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Summary: Background: The Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant has been associated with liver steatosis, high alanine transaminase (ALT) levels and reduced plasma levels of liver‐derived triglyceride‐rich lipoproteins. Objectives: The objectives of this study were to investigate in a group of obese children the association among the 167K allele of TM6SF2 gene and ALT, cholesterol and triglycerides levels, and hepatic steatosis, and to evaluate the potential interaction between this variant and the I148M patatin like phospholipase 3 gene (PNPLA3) polymorphism on liver enzymes. Methods: We genotyped 1010 obese children for TM6SF2 E167K and PNPLA3 I148M polymorphisms. Anthropometrical and biochemical data were collected. Ultrasound imaging of the liver was performed. Results: The 167K allele showed an association with steatosis (P < 0.0001), higher ALT levels (P < 0.001) and lower total cholesterol (P < 0.00001), low‐density lipoprotein cholesterol (P < 0.0001), triglycerides (P = 0.02) and non‐high‐density lipoprotein cholesterol levels (P < 0.000001). The subjects homozygous for the PNPLA3 148M allele carrying the rare variant of TM6SF2 showed an odds ratio of 12.2 (confidence interval 3.8–39.6, P = 0.000001) to present hypertransaminasaemia compared with the remaining patients. Conclusion: Although the TMS6SF2 E167K variant predisposes the obese children to non‐alcoholic fatty liver disease, there is an association between this variant and lower levels of cardiovascular risk factors. Overall, the data suggest differential effects of TMS6SF2 E167K variant on liver and heart health. [ABSTRACT FROM AUTHOR]

What is already known about this subject Fasting triglycerides above 1.17 mmol/L have been shown to be useful to select obese children and adolescents who may present impaired glucose tolerance in a Canadian cohort., Fasting plasma glucose is associated with the risk to present impaired glucose tolerance in several cohorts of obese children and adolescents., What this study adds When applied to Italian cohorts of obese children and adolescents, the triglycerides cut-off of 1.17 mmol/L has similar validity as in the Canadian cohort to select patients who may present impaired glucose tolerance., Fasting plasma glucose and fasting triglycerides can be combined to obtain an accurate criterion to select obese children and adolescents who may present impaired glucose tolerance., Objectives We aimed to validate fasting triglycerides > 1.17 mmol L−1, a criterion recently proposed for selecting obese children at risk of impaired glucose tolerance ( IGT), and to assess whether the accuracy of triglycerides ( TG) can be improved by the use of other variables. Methods We studied an Italian cohort of 817 obese children and adolescents (8-18.4 years) who underwent clinical examination, fasting blood analysis and the oral glucose tolerance test ( OGTT). The discriminative properties of TG > 1.17 mmol L−1 were assessed and compared with those observed in a Canadian cohort from which this criterion was derived: 71.4 [57.8-85.1]% sensitivity and 64.1 [57.7-70.4]% specificity. The possible contribution of other variables was evaluated by assessing the net reclassification improvement ( NRI), i.e., the net increase in the percentage of subjects correctly classified. Results Thirty-nine children (4.7%) had IGT. The 1.17 mmol L−1 TG threshold showed 66.6 [51.8-81.4]% sensitivity and 68.2 [64.9-71.5]% specificity, thus successfully validated. Fasting plasma glucose ( FPG) was independently associated with IGT (odds ratio = 3.86 [2.09-7.14], P < 0.001), besides TG. The bivariate criterion of TG ≥ 1.13 mmol L−1 plus FPG ≥ 4.44 mmol L−1 had a 69.2 [54.7-83.7]% sensitivity and a 78.2 [76.8-79.6]% specificity, thus displaying a 12.6% NRI ( P < 0.001) compared with TG>1.17 mmol L−1. Conclusions TG > 1.17 mmol L−1 is a useful criterion to detect roughly 66% of obese children with IGT through OGTT performed in about 33% of all obese children. However, the ' TG≥1.13 mmol L−1 plus FPG≥4.44 mmol L−1' criterion improved discrimination accuracy, leading to the possibility of detecting even more than 66% of obese children with IGT though limiting OGTT to just 25% of all obese children. [ABSTRACT FROM AUTHOR]

The present report describes the haematological and serological findings observed in a dairy sheep farm during an aborting outbreak. Fifty ewes divided into two groups were included in the study: group A consisted of 35 healthy ewes and group B consisted of 15 ill subjects. From each ewe, blood samples were collected for microscopic examination and serological assay. After 3 months, all ewes were subjected to microscopic examination, serological and biochemical assay. Morula-containing granulocytes characteristic of A. phagocytophilum was observed in all animals of group B. Antibodies against A. phagocytophilum were observed in only one animal of group A. Seroconversion was observed after 3 months in five ewes of group A and all animals of group B. Only one subject with negative serology was positive to PCR. Our results confirm the endemicity of sheep tick-borne fever (TBF) in Sicily and the problem to breeding in an endemic area. We suggest that is necessary to combine the different assays depending on the stage of infection for a correct diagnosis in endemic areas. Periodic evaluation of seroconversion could be helpful to evaluate the progression of TBF in a flock. [ABSTRACT FROM AUTHOR]

BACKGROUND: Melanocortin-4 receptor (MC4R) mutations have been reported as the most common single genetic cause of obesity in some populations and it has been suggested that they may be responsible for more than 4% of early-onset obesity. OBJECTIVES: To verify the presence of mutations of the MC4R coding region in children from southern Italy with early-onset obesity. SUBJECTS AND METHODS: Two-hundred and eight unrelated obese children and adolescents were included in the study. The average age at obesity onset was 4.5±2.6y. MC4R coding region was screened using both single-strand conformation polymorphism (SSCP) analysis and denaturing high-performance liquid chromatography (DHPLC). Automatic sequencing of PCR products of all individuals that showed an aberrant SSCP and/or DHPLC pattern was performed. RESULTS: One novel missense mutation and one previously described polymorphism (Vall03lle) were identified. The missense mutation C142T, resulting in the substitution of proline with serine at codon 48, within the first MC4R transmembrane domain, was detected at the heterozygous state in a 15-y-old obese girl (body mass index (BMI) = 35 kg/m²) who has been obese since she was 8 y old. The mutation co-segregated with the obesity phenotype for over three generations and was not found in the control population. CONCLUSIONS: Our data show MC4R obesity causing mutations in less than 0.5% of the patients (ie 1 out of 208 patients) and therefore indicate a low prevalence of MC4R variants in the obese population from southern Italy. The specific genetic background of the Mediterranean population could make it difficult for MC4R mutations to produce an essentially polygenic trait such as common obesity, at least during childhood. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although linkage studies strongly suggest that proopiomelanocortin (POMC) alterations could play a role in the genetic predisposition to obesity, systematic POMC mutational analysis did not completely confirm this hypothesis. OBJECTIVES: To verify the presence of mutations of the POMC coding region in Italian children with very early onset obesity. SUBJECTS AND METHODS: Eighty seven unrelated Italian obese children and adolescents were studied. Mean age at obesity onset was 4.7 ± 2.5y. The POMC gene coding region was screened using single-strand conformation polymorphism (SSCP) analysis. Bi-directional automatic sequencing of PCR products was performed for all individuals who showed an aberrant SSCP pattern. RESULTS: Three new mutations have been identified in the heterozygous state in three patients: (a) G3834C, resulting in the substitution of Ser with Thr at codon 7 within the POMC signal peptide; (b) C3840T, resulting in the substitution of Ser with Leu at codon 9 of the pre-proopiomelanocortin signal peptide; and (c) C7406G, producing the substitution of Arg with Gly at codon 236 within the β-endorphin peptide. A polymorphism consisting of a 9 bp insertion, AGC AGC CGC, between position 6997 and 6998 has been found at the heterozygous state in nine patients. They showed leptin levels adjusted for BMI, gender and pubertal stage significantly higher than obese subjects homozyous for the POMC wild-type allele. CONCLUSIONS: Mutations in codons 7 and 9 of the signal peptide may alter the translocation of the pre-proopiomelanocortin into the endoplasmic reticulum and, therefore, can be implicated in obesity. Although further studies are required, the polymorphism between position 6997 and 6998 may represent one of the genetic variations that explain the linkage between obesity and POMC. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 3-year-old boy who was admitted at Ospedale Bambino Gesu Hospital in Rome, Italy due to hypocortisolism and early-onset severe obesity. The patient had a history of hypoglycaemia days after his birth. Results from sequencing analysis of the patient revealed a homozygous single substitution C20CT, indicating a presence of a stop codon Gln68X. The case illustrates the combined effect of hair pigmentation of the Agouti inverse agonism.

Background: The diagnosis of monogenic obesity is burdened by frequent variants of uncertain significance (VUS). We describe our real-life approach of variant reassessment over time and we assess whether inconclusive variants are decreasing in monogenic obesity., Methods: We tested for monogenic obesity (genes: LEPR, POMC, ADCY3, PCSK1, CARTPT, SIM1, MRAP2, LEP, NTRK2, BDNF, KSR2, MAGEL2, SH2B1, MC4R, MC3R) in 101 children/adolescents (11.7 [7.3-13.7] years, 3.6 [3.3-4.0] z-BMI) in Verona and 183 (11.3 [8.4-12.2] years, 3.2 [2.7-3.9] z-BMI) in Naples from January 2020 to February 2023. In March-July 2024 we reassessed the baseline variants by updated software interpretation and literature renavigation., Results: We initially found 20 VUS, 4 Likely Pathogenic (LP), 5 Likely Benign (LB) and 1 benign variant in 33 individuals. At follow-up, 6 VUS were reclassified as benign/LB, one LP as pathogenic and 3 LB as benign. Overall, 10/30 variants (6/18 in Verona, 3/11 in Naples and a variant found in both centres) were reclassified, leading to a less uncertain report for 13 of 33 variant-carrying patients. Monogenic obesity was diagnosed in 3 probands in Verona and 4 in Naples, carrying variants at MC4R or NTRK2., Conclusion: Our variant reassessment was effective to improve classification certainty for the 39% of patients and suggested that the molecular diagnosis of monogenic obesity is becoming more accurate over time., (© 2024 The Author(s). Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Aim: To determine (i) prevalence and the risk factors for acute kidney injury (AKI) in children hospitalised for febrile urinary tract infection (fUTI) and (ii) role of AKI as indicator of an underlying VUR. AKI, in fact, is favoured by a reduced nephron mass, often associated to VUR., Methods: This retrospective Italian multicentre study enrolled children aged 18 years or younger (median age = 0.5 years) discharged with a primary diagnosis of fUTI. AKI was defined using Kidney Disease/Improving Global Outcomes serum creatinine criteria., Results: Of 849 children hospitalised for fUTI (44.2% females, median age 0.5 years; IQR = 1.8), 124 (14.6%) developed AKI. AKI prevalence rose to 30% in the presence of underlying congenital anomalies of the kidney and urinary tract (CAKUT). The strongest AKI predictors were presence of CAKUT (OR = 7.5; 95%CI: 3.8-15.2; p = 9.4e-09) and neutrophils levels (OR = 1.13; 95%CI: 1.08-1.2; p = 6.8e-07). At multiple logistic regression analysis, AKI during fUTI episode was a significant indicator of VUR (OR = 3.4; 95%CI: 1.7-6.9; p = 0.001) despite correction for the diagnostic covariates usually used to assess the risk of VUR after the first fUTI episode. Moreover, AKI showed the best positive likelihood ratio, positive predictive value, negative predictive value and specificity for VUR., Conclusion: AKI occurs in 14.6% of children hospitalised for fUTI and is a significant indicator of VUR., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Introduction: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with an elusive etiology. While environmental factors have been considered, familial ALS cases have raised the possibility of genetic involvement. This genetic connection is increasingly evident, even in patients with sporadic ALS. We allowed access to the genetic test to all patients attending our clinic to identify the prevalence and the role of genetic variants in the development of the disease and to identify patients with potentially treatable forms of the disease., Materials and Methods: 194 patients with probable or definite ALS, were enrolled. A comprehensive genetic testing was performed, including sequencing all exons of the SOD1 gene and testing for hexanucleotide intronic repeat expansions (G4C2) in the C9orf72 gene using fluorescent repeat-primed PCR (RP-PCR). Whole Exome NGS Sequencing (WES) was performed, followed by an in silico multigene panel targeting neuromuscular diseases, spastic paraplegia, and motor distal neuropathies. We conducted statistical analyses to compare different patient groups., Results: Clinically significant pathogenetic variants were detected in 14.43% of cases. The highest prevalence of pathogenetic variants was observed in fALS patients, but a substantial proportion of sALS patients also displayed at least one variant, either pathogenetic or of uncertain significance (VUS). The most observed pathogenetic variant was the expansion of the C9orf72 gene, which was associated with a shorter survival. SOD1 variants were found in 1.6% of fALS and 2.5% of sALS patients., Discussion: The study reveals a significant number of ALS patients carrying pathogenic or likely pathogenic variants, with a higher prevalence in familial ALS cases. The expansion of the C9orf72 gene emerges as the most common genetic cause of ALS, affecting familial and sporadic cases. Additionally, SOD1 variants are detected at an unexpectedly higher rate, even in patients without a familial history of ALS, underscoring the crucial role of genetic testing in treatment decisions and potential participation in clinical trials. We also investigated variants in genes such as TARDBP, FUS, NEK1, TBK1, and DNAJC7, shedding light on their potential involvement in ALS. These findings underscore the complexity of interpreting variants of uncertain significance (VUS) and their ethical implications in patient communication and genetic counseling for patients' relatives., Conclusion: This study emphasizes the diverse genetic basis of ALS and advocates for integrating comprehensive genetic testing into diagnostic protocols. The evolving landscape of genetic therapies requires identifying all eligible patients transcending traditional familial boundaries. The presence of VUS highlights the multifaceted nature of ALS genetics, prompting further exploration of complex interactions among genetic variants, environmental factors, and disease development., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Behçet's disease (BD) is a heterogeneous multifactorial autoinflammatory disease characterized by a plethora of clinical manifestations. Cutaneous lesions are considered hallmarks of the disease. However, their evolution over time and a thorough description are scarcely reported in non-endemic regions. The aim of this study was to detail BD skin manifestations and their evolution over time in Italy, as well as the dermatological prognostic impact of specific cutaneous features in long-standing disease. Data were collected in a double fashion, both retrospectively and prospectively, from the AutoInflammatory Disease Alliance (AIDA) international registry dedicated to BD, between January 2022 and December 2022. A total of 458 Italian patients were included. When assessing skin manifestations course, the constant or sporadic presence or absence of cutaneous involvement between onset and follow-up was considered. Oral ulcers (OU) (88.4%) and genital ulcers (GU) (52.6%), followed by skin involvement (53.7%) represented the most common presenting mucocutaneous manifestations at disease onset. Up to the time of enrolment into the AIDA registry, 411 (93.8%) patients had suffered from OU and 252 (57.9%) from GU; pseudofolliculitis (PF) accounted for the most common skin manifestation (170 patients, 37.1%), followed by erythema nodosum (EN) (102 patients, 22.3%), skin ulcers (9 patients, 2%) and pyoderma gangrenosum (4 patients, 0.9%). A prospective follow-up visit was reported in 261/458 patients; 24/148 (16.2%) subjects with skin involvement as early as BD onset maintained cutaneous lesions for the entire period of observation, while 120 (44.1%) patients suffered from sporadic skin involvement. Conversely, 94/113 (83.2%) with no skin involvement at disease onset did not develop skin lesions thereafter. At follow-up visits, cutaneous involvement was observed in 52 (20%) patients, with a statistically significant association between PF and constant skin involvement (p = 0.031). BD in Italy is characterized by a wide spectrum of clinical presentations and skin manifestations in line with what is described in endemic countries. Patients with skin disease at the onset are likely to present persistent cutaneous involvement thereafter; mucocutaneous lesions observed at the onset, especially PF, could represent a warning sign for future persistent skin involvement requiring closer dermatological care., (© 2023. The Author(s).)

Objectives: To describe the ophthalmological characteristics in a Juvenile idiopathic arthritis (JIA) cohort and to evaluate how therapeutic advances have changed the course of the uveitis., Methods: Analysis of a retrospective cohort study of consecutive JIA pediatric patients including JIA-associated uveitis (JIA-U) and comparison with a previous study in the same uveitis center assessed before the wide-spread of biological therapy., Results: The total of 49 JIA patients were analyzed, of whom 18 JIA-U, compared with a JIA-U past cohort of 66 patients. Systemic corticosteroids were used significantly less in the current JIA-U group (p = 0.008) than in the past one. JIA-U present cohort was on therapy more frequently with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) than the past group (p = 0.039), mostly treated with methotrexate (93.3%). Furthermore, a larger use of biologic disease-modifying anti-rheumatic drugs (bDMARDs) was described in the current JIA-U group (p = 0.005) also associated with csDMARDs (p = 0.003). Adalimumab was used more (72.7%) in the present JIA-U cohort compared to a larger treatment with infliximab (61.5%) in the past (p = 0.005). Higher number of uveitis recurrences was observed in the previous cohort compared to the current one (p = 0.005). Fewer complications were described in this study than in the previous: posterior synechiae (p = 0.007), cataract (p < 0.001), band keratopathy (p < 0.001), and elevated intraocular pressure (IOP) (p = 0.047)., Conclusion: Current therapies reduced the uveitis recurrences and ocular complications including cataract due also to the lower use of corticosteroids. The new close collaboration with the pediatric rheumatologic center in the same University has contributed to the care improvement and decrease of uveitis complications., (© 2021. The Author(s).)

Adequate and balanced nutrition is essential to promote optimal child growth and a long and healthy life. After breastfeeding, the second step is the introduction of complementary feeding (CF), a process that typically covers the period from 6 to 24 months of age. This process is, however, still highly controversial, as it is heavily influenced by socio-cultural choices, as well as by the availability of specific local foods, by family traditions, and pediatrician beliefs. The Società Italiana di Pediatria Preventiva e Sociale (SIPPS) together with the Federazione Italiana Medici Pediatri (FIMP), the Società Italiana per lo Sviluppo e le Origine della Salute e delle Malattie (SIDOHaD), and the Società Italiana di Nutrizione Pediatrica (SINUPE) have developed evidence-based recommendations for CF, given the importance of nutrition in the first 1000 days of life in influencing even long-term health outcomes. This paper includes 38 recommendations, all of them strictly evidence-based and overall addressed to developed countries. The recommendations in question cover several topics such as the appropriate age for the introduction of CF, the most appropriate quantitative and qualitative modalities to be chosen, and the relationship between CF and the development of Non-Communicable Diseases (NCDs) later in life.

Objective: To evaluate the effectiveness of Tocilizumab (with or without corticosteroids) in a real-life context among moderate-to-severe COVID-19 patients hospitalized at the Infectious Diseases ward of two hospitals in Lazio region, Italy, during the first wave of SARS-CoV-2 pandemic., Method: We conducted a retrospective cohort study among moderate-to-severe COVID-19 pneumonia to assess the influence of tocilizumab (with or without corticosteroids) on: 1) primary composite outcome: risk for death/invasive mechanical ventilation/ICU-transfer at 14 days from hospital admission; 2) secondary outcome: COVID-related death only. Both outcomes were also assessed at 28 days and restricted to baseline more severe cases. We also evaluated the safety of tocilizumab., Results: Overall, 412 patients were recruited, being affected by mild (6.8%), moderate (66.3%) or severe (26.9%) COVID-19 at baseline. The median participant' age was 63 years, 56.5% were men, the sum of comorbidities was 1.34 (±1.44), and the median time from symptom onset to hospital admission was 7 [3-10] days. Patients were subdivided in 4 treatment groups: standard of care (SoC) only (n = 172), SoC plus corticosteroid (n = 65), SoC plus tocilizumab (n = 50), SoC plus tocilizumab and corticosteroid (n = 125). Twenty-six (6.3%) patients underwent intubation, and 37 (9%) COVID-related deaths were recorded. After adjusting for several factors, multivariate analysis showed that tocilizumab (with or without corticosteroids) was associated to improved primary and secondary outcomes at 14 days, and at 28-days only when tocilizumab administered without corticosteroid. Among more severe cases the protective effect of tocilizumab (± corticosteroids) was observed at both time-points. No safety concerns were recorded., Conclusion: Although contrasting results from randomized clinical trials to date, in our experience tocilizumab was a safe and efficacious therapeutic option for patients with moderate-to-severe COVID-19 pneumonia. Its efficacy was improved by the concomitant administration of corticosteroids in patients affected by severe-COVID-19 pneumonia at baseline., Competing Interests: No competing interests to declare.

Background and Aims: Birth weight (BW) has been associated with the risk of obesity and metabolic derangements in children and adults. The aims of this study were: i. to evaluate the distribution of BW in a sample of overweight and obese children and adolescents compared with the general reference population; ii. to explore the relationship between the BW and insulin resistance and other cardiometabolic derangements in a population of children and adolescents with overweight and obesity., Methods and Results: 710 overweight and obese children and adolescents were recruited and categorized into small (SGA), appropriate (AGA), and large (LGA) for gestational age, according to the BW percentile. Arterial blood pressure, lipid profile, glucose metabolism and hepatic steatosis were evaluated to assess cardiometabolic obesity-related derangements. The distribution of BW categories in our population was significantly different compared with the general population (SGA 6.9% vs. 8.6%, AGA 74.6% vs. 81.4%, LGA 18.5% vs. 10%; p < 0.0001). We found a higher frequency of prediabetes conditions (21.7% vs 8.9%, OR 2.97, 95% CI 1.38-6.38, p = 0.005) and borderline/high low-density lipoprotein cholesterol (31.8% vs 18.6%, OR 2.13, 95% CI 1.09-4.18, p = 0.033) in overweight and obese children born SGA compared to those born non-SGA, independently of age, sex, and BMI., Conclusions: BW is a risk factor of cardiometabolic derangements in a population of children and adolescents with overweight and obesity. Therefore, adequate obesity prevention strategies should be planned for children born SGA to minimize their risk to become obese and to reduce their short- and long-term cardiometabolic risks., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aim: The association between non-alcoholic fatty liver (NAFL) and the variant rs641738 within the membrane bound O-acyltransferase domain-containing 7 (MBOAT7) gene is currently uncertain, especially in the paediatric population. We examined whether there is an association between this genetic variant and NAFL in a large multicentre, hospital-based cohort of Italian overweight/obese children., Methods and Results: We studied 1760 overweight or obese children [mean age (SD): 11.1(2.9) years, z-body mass index (zBMI) 3.2(0.9)], who underwent ultrasonography for the diagnosis of NAFL. A subgroup of these children (n = 182) also underwent liver biopsy. Genotyping of the MBOAT7 rs641738 polymorphism was performed by TaqMan-Based RT-PCR system in each subject. Overall, 1131 (64.3%) children had ultrasound-detected NAFL; 528 (30%) had rs641738 CC genotype, 849 (48.2%) had rs641738 CT genotype, and 383 (21.8%) had rs641738 TT genotype, respectively. In the whole cohort, the interaction of MBOAT7 genotypes with zBMI was not associated with NAFL after adjustment for age, sex, serum triglycerides, serum alanine aminotransferase levels and patatin-like phospholipase domain-containing protein-3 (PNPLA3) genotype (adjusted-odds ratio 1.02 [95% CI 0.98-1.06]). Similarly, no association was found between MBOAT7 genotypes and NAFL after stratification by obesity status. MBOAT7 genotypes were not associated with the presence of non-alcoholic steatohepatitis or the stage of liver fibrosis in a subgroup of 182 children with biopsy-proven NAFLD., Conclusions: The results of this study did not show any significant contribution of MBOAT7 rs641738 polymorphism to the risk of having either NAFL on ultrasonography or NASH on histology in a large hospital-based cohort of Italian overweight/obese children., Competing Interests: Declaration of competing interest The Authors have no potential conflicts of interest to disclose., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objectives: Recent evidence linked early menarche to a higher risk of insulin-resistance (IR) and nonalcoholic fatty liver disease (NAFLD) in adulthood. We aimed to evaluate the impact of early menarche on glucose derangements and NAFLD in a sample of Italian adolescents with obesity., Methods: Anthropometric and biochemical evaluations were conducted in all the enrolled 318 obese patients (mean age 12.31 ± 2.95 years). NAFLD was defined by the presence of ultrasound detected liver steatosis and/or alanine transaminase (ALT) levels >40 IU/L., Results: Patients with early menarche showed both higher homeostasis model assessment of insulin-resistance (HOMA-IR) (p=0.008) and ALT (p=0.02) values, an increased prevalence of NAFLD (p=0.001), and lower Matsuda and Insulinogenic Index (IGI) values than the other obese patients. The association between early menarche and both ALT and Matsuda Index remained significant in General Linear Models (GLMs) in which respectively body mass index standard deviation score (BMI-SDS) and Matsuda Index, and BMI-SDS were included as covariates. Patients with early menarche also showed a higher risk of both HOMA-IR>3 (OR 1.69, CI 1.05-2.70, p=0.02) and NAFLD (OR 1.10, CI 1.01-1.21, p=0.03)., Conclusions: Girls with obesity presenting early menarche showed higher HOMA-IR levels, lower Matsuda Index and IGI values, and higher risk of NAFLD compared to girls without early menarche., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Importance: Face masks have been associated with effective prevention of diffusion of viruses via droplets. However, the use of face masks among children, especially those aged younger than 3 years, is debated, and the US Centers for Disease Control and American Academy of Physicians recommend the use of face mask only among individuals aged 3 years or older., Objective: To examine whether the use of surgical facial masks among children is associated with episodes of oxygen desaturation or respiratory distress., Design, Setting, and Participants: This cohort study was conducted from May through June 2020 in a secondary-level hospital pediatric unit in Italy. Included participants were 47 healthy children divided by age (ie, group A, aged ≤24 months, and group B, aged >24 months to ≤144 months). Data were analyzed from May through June 2020., Interventions: All participants were monitored every 15 minutes for changes in respiratory parameters for the first 30 minutes while not wearing a surgical face mask and for the next 30 minutes while wearing a face mask. Children aged 24 months and older then participated in a walking test for 12 minutes., Main Outcomes and Measures: Changes in respiratory parameters during the use of surgical masks were evaluated., Results: Among 47 children, 22 children (46.8%) were aged 24 months or younger (ie, group A), with 11 boys (50.0%) and median (interquartile range [IQR]) age 12.5 (10.0-17.5) months, and 25 children (53.2%) were aged older than 24 months to 144 months or younger, with 13 boys (52.0%) and median (IQR) age 100.0 (72.0-120.0) months. During the first 60 minutes of evaluation in the 2 groups, there was no significant change in group A in median (IQR) partial pressure of end-tidal carbon dioxide (Petco2; 33.0 [32.0-34.0] mm Hg; P for Kruskal Wallis = .59), oxygen saturation (Sao2; 98.0% [97.0%-99.0%]; P for Kruskal Wallis = .61), pulse rate (PR; 130.0 [115.0-140.0] pulsations/min; P for Kruskal Wallis = .99), or respiratory rate (RR; 30.0 [28.0-33.0] breaths/min; P for Kruskal Wallis = .69) or for group B in median (IQR) Petco2 (36.0 [34.0-38.0] mm Hg; P for Kruskal Wallis = .97), Sao2 (98.0% [97.0%-98.0%]; P for Kruskal Wallis = .52), PR (96.0 [84.0-104.5] pulsations/min; P for Kruskal Wallis test = .48), or RR (22.0 [20.0-25.0] breaths/min; P for Kruskal Wallis = .55). After the group B walking test, compared with before the walking test, there was a significant increase in median (IQR) PR (96.0 [84.0-104.5] pulsations/min vs 105.0 [100.0-115.0] pulsations/min; P < .02) and RR (22.0 [20.0-25.0] breaths/min vs 26.0 [24.0-29.0] breaths/min; P < .05)., Conclusions and Relevance: This cohort study among infants and young children in Italy found that the use of facial masks was not associated with significant changes in Sao2 or Petco2, including among children aged 24 months and younger.

Background: Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-old girl. No other cases have been reported yet. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) to identify possible alterations in PROKR2., Methods: We analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels > 0.3 IU/L or peak-LH > 5 IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD)., Results: No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD)., Conclusions: As for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

Objectives: The prognosis of brain metastatic colorectal cancer patients (BMCRC) is poor. Several local treatments have been used, but the optimal treatment choice remains an unresolved issue. We evaluated the clinical outcomes of a large series of BMCRC patients treated in several Italian centers using stereotactic radiosurgery (SRS)., Methods: 185 BMCRC patients for a total of 262 lesions treated were evaluated. Treatments included surgery followed by post-operative SRS to the resection cavity, and SRS, either single-fraction, then hypofractionated SRS (HSRS). Outcomes was measured in terms of local control (LC), toxicities, brain distant failure (BDF), and overall survival (OS). Prognostic factors influencing survival were assed too., Results: The median follow-up time was 33 months (range 3-183 months). Surgery plus SRS have been performed in 28 (10.7%) cases, SRS in 141 (53.8%), and HSRS in 93 (35.5%). 77 (41.6%) patients received systemic therapy. The main total dose and fractionation used were 24 Gy in single fraction or 24 Gy in three daily fractions. Local recurrence occurred in 32 (17.3%) patients. Median, 6 months,1-year-LC were 86 months (95%CI 36-86), 87.2% ± 2.8, 77.8% ± 4.1. Median,6 months,1-year-BDF were 23 months (95%CI 9-44), 66.4% ± 3.9, 55.3% ± 4.5. Median,6 months,1-year-OS were 7 months (95% CI 6-9), 52.7% ± 3.6, 33% ± 3.5. No severe neurological toxicity occurred. Stage at diagnosis, Karnofsky Performance Status (KPS), presence and number of extracranial metastases, and disease-specific-graded-prognostic-assessment (DS-GPA) score were observed as conditioning survival., Conclusion: SRS/HSRS have proven to be an effective local treatment for BMCRC. A careful evaluation of prognostic factors as well as a multidisciplinary evaluation is a valid aid to manage the optimal therapeutic strategy for CTC patients with BMs., Advances in Knowledge: The prognosis of BMCRC is poor. Several local treatments was used, but optimal treatment choice remains undefined. Radiosurgery has proven to be an effective local treatment for BMCRC. A careful evaluation of prognostic factors and a multidisciplinary evaluation needed.

Context: Up to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade optic pathway gliomas (OPGs) that can result in endocrine dysfunction. Data on prevalence and type of endocrine disorders in NF1-related OPGs are scarce., Objectives: The aim of the study was to determine the prevalence of endocrine dysfunctions in patients with NF1 and OPGs and to investigate predictive factors before oncological treatment., Design: Multicenter retrospective study., Settings and Patients: Records were reviewed for 116 children (64 females, 52 males) with NF1 and OPGs followed at 4 Italian centers., Main Outcome Measures: We evaluated endocrine function and reviewed brain imaging at the time of OPG diagnosis before radio- and chemotherapy and/or surgery. OPGs were classified according to the modified Dodge classification., Results: Thirty-two children (27.6%) with a median age of 7.8 years had endocrine dysfunctions including central precocious puberty in 23 (71.9%), growth hormone deficiency in 3 (9.4%), diencephalic syndrome in 4 (12.5%), and growth hormone hypersecretion in 2 (6.2%). In a multivariate cox regression analysis, hypothalamic involvement was the only independent predictor of endocrine dysfunctions (hazard ratio 5.02 [1.802-13.983]; P = .002)., Conclusions: Endocrine disorders were found in approximately one-third of patients with Neurofibromatosis type 1 and OPGs before any oncological treatment, central precocious puberty being the most prevalent. Sign of diencephalic syndrome and growth hormone hypersecretion, although rare, could be predictive of optic pathway gliomas in NF1. Tumor location was the most important predictor of endocrine disorders, particularly hypothalamic involvement., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Two different systems for the screening and diagnosis of hypertension (HTN) in children currently coexist, namely, the guidelines of the 2017 American Academy of Pediatrics (AAP) and the 2016 European Society for Hypertension (ESH). The two systems differ in the lowered cut-offs proposed by the AAP versus ESH., Objectives: We evaluated whether the reclassification of hypertension by the AAP guidelines in young people who were defined non-hypertensive by the ESH criteria would classify differently overweight/obese youth in relation to their cardiovascular risk profile., Methods: A sample of 2929 overweight/obese young people (6-16 years) defined non-hypertensive by ESH (ESH - ) was analysed. Echocardiographic data were available in 438 youth., Results: Using the AAP criteria, 327/2929 (11%) young people were categorized as hypertensive (ESH - /AAP + ). These youth were older, exhibited higher body mass index, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), triglycerides, total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio, blood pressure, left ventricular mass index and lower HDL-C ( p  <0.025-0.0001) compared with ESH - /AAP - . The ESH - /AAP + group showed a higher proportion of insulin resistance (i.e. HOMA-IR ≥3.9 in boys and 4.2 in girls) 35% vs . 25% ( p  <0.0001), high TC/HDL-C ratio (≥3.8 mg/dl) 35% vs . 26% ( p  = 0.001) and left ventricular hypertrophy (left ventricular mass index ≥45 g/h 2.16 ) 67% vs . 45% ( p  = 0.008) as compared with ESH - /AAP - ., Conclusions: The reclassification of hypertension by the AAP guidelines in young people overweight/obese defined non-hypertensive by the ESH criteria identified a significant number of individuals with high blood pressure and abnormal cardiovascular risk. Our data support the need of a revision of the ESH criteria.

Objectives: To identify which factors can influence the patients' perception of protective isolation following Haematopoietic Stem Cell Transplantation (HSCT)., Methods: This is a prospective study conducted in 10 Italian centres, members of the Italian Group of stem cell transplant (GITMO). Patients' perception of protective isolation was assessed using the ISOLA scale between 7 and 9 days post-transplant. Statistical linear regression analysis was performed., Results: The participants were 182 adult patients receiving autologous (48%) or allogeneic (52%) HSCT in protective isolation. Male sex (β = .152), education level (β = -.245), double room (β = .186), satisfaction with visiting hours (β = -.174) and emotional support from nurses (β = -.169) were independently associated with isolation-related suffering. Significant predictors of the relationship with oneself included body temperature (β = -.179), fatigue (β = -.192) and emotional support from nurses (β = -.292). Factors independently associated with the relationship with others were education (β = -.230), chemotherapy cycles (β = -.218), pain (β = .150) and satisfaction with visiting hours (β = -.162)., Conclusion: Healthcare providers should pay greater attention in caring for those patients who are at risk for a negative isolation experience. Nurses should provide emotional support., (© 2019 John Wiley & Sons Ltd.)

Background: Nonalcoholic fatty liver disease (NAFLD) is the commonest liver disease in children and adolescents in Western countries. Complex traits arise from the interplay between environmental and genetic factors in the pathogenesis of NAFLD., Aims: We examined the association between NAFLD and eleven single nucleotide polymorphisms (SNPs) at genetic loci potentially associated with liver damage (GCKR, MBOAT7, GPR120), oxidative stress (SOD2), lipid metabolism (PNPLA3, TM6SF2, LPIN1, ELOVL2, FADS2, MTTP) and fibrogenesis (KLF6) in a paediatric population. A genetic risk score (GRS) was performed taking into account both these SNPs and clinical risk factors., Methods: We recruited a cohort of 514 obese children and adolescents (mean age [±SD]: 11.2 ± 2.8 years, z-BMI 3.3 ± 0.8). NAFLD was identified by ultrasonography. Genotyping was performed by TaqMan-based RT-PCR system., Results: The overall prevalence of NAFLD was 67.5% (347 patients). Among the eleven genotyped SNPs, the genetic variants in TM6SF2 rs58542926 (OR = 4.13, p = 0.002), GCKR rs1260326 (OR = 1.53, p = 0.003), PNPLA3 rs738409 (OR = 1.58, p = 0.004) and ELOVL2 rs2236212 (OR = 1.34, p = 0.047) were significantly associated with a higher risk of NAFLD. Addition of a 11-polymorphism GRS to established clinical risk factors significantly (albeit modestly) improved the discriminatory capability of the regression model for predicting the risk of NAFLD (with SNPs C-statistic 0.81 [95%CI 0.75-0.88] vs. 0.77 [0.70-0.84] without SNPs; p = 0.047)., Conclusions: NAFLD was strongly associated with three genetic variants, TM6SF2 rs58542926, PNPLA3 rs738409 and GCKR rs1260326, and more slightly with ELOVL2 rs2236212, in obese children and adolescents. Addition of a 11-polymorphism GRS to clinical risk factors improved the predictability of NAFLD., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Asthma is the most frequent chronic disease in childhood. Chest tightness, cough, wheezing and dyspnoea during or after exercise may be unique manifestations of asthma in up to 90% of subjects. Physical activity may be reduced by uncontrolled asthma symptoms and parental beliefs, impairing physical fitness of asthmatic children. Clinicians working in the field of allergy are aware of evidence supporting the benefits of physical activity for patients with asthma. Treatment of asthma is required in order to obtain its control and to avoid any limitation in sports and active play participation. As exercise performance in children with controlled asthma is not different from that of healthy controls, any exercise limitation cannot be accepted. Overweight and obesity may interfere with asthma and exercise, leading to dyspnoea symptoms. Evidences on the effect of insulin resistance on airway smooth muscle and on bronchial hyperactivity are presented. CONCLUSION: Exercise is part of the strategy to obtain the best control of asthma in childhood, but we have to optimise the asthma control therapy before starting exercise programming. Furthermore, it is crucial to give best attention on the effects of obesity and insulin resistance, because they could in turn influence patients' symptoms., (Copyright © 2018 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The non-classical HLA-class I molecule-g (HLA-G) gene shows a deletion/insertion (del/ins) polymorphism of a 14-base-pair sequence (14 bp) in the exon 8 at the 3' untranslated region. The presence of the 14 bp insertion allele has been associated to lower soluble HLA-G protein production, a protein with anti-inflammatory activities. So far, no studies have investigated the relationship between HLA-G 14 bp del/ins polymorphism and metabolic features of obese children and adolescents. We aimed to assess if the HLA-G ins/del polymorphism, and in particular the HLA-G ins/ins genotype determining lower sHLA-G production, is associated to insulin resistance (evaluated by homeostasis model assessment [HOMA]) in a population of obese children., Methods: We enrolled 574 obese children and adolescents. Anthropometric and laboratory data were collected. The white blood cell (WBC) count was evaluated as surrogate marker of inflammation. C-reactive protein (CRP) was available in 48 patients. HOMA was calculated. Patients were genotyped for the HLA-G del/ins polymorphism., Results: Subjects carrying the HLA-G ins/ins genotype, presented with higher HOMA, WBC and CRP values, compared to del/ins and del/del genotypes (P ≤ 0.0009, ≤0.02 and ≤0.0001, respectively). Comparison of the regression line slopes, performed for HOMA and WBC on the basis of HLA-G genotypes, showed that subjects carrying the HLA-G ins/ins genotype presented with a stronger correlation between HOMA and WBC, compared to the other genotypes (Model r 2 3.13%, P ≤ 0.006)., Conclusions: We showed a strong association between HLA-G 14 bp ins/ins genotype and HOMA in obese children and adolescents. This association could be hypothetically modulated by subclinical inflammation., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: We aimed to evaluate whether the metabolically healthy obese (MHO) phenotype was associated with hepatic steatosis (HS) or left ventricular hypertrophy (LVH) in young people with overweight (OW), obesity (OB) and morbid obesity (MOB) and whether the prevalence of these comorbidities was affected by OB severity., Methods and Results: An abdominal ultrasound was performed in 1769 children and adolescents, mean age 10.6 years (range 5-18) with MHO phenotype, defined as the absence of traditional cardiometabolic risk factors, in order to identify HS. In a subsample of 177 youth the presence of LVH, defined by 95th percentile of LV mass/h 2.7 for age and gender, was also analyzed. The prevalence of HS increased from 23.0% in OW to 27.8% in OB and 45.1% in MOB (P < 0.0001). The proportion of LVH increased from 36.8% in OW to 57.9% in OB and 54.5% in MOB (P < 0.05). As compared with OW, the odds ratio (95% CI) for HS was 2.18 (1.56-3.05), P < 0.0001) in OB and 6.20 (4.26-9.03), P < 0.0001) in MOB, independently of confounding factors. The odds ratio for LVH was 2.46 (1.20-5.06), P < 0.025) in OB and 2.79 (1.18-6.61), P < 0.025) in MOB, as compared with OW., Conclusion: In spite of the absence of traditional cardiometabolic risk factors, the prevalence of HS and LVH progressively increased across BMI categories. MHO phenotype does not represent a "benign" condition in youth., (Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

PNPLA3 and MTP genes have been associated with liver steatosis and chronic hepatitis C. We studied the influence of MTP and PNPLA3 polymorphisms in 114 Italian patients with chronic hepatitis C, evaluating the histological and clinical presentation of liver disease. The study confirmed the association of PNPLA3 polymorphisms with liver steatosis (p=0.041), but did not show any additive effect of MTP polymorphisms in the development of steatosis. MTP polymorphisms do not seem to influence PNPLA3 in the development of liver steatosis. Further studies with a larger number of patients are required.

Introduction: Since standardization of the ICCS terminology, only two small case series of children with extraordinary daytime only urinary frequency (EDOUF) have been published. The aims of the present study were i) to describe a large cohort of children affected by EDOUF, to evaluate its rate among the main micturition pediatric disturbances, and to determine if there is different EDOUF onset among seasons; ii) to investigate possible associations with urodynamic abnormalities by non-invasive techniques; iii) to evaluate whether postponing micturition exercise (PME) can objectively verify the anamnestic data hinting at the EDOUF diagnosis; and iv) to determine the effect of postponing micturition at home., Material and Methods: We reviewed the records of all patients with EDOUF, nocturnal enuresis, and/or overactive bladder firstly examined from March 2012 to February 2016. We evaluated post-void residual and bladder wall thickness by urinary ultrasound and uroflowmetry and recorded the season in which the EDOUF started. Through the PME, the EDOUF diagnosis was confirmed if patients were able to postpone micturition reaching at least 80% of the expected bladder capacity without showing urinary incontinence. At home, we recommended postponing micturition for a maximum of 3 h if EDOUF affected the normal daily activities of both children and parents. We set a telephone interview for 3 months later., Results: The clinical characteristics of the EDOUF population are shown in the Table. The EDOUF rate was 12.1%. The rate of EDOUF onset was significantly lower during the summer than in other seasons (p = 0.02) and the OR for onset of EDOUF in the summer - compared with the other seasons - was 0.37 (95% CI 0.18-0.74; p = 0.005). Eighty-five (80.2%) patients reported an intermittent trend of the EDOUF with variable periods of improvement and worsening. All the EDOUF patients had normal uroflowmetry, 1/106 had post-micturition bladder wall thickness >5 mm and one post-void residual. At the PME, 106 out of 106 (100%) patients with EDOUF were able to reach at least 80% of the EBC without showing urinary incontinence or urgency incontinence. After 3 months, in 98.1% of the patients the symptoms had disappeared or improved., Discussion and Conclusions: Childhood EDOUF is rather common and is generally associated with normal non-invasive urodynamic patterns. The PME allows verification of anamnestic data of EDOUF. The sole recommendation to postpone micturition for a maximum of 3 h or until the micturition postponement became stressful could be considered as a possible approach., (Copyright © 2018 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Context: Young-onset obesity is strongly associated with the early development of type 2 diabetes (T2D). Genetic risk scores (GRSs) related to T2D might help predicting the early impairment of glucose homeostasis in obese youths., Objective: Our objective was to investigate the contributions of four GRSs (associated with: T2D [GRS-T2D], beta-cell function [GRS-β], insulin resistance [GRS-IR], and body mass index) to the variation of traits derived from oral glucose tolerance test (OGTT) in obese and normal-weight children and young adults., Design: This was a cross-sectional association study., Patients: A total of 1076 obese children/adolescents (age = 11.4 ± 2.8 years) and 1265 normal-weight young volunteers (age = 21.1 ± 4.4 years) of European ancestry were recruited from pediatric obesity clinics and general population, respectively., Intervention: Standard OGTT was the intervention in this study., Main Outcome Measures: Associations between GRSs and OGTT-derived traits including fasting glucose and insulin, insulinogenic index, insulin sensitivity index, disposition index (DI) and associations between GRSs and pre-diabetic conditions were measured., Results: GRS-β significantly associated with fasting glucose (β = 0.019; P = 3.5 × 10 -4 ) and DI (β = -0.031; P = 8.9 × 10 -4 , last quartile 18% lower than first) in obese children, and nominally associated with fasting glucose (β = 0.009; P = 0.017) and DI (β = -0.030; P = 1.1 × 10 -3 , last quartile 11% lower than first) in normal-weight youths. GRS-T2D showed weaker contribution to fasting glucose and DI compared to GRS-β, in both obese and normal-weight youths. GRS associated with insulin resistance and GRS associated with body mass index did not associate with any traits. None of the GRSs associated with prediabetes, which affected only 4% of participants overall., Conclusion: Single nucleotide polymorphisms identified by genome-wide association studies to influence beta-cell function were associated with fasting glucose and indices of insulin secretion in youths, especially in obese children.

Background & Aims: A common non-synonymous polymorphism, E167K, in transmembrane six superfamily member 2 (TM6SF2) gene has been recently associated with an increased hepatic triglyceride content, dyslipidemia and liver fibrosis in NAFLD patients. We investigated possible associations between the TM6SF2 variants and liver lesions in chronic hepatitis C., Patients and Methods: 148 consecutive patients with biopsy proven anti-HCV/HCV-RNA-positive chronic hepatitis, naive for antiviral therapy, were genotyped for TM6SF2 E167K and PNPLA3 I148M variants., Results: The score of liver steatosis was higher in the 18 patients with TM6SF2 E167K variant (mean 1.9 ± 1.3) than in the 130 homozygotes for TM6SF2 167E allele (1.1 ± 1.1, P = 0.02), and the prevalence of a steatosis score ≥ 3 was 33.3% vs. 12.3% respectively (P = 0.02). No difference in necroinflammatory or fibrosis scores was found between the two groups. A general linear model identified as independent predictors of steatosis TM6SF2 E167K and PNPLA3 M148M variants and waist circumference (P = 0.0376, P = 0.0069 and P = 0.0273 respectively)., Conclusions: This is the first demonstration that TM6SF2 E167K variant is an independent predictor of liver steatosis in chronic hepatitis C., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Twenty-five patients with Niemann Pick disease type C (age range: 7 months to 44 years) were enrolled in an Italian independent multicenter trial and treated with miglustat for periods from 48 to 96 months., Methods: Based on the age at onset of neurological manifestations patients' phenotypes were classified as: adult (n = 6), juvenile (n = 9), late infantile (n = 6), early infantile (n = 2). Two patients had an exclusively visceral phenotype. We clinically evaluated patients' neurological involvement, giving a score of severity ranging from 0 (best) to 3 (worst) for gait abnormalities, dystonia, dysmetria, dysarthria, and developmental delay/cognitive impairment, and from 0 to 4 for dysphagia. We calculated a mean composite severity score transforming the original scores proportionally to range from 0 to 1 to summarize the clinical picture of patients and monitor their clinical course., Results: We compared the results after 24 months of treatment in 23 patients showing neurological manifestations. Stabilization or improvement of all parameters was observed in the majority of patients. With the exception of developmental delay/cognitive impairment, these results persisted after 48-96 months in 41 - 55% of the patients (dystonia: 55%, dysarthria: 50%, gait abnormalities: 43%, dysmetria: 41%, respectively). After 24 months of therapy the majority of the evaluable patients (n = 20), demonstrated a stabilization or improvement in the ability to swallow four substances of different consistency (water: 65%, purée: 58%, little pasta: 60%, biscuit: 55%). These results persisted after 48-96 months in 40-50% of patients, with the exception of water swallowing. Stabilization or improvement of the composite severity score was detected in the majority (57%) of 7 patients who were treated early (within 3.5 years from onset) and rarely in patients who received treatment later., Conclusions: The results of this study suggest that miglustat treatment can improve or stabilize neurological manifestations, at least for a period of time; the severity of clinical conditions at the beginning of treatment can influence the rate of disease progression. This conclusion applies particularly to patients with juvenile or adult onset of the disease., Trial Registration: EudraCT number 2006-005842-35.

Objectives: To investigate whether the functional variant Q63R of the cannabinoid 2 (CB2) receptor is associated with susceptibility to oligo/poly-articular juvenile idiopathic arthritis (JIA) and with its clinical features., Method: A total of 171 Italian children with oligoarticular/rheumatoid factor negative poly-articular JIA and 600 healthy controls were enrolled in the study and genotyped., Results: A significant difference in genotype distribution of the CB2 Q63R variant (CNR2 rs35761398) between oligo/poly-articular JIA patients and controls was found (p = 0.001). The R63 variant was associated with increased rates of relapse (p = 0.0001)., Conclusions: This study indicates that the CB2 receptor contributes to susceptibility to oligo/polyarticular JIA and to the severity of its clinical course.

Obesity in childhood is associated with the presence of complications that can undermine health immediately or in the long term. Several conditions, such as pulmonary or orthopedic complications are strictly associated with the severity of overweight, since they are directly associated to the mechanic stress of fat tissue on the airways or on the bones. Other conditions, such as metabolic or liver complications, although increasing with the extent of overweight, are associated with insulin resistance, which can be modulated by different other factors (ethnicity, genetics, fat distribution) and can occur in overweight children as well. No less important are psychological correlates, such as depression and stigma, which can seriously affect the health related quality of life. Pediatric services for the care of childhood obesity need to be able to screen overweight and obese children for the presence of physical and psychological complications, which can be still reversed by weight loss. This article provides pediatricians a comprehensive update on the main complications in obese children and adolescents and their treatment.

Haptoglobin (Hp), serum amyloid A (SAA), C-reactive protein (CRP), and white blood cells (WBC) were assessed in 20 dogs divided into 2 groups. The dogs of group A were not subjected to hunting exercise (control group), while the dogs of group B were subjected to hunting exercise for 3 hr (experimental group). Blood samples were collected from each animal before hunting (T0), immediately after 3 hr of hunting (T1), and after 1 hr of recovery (T2). The general linear model (GLM) repeated measures procedure showed a significant difference between the 2 groups (P < 0.0001) and a significant rise (P < 0.0001) in concentration of Hp, SAA, and CRP after hunting exercise, with a consequent decline during recovery period in group B. These parameters could be considered valid and easily obtainable biomarkers in relation to hunting stress in dogs. Additional studies will continue to elucidate the magnitude and the time of response of other acute phase proteins.

The patatin-like phospholipase domain-containing 3 gene (PNPLA3) and the apolipoprotein C3 gene (APOC3) have been studied in relation to liver steatosis and liver disease outcome. The aim of this study was to evaluate the influence of PNPLA3 p.I148M and APOC3 rs2854116 and rs2854117 polymorphisms on the clinical and histological presentation of chronic hepatitis C in an Italian population and their relationship with viral and anthropometric parameters. Patients with hepatitis C (n = 166) entered the study receiving a clinical, histological, virological and biochemical evaluation. APOC3 (rs2854116 and rs2854117) and PNPLA3 (p.I148M) variants were genotyped. PNPLA3 polymorphisms were associated with liver steatosis, which was significantly higher in patients with p.148I/M (P = 0.034) and p.148M/M (P = 0.004) variants than those homozygous for the PNPLA3 wild type. Excluding patients with HCV genotype 3, the association with liver steatosis and PNPLA3 variants was more marked (p.148I/I genotype vs p.148I/M, P = 0.02, and vs p.148M/M, P = 0.005). The APOC3 polymorphism was not associated with any of the evaluated parameters. Among the interacting factors, BMI and waist circumference correlated with liver steatosis (P = 0.008 and 0.004, respectively). Relationship between waist circumference and liver steatosis was analysed for the different PNPLA3 genotypes. Homozygous 148M patients showed a stronger correlation between waist circumference and steatosis than those carrying the other genotypes (P = 0.0047). In our hepatitis C-infected population, the PNPLA3 polymorphism influenced the development of liver steatosis, but not fibrosis progression. APOC3 polymorphisms had no effect on the development of steatosis and no influence on the PNPLA3 polymorphism. The amount of abdominal fat can increase the association of PNPLA3 p.I148M with liver steatosis., (© 2013 John Wiley & Sons Ltd.)

Aim: To screen for neurological and behavioural disorders in a paediatric cohort of patients with coeliac disease (CD) in order to detect possible differences related to compliance with gluten-free diet (GFD)., Methods: We recruited a cohort of 139 patients divided into three groups: A (40 patients with newly diagnosed CD), B (54 patients with CD in remission after GFD) and C (45 patients with potential CD). Patients first underwent a screening neurological visit, detecting signs associated with CD, and then were evaluated with Pediatric Symptom Checklist (PSC), a psychosocial screen for cognitive, emotional and behavioural problems., Results: In the group B as compared to group A, there was a statistically significant decrease (p < 0.05) in the incidence of chronic fatigue, headache and inattention. The same applied to patients compliant to GFD vs. non-compliant. Potential coeliacs turning into overt CD had a higher incidence of headache and inattention compared with potential coeliacs showing normal mucosa. The PSC mean score in group A was statistically higher than in group B., Conclusion: Gluten-free diet had a positive impact on neuropsychiatric symptoms. We suggest the use of PSC in the routine follow-up of coeliacs in order to allow an early detection of psychosocial problems., (©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

West syndrome or infantile spasms is one of the most frequent epileptic syndromes in the first year of life. The clinical symptoms of infantile spasms are very different than any other type of seizure because of both the absence of paroxysmal motor phenomena (i.e., as in a convulsion) and the lack of significant duration of loss of consciousness (i.e., as in absence epilepsy). Infantile spasms may lead to misdiagnosis by pediatricians and other primary care providers. We assessed the missed diagnoses prior to the diagnosis of infantile spasms. We hypothesized that a delay in treatment may have consequences on neurologic outcome. We conducted a multicenter, retrospective, observational study to evaluate occurrence of misdiagnosis and its possible consequences. We performed a multivariate analysis to evaluate the risk for the outcome 2 years after the diagnosis of infantile spasms. We included 83 infants over a 5-year period. The majority of consulted physicians (301 of 362) did not suggest any specific diagnosis while the others suggested gastroesophageal reflux (7 %), constipation (7 %), or colitis (3 %). Results indicated that a poor outcome was related to a delay in diagnosis, which was observed regardless of the existence of cognitive involvement prior to the start of infantile spasms (Relative Risk: RR 12.08 [1.52-96.3]). These results highlight the importance of making an early diagnosis of infantile spasms.

Obesity is a complex public health issue. Recent data indicate the increasing prevalence and severity of obesity in children. Severe obesity is a real chronic condition for the difficulties of long-term clinical treatment, the high drop-out rate, the large burden of health and psychological problems and the high probability of persistence in adulthood. A staged approach for weight management is recommended. The establishment of permanent healthy lifestyle habits aimed at healthy eating, increasing physical activity and reducing sedentary behavior is the first outcome, because of the long-term health benefits of these behaviors. Improvement in medical conditions is also an important sign of long-term health benefits. Rapid weight loss is not pursued, for the implications on growth ad pubertal development and the risk of inducing eating disorders. Children and adolescents with severe obesity should be referred to a pediatric weight management center that has access to a multidisciplinary team with expertise in childhood obesity. This article provides pediatricians a comprehensive and evidence based update on treatment recommendations of severe obesity in children and adolescents.

Purpose: To investigate the electroclinical features and the outcome of patients with typical absences starting before the 3 years of life., Methods: We reviewed the clinical data of patients with absences started before 3 years observed over a 15-year period. Mutation analysis of SLC2A1 (GLUT-1) gene was performed when possible. Their clinical features were compared with those of subjects with a diagnosis of childhood absence epilepsy (CAE)., Results: Among 33 children with absence epilepsy starting before 3 years of life, there were 20 boys and 13 girls. Mean seizure onset was at 28.0 ± 8.3 (range: 8-36) months of life. Two children displayed borderline intellectual functioning at long-term follow-up. Twenty-eight (85%) patients showed excellent response to therapy. Three subjects evolved into a different form of idiopathic generalized epilepsy (IGE). No SLC2A1 mutation was identified in 20 (60.6%) patients tested. The main clinical features of patients with early-onset absences did not differ from those of CAE except for increased prevalence of males (p=0.002) and longer treatment duration (p=0.001) in the former., Conclusions: Strong similarities in the electroclinical features and outcome between children with early-onset absences and those with CAE support the view that these conditions are part of the wide spectrum of IGE., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Antibiotic therapy is a crucial and often life-saving strategy. This study assessed the ability to prescribe antibiotic therapy among a series of Italian postgraduate students in geriatrics and internal medicine. Participants were administered an anonymous questionnaire consisting of self-assessment of their ability to prescribe antibiotics and then manage a case of community-acquired pneumonia. The Wilcoxon test for comparisons between two independent samples was used for statistical analysis. Almost half the 70 students considered their knowledge of antibiotic therapy insufficient and were not satisfied with the notions received during their studies. Indeed, the change in antibiotic therapy required to control acute exacerbation of pneumonia was correctly identified by only 36% of students. Moreover, 38% of them gave the correct answer on factors influencing the duration of antibiotic therapy in the presence of definite improvement of pneumonia. No significant difference was found between the responses of residents in geriatrics and internal medicine. Overall, our study shows that nearly half of our students think they have inadequate antibiotic prescribing skills. This is confirmed by a low ability to establish the best management of the clinical case. To repair this severe shortcoming, different training methods need to be compared and more effective forms of instruction adopted.

Iron deficiency has been linked to obesity. Hepcidin is the main regulator of iron homeostasis and is higher in obese children compared to controls. To gain insight into the link between obesity and hepcidin, we performed an intervention study in 15 obese children. These children were subjected to a 6-month weight loss program and underwent physical examination and iron status and absorption as well as hepcidin, interleukin-6 and leptin serum levels evaluation at baseline and after the weight loss program. After the program all children reduced their body mass index standard deviation score (BMI SDS) of at least 0.5. We observed a significant decrease in hepcidin (P=0.003) and leptin levels (P=0.005), and a significant increase in iron absorption (P=0.02). A direct correlation between the measure of hepcidin and leptin reduction was observed and this correlation appeared significant (r²=0.33, P=0.003) when adjusted for interleukin-6 and BMI SDS variations. In conclusion, we have shown that, in obese children, BMI reduction is associated with hepcidin reduction, potentially improving iron status and absorption. Implications of these findings could be considered in the management of obese children with poor iron status.

Background: Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is a strong candidate gene in autoimmunity susceptibility. In particular, the CTLA4 CT60 A/G dimorphism has been associated with celiac disease (CD) and was reported to be strongly associated with autoimmune thyroid disease (AITD)., Aims: This study aimed to investigate the possible influences of the CTLA4 CT60 A/G polymorphism in the susceptibility of Italian children to CD and in the predisposition to develop AITD in children with CD., Patients and Methods: We genotyped 317 Italian celiac children, including 44 patients (13.9%) who developed AITD after CD diagnosis and 350 controls., Results: The CTLA4 CT60 GG genotype distribution did not show any significant difference between children with CD and control population (p=0.4). On the contrary, the frequency of the GG genotype was significantly higher in patients with CD complicated with AITD than in control subjects (p=0.002) and CD patients without AITD (p=0.02)., Conclusion: Our data show a significant effect of the CTLA4 CT60G allele at the homozygous state on the risk of developing AITD in children with CD and suggest that the reported association of the CTLA4 CT60 A/G polymorphism with CD is limited to the subgroup of patients who are or will be complicated with AITD.

In 2005, the Azienda Ospedaliero-Universitaria of Trieste (AOUT) activated the hospital-based post-acute geriatric evaluation and management unit (PAGEMU). The purpose of the study is to illustrate the activities of the PAGEMU, and to evaluate the effects of personalized and multidisciplinary care on geriatric inpatients. The evaluation for admission in PAGEMU included general admitting criteria, co-morbidity, autonomy, and assessment of the patient's pre-morbid functional status. During the stay, inpatients completed their treatment plan, comprehensive geriatric assessment was carried out, and rehabilitation and nutritional interventions were implemented. If necessary, a new diagnostic-therapeutic plan was provided. A number of 826 patients were evaluated for admission in PAGEMU (612 patients from surgical departments and 214 from medical wards). The mean length of stay was 19.55 days. Re-evaluation of patients at discharge showed a statistically significant improvement in co-morbidity and in self-sufficiency, not in cognitive or mood status. PAGEMU is a valid model both for patient-oriented and for management-oriented objectives, shortening the length of stay in acute care settings and increasing hospital turnover.

Background: Coeliac disease is a complex disorder influenced by environmental and genetic factors. A genome wide linkage study identified the myosin IXB (MYO9B) as a gene possibly associated with coeliac disease. Recently, a Dutch study reported a strong association of a single SNP, rs 2305764, of MYO9B with coeliac disease. However, two successive studies carried out on British and Swedish/Norwegian cohorts reported lack of association of the MYO9B variant with coeliac disease., Aims: The aim of the present study is to verify the effects of the MYO9B rs 2305764 polymorphism on disease risk in a Mediterranean population of coeliac children., Patients and Methods: To address this issue, an association study was performed in 223 (127 females) Italian coeliac children and adolescents and in 600 controls., Results: The allelic frequencies of the MYO9B rs 2305764 polymorphism found in our patients and in the population control were not statistically different (P=0.46)., Conclusion: The MYO9B gene rs 2305764 polymorphism is not associated to coeliac disease in coeliac children from Southern Italy. This is in accordance with the most recent reports. Ethnic differences or a false positive result might explain the discrepancy with the Dutch study.

Background: Melanocortin-4 receptor (MC4R) mutations have been reported as the most common single genetic cause of obesity in some populations and it has been suggested that they may be responsible for more than 4% of early-onset obesity., Objectives: To verify the presence of mutations of the MC4R coding region in children from southern Italy with early-onset obesity., Subjects and Methods: Two-hundred and eight unrelated obese children and adolescents were included in the study. The average age at obesity onset was 4.5+/-2.6 y. MC4R coding region was screened using both single-strand conformation polymorphism (SSCP) analysis and denaturing high-performance liquid chromatography (DHPLC). Automatic sequencing of PCR products of all individuals that showed an aberrant SSCP and/or DHPLC pattern was performed., Results: One novel missense mutation and one previously described polymorphism (Vall03Ile) were identified. The missense mutation C142T, resulting in the substitution of proline with serine at codon 48, within the first MC4R transmembrane domain, was detected at the heterozygous state in a 15-y-old obese girl (body mass index (BMI)=35 kg/m(2)) who has been obese since she was 8 y old. The mutation co-segregated with the obesity phenotype for over three generations and was not found in the control population., Conclusions: Our data show MC4R obesity causing mutations in less than 0.5% of the patients (ie 1 out of 208 patients) and therefore indicate a low prevalence of MC4R variants in the obese population from southern Italy. The specific genetic background of the Mediterranean population could make it difficult for MC4R mutations to produce an essentially polygenic trait such as common obesity, at least during childhood.

The molecular basis for the considerable variation of serum bilirubin levels and the incidence of gallstone formation in patients with congenital dyserythropoietic anemia (CDA) type II are unknown. We show that the combined effect of an increased bilirubin load caused by dyserythropoiesis in CDA II and decreased bilirubin conjugation caused by reduced expression of uridine diphosphate glucuronosyl transferase (UGT1A) would increase the risk of hyperbilirubinemia (P <.005) and gallstone formation (chi(2): P <. 001). The rate of gallstone formation in patients with CDA II is 4. 75-fold the rate of patients without Gilbert's syndrome, and gallstone diagnosis occurs at a younger age (P < 0.01). These findings should be considered during the follow-up of patients with CDA II.