid (HA) its globular domain. C1q bound to HA was able to induce adhesion and proliferation of mesothelioma cells (MES) enhancement of ERK1/2, SAPK/JNK, and p38 phosphorylation; however, it did not activate the complement cascade. Consistent with the modular organization of the globular domain, we demonstrated that C1q may bind to HA through ghA module, whereas it may interact with human MES through the ghC. In conclusion, C1q highly expressed in MPM binds to HA and enhances the tumor growth promoting cell adhesion and proliferation. These data can help develop novel diagnostic markers and molecular targets for MPM.

A complete duplication of X chromosome resulting in a tricentric isochromosome originated by centromere repositioning. - Villa, N; Conconi, D; Benussi, D Gambel; Tornese, G; Crosti, F; Sala, E; Dalprà, L; Pecile, V (Mol Cytogenet, 2017)
BACKGROUND: Neocentromeres are rare and considered chromosomal aberrations, because a non-centromeric region evolves in an active centromere by mutation. The literature reported several structural anomalies of X chromosome and they influence the female reproductive capacity or are associated to Turner syndrome in the presence of monosomy X cell line. CASE PRESENTATION: We report a case of chromosome X complex rearrangement found in a prenatal diagnosis. The fetal karyotype showed a mosaicism with a 45,X cell line and a 46 chromosomes second line with a big marker, instead of a sex chromosome. The marker morphology and fluorescence in situ hybridization (FISH) characterization allowed us to identify a tricentric X chromosome constituted by two complete X chromosome fused at the p arms telomere and an active neocentromere in the middle, at the union of the two Xp arms, where usually are the telomeric regions. FISH also showed the presence of a paracentric inversion of both Xp arms. Furthermore, fragility figures were found in 56% of metaphases from peripheral blood lymphocytes culture at birth: a shorter marker chromosome and an apparently acentric fragment frequently lost. CONCLUSIONS: At our knowledge, this is the first isochromosome of an entire non-acrocentric chromosome. The neocentromere is constituted by canonical sequences but localized in an unusual position and the original centromeres are inactivated. We speculated that marker chromosome was the result of a double rearrangement: firstly, a paracentric inversion which involved the Xp arm, shifting a part of the centromere at the p end and subsequently a duplication of the entire X chromosome, which gave rise to an isochromosome. It is possible to suppose that the first event could be a result of a non-allelic homologous recombination mediated by inverted low-copy repeats. As expected, our case shows a Turner phenotype with mild facial features and no major skeletal deformity, normal psychomotor development and a spontaneous development of puberty and menarche, although with irregular menses since the last follow-up.

A congenital purplish tumour. - Matarazzo, L; Delise, A; Zennaro, F; Bussani, R; Demarini, S; Berti, I; Ventura, A (Arch Dis Child Educ Pract Ed, 2017)
Keywords: Congenital Abnormalities; Humans; India; Infant; Infant, Newborn; Knee; Male; Neonatology; Neoplasms; Treatment Outcome

Cubosomes for in vivo fluorescence lifetime imaging. - Biffi, Stefania; Andolfi, Laura; Caltagirone, Claudia; Garrovo, Chiara; Falchi, Angela M; Lippolis, Vito; Lorenzon, Andrea; Macor, Paolo; Meli, Valeria; Monduzzi, Maura; Obiols-Rabasa, Marc; Petrizza, Luca; et al. (Nanotechnology, 2017)
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

Curcumin Anti-Apoptotic Action in a Model of Intestinal Epithelial Inflammatory Damage. - Loganes, Claudia; Lega, Sara; Bramuzzo, Matteo; Vecchi Brumatti, Liza; Piscianz, Elisa; Valencic, Erica; Tommasini, Alberto; Marcuzzi, Annalisa (Nutrients, 2017)
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

CYP3A genes and the association between prenatal methylmercury exposure and neurodevelopment. - Llop, Sabrina; Tran, Van; Ballester, Ferran; Barbone, Fabio; Sofianou-Katsoulis, Aikaterini; Sunyer, Jordi; Engström, Karin; Alhamdow, Ayman; Love, Tanzy M; Watson, Gene E; Bustamante, Mariona; Murcia, Mario; et al. (Environ Int, 2017)
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

DEFB1 polymorphisms and salivary hBD-1 concentration in Oral Lichen Planus patients and healthy subjects. - Polesello, Vania; Zupin, Luisa; Di Lenarda, Roberto; Biasotto, Matteo; Pozzato, Gabriele; Ottaviani, Giulia; Gobbo, Margherita; Crovella, Sergio; Segat, Ludovica (Arch Oral Biol, 2017)
OBJECTIVES: The aetiology of Oral Lichen Planus (OLP), a chronic inflammatory disease of oral mucosa, is not yet well understood. Since innate immunity may be hypothesized as involved in the susceptibility to OLP, we studied human beta defensin 1 (hBD-1) an antimicrobial peptide constitutively expressed in the saliva, looking at functional genetic variants possibly able to diminish hBD-1 production an consequently conferring major susceptibility to OLP. DESIGN: We analysed three DEFB1 polymorphisms at 5' UTR, -52G>A (rs1799946), -44C>G (rs1800972), -20G>A (rs11362) and two DEFB1 polymorphisms at 3'UTR, c*5G>A (rs1047031), c*87A>G (rs1800971), with the aim of correlating these genetic variants and hBD-1 salivary level in a group of OLP patients and in healthy subjects. We also evaluated hBD-1 salivary concentrations, using ELISA, in OLP and healthy controls. RESULTS: We compared hBD-1 concentrations in OLP and healthy subjects: hBD-1 concentration was significantly higher in OLP patients respect to control. When considering the correlation between DEFB1 polymorphisms genotypes and hBD-1 expression levels, significant results were obtained for SNPs -52G>A (p=0.03 both in OLP patients and healthy individuals) and -44C>G (p=0.02 in OLP patients). CONCLUSIONS: hBD-1 production was different between OLP and healthy subjects (not age-matched with OLP). DEFB1 gene polymorphisms, -52G>A and -44C>G, correlated with hBD-1 salivary concentrations.
Keywords: 5' Untranslated Regions; Adult; Aged; Aged, 80 and over; beta-Defensins; Female; Genetic Predisposition to Disease; Genotype; Humans; Lichen Planus, Oral; Male; Middle Aged; Polymorphism, Single Nucleotide; Saliva; Sequence Analysis, DNA

Defects in mitochondrial energetic function compels Fanconi Anaemia cells to glycolytic metabolism. - Cappelli, Enrico; Cuccarolo, Paola; Stroppiana, Giorgia; Miano, Maurizio; Bottega, Roberta; Cossu, Vanessa; Degan, Paolo; Ravera, Silvia (Biochim Biophys Acta Mol Basis Dis, 2017)
Energetic metabolism plays an essential role in the differentiation of haematopoietic stem cells (HSC). In Fanconi Anaemia (FA), DNA damage is accumulated during HSC differentiation, an event that is likely associated with bone marrow failure (BMF). One of the sources of the DNA damage is altered mitochondrial metabolism and an associated increment of oxidative stress. Recently, altered mitochondrial morphology and a deficit in the energetic activity in FA cells have been reported. Considering that mitochondria are the principal site of aerobic ATP production, we investigated FA metabolism in order to understand what pathways are able to compensate for this energy deficiency. In this work, we report that the impairment in mitochondrial oxidative phosphorylation (OXPHOS) in FA cells is countered by an increase in glycolytic flux. By contrast, glutaminolysis appears lower with respect to controls. Therefore, it is possible to conclude that in FA cells glycolysis represents the main pathway for producing energy, balancing the NADH/NAD ratio by the conversion of pyruvate to lactate. Finally, we show that a forced switch from glycolytic to OXPHOS metabolism increases FA cell oxidative stress. This could be the cause of the impoverishment in bone marrow HSC during exit from the homeostatic quiescent state. This is the first work that systematically explores FA energy metabolism, highlighting its flaws, and discusses the possible relationships between these defects and BMF.
Keywords: Cell Line; Fanconi Anemia; Glycolysis; Humans; Mitochondria; Oxidative Phosphorylation; Oxidative Stress

Describing Kawasaki shock syndrome: results from a retrospective study and literature review. - Taddio, Andrea; Rossi, Eleonora Dei; Monasta, Lorenzo; Pastore, Serena; Tommasini, Alberto; Lepore, Loredana; Bronzetti, Gabriele; Marrani, Edoardo; Mottolese, Biancamaria D'Agata; Simonini, Gabriele; Cimaz, Rolando; Ventura, Alessandro (Clin Rheumatol, 2017)
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

Diagnosis and management of newly diagnosed childhood autoimmune haemolytic anaemia. Recommendations from the Red Cell Study Group of the Paediatric Haemato-Oncology Italian Association. - Ladogana, Saverio; Maruzzi, Matteo; Samperi, Piera; Perrotta, Silverio; Del Vecchio, Giovanni C; Notarangelo, Lucia D; Farruggia, Piero; Verzegnassi, Federico; Masera, Nicoletta; Saracco, Paola; Fasoli, Silvia; Miano, Maurizio; et al. (Blood Transfus, 2017)
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

Dynamic quadripolar radiofrequency treatment of vaginal laxity/menopausal vulvo-vaginal atrophy: 12-month efficacy and safety. - Vicariotto, Franco; De Seta, Francesco; Faoro, Valentina; Raichi, Mauro (Minerva Ginecol, 2017)
BACKGROUND: Twelve-month extension of a previous spontaneous exploratory study investigating safety and efficacy of a new low-energy dynamic quadripolar radiofrequency (DQRF) device in: A) premenopausal women with symptoms of vaginal laxity, with special reference to dysuria, urinary incontinence and unsatisfactory sexual life (vaginal laxity arm of the study); B) postmenopausal women with vulvovaginal atrophy/genitourinary syndrome of menopause (VVA/GSM) and VVA/GSM-related symptoms (VVA/GSM arm of the study). DQRF treatment schedule in both study arms: 4 to 6 procedures of 15 to 20 min every 14 days (vaginal laxity, range 12-17 days; VVA/GSM, range 13-16). Operative temperatures in vaginal target tissues during procedure: vaginal laxity, 42 °C (range 40-43 °C); VVA/GSM, 40 °C (range 40-42 °C). METHODS: In the vaginal laxity arm of the study, 25 women with subjective sensation of vaginal introital laxity (very to slightly loose). Assessment of urinary incontinence, satisfaction with sexual relationship and contribution of pelvic organ prolapse: Vaginal Laxity Questionnaire (VLQ, Italian certified translation) and short form of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12, Italian certified translation). Further evaluation of sexual gratification: Sexual Satisfaction Questionnaire (SSQ). In the VVA/GSM arm of the study, 32 women with objective evidence of VVA and vaginal dryness and/or dyspareunia as most bothersome symptoms. Assessment of VVA/GSM symptoms and overall satisfaction with sexual life: specifically designed 10-cm visual analogue scales. RESULTS: All 4 to 6 planned DQRF sessions were well tolerated in both the vaginal laxity and VVA/GSM arms of the study, with no troubling pain, thermal injury or other immediate adverse effects during all the procedures. All screened women completed the planned DQRF treatment sessions in both arms of the extension study. There was no participant attrition with only a few occasionally missing visits over the 12-month follow-up period. Improvements were rapid in self-perception of introital looseness and related symptoms like dysuria/urinary incontinence and unrewarding sexual relationship (vaginal laxity patients) and atrophy-related symptoms including painful and unsatisfactory sexual activity (VVA/GSM patients). Participating women consistently reported wide-spectrum strong clinical improvements by the end of the planned DQRF sessions. Clinical improvements remained steady for the whole follow-up period in postmenopausal women; a statistically non-significant tendency to slight deterioration in VLQ, PISQ-12 and SSQ mean scores was detected after 6 to 9 months of follow-up in the vaginal laxity arm of the study. CONCLUSIONS: Safety was excellent during all DQRF procedures and over the 12 months following the end of the treatment sessions. VLQ, PISQ-12 and SSQ scores (women with vaginal laxity), VAS self-evaluation of VVA/GSM symptoms and overall satisfaction with sexual life (women with VVA/GSM symptoms) improved rapidly, reaching almost normal levels by the last DQRF session and suggesting rapid, but also persistent, vaginal rejuvenation in both indications. A late tendency to some slight deterioration in women treated for vaginal laxity suggests such women might benefit from new DQRF treatments 6 to 9 months after the previous cycle.
Keywords: Adult; Atrophy; Dyspareunia; Electric Stimulation Therapy; Female; Follow-Up Studies; Humans; Italy; Middle Aged; Orgasm; Patient Satisfaction; Pelvic Organ Prolapse; Postmenopause; Premenopause; Sexual Behavior; Surveys and Questionnaires; Time Factors; Treatment Outcome; Urinary Incontinence; Vagina; Vaginal Diseases; Vulva

Early-life nutritional exposures and lifelong health: immediate and long-lasting impacts of probiotics, vitamin D, and breastfeeding. - Berti, Cristiana; Agostoni, Carlo; Davanzo, Riccardo; Hyppönen, Elina; Isolauri, Erika; Meltzer, Helle M; Steegers-Theunissen, Régine P M; Cetin, Irene (Nutr Rev, 2017)
Pregnancy and infancy comprise the most critical stages for conditioning an individual's health, with a number of implications for subsequent risks of morbidity, mortality, and reproductive health. Nutrition may influence both the overall pregnancy outcome and the growth trajectory and immune system of the fetus and infant, with short- and long-term effects on the health of the offspring. Within this context, leading experts at Expo Milano 2015 in Milan, Italy, discussed up-to-date knowledge while providing suggestions and challenges before, during, and after pregnancy. This narrative review summarizes the key issues raised by the experts concerning the interplay between the nutritional environment from conception to early infancy and the offspring's immediate and lifelong health, with a particular focus on epigenetic mechanisms, probiotics, vitamin D, and breastfeeding. Taken together, the findings strengthen the awareness that nutritional exposures occurring from preconception to the postnatal period may be strong determinants of the offspring's health and may provide supportive evidence for current nutritional recommendations and guidelines for pregnant women and infants. Critical topics to be addressed in future research and translated into recommendations of public health relevance are also highlighted.
Keywords: Breast Feeding; Diet; Female; Humans; Infant; Infant Nutritional Physiological Phenomena; Meta-Analysis as Topic; Nutritional Status; Pregnancy; Pregnancy Outcome; Probiotics; Vitamin D

Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations. - Xue, Yali; Mezzavilla, Massimo; Haber, Marc; McCarthy, Shane; Chen, Yuan; Narasimhan, Vagheesh; Gilly, Arthur; Ayub, Qasim; Colonna, Vincenza; Southam, Lorraine; Finan, Christopher; Massaia, Andrea; et al. (Nat Commun, 2017)
The genetic features of isolated populations can boost power in complex-trait association studies, and an in-depth understanding of how their genetic variation has been shaped by their demographic history can help leverage these advantageous characteristics. Here, we perform a comprehensive investigation using 3,059 newly generated low-depth whole-genome sequences from eight European isolates and two matched general populations, together with published data from the 1000 Genomes Project and UK10K. Sequencing data give deeper and richer insights into population demography and genetic characteristics than genotype-chip data, distinguishing related populations more effectively and allowing their functional variants to be studied more fully. We demonstrate relaxation of purifying selection in the isolates, leading to enrichment of rare and low-frequency functional variants, using novel statistics, DVxy and SVxy. We also develop an isolation-index (Isx) that predicts the overall level of such key genetic characteristics and can thus help guide population choice in future complex-trait association studies.
Keywords: European Continental Ancestry Group; Gene Frequency; Genetic Variation; Genetics, Population; Genome, Human; Humans; Polymorphism, Single Nucleotide; Whole Genome Sequencing

Epratuzumab and Blinatumomab as Therapeutic Antibodies for Treatment of Pediatric Acute Lymphoblastic Leukemia: Current Status and Future Perspectives. - Franca, Raffaella; Favretto, Diego; Granzotto, Marilena; Decorti, Giuliana; Rabusin, Marco; Stocco, Gabriele (Curr Med Chem, 2017)
BACKGROUND: More than 85% of children affected by acute lymphoblastic leukemia (ALL) are successfully treated; however relapse remains a remarkable clinical concern, with 50-60% of relapsing patients facing a fatal outcome. Management of relapsed patients includes standardized intensive risk-adapted regimens based on conventional drugs, and hematopoietic stem cells transplantation for patients with unfavourable features. Biological drugs, in particular the monoclonal antibody epratuzumab and the bi-functional recombinant single chain peptide blinatumomab, have been recently recognized as novel potential agents to be integrated in salvage ALL therapy to further improve rescue outcome. METHODS: A systematic search of peer-reviewed scientific literature and clinical trials in public databases has been carried out. Both clinical and pre-clinical studies have been included to summarize recent evidence on epratuzumab and blinatumomab for salvage ALL therapy. RESULTS: Sixty-two papers and 25 clinical trials were included. Although not all patients responded properly to these agents, their use in relapsed and refractory pediatric ALL seems promising. CONCLUSION: Phase 3 studies have recently begun and more consistent results about epratuzumab and blinatumomab safety and efficacy in comparison to conventional therapies are expected in the next years. Epratuzumab seems safe in the dosing scheme proposed in ALL, but its efficacy over the conventional chemotherapy is still questionable. Blinatumomab has shown promising results in high risk cases such as elder adult patients and conclusive studies on pediatric ALL are needed. Patient inter-individual variability to these agents has not been investigated in depth, but this issue needs to be addressed, in particular for blinatumomab.
Keywords: Antibodies, Bispecific; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Child; Clinical Trials as Topic; Half-Life; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sialic Acid Binding Ig-like Lectin 2

Essure Permanent Birth Control, Effectiveness and Safety: An Italian 11-Year Survey. - Franchini, Mario; Zizolfi, Brunella; Coppola, Carmela; Bergamini, Valentino; Bonin, Cecilia; Borsellino, Giovanni; Busato, Enrico; Calabrese, Stefania; Calzolari, Stefano; Fantin, Gian Piero; Giarrè, Giovanna; Litta, Piero; et al. (J Minim Invasive Gynecol, 2017)
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

Extent, Time Course, and Moderators of Antipsychotic Treatment in Youth With Mood Disorders: Results of a Meta-Analysis and Meta-Regression Analyses. - Cervesi, Chiara; Park, Su Young; Galling, Britta; Molteni, Silvia; Masi, Gabriele; Gerhard, Tobias; Olfson, Mark; Correll, Christoph U (J Clin Psychiatry, 2017)
OBJECTIVE: To meta-analytically examine the trends and correlates of antipsychotic use in youth with mood disorders. METHODS: Systematic literature search without language restriction in PubMed/MEDLINE/PsycINFO from database inception through March 2015 using the following search terms: (antipsychotic* OR neuroleptic* OR "dopamine blocker*" OR antidopaminergic) AND (child* OR adolescen* OR pediatric OR youth) AND (prescription* OR prescrib* OR use OR utilization OR database OR pharmacoepidemiolog* OR frequency OR rate OR rates). Random effects meta-analysis and meta-regression analyses were conducted. STUDY SELECTION: Included were studies reporting on the frequency of (1) mood disorders in antipsychotic-treated youth (≤ 19 years) and (2) antipsychotic use in youth with mood disorders. DATA ABSTRACTION: Two independent investigators abstracted data on study, patient, and treatment characteristics. RESULTS: Forty-one studies were meta-analyzed (N = 518,919, mean ± SD age = 12.8 ± 1.8 years, males = 65.7%). Altogether, 24.2% of antipsychotic-treated youth had a mood disorder diagnosis (studies = 34, depression spectrum disorder = 10.9%, bipolar spectrum disorder = 13.6%). In longitudinal studies, the overall proportion increased significantly from 17.3% in 2000 (range, 1996-2009) to 24.5% in 2006 (range, 2004-2011) (odds ratio [OR] = 1.50; 95% confidence interval [CI], 1.26-1.79; P < .0001). This increase was driven entirely by bipolar spectrum diagnoses (2001 = 11.1%, 2006 = 16.3%, P < .0001), rather than depression spectrum diagnoses (2001 = 9.1%, 2007 = 9.2%, P = .77). Among youth with mood disorders (8 studies), 24.0% received antipsychotics (depression spectrum disorder = 4.6%; bipolar spectrum disorder = 44.0%). CONCLUSIONS: The proportion of youth with mood disorder diagnoses increased significantly among antipsychotic-treated youth, driven entirely by an increase in youth with bipolar spectrum disorders. Progress in understanding the reasons for these trends and for an evaluation of the appropriateness of the observed antipsychotic prescribing requires more detailed information than is available in traditional pharmacoepidemiologic databases.
Keywords: Adolescent; Antipsychotic Agents; Bipolar Disorder; Child; Cross-Sectional Studies; Drug Utilization; Female; Humans; Longitudinal Studies; Male; Mood Disorders; Off-Label Use; Regression Analysis