Similar causes of various reproductive disorders in early life

During the past few decades, scientific evidence has been accumulated concerning the possible adverse effects of the exposure to environmental chemicals on the well-being of wildlife and human populations. One large and growing group of such compounds of anthropogenic or natural origin is referred to as endocrine-disrupting chemicals （EDCs）, due to their deleterious action on the endocrine system. This concern was first focused on the control of reproductive function particularly in males, but has later been expanded to include all possible endocrine functions. The present review describes the underlying physiology behind the cascade of developmental events that occur during sexual differentiation of males and the specific role of androgen in the masculinization process and proper organogenesis of the external male genitalia. The impact of the genetic background, environmental exposures and lifestyle factors in the etiology of hypospadias, cryptorchidism and testicular cancer are reviewed and the possible role of EDCs in the development of these reproductive disorders is discussed critically. Finally, the possible direct and programming effects of exposures in utero to widely use therapeutic compounds, environmental estrogens and other chemicals on the incidence of reproductive abnormalities and poor semen quality in humans are also highlighted.

Congenital hyperinsulinism:Role of fluorine-18L-3, 4 hydroxyphenylalanine positron emission tomography scanning

Congenital hyperinsulinism(CHI) is a rare but complex heterogeneous disorder caused by unregulated secre-tion of insulin from the β-cells of the pancreas leading to severe hypoglycaemia and neuroglycopaenia. Swift diagnosis and institution of appropriate management is crucial to prevent or minimise adverse neurodevel-opmental outcome in children with CHI. Histologically there are two major subtypes of CHI, diffuse and focal disease and the management approach will significantly differ depending on the type of the lesion. Patients with medically unresponsive diffuse disease require a near total pancreatectomy, which then leads on to the de-velopment of iatrogenic diabetes mellitus and pancre-atic exocrine insufficiency. However patients with focaldisease only require a limited pancreatectomy to re-move only the focal lesion thus providing complete cure to the patient. Hence the preoperative differentiation of the histological subtypes of CHI becomes paramount in the management of CHI. Fluorine-18L-3, 4-hydroxy-phenylalanine positron emission tomography(18F-DOPA-PET) is now the gold standard for pre-operative differentiation of focal from diffuse disease and locali-sation of the focal lesion. The aim of this review article is to give a clinical overview of CHI, then review the role of dopamine in β-cell physiology and finally discuss the role of 18F-DOPA-PET imaging in the management of CHI.

Molecular mechanisms of protein induced hyperinsulinaemic hypoglycaemia

The interplay between glucose metabolism and that of the two other primary nutrient classes, amino acids and fatty acids is critical for regulated insulin secretion. Mitochondrial metabolism of glucose, amino acid and fatty acids generates metabolic coupling factors(such as ATP, NADPH, glutamate, long chain acyl-CoA and diacylglycerol) which trigger insulin secretion. The observation of protein induced hypoglycaemia in patients with mutations in GLUD1 gene, encoding the enzyme glutamate dehydrogenase(GDH) and HADH gene, encoding for the enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase has provided new mechanistic insights into the regulation of insulin secretion by amino acid and fatty acid metabolism. Metabolic signals arising from amino acid and fatty acid metabolism converge on the enzyme GDH which integrates both signals from both pathways and controls insulin secretion. Hence GDH seems to play a pivotal role in regulating both amino acid and fatty acid metabolism.

儿童Fabry病的临床表现:来自Fabry病转归调查的数据

Background:Fabry disease is a rare X-linked disorder caused by deficient activity of the enzyme α-galactosidase A.This produces progressive lysosomal accumulation of globotriaosylceramide throughout the body,leading to organ failure and premature death.Aim:Here,we present the clinical manifestations of Fabry disease in children enrolled in FOS-the Fabry Outcome Survey-a European database of the natural history of Fabry disease and the effects of enzyme replacement therapy with agalsidase alfa(Replagal(tm)).Methods:Currently,there are 545 patients in FOS,from 11 European countries.We analysed the baseline demographic and clinical characteristics of 82 of these patients(40 boys,42 girls)who were below 18 y of age.The median age at evaluation(defined as the median age at entry into FOS)was 12.5 and 13.2 y for boys and girls,respectively.Results:The most frequent early clinical manifestations of Fabry disease were neurological(acroparaesthesiae,altered temperature sensitivity)and gastrointestinal symptoms(altered bowel habits and abdominal pain),which were documented in about 80%and 60%of patients,respectively,at the time of evaluation and subsequent entry into FOS.Tinnitus,vertigo,fatigue and angiokeratoma were present in over 40%of patients.Symptoms were noted in early childhood and occurred with similar frequency in boys and girls,although the onset of symptoms was 2-5 y later in girls than in boys.There was an approximately 3-y delay from onset of symptoms to diagnosis,and patients were frequently misdiagnosed.Conclusion:Although the life-threatening complications of Fabry disease,such as stroke and renal and heart failure,are not seen in children,the present analysis shows that other symptoms are common and may have an impact on quality of life.

Epidemiology and phenotypes of diabetes in children and adolescents in non-European-origin populations in or from Western Pacific region

BACKGROUND Type 1 diabetes(T1D)incidence varies substantially between countries/territories,with most studies indicating increasing incidence.In Western Pacific region(WPR),reported rates are much lower than European-origin populations.In contrast,there are reports of substantial numbers of young people with type 2 diabetes(T2D).A deeper understanding of T1D and T2D in the WPR may illuminate factors important in pathogenesis of these conditions.Furthermore,with varying resources and funding for diabetes treatment in this region,there is a need to more clearly determine the current burden of disease and also any gaps in knowledge.AIM To compile and summarise published epidemiologic and phenotypic data on childhood diabetes in non-European populations in and from WPR.METHODS Research articles were systematically searched from PubMed(MEDLINE),Embase,Cochrane library,and gray literature.Primary outcome measures were incidence and prevalence,with secondary measures including phenotypic descriptions of diabetes,including diabetes type categorization,presence of diabetic ketoacidosis(DKA)at onset,autoantibody positivity,Cpeptide levels,and human leucocyte antigen phenotype.Extracted data were collected using a customized template.Three hundred and thirty relevant records were identified from 16 countries/territories,with analysis conducted on 265(80.3%)records published from the year 2000.RESULTS T1D incidence ranged from<1-7.3/100000 individuals/year,rates were highest in emigrant/mixed populations and lowest in South-East Asia,with most countries/territories(71.4%)having no data since 1999.Incidence was increasing in all six countries/territories with data(annual increases 0.5%-14.2%,highest in China).Peak age-of-onset was 10-14 years,with a female case excess.Rate of DKA at onset varied from 19.3%-70%.Pancreatic autoantibodies at diagnosis were similar to European-origin populations,with glutamic acid decarboxylase-65 autoantibody frequency of 44.1%-64.5%,insulinoma-associated 2 autoantibody 43.5%-70.7%,and zinc transporter-8 autoantibody frequency 54.3%(one study).Fulminant T1D also occurs.T2D was not uncommon,with incidence in Japan and one Chinese study exceeding T1D rates.Monogenic forms also occurred in a number of countries.CONCLUSION T1D is less common,but generally has a classic phenotype.Some countries/territories have rapidly increasing incidence.T2D is relatively common.Registries and studies are needed to fill many information gaps.

对22例患者的队列研究所发现的一种罕见的甲状腺发育不全的变异情况:甲状腺偏侧缺如症及有家族性因素但无Pax8基因的变异

Thyroid hemiagenesis is a rare form of thyroid dysgenesis of which some familial cases have been reported, including one associated with a heterozygous mutation in the Pax8 gene. However, the physiopathology remains not well known. The objectives of this study were 1) to describe the clinical features, 2) to look for familial clustering, and 3) to search for Pax8 mutations in a relatively large cohort of affected patients. A family history of thyroid dysgenesis was found in nine patients (40% ), whose affected relatives had ectopic thyroid (n = 4), athyreosis (n = 1), thyroid hemiagenesis (n = 2), or thyroglossal duct cysts (n = 2). Screening for Pax8 mutations identified abnormal migration profiles by SSCP analysis in 3 patients, but direct sequencing did not show coding region mutations in any of the 22 patients. In conclusion, this study provides the first evidence that thyroid hemiagenesis can occur as a familial disorder associated with any form of thyroid dysgenesis. This finding supports both a common underlying mechanism to the various abnormalities in thyroid development and a role for genetic factors; however, our results from Pax8 analysis suggest that this gene may not be a key factor.

Is There a Correlation between Body Weight and Awareness of Healthy Life Style Components in Children?

Background: Incidence of obesity in children is increasing worldwide. Healthy eating and exercise are the major components of a healthy life style in the community. Objective: we aim to assess the knowledge of healthy eating and exercise in children?of varying weight?and to explore the correlation between knowledge and bodyweight. Method: School children are invited to fill in a 2 questions quiz about healthy life style.?BMI is calculated and children are classified into obese, overweight, normal and underweight. Answers are scored and results compared for different categories of the BMI. Results: 445 children participated. Age range (mean) was 7 - 13 (10) years. 67 were obese, 59 overweight, 237 normal weight and 34 were underweight. In the food question, 22%, 20%, 23% 15% of obese, overweight, underweight and normal weight children respectively gave wrong answers compared to 17.5%, 15% and 14.7%, 13.3% for the exercise question. Neither of the results was statistically significant. Boys are more knowledgeable about exercise than girls (P = 0.03). Conclusion: There is no difference in the level of knowledge about healthy eating and exercise among children with varying body weights. Tackling children behavior and attitude towards food and exercise is as important as improving their knowledge.

Repetitiveness of the oral glucose tolerance test in children and adolescents

BACKGROUND Data regarding the most suitable diagnostic method for the diagnosis of glucose impairment in asymptomatic children and adolescents are inconclusive.Furthermore,limited data are available on the reproducibility of the oral glucose tolerance test(OGTT)in children and adolescents who are obese(OB).AIM To investigate the usefulness of the OGTT as a screening method for glucose dysregulation in children and adolescents.METHODS Eighty-one children and adolescents,41 females,either overweight(OW),OB or normal weight(NW)but with a strong positive family history of type 2 diabetes mellitus(T2DM),were enrolled in the present observational study from the Outpatient Clinic of Paediatric Endocrinology of the University Hospital of Patras in Greece.One or two 3-h OGTTs were performed and glucose,insulin and Cpeptide concentrations were measured at several time points(t=0 min,t=15 min,t=30 min,t=60 min,t=90 min,t=120 min,t=180 min).RESULTS Good repetitiveness was observed in the OGTT response with regard to T2DM,while low repetitiveness was noted in the OGTT response with regard to impaired glucose tolerance(IGT)and no repetitiveness with regard to impaired fasting glucose(IFG).In addition,no concordance was observed between IFG and IGT.During the 1st and 2nd OGTTs,no significant difference was found in the glucose concentrations between NW,OW and OB patients,whereas insulin and C-peptide concentrations were higher in OW and OB compared to NW patients at several time points during the OGTTs.Also,OW and OB patients showed a worsening insulin and C-peptide response during the 2nd OGTT as compared to the 1st OGTT.CONCLUSION In mild or moderate disorders of glucose metabolism,such as IFG and IGT,a diagnosis may not be reached using only one OGTT,and a second test or additional investigations may be needed.When glucose metabolism is profoundly impaired,as in T2DM,one OGTT is probably more reliable and adequate for establishing the diagnosis.Excessive weight and/or a positive family history of T2DM possibly affect the insulin and C-peptide response in the OGTT from a young age.

Association of Vitamin D Deficiency with Diabetic Retinopathy in Young People with Type 1 Diabetes Mellitus

Background: Diabetic retinopathy is among the most common diabetic complications, and is one of the leading causes of blindness in the world. Recent studies have linked vitamin D to the pathogenesis of diabetes and there is growing evidence that vitamin D can interfere with the mechanisms involved in diabetes and its complications. Despite improvements in treatment, diabetic retinopathy remains a significant complication of type 1 diabetes mellitus. Identification of early treatable predictors of diabetic retinopathy such as vitamin D deficiency, may allow more aggressive management of those at high risk. Purpose: To assess the association of vitamin D deficiency with diabetic retinopathy in young people with type 1 diabetes mellitus. Design: Observational study with case control design. Method: 60 young people with type 1 diabetes aged between 11 to 24 years were included in this study. Among them, 30-young people have diabetic retinopathy and 30-young people do not have diabetic retinopathy. Purposive sampling technique was applied as per inclusion criteria. Statistical analysis of the results was done by using computer-based software, SPSS version 26. P value of less than 0.05 was considered as statistically significant. Results: Vitamin D deficiency was present in 83% of the young people with diabetic retinopathy and in 53% without diabetic retinopathy. The mean vitamin D level in young people with and without diabetic retinopathy was 17.38 ± 3.77 ng/ml and 20.15 ± 5.06 ng/ml respectively and the difference was statistically significant (p = 0.019). Vitamin D deficiency was increased with the severity of diabetic retinopathy. Univariate and multivariate logistic regression showed vitamin D deficiency was independently associated with diabetic retinopathy with a crude odds ratio of 5.69 with a p value of 0.008 and adjusted odds ratio of 16.08 with a p value of 0.002 respectively. Conclusion: Result of the study revealed that vitamin D deficiency was strongly associated with diabetic retinopathy in young people with type 1 diabetes mellitus.

N-Acetylcysteine Amide(NACA) Reduces Cell Death after Oxidative Stress in a Porcine Embryonic Kidney Cell Line

Introduction: Oxidative stress may have detrimental effects on different structures of the cells, such as the DNA. Recently, we have published a study demonstrating that N-Acetylcysteine amide (NACA) displayed anti-inflammatory properties on the brain after exposure to oxidative stress in an established neonatal piglet model, imitating perinatal asphyxia. As different clinical studies have shown an association between the severity of hypoxic-ischemic encephalopathy and damage of the kidneys, we investigated a possible protective effect of NACA against H2O2-induced oxidative stress using a porcine epithelial-like embryonic kidney cell line (EFN-R). Objective: To investigate a potential protective effect of NACA on cells of a porcine embryonic kidney cell line exposed to H2O2. Methods: We subjected the cells to different concentrations of H2O2 for variable time periods, seeking the optimal dose-response for the experiments. Based on the results of these investigations, we exposed the cells to 100 μMol of H2O2 and/or 750 μM of NACA for 24 hours. Some of the cells would receive NACA either one hour before or one hour after exposure to H2O2. Results: The viability of the investigated EFN-R cells revealed that both, the group treated with NACA before exposure to H2O2 and the group treated with NACA after exposure to H2O2, exhibited significantly higher cell viability compared to the H2O2 group (p < 0.001 and p < 0.01, respectively). Discussion: The increased viability of the cells may indicate that NACA could play an important role in reducing oxidative stress. Taking the results from our previous study into consideration, our findings may strengthen the theory that NACA may have organ protective properties for neonates exposed to oxidative stress.

加压素渗透压调节正常的下丘脑性无渴感高钠血症综合征

无渴感高钠血症在儿童是一种罕见疾病,由渴感的渗透调节失常引起,并最终将打破水的动态平衡,导致体液慢性高渗透压状态。无渴感常与调节血浆渗透压的加压素分泌异常相关联。这是因为下丘脑内控制渴感的渗透压感受器与调节加压素分泌的中枢位置紧密相连。多种导致下丘脑损伤的病变(血管异常、肿瘤、肉芽肿性疾病及创伤等)均可引起该综合征。此次报道1例因高钠血症脱水导致体重明显减轻的12岁男性患儿, 其渴感的渗透调节存在选择性异常而加压素分泌正常。同时没发现存在明显的结构异常。至今为止,仅有6 例类似的患儿见诸报道。结论:当脱水患儿不觉得口渴时,应怀疑其是否存在下丘脑性无渴感高钠血症。同时要检查其抗利尿功能,因为这种情况下其加压素的渗透压调节可能已发生了改变。

二甲双胍治疗青少年多囊卵巢综合征的随机安慰剂对照试验

Objective: To determine whether metformin or placebo could,in conjunction with healthy lifestyle counseling,decrease serum testosterone levels and related aberrations in adolescents with hyperandrogenism,hyperinsulinemia,and polycystic ovarian syndrome. Design: Randomized,placebo-controlled,double-blind trial. Setting: Pediatric university teaching hospital. Participants: Twenty-two adolescents aged 13 to 18 years with hyperinsulinemia and polycystic ovarian syndrome. Intervention: Participants were randomly assigned to take a 12-week course of either metformin or placebo. Main Outcome Measures: Pretreatment and posttreatment oral glucose tolerance tests,fasting lipid profiles,and clinical measurements. Results: There was a significant decline in mean serum testosterone concentration with metformin (-38.3 ng/dL) compared with placebo (-0.86 ng/dL) (95% confidence interval,-∞ to -0.29 for the mean difference between groups). At completion,the relative risk of menses was 2.50 times higher in the metformin group compared with the placebo (95% confidence interval,1.12 to 5.58). Measures of insulin sensitivity,including insulin area under the curve and HOMA (homeostasis model assessment)-,demonstrated improvement only with metformin,but these did not reach statistical significance. High-density lipoprotein cholesterol levels increased by 6.98 mg/dL with metformin vs a decrease of -2.33 mg/dL with placebo (95% confidence interval,0.78 to 18.23 for the mean difference between groups). There were no significant changes in body mass index,hirsutism,triglyceride levels,or total and low-density lipoprotein cholesterol levels. Conclusion: Metformin significantly lowered total testosterone concentrations,increased the likelihood of menses,and improved high-density lipoprotein cholesterol levels without affecting measures of insulin sensitivity or body weight.

欧洲儿童和青少年2型糖尿病的发病情况

Aim: The aim of the study was to review the published and unpublished data on type 2 diabetes in European children in order to determine how common this problem is in the dominantly Caucasian population. Methods: The MEDLINE database was searched and a questionnaire was distributed among European Childhood Obesity Group (ECOG) representatives from 16 countries. Results: One hundred and eighty-four children with type 2 diabetes were diagnosed in Europe, 144 of them of Caucasian origin. The majority of them were overweight females and, had positive family history for type 2 diabetes mellitus. Conclusion: Because of the significant rates of type 2 diabetes in Europe, screening for it in obese children and adolescents is highly recommended.

Genetics of congenital hypothyroidism: Modern concepts

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamic-pituitary in origin (central CH). In most cases, primary CH is caused by a developmental malformation of the gland (thyroid dysgenesis, TD) or by a defect in thyroid hormones synthesis (dyshormonogenesis, DH). TD represents about 65% of CH and a genetic cause is currently identified in fewer than 5% of patients. The remaining 35% are cases of DH and are explained with certainty at the molecular level in more than 50% of cases. The etiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detailed phenotypic description of patients, high-throughput sequencing technologies, and the use of animal models have made it possible to discover new genes involved in the development or function of the thyroid gland. This paper reviews all the genetic causes of CH. The modes by which CH is transmitted will also be discussed, including a new oligogenic model. CH is no longer simply a dominant disease for cases of CH due to TD and recessive for cases of CH due to DH, but a far more complex disorder.

我们是否应该治疗肥胖儿童中的亚临床甲状腺功能减退症患者？

当检查肥胖或超重儿童时，常常会要求对他们进行甲状腺功能的检查。促甲状腺素轻度升高伴甲状腺素正常——亚临床甲状腺功能减退症（高促甲状腺素血症），是一个常见的发现。孤立升高的促甲状腺素最好定义为高促甲状腺素血症，而不是亚临床甲状腺功能减退症，并且这个定义里不包括有临床症状的患者、甲状腺抗体阳性的患者、甲状腺肿大或有相关甲状腺疾病的患者。

Health- related quality of life among adolescents with type 1 diabetes since the second wave of the COVID- 19 pandemic in Germany

Objective The COVID-19 pandemic had an impact on everyday life and in general,reduced the health-related quality of life(HRQoL)of adolescents.In this study,we assess the HRQoL of adolescents with type 1 diabetes(T1D)in Germany since the second wave of the COVID-19 pandemic by using self-report and parent-proxy reports,to identify risk factors,to compare to peers and to examine the agreement of HRQoL between parents and their children.Methods A total of 445 adolescents(12–18 years)and 413 parents participated in an anonymous cross-sectional survey conducted at three German diabetes centres from January 2021 to June 2022.Inclusion criteria were diabetes duration≥1year and German-speaking.Teen HRQoL was assessed by using self-report and parent-proxy report versions of the KIDSCREEN-10 index.Results The majority of adolescents reported average(75.5%)HRQoL.Approximately 11.3%of teens reported high and 13.2%low HRQoL.Teen’s female gender,older age,higher diabetes burden and parental depression symptoms contributed to lower self-reported HRQoL among teens.For parent-proxy reports,increasing diabetes burdens,parental depression symptoms,non-migrant status,high education and ketoacidosis contributed to lower scores on teen HRQoL.The mean scores of the KIDSCREEN-10 index for adolescents did not differ from the German norm.In comparison to healthy peers during the first wave of the pandemic,adolescents in the current study reported higher HRQoL.The overall teen-parent agreement was fair although parents reported significantly lower teen HRQoL than adolescents did.Conclusions HRQoL of most adolescents with T1D during the COVID-19 pandemic was average with parents reporting significantly lower scores.Self-reported and parent-proxy-reported HRQoL and the level of agreement due to different perspectives can provide important information for clinical care and intervention planning.