Inverse Association Between Hypothalamic N-Acetyl Aspartate/Creatine Ratio and Indices of Body Mass in Adolescents with Obesity.

BACKGROUND: Approximately 10% of adolescents worldwide are overweight or obese, hence the urgent and universal need to elucidate possible mechanisms that lead to obesity in the adolescent population. OBJECTIVES: We examined the hypothalamic metabolism and its relationship with physical development in obese and eutrophic adolescents. METHODS: We performed a case-control study with 115 adolescents between 11 and 18 years of age, to compare obese (BMI z-score ≥ 2) and nonobese individuals (eutrophic controls; BMI z-score ≤ 1). The following hypothalamic metabolite ratios were examined as primary outcomes: glutamate/creatine (Cr), the sum of glutamate and glutamine/Cr, N-acetylaspartate (NAA)/Cr, myoinositol/Cr, and total choline/Cr (glycerophosphocholine +  phosphocholine/Cr), quantified by magnetic resonance spectroscopy. BMI z-scores, pubertal status, and scores on the Yale Food Addiction Scale, the Binge Eating Scale, and the Child Depression Inventory were assessed as secondary outcomes. Pearson coefficients (r) or nonparametric Spearman correlation (rho) analyses were performed between hypothalamic metabolite ratios and other parameters, such as BMI z-scores, physical development, food habits, depression symptoms, and serum protein concentrations (cytokines, hormones, and neuropeptides). RESULTS: Adolescents with obesity showed a lower hypothalamic NAA/Cr ratio (0.70 ± 0.19) compared to their eutrophic counterparts (0.84 ± 0.20; P = 0.004). The NAA/Cr ratio was negatively correlated with BMI z-scores (r = -0.25; P = 0.03) and serum insulin (rho = -0.27; P = 0.04), C-peptide (rho = -0.26; P = 0.04), amylin (r = -0.27; P = 0.04), ghrelin (rho = -0.30; P = 0.02), and neuropeptide Y (r = -0.27; P = 0.04). Also, the NAA/Cr ratio was positively correlated with circulating IL-8 levels (rho = 0.26; P = 0.04). CONCLUSIONS: High BMI z-scores are associated with lower hypothalamic NAA/Cr ratios. The negative correlations found between the NAA/Cr ratio and serum cytokines, hormones, and neuropeptides suggest a broad cross-talk linking hormonal imbalances, neurohumoral alterations, and hypothalamic functions in adolescents with obesity.

Sex dimorphism in inflammatory response to obesity in childhood.

BACKGROUND: Childhood overweight and obesity are a global concern, with prevalence rising dramatically over the last decades. The condition is caused by an increase in energy intake and reduction of physical activity, leading to excessive fat accumulation, followed by systemic chronic inflammation and altered function of immune cell responses. This study aimed at providing new insights regarding sex-specificity on the inflammatory response to obesity in the young patient. DESIGN: Forty-three Brazilian obese adolescents (Female = 22 and Male=21, BMI (body mass index) Z-score average = 2.78 ± 0.51) and forty-nine eutrophic adolescents (Female = 24 and Male = 25, BMI Z-score average = -0.35 ± 0.88) were enrolled in the study. Anthropometrical analyses and blood cell counts were carried out. Using Luminex®xMAP™ technology, circulating serum cytokines, chemokines, and inflammatory biomarkers were analyzed. Two-way ANOVA test, Tukey's test, and Spearman's correlation coefficient were employed, with a significance threshold set at p < 0.05. RESULTS: We identified increased levels of serum amyloid A (SAA), platelets, and leukocytes solely in male obese patients. We found a noteworthy sex-dependent pattern in regard to inflammatory response: obese boys showed higher TNFß, IL15, and IL2 and lower IL10 and IL13, while obese girls showed increased TNFα, CCL3, CCL4, and IP10 content in the circulation. BMI Z-score was significantly linearly correlated with neutrophils, leukocytes, platelets, SAA, TNFα, CCL3, CCL4, IP10, and IL13 levels within the entire cohort (non-sex-dependent). CONCLUSIONS: Our data support a complex relationship between adiposity, blood cell count, and circulating inflammatory cytokine content. High SAA levels suggest that this factor may play a critical role in local and systemic inflammation. In the eutrophic group, females presented a lower status of inflammation, as compared to males. Both obese boys and girls showed an increased inflammatory response in relation to eutrophic counterparts. Taken together, results point out to clear sex dimorphism in the inflammatory profile of obese adolescents.

Bone age determination in eutrophic, overweight and obese Brazilian children and adolescents: a comparison between computerized BoneXpert and Greulich-Pyle methods.

BACKGROUND: Bone age determination is usually employed to evaluate growth disorders and their treatment. The Greulich-Pyle method is the simplest and most frequently used type of evaluation, but it presents huge interobserver variability. The BoneXpert is a computer-automated method developed to avoid significant bone age variability among distinct observers. OBJECTIVE: To compare the BoneXpert and Greulich-Pyle methods of bone age determination in eutrophic children and adolescents, as well as in overweight and obese pediatric patients. MATERIALS AND METHODS: The sample comprised 515 participants, 253 boys (159 eutrophic, 53 overweight and 41 obese) and 262 girls (146 eutrophic, 76 overweight and 40 obese). Left hand and wrist radiographs were acquired for bone age determination using both methods. RESULTS: There was a positive correlation between chronological age and Greulich-Pyle, chronological age and BoneXpert, and Greulich-Pyle and BoneXpert. There was a significant increase (P<0.05) in bone age in both the Greulich-Pyle and BoneXpert methods in obese boys when compared to eutrophic or overweight boys of the same age. In girls, there was an increase in bone age in both obese and overweight individuals when compared to eutrophic girls (P<0.05). The Greulich-Pyle bone age was advanced in comparison to that of BoneXpert in all groups, except in obese boys, in which bone age was similarly advanced in both methods. CONCLUSION: The BoneXpert computer-automated bone age determination method showed a significant positive correlation with chronological age and Greulich-Pyle. Furthermore, the impact of being overweight or obese on bone age could be identified by both methods.

Height Increment and Laboratory Profile of Boys Treated With Aromatase Inhibitors With or Without Growth Hormone.

Aromatase inhibitors (AIs) have been used to recover height loss due to their capacity to delay growth plate closure. Long-term studies describing final heights are needed to determine the efficacy and safety profiles of these drugs for the treatment of impaired growth. This study aims to identify the therapeutic efficiency of AIs in improve growth and to describe potential adverse effects during treatment. Retrospective data analysis of 96 adolescents, among which 22 patients already attained near-final height, were followed at outpatient clinics of two referral centers. Patients were all in puberty and present idiopathic decrease in predicted adult height. Patients were treated with Anastrozole (ANZ: 1 mg/day) or Letrozole (LTZ: 2.5 mg/day) with/without recombinant human growth hormone (0.05 mg/kg/day) for 1.0 to 3.5 years (2.1±1.2 years). Height gain, body mass index, lipid, liver enzyme, gonadotropins and testosterone levels were described before and at the end of treatment. Predicted adult height (PAH) and NF height were compared with the TH. The height SDS (adjusted to bone age) significantly increased (p<0.05) in all groups [0.8±0.7 (ANZ), 0.7±0.7 (ANZ+GH), 0.3±0.5 (LTZ), and 1.2±0.8 (LTZ+GH)]; the latter group exhibited the highest increment of PAH and growth recovery to the TH (p<0.004). No significant side effects were observed. AI treatment, especially when used in association with GH was able to improve growth and the attainment of familial target height.

Central precocious puberty caused by mutations in the imprinted gene MKRN3.

BACKGROUND: The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS: We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS: We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS: Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.).

Comparison of methods for the measurement of body composition in overweight and obese Brazilian children and adolescents before and after a lifestyle modification program.

AIM: To compare the body composition of overweight children and adolescents by bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA) before and after physical activity program. METHODS: One hundred and eleven patients with mean age (SD) of 12 (1.9) participated in the study. We assessed the weight, height, waist circumference (WC), and body composition by DXA and BIA. Patients underwent a program of diet and physical activity (1 h 30 min/day, 3 times a week for 3 months) and were evaluated before and after this period. RESULTS: Mean initial zBMI were 2.3 (0.5) and waist SDS 5.9 (1.8). Significant differences were observed when we compared the measurements taken by DXA and BIA, respectively: total body fat percentage (40 and 31.5) and fat-free mass (43.1 and 50.6 kg). Regarding the trunk fat by DXA, there was a positive correlation with the WC/height ratio (r = 0.65; p < 0.01). After the intervention period, we observed a reduction in the zBMI, waist SDS, and total body fat and increase of fat-free mass by DXA. BIA only detected reduction in fat. CONCLUSION: BIA underestimates the percentage of fat and overestimates fat-free mass in relation to DXA. There is positive correlation between trunk fat and the ratio WC/height. In addition, DXA detected changes in body composition induced by a short period of physical training, unlike BIA.

Risk of Atherosclerosis in Patients with Ataxia Telangiectasia.

BACKGROUND AND AIMS: Evaluate the nutritional status, plasma concentration of vitamin E and markers of cardiovascular risk in ataxia telangiectasia (AT) patients. METHODS: Cross-sectional study with 13 patients with AT and 22 healthy controls, evaluating the following factors: nutritional status, food intake, lipid profile, plasma concentration of vitamin E, malondialdehyde and high sensitivity C-reactive protein, linking them with atherosclerosis risk in AT patients. RESULTS: Average age was 14.6 in the AT group, 30.8% were malnourished and 23.1% had stunting. A greater impairment of lean body mass was found in these patients. Concentrations of triglycerides (TG), total cholesterol (CT), LDL-c, non-HDL cholesterol (NHDL-c) were significantly higher in patients and HDL-c, lower. Vitamin E/total lipids and vitamin E/TG ratios were lower in the AT group, and significant inverse correlation between these ratios and NHDL-c, CT/HDL-c, and LDL-c/HDL-c, log TG/HDL-c was observed in the AT group. Alanine aminotransferase correlated directly and significantly with NHDL-c, CT/HDL-c and LDL-c/HDL-c, in patients. CONCLUSION: The alterations of lipid metabolism biomarkers suggestive of atherosclerotic risk of male AT patients coupled with lower vitamin E/total lipids ratio and low lean body mass may complicate the clinical course of the disease and emphasizes the importance of multidisciplinary care, routine monitoring of cardiovascular biomarkers and appropriate nutritional guidance.

Trio-based whole exome sequencing in patients with ectopic posterior pituitary.

Introduction: Ectopic posterior pituitary (EPP) is a rare congenital abnormality, sometimes associated with other midline defects, such as pituitary stalk interruption syndrome (PSIS), in which thin or absent pituitary stalk and anterior pituitary hypoplasia are combined to EPP. Most cases are sporadic, with few reports of familial cases, and many congenital hypopituitarism (CH) cases remain unsolved. Objective: To search for candidate genes associated with this condition, we performed trio-based whole-exome sequencing (WES) on patients with EPP, including two familial cases. Methods: This study included subjects with EPP and PSIS diagnosed by a simple MRI protocol (FAST1.2). We performed two distinct analyses in the trio-based WES. We looked for previously described genes associated with pituitary development. Next, we investigated the whole exome for variants inherited in a pattern consistent with a monogenic etiology. Results: Ten families were evaluated; eight were composed of a child with EPP and healthy parents, one has two affected siblings, and one family has a son and mother with EPP. When analyzing the previously described candidate variants associated with pituitary development, we found variants in GLI2 and FGFR1 in three families. We also found six other variants of interest in three patients: KMT2A, GALR3, RTN4R, SEMA3A, NIPBL, and DSCAML1. Conclusion: The analysis allowed us to find previously reported and not reported GLI2 variants, all inherited from healthy parents, which reinforces the incomplete penetrance pattern of GLI2 variants in the development of EPP and draws attention to possible future functional studies of those variants that have a recurrent expression in CH. We also found novel FGFR1 and SEMA3A variants that suggest an oligogenic mechanism in PSIS and EPP, as seen in patients with hypogonadotropic hypogonadism. We report the first case of a patient with Wiedemann-Steiner syndrome and PSIS, suggesting that the KMT2A gene may be related to pituitary development. Furthermore, the trios' analysis allowed us to find five other variants of interest. Future investigations may clarify the roles of these variants in the etiology of EPP and PSIS.

Metabolic risk factors in prepubertal and pubertal patients with overweight and obesity.

OBJECTIVES: Metabolic syndrome (MetS) is a cluster of conditions linked to obesity that increases cardiovascular risk. We evaluated the frequency of clinical abnormalities associated with overweight and obesity in childhood, to determine whether a diagnosis of MetS is appropriate in this population. METHODS: Cross-sectional study with 116 pubertal and prepubertal children with a mean age (SD) of 10.9 (2.5) years, with overweight and obesity. We defined MetS using the International Diabetes Federation criteria, regardless of the age. RESULTS: 45 patients met the criteria, 20 had at least one metabolic abnormality in addition to a high waist circumference (WC), and seven with WC below percentile 90th, had at least one metabolic abnormality. The prepubertal had higher zBMI [3.1 (2.6-3.8) vs. 2.8 (2.4-3.3); p=0.037], less lean body mass (kg) [27.13 (7.3) vs. 34.13 (9.8); p=0.005] and a similar frequency of non-alcoholic fatty liver disease (NAFLD) compared to the pubertal [44.7 vs. 35.9; p=0.323]. Prepubertal with NAFLD had higher zBMI, lower HDL levels, higher TG/HDL ratios and higher fat percentages; while pubertal with NAFLD had higher WC/height, aspartate aminotransferase and oxaloacetic transaminase. CONCLUSIONS: The diagnosis of MetS in childhood is not fundamental. Individualized management, focusing on the earliest age groups, in which we identified a more severe degree of obesity, should be done. We also recommend screening for NAFLD in all ages, due to the high prevalence observed.

Hepatic fibrosis: a manifestation of the liver disease evolution in patients with Ataxia-telangiectasia.

BACKGROUND: Ataxia-telangiectasia (A-T) is a DNA repair disorder characterized by changes in several organs and systems. Advances in clinical protocols have resulted in increased survival of A-T patients, however disease progression is evident, mainly through metabolic and liver changes. OBJECTIVE: To identify the frequency of significant hepatic fibrosis in A-T patients and to verify the association with metabolic alterations and degree of ataxia. METHODS: This is a cross-sectional study that included 25 A-T patients aged 5 to 31 years. Anthropometric data, liver, inflammatory, lipid metabolism and glucose biomarkers (oral glucose tolerance test with insulin curve-OGTT) were collected. The Cooperative Ataxia Rating Scale was applied to assess the degree of ataxia. The following were calculated: Homeostasis Model Assessment-Insulin Resistance, Homeostasis Model Assessment-Adiponectin (HOMA-AD), Matsuda index, aspartate aminotransferase (AST): platelet ratio index, nonalcoholic fatty liver disease fibrosis score and BARD score. Liver ultrasonography and transient liver elastography by FibroScan® were performed. RESULTS: Significant hepatic fibrosis was observed in 5/25 (20%). Patients in the group with significant hepatic fibrosis were older (p < 0.001), had lower platelet count values (p = 0.027), serum albumin (p = 0.019), HDL-c (p = 0.013) and Matsuda index (p = 0.044); and high values of LDL-c (p = 0.049), AST (p = 0.001), alanine aminotransferase (p = 0.002), gamma-glutamyl transferase (p = 0.001), ferritin (p = 0.001), 120-min glycemia by OGTT (p = 0.049), HOMA-AD (p = 0.016) and degree of ataxia (p = 0.009). CONCLUSIONS: A non-invasive diagnosis of significant hepatic fibrosis was observed in 20% of A-T patients associated with changes in liver enzymes, ferritin, increased HOMA-AD, and the severity of ataxia in comparison with patients without hepatic fibrosis.

Childhood obesity: an ecological perspective.

OBJECTIVE: To describe the participation of the environment in the childhood obesity epidemic, since childhood obesity currently represents a great challenge, with high prevalence worldwide, including in Brazil. DATA SOURCE: Survey of articles published in the last 10 years in PubMed, evaluating the interface between the environment and childhood obesity. DATA SYNTHESIS: Recent studies show that the environment is very important in the etiopathogenesis of obesity and its comorbidities. Therefore, factors such as air pollution, exposure to chemical substances that interfere with the metabolism, excessive consumption of ultra-processed foods, changes in the intestinal microbiota, and sedentary lifestyle are associated with increased obesity, insulin resistance, type 2 diabetes, and changes in lipid metabolism. These factors have a greater impact on some stages of life, such as the first thousand days, as they affect the expression of genes that control the adipogenesis, energy expenditure, and the mechanisms for hunger/satiety control. CONCLUSIONS: Environmental aspects must be taken into account in the prevention and treatment of childhood obesity, both from the individual and the population point of view, with adequate and comprehensive public health policies.

The impact of COVID-19 in children and adolescents with obesity in Brazil.

Objective: The primary goal of the study was to evaluate weight gain in children and adolescents with obesity during the COVID-19 pandemic period, and compare it with the period before the pandemic. Methods: The sample comprised 68 children with obesity aged between 7 and 18 years, 30 (44.1%) boys and 38 (55.9%) girls, who were attended at the pediatric endocrinology clinic of the Irmandade da Santa Casa de Misericórdia de São Paulo, SP, Brazil. Weight gain in the sample in the pre-lockdown period (December 2, 2018 to March 11, 2020) was compared with that in the lockdown period (March 11, 2020 to February 21, 2021). Results: Approximately one year before the start of the pandemic period, the mean (SD) chronological age was 10.1 years old (± 2.4), and an average weight gain of 4.4 kg (± 4.8) was observed during the pre-lockdown period described. One year after the start of the pandemic, mean (SD) chronological age was 11.8 years old (± 2.4), and an average weight gain of 8.5 kg (± 7.6) was observed in the lockdown period described. When we compared the weight gain in the two periods, it was higher in the pandemic period, both in girls and boys (p = 0.013 and 0.035, respectively). Conclusion: The results of the study show that the period of social isolation adopted to mitigate the COVID-19 pandemic was associated with increased weight gain in the studied population, probably due to a reduction in physical activities and an increase in energy consumption.

Probiotic therapy outcomes in body composition of children and adolescent with obesity, a nonrandomized controlled trial.

Objective: The objective of this study was to evaluate the impact of probiotic supplementation therapy on anthropometric values and body composition of children and adolescent with obesity. Subjects and Methods: This is a nonrandomized controlled, prospective, double-blind interventional clinical trial with primary data analysis. The sample comprised 44 pubertal children and adolescent (8-17 years old) with obesity. The patients were allocated to probiotic (Lactobacillus rhamnosus) or placebo group, with matching of gender and chronological age. Both groups received nutritional guidance, and were followed for six months. In all patients the anthropometric assessment was carried out by a nutritionist and data on weight, height and waist circumference (WC) were collected. Body composition was assessed using dual emission X-ray absorptiometry (DXA). Results: After six months, both groups had increased weight, height but reduced body index mass (BMI) standard deviation score, with no differences between groups. After the intervention, both groups showed a reduction in the percentage of total body fat and an increase in lean mass, but only the placebo group showed a reduction in the percentage of trunk fat. However, the variation in these parameters did not differ between groups. Conclusion: The probiotic group does not seem to have benefited from supplementation. However, we suggest that this reduction in BMI SDS in both groups may have occurred due to improvements in diet because of the nutritional advice given throughout the therapy. We concluded that supplementation with this strain of probiotic was not effective in promoting weight loss or improving the body composition of this population.

Whole Exome Sequencing in Patients With Ectopic Posterior Pituitary.

Context: Ectopic posterior pituitary (EPP), a condition in which the posterior pituitary gland is displaced due to defective neuronal migration, is frequently associated with hypopituitarism. Genetic variants play a role, but many cases remain unexplained. Objective: A large EPP cohort was studied to explore the importance of genetic variants and how they correlate with clinical findings. Methods: Whole exome sequencing was performed on a discovery sample of 27 cases to identify rare variants. The variants that met the criteria for rarity and biological relevance, or that were previously associated with EPP (ROBO1 and HESX1), were then resequenced in the 27 cases plus a replication sample of 51 cases. Results: We identified 16 different variants in 12 genes in 15 of the 78 cases (19.2%). Complete anterior pituitary deficiency was twice as common in cases with variants of interest compared to cases without variants (9/15 [60%] vs 19/63 [30.1%], respectively; Z test, P = 0.06). Breech presentation was more frequent in the variant positive group (5/15 vs 1/63; Z test, P = 0.003). Four cases had variants in ROBO1 and 1 in HESX1, genes previously associated with EPP. The ROBO1 p.S18* variant has not been reported previously; ROBO1 p.Q1227H has not been associated with EPP previously. Conclusion: EPP cases with variants of interest identified in this study were more likely to present with severe clinical disease. Several variants were identified in genes not previously associated with EPP. Our findings confirm that EPP is a multigenic disorder. Future studies are needed to identify additional genes.

Extra-pituitary midline structural abnormalities associated with ectopic posterior pituitary detected on a new rapid MRI protocol (FAST1.2).

Objective: Test if the MRI FAST1.2 protocol can detect extra-pituitary midline structural brain abnormalities in patients with ectopic posterior pituitary (EPP), and highlighting their radiological-laboratory correlations. Subjects and methods: Cross-sectional study of patients with EPP and control group. All individuals were submitted to FAST1.2, which combines the FAST1 protocol developed by our group with 3D T2DRIVE imaging. Results: We evaluated 36 individuals with EPP and 78 as control group. Pituitary stalk (PS) was identified in 7/36 patients in EPP group by FAST1, and in 24/36 patients in FAST1.2 (p < 0.001). FAST1 failed to detect PS in one individual in the control group, while the FAST1.2 defined the PS in all individuals. In EPP group, eleven had interhypothalamic adhesion (IHA), three septo-optic dysplasia, and one cerebellar malformation. We didn't observe higher frequency of panhypopituitarism or developmental delay in patients with IHA. In control group, three had pars intermedia cysts, one hydrocephalus, and one hypothalamic hamartoma. Conclusion: FAST1.2 allows confident recognition of midline structural abnormalities, including the pituitary stalk and IHA, thereby making MRI acquisition faster and with no need for contrast administration. IHA could be associated with defects in neuronal migration, as occur in patients with EPP, with no clinical significance.

Adding T2-Weighted Images to FAST1 Protocol to Evaluate the Anatomy of the Hypothalamic-Pituitary Region.

INTRODUCTION: Ectopic posterior pituitary (EPP) is a malformation of the hypothalamic-pituitary region presented as a spectrum from isolated growth hormone deficiency (GHD) to multiple pituitary hormone deficiencies (MPHDs). Our goal was to establish whether the FAST1.2 protocol, which combines the FAST1 protocol with 3D-T2 DRIVE images, could identify the pituitary stalk (PS) and the regional anatomy more accurately. METHODS: A retrospective study of 36 individuals with EPP and hypopituitarism and a control group of 78 individuals with eutopic posterior pituitary was conducted. All individuals were submitted to FAST1.2. The position and size of the pituitary lobes were described, and the presence/absence of the PS was confirmed. RESULTS: FAST1 identified the PS in 19% of individuals with EPP, while FAST1.2 identified the PS in 67% (p < 0.001). In the FAST1.2 protocol, the PS was visible in all control individuals. All EPP patients with isolated GHD had visible PS in FAST1.2, while only 58.6% of MPHD cases had visible PS. The size of the anterior lobe and the anteroposterior length of the posterior pituitary were smaller in the EPP group versus controls (p < 0.001). We noticed a reduced anterior pituitary lobe in both diameters in MPHD patients (p < 0.05). Six patients acquired new pituitary hormone deficiencies not recognized at the time of MRI; in this group, only 1 patient had a PS not visible in FAST1.2. DISCUSSION/CONCLUSION: The FAST1.2 protocol could prevent the misdiagnosis of idiopathic GHD in patients with short stature and could also be important in the progression to MPHD. The PS could be considered a predictor of hypopituitarism, but its use as an isolated indicator for the progression to MPHD is not recommended. Our results reinforce the use of the size of the anterior lobe as a predictor of hypopituitarism and a possible predictor of the degree of pituitary insufficiency. The FAST1.2 protocol could be used as an alternative to gadolinium administration, as a cheaper and faster method, while eliminating the potential risks associated with the administration of contrast media.

Six HIT Sessions Improve Cardiorespiratory Fitness and Metabolic Flexibility in Insulin Resistant and Insulin Sensitive Adolescents with Obesity.

To evaluate the effect of high-intensity interval training (HIT) on the cardiorespiratory performance and substrate oxidation pattern in insulin-resistant and insulin-sensitive obese adolescents. METHODS: We recruited 25 obese adolescents in three schools, and trained them in six HIT sessions, comprising of six series at 100% and recovery at 50% peak velocity (Vpeak). For the evaluation, the participants were divided into two groups: insulin-resistant (IR, n = 12; HOMA index ≥3.16) and insulin-sensitive (IS, n = 13). All participants underwent cardiopulmonary and indirect calorimetry testing. We compared the effects of HIT before and after the intervention among the two groups. The data were analyzed using Student's t and Mann-Whitney (intergroup comparisons) and Student's t and Wilcoxon (pre- and post-training comparisons) tests; and Cohen's d (influence of HIT). RESULTS: There was a significant post-training increase in Vpeak, oxygen consumption (VO2), velocity (V), and heart rate (HR) at the exertion intensity at the first ventilatory anaerobic threshold (VAT1) in both groups (p < 0.05; d < 0.02). The exercise promoted changes in substrate oxidation rates of the groups, with an increase in carbohydrate oxidation (CHOox) for both IR (p = 0.064) and IS (p = 0.034). CONCLUSION: Six HIT sessions improved cardiorespiratory performance in both groups and increased CHOox in insulin-sensitive obese adolescents, suggesting its utility for increasing physical fitness and controlling glycemia in these population groups.

Sex-Dependent Dyslipidemia and Neuro-Humoral Alterations Leading to Further Cardiovascular Risk in Juvenile Obesity.

Objective: Childhood obesity is a growing concern as the World Health Organization (WHO) states that ~10% of adolescents worldwide are overweight or obese. This condition is the reflex of energy imbalance between the calories consumed and those expended. Sex-related responses associated with dyslipidemia, hormonal alterations, and neuro-humoral disruptions in childhood obesity are the focus of the present investigation. Methods: Ninety-two Brazilian adolescents were enrolled and divided between obese and eutrophic groups. Obesity was assessed using body mass index Z-score according to age and weight. Anthropometrical analyses, blood pressure, blood lipids, metabolism-regulating hormones, and neuropeptides were carried out. Results: Systolic blood pressure was higher in female and male patients with obesity. Obese females presented alterations in lipid profile and an augment of cardiovascular disease prediction ratios TC/HDL, TG/HDL, LDL/HDL, and VLDL/HDL. The levels of leptin, GIP, and neuropeptide showed sex-dimorphism in obesity. The obese adolescents presented increased levels of circulating insulin, c-peptide, amylin, glucagon, and GLP-1. Correlation analysis showed significant linearity between body mass index, blood pressure, lipids, lipoproteins, hormones, and neuropeptides content. Conclusions: Our data support an existing link associating hypertension, dyslipidemia, and neuro-hormonal imbalance in childhood obesity. We also described a sex-dependent pattern in childhood obesity-associated dyslipidemia and blood pressure in female patients with obesity solely.

Assessment of intima-media thickness of the carotid artery and intraluminal diameter of the brachial artery as cardiovascular risk markers in Brazilian adolescents with overweight or obesity.

Background The intima-media thickness of the carotid artery (cIMT) and endothelial dysfunction are associated with cardiovascular (CV) disease. Objectives To evaluate the correlation between cIMT, brachial intraluminal diameter and flow-mediated vasodilation on the reactive hyperemia phase in adolescents with obesity with predictors of CV risk. Methods Seventy-three pubertal patients with overweight or obesity were evaluated (45 girls) with a mean (standard deviation [SD]) age of 12.9 (2.5) years. Patients underwent anthropometric measurements and had the lipid profile, oral glucose tolerance test (oGTT) and serum intercellular adhesion molecule-1 (sICAM-1) levels analyzed. The ratios of the waist circumference (WC)/height (WHtR) and triglycerides (TG)/high-density lipoprotein cholesterol (HDL-C), homeostatic model assessment of insulin resistance (HOMA-IR), the Matsuda index and insulin area under the curve (AUC) were calculated. All patients were evaluated for cIMT and arterial blood flow velocity of the brachial artery. Results 75.3% of the patients had high cIMT values. We found a positive correlation between WHtR and cIMT (r = 0.233; p = 0.050). There was a positive correlation between sICAM-1 and insulin AUC (r = 0.323; p = 0.012) and WHtR (r = 0.258; p = 0.047). Patients with abnormal arterial dilation had higher sICAM-1 values (p = 0.02) despite having smaller WHtR (p = 0.046). Conclusions These adolescents with obesity had high cIMT values. Insulin resistance was associated with sICAM-1. Endothelial dysfunction was positively correlated with sICAM-1. There is no consensus about what the best laboratorial approach to evaluate insulin resistance in adolescents is, and the cutoff values of each method are arbitrary. So, as we saw earlier, the association between anthropometric data (WHtR) and ultrasound findings could be useful to evaluate the CV risk of these adolescents with obesity, because of its practical, direct and low-cost value.

Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development.

Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome (PSIS) for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified seven variants, four of which putatively damaging, in FAT2 and DCHS2 in six patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency and two presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2-/- mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4-/- and Dchs1-/- mouse mutants but all animal models displayed normal commitment to the anterior pituitary cell type. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption.