Persistent influence of precession on northern ice sheet variability since the early Pleistocene.

Prior to ~1 million years ago (Ma), variations in global ice volume were dominated by changes in obliquity; however, the role of precession remains unresolved. Using a record of North Atlantic ice rafting spanning the past 1.7 million years, we find that the onset of ice rafting within a given glacial cycle (reflecting ice sheet expansion) consistently occurred during times of decreasing obliquity whereas mass ice wasting (ablation) events were consistently tied to minima in precession. Furthermore, our results suggest that the ubiquitous association between precession-driven mass wasting events and glacial termination is a distinct feature of the mid to late Pleistocene. Before then (increasing), obliquity alone was sufficient to end a glacial cycle, before losing its dominant grip on deglaciation with the southward extension of Northern Hemisphere ice sheets since ~1 Ma.

Plasma dosage of ghrelin, IGF-1, GLP- 1 and leptin related to gastric emptying and esophageal pH-impedance in children with obesity.

PURPOSE: The main aim of the study was to assess the relationship between leptin, ghrelin, insulin-like growth factor 1 (IGF-1), and glucagon-like peptide 1 (GLP-1) blood levels and gastric motility in children with obesity compared to healthy children. Secondary aims were to assess the possible association between these hormones and obesity, reflux impedance parameters, reflux symptoms, other GI disorders, and quality-of-life scores within the same groups. METHODS: Children with obesity plus GERD symptoms and 2 control groups of children with obesity without GERD and healthy lean children aged 4-17 years underwent an auxological evaluation, an assessment of gastro-intestinal symptoms and quality of life, hormonal dosages, and an evaluation of gastric emptying time (GET) through 13C-octanoic acid breath test. RESULTS: No significant association was found between hormones and gastric motility. Leptin and ghrelin levels were significantly associated with obesity parameters. No significant differences were found between GET and hormones of the patients with obesity, either with or without GERD. CONCLUSION: Although we found an association between auxological parameters and both leptin and ghrelin levels, this association did not imply an effect on the upper GI motility. Therefore, our hypothesis that alterations of these hormones in children with obesity could affect gastric emptying, triggering GERD, was not supported by our data.

Glucokinase deficit and birthweight: does maternal hyperglycemia always meet fetal needs?

AIMS: Many authors do not recommend hypoglycemic treatment during pregnancy in women affected by monogenic diabetes due to heterozygous glucokinase (GCK) mutations (MODY 2) in case of affected fetus, because maternal hyperglycemia would be necessary to achieve a normal birthweight. We aimed to evaluate differences in birthweight between MODY 2 affected children according to the parent who carried the mutation. METHODS: We retrospectively studied 48 MODY 2 affected children, whose mothers did not receive hypoglycemic treatment during pregnancy, divided into two groups according to the presence of the mutation in the mother (group A) or in the father (group B). Data were extracted from the database of the Regional Centre of Pediatric Diabetology of the University of Campania, Naples, collected from 1996 to 2016. We analyzed birthweight and centile birthweight. RESULTS: Percentage of small for gestational age was significantly higher in group B than in group A. We found three large for gestational age in the group that inherited the deficit from the mother, all with the same novel GCK mutation (p.Lys458-Cys461del). CONCLUSIONS: We hypothesize that not all MODY 2 affected fetuses need the same levels of hyperglycemia to have an appropriate growth, maybe because different kinds of GCK mutations may result in different phenotypes. Consequently, a "tailored therapy" of maternal hyperglycemia, based on fetal growth frequently monitored through ultrasounds, is essential in MODY 2 pregnancies.

Disorders of glucose metabolism in Prader-Willi syndrome: Results of a multicenter Italian cohort study.

BACKGROUND AND AIMS: Prader-Willi syndrome (PWS) is characterized by a high incidence of altered glucose metabolism (AGM). However, epidemiological data on impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) are still discordant. METHODS AND RESULTS: We performed a multicenter study based on 274 PWS patients [144 females, aged 20.3 ± 10.4 yrs (range: 8.1-50.1 years)] evaluating the prevalence for AGM in the entire group, and according to age (children <10 yrs; adolescents 10-18 yrs, and adults >18 yrs), Body Mass Index (BMI = kg/m(2)), gender, genotypes (deletion or uniparental disomy for chromosome 15), and GH therapy (GHT) (untreated, previously or currently treated). Altogether, AGM was detected in 67 (24.4%) of patients (0.7% IFG, 10.2% IGT, 13.5% T2DM). The prevalence of AGM was correlated to age (p = 0.001), BMI (p = 0.001) and HOMA-IR (p = 0.001). However, gender, genotype, and GHT did not influence AGM development in univariate analysis. These data were confirmed as positive predictors when inserted in a multivariate analysis model. CONCLUSION: This study is the first report on the prevalence of AGM in a large population of PWS. Overall, PWS subjects show a high prevalence of AGM that appears more common in obese and adult subjects. Our data confirm the main role of obesity on the individual metabolic risk clustering in PWS, and thus reinforce the concept that improvement in weight control remains the most important goal of any PWS treatment program.

[Health consequences of obesity in children and adolescents]. / Conseguenze dell'obesità sulla salute del bambino e dell' adolescente.

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.

Health-related quality of life and treatment preferences in adolescents with type 1 diabetes. The VIPKIDS study.

A multi-centre, observational, cross-sectional study was carried out to determine whether the health-related quality of life (HRQOL) of adolescents with type 1 diabetes is affected by different insulin treatment systems, and which features of HRQOL are impacted by the respective insulin treatment. The study regarded 577 adolescents, aged 10-17 years, with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) (n = 306) or multiple daily injections (MDI) (n = 271). The Insulin Delivery System Rating Questionnaire was validated in Italian and was self-completed by the subjects during a routine visit to the centres. Subjects were compared following the domains of the questionnaire. Good HRQOL was seen in subjects treated with either MDI or CSII. Significant differences were not found in the domains for general diabetes, including diabetes worries, social burden and psychological well-being. Multiple quantile regression analysis showed that CSII confers significant advantages in terms of HRQOL with improvements in treatment satisfaction, perceived clinical efficacy and reduction in treatment interference with daily activities. This favourable impact was more evident in subjects reporting lower HRQOL scores, suggesting that CSII may be especially useful for individuals perceiving a poor HRQOL. Analysis of the domains indicated that CSII was associated with a higher HRQOL than MDI. Life-course HRQOL evaluation using a standardised questionnaire can ensure better chronic disease management. This is particularly important when providing individualised care for adolescents, as they become increasingly responsible for managing their diabetes.

[Management of children and adolescents with severe obesity]. / Il percorsi terapeutico del bambino e dell' adolescente con obesità grave.

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.

Four novel UCP3 gene variants associated with childhood obesity: effect on fatty acid oxidation and on prevention of triglyceride storage.

OBJECTIVE: The objective of the study was to look for uncoupling protein 3 (UCP3) gene variants in early-onset severe childhood obesity and to determine their effect on long-chain fatty acid oxidation and triglyceride storage. METHODS AND RESULTS: We identified four novel mutations in the UCP3 gene (V56M, A111V, V192I and Q252X) in 200 children with severe, early-onset obesity (body mass index-standard deviation score >2.5; onset: <4 years) living in Southern Italy. We evaluated the role of wild-type (wt) and mutant UCP3 proteins in palmitate oxidation and in triglyceride storage in human embryonic kidney cells (HEK293). Palmitate oxidation was ∼60% lower (P<0.05; P<0.01) and triglyceride storage was higher in HEK293 cells expressing the four UCP3 mutants than in cells expressing wt UCP3. Moreover, mutants V56M and Q252X exerted a dominant-negative effect on wt protein activity (P<0.01 and P<0.05, respectively). Telmisartan, an angiotensin II receptor antagonist used in the management of hypertension, significantly (P<0.05) increased palmitate oxidation in HEK293 cells expressing wt and mutant proteins (P<0.05; P<0.01), including the dominant-negative mutants. CONCLUSIONS: These data indicate that protein UCP3 affects long-chain fatty acid metabolism and can prevent cytosolic triglyceride storage. Our results also suggest that telmisartan, which increases fatty acid oxidation in rat skeletal muscle, also improves UCP3 wt and mutant protein activity, including the dominant-negative UCP3 mutants.

A case of Klinefelter syndrome, mosaicism (46,XY/47,XXY), associated with anorexia nervosa.

We report the case of a 12.4-yr-old boy who presented Klinefelter syndrome (KS) mosaicism (46,XY/47,XXY), associated with mental retardation and anorexia nervosa (AN). KS was undiagnosed before hospitalization in a psychiatric unit. The patient was referred to a child psychiatric unit for restrictive eating. The medical history showed long standing feeding difficulties and failure to thrive. The patient was pre-pubertal and other clinical characteristics were: microcephaly, short stature and dysmorphic traits. Cytogenetic analysis revealed a mosaicism, 46,XY[11] and 47,XXY[19] karyotype. The psychiatric assessment demonstrated the presence of AN and low mood. No specific pathophysiological links between the alterations of KS and the development of AN should be hypothesized on the basis of this case report. In pre-pubertal boys with mental disorders, the possibility of KS should be considered, independently of the presence of eating disorders. Nevertheless, the case shows that KS can be first detected during an assessment for eating disorders. Few cases of the association of KS with AN have been previously reported in literature. This is the first description of KS, mosaicism (46,XY/47,XXY), associated with AN and mental retardation. This case report illustrates the need, for clinicians who work with eating disorders, to investigate the possible association between AN and KS, a rare but intriguing one.

Insulin resistance is a risk factor for high blood pressure regardless of body size and fat distribution in obese children.

BACKGROUND AND AIM: The prevalence of children with hypertension is increasing, especially in obese children. This study was to assess the relationship between blood pressure, indexes of adiposity, body fat distribution and insulin resistance. SAMPLE: 1044 children (M/F: 484/560; aged 6-11 years). Anthropometry and blood pressure were measured and fasting blood samples were tested for triacylglycerol, total cholesterol, HDL cholesterol, glucose, insulin and ALT. The prevalence of high blood pressure in overweight males and females was 14.3 and 6.4%, respectively (chi(2)=16.73, p<0.001) and in obese it was 40.4 and 32.8%, respectively (chi(2)=5.56, p<0.001). High blood pressure increased progressively with BMI z-score categories (chi(2)=67.99, p<0.001) as well as with waist/height ratio (W/Hr) categories (chi(2)=23.51, p<0.001). Hypertensive subject had significantly higher insulin (15.6+/-9.8 vs 11.9+/-7.2, p<0.001 and 20.63+/-14.7 vs 15.26+/-9.8, p<0.001 in males and females respectively) and HOMA(IR) (3.23+/-2.1 vs 2.42+/-1.49, p<0.001 and 4.12+/-2.87 vs 3.07+/-1.98, p<0.001 in males and in females, respectively) than non-hypertensive ones. Among metabolic and cardiovascular risk factors, HOMA(IR) was the only variable able to predict high blood pressure in obese boys and girls, in addition to BMI or body fat distribution (waist, W/Hr). The highest HOMA(IR) category was the most important predicting factor of high blood pressure in overweight and obese children in addition to body size or body fat distribution. CONCLUSIONS: Blood pressure is associated with the degree of overweight and the indices of body fat distribution. Insulin resistance is an independent additional risk factor for hypertension.

A survey on Prader-Willi syndrome in the Italian population: prevalence of historical and clinical signs.

Clinical criteria for the diagnosis of Prader-Willi Syndrome (PWS) were established by consensus in 1993 (Holm et al.). Specific molecular testing is now available and the purpose of diagnostic criteria has shifted to identify individuals to test, thus avoiding the expense of unnecessary analysis. The aim of this study was to find clinical indicators to select patients with suspected PWS for laboratory testing. We analyzed the prevalence of clinical signs and symptoms in 147 genetically diagnosed Italian patients with PWS (67 males and 80 females), aged from 9 months to 34.6 years (13.6 +/- 8.3 years), using the consensus diagnostic criteria, and according to age, sex and type of genetic abnormality. The prevalence of several clinical features changed significantly with age, but very few with sex. According to genetic subtypes (deletion vs UPD), only hypopigmentation and acromicria were more frequent in patients with deletion. Some criteria considered as minor or supportive by Holm et al. have higher prevalence than some major criteria. In conclusion, in order to identify patients with suspected PWS to submit to laboratory testing, we recommend a classification of clinical criteria according to age, giving more attention to those so-called minor or supportive criteria.

Is resistin a link between highly active antiretroviral therapy and fat redistribution in HIV-infected children?

OBJECTIVES: To assess the features of fat redistribution, detected by clinical and ultrasound (US) methods, and the presence of metabolic disorders in HIV-infected children undergoing antiretroviral therapy. To evaluate if serum levels of resistin, a hormone produced only by visceral adipose tissue, are a marker of fat redistribution in these patients. DESIGN AND METHODS: Forty-five consecutive symptomatic HIV-infected children were considered for inclusion in the study. Patients were enrolled if treated for at least 6 months with antiretroviral therapy with or without protease inhibitor (PI) and if compliant to the study protocol. Patients were evaluated for: anthropometric measures, fat redistribution by clinical and US methods, serum lipids, parameters of insulin resistance by homeostasis model assessment for insulin resistance, serum resistin levels by an enzyme-linked immunosorbent assay. RESULTS: Eighteen children fulfilled the inclusion criteria and were enrolled in the study. Twelve (66%) children had clinical and/or US evidence of fat redistribution; 9 (75%) of them were on PI therapy; only 3 of 6 children without fat redistribution were on PI therapy (p<0.05). Serum lipids and insulin resistance parameters did not differ between children with or without fat redistribution. There was a highly significant linear correlation between visceral fat detected by US and circulating resistin levels (r=0.87; p<0.0001). CONCLUSIONS: Fat redistribution occurred in most HIV-infected children undergoing PI therapy. Because serum resistin levels reflect the amount of visceral fat, they could be considered a sensitive marker of fat redistribution in HIV-infected children.

Update on coeliac disease and type 1 diabetes mellitus in childhood.

The increased prevalence of coeliac disease (CD) among children with type 1 diabetes mellitus (DM1) implies that there is more than a simple association. A link between the gut immune system and DM1 has been suggested both in animal models and in humans. We review the literature on the epidemiology and genetic and clinical aspects shared by these two diseases and speculate on the role of gluten on the possible relationship between CD and DM1, on the basis of recent animal and human studies. The data suggest a failure in oral tolerance mechanisms in DM1 other than that in CD. It remains to be understood why only a small proportion of patients with DM1 proceed to the production of coeliac-associated antibodies and to overt enteropathy.

Insulin resistance and impaired glucose tolerance in obese children and adolescents from Southern Italy.

BACKGROUND AND AIM: Obesity in children may lead to insulin resistance and impaired glucose regulation over time. The aim of this study was to investigate the insulin resistance status and the frequency of impaired glucose regulation in obese children and adolescents from the Campania region (Southern Italy), where the prevalence of obesity is among the highest in Europe. METHODS AND RESULTS: We studied 100 (62 male) Italian obese children and adolescents (mean age 10.1+/-2.7 years) and 50 (27 male) normal weight healthy subjects (mean age 10.2+/-2.7 years). Anthropometric measures and biochemical tests were performed in all subjects. In obese patients an oral glucose tolerance test was also performed. The estimate of insulin resistance was calculated by a homeostasis model assessment (HOMA) index. A cut-off HOMA level of >2.5 in children and >4.0 in adolescents was used to identify an insulin-resistance status. Insulin resistance was found in 40.8% of obese children and 41.2% of obese adolescents, whereas it was found in 3.0% of normal children and none of the 17 normal adolescents (p<0.0001 and p<0.002, respectively). None of the subjects had impaired fasting glucose or diabetes, while 4 obese patients had impaired glucose tolerance (4%). CONCLUSIONS: Impaired glucose tolerance is still rare whereas insulin-resistance is already detectable in more than 40% of obese children and adolescents in Southern Italy. Our observations confirm that metabolic risk factors can be found at a very early age and strengthen the case for implementing programmes for prevention and treatment of childhood obesity.

Management of diabetes in childhood: are children small adults?

Diabetes in childhood is the most common chronic disease and generally fits the type 1 category, even though other forms of non-autoimmune diabetes are now emerging in this age. At variance with adults, children and adolescents undergo physiological process, which may frequently require adjustments of clinical management of diabetes. Moreover, the hormonal and psychological changes during puberty may be crucial in conditioning management. Furthermore, common illnesses frequently affecting children may also destabilise metabolic control. Consequently, education in children is the cornerstone of treatment. This review focuses on the several and peculiar aspects of practical management of diabetes in paediatric age, which require professional figures such as paediatricians, nurses, dieticians, psychologists, social assistants originally trained in paediatric area, able to deal with the age-related medical, educational, nutritional and behavioural issues of diabetes.

Adrenocortical tumor in a boy: final height is not impaired despite a severe advancement of bone age.

The long-term sequelae on the growth pattern in successfully resected virilizing adrenal tumors (ACT) have not been clearly defined. We report on 10 years follow-up of a boy with virilizing ACT until the attainment of final height. This is the first clinical description in a boy with a marked advancement of bone age, indicating that despite advanced physical and skeletal maturity the prognosis on growth is good, provided that regression of virilization is obtained.

Comparison between different methods to assess the prevalence of obesity in a sample of Italian children.

The aim of this study was to compare how different diagnostic criteria can influence the estimation of obesity in children. Five hundred and eighty-seven children from Southern Italy were evaluated for the presence of obesity according to six different methods: two using Ideal Body Weight, according to Tanner and the National Center for Health Statistics, and four using Body Mass Index, according to Rolland-Cachera, Must, Cole (International Obesity Task Force) and the Centers for Disease Control and Prevention. Large discrepancies were found between old and new methods in identifying childhood obesity with respect to absolute prevalence, differences between the sexes, and age-related trends. The use of different weight-height indices, the employment of different cut-off points, the large differences between the reference populations, and the different time periods of data collection explain differences between methods. This should be always taken into consideration when data from different epidemiological or clinical studies are compared.

Severe clinical onset of diabetes and increased prevalence of other autoimmune diseases in children with coeliac disease diagnosed before diabetes mellitus.

AIMS/HYPOTHESIS: To analyse whether the time of diagnosis of coeliac disease with respect to the clinical onset of diabetes could differentiate subgroups of varying severity in patients with both diseases. METHODS: We investigated 383 patients with Type I (insulin-dependent) diabetes mellitus for coeliac disease. Sex distribution, age at diagnosis of diabetes, prevalence of ketoacidosis at the onset of diabetes and prevalence of other autoimmune diseases were compared in patients. We divided these patients according to whether coeliac disease was diagnosed before (Group A, n=8) or after (Group B, n=24) diabetes onset and whether they had presented clinical symptoms of coeliac disease. Group C (n=351) included diabetic patients without coeliac disease. RESULTS: Out of 383 Type I diabetic patients we found 32 coeliac subjects (8.3%). There was a higher number of girls (p=0.003), but similar age and prevalence of ketoacidosis compared with Group C; 18.7% had a third autoimmune disorder. The higher number of girls was confirmed in Groups A and B in comparison to Group C (p=0.013), while higher prevalence of both ketoacidosis (p=0.009) and other autoimmune diseases (p=0.001) was found only in Group A. Compared with symptomatic patients, asymptomatic subjects in Group B had a lower number of girls, older age at diabetes onset, lower prevalence of ketoacidosis and no other associated autoimmune disease. CONCLUSIONS/INTERPRETATION: A wide clinical spectrum characterises the association of coeliac disease and diabetes mellitus, with a severe clinical presentation (higher prevalence of ketoacidosis at the onset and occurrence of other autoimmune diseases) when coeliac disease is diagnosed before diabetes. Distinct phenotypes might imply the contribution of a peculiar genetic background.