Association between new onset type 1 diabetes and real-world antibiotics and neonicotinoids' exposure-related gut microbiota perturbation.

BACKGROUND: The real-world exposure levels of non-therapeutic antibiotics and neonicotinoids in type 1 diabetes (T1D) children and their associations as environmental triggers through gut microbiota shifts remained unknown. We thus investigated the antibiotics and neonicotinoids' exposure levels and their associations with gut microbiota in pediatric T1D. METHODS: Fifty-one newly onset T1D children along with 67 age-matched healthy controls were recruited. Urine concentrations of 28 antibiotics and 12 neonicotinoids were measured by mass spectrometry. Children were grouped according to the kinds of antibiotics' and neonicotinoids' exposures, respectively. The 16S rRNA of fecal gut microbiota was sequenced, and the correlation with urine antibiotics and neonicotinoids' concentrations was analyzed. RESULTS: The overall detection rates of antibiotics were 72.5% and 61.2% among T1D and healthy children, whereas the neonicotinoids detection rates were 70.6% and 52.2% (P = 0.044). Children exposed to one kind of antibiotic or two or more kinds of neonicotinoids had higher risk of T1D, with the odd ratios of 2.579 and 3.911. Furthermore, co-exposure to antibiotics and neonicotinoids was associated with T1D, with the odd ratio of 4.924. Antibiotics or neonicotinoids exposure did not affect overall richness and diversity of gut microbiota. However, children who were exposed to neither antibiotics nor neonicotinoids had higher abundance of Lachnospiraceae than children who were exposed to antibiotics and neonicotinoids alone or together. CONCLUSION: High antibiotics and neonicotinoids exposures were found in T1D children, and they were associated with changes in gut microbiota featured with lower abundance of butyrate-producing genera, which might increase the risk of T1D.

Final adult height of children with idiopathic short stature: a multicenter study on GH therapy alone started during peri-puberty.

BACKGROUND: To evaluate the efficacy of GH in improving FAH in ISS children in a multicenter study. METHODS: A real-world observation was carried out. Children with ISS in seven hospitals in China were enrolled. The height gains standard deviation score and the height gain over the target height were evaluated. RESULTS: There were 344 ISS patients (217 boys and 127 girls). The baseline average age of boys and girls was 12.7 and 11.7 years, with bone age of 11.7 and 10.1 years, respectively. The baseline height SDS of boys and girls was - 3.07 and - 2.74, and the FAH SDS was - 1.91 and - 1.38, respectively. Compared with the baseline height SDS, the FAH SDS was significantly increased in both boys and girls (both P = 0.0000). The FAH SDS was the highest (gain by 1.54 SD) in the ≥2y treatment course group. Two hundred eighteen patients (218/344, 63.4%) had a FAH SDS > - 2 SD. Among these patients, girls in the 1-2y treatment course group and ≥ 2y group had a FAH SDS higher than TH SDS. Even in the control group, a spontaneous catch-up growth of 1.16 SD was observed. A multivariate linear regression model was used to analyze the results, with FAH SDS as the dependent variable. It was found that the treatment course and baseline height SDS in the boys' model were statistically significant (P < 0.05), whereas the baseline height SDS and baseline bone age significantly affected the girls' FAH SDS (P < 0.05). CONCLUSIONS: Both girls and boys of ISS improved FAH by GH therapy even if treatments begin over 10 years old and majority of them reached TH. Some peri-puberty ISS will have a spontaneous height gain. We recommend the course of GH treatment more than 2 years for girls, and longer courses for boys.

Adropin and glucagon-like peptide-2 are associated with glucose metabolism in obese children.

BACKGROUND: The interaction of adropin, glucagon-like peptide-2 (GLP2), angiopoietin-like protein 4 (ANGPTL4), and with childhood obesity and glucose metabolism is inconsistent. This study is to evaluate the association of the three cytokines and glucose homeostasis. METHODS: This was a cross-sectional study of children with obesity ranging from 5 to 14 years compared to age- and sex-matched children of normal weight. Fasting plasma glucose (FPG), oral glucose tolerance test 2-hour plasma glucose (OGTT2hPG), and insulin (INS) were measured, and serum adropin, GLP2, and ANGPTL4 levels were measured by enzyme-linked immunosorbent assay. The body mass index (BMI), BMI-Z scores, waist-to-hip ratio (WHR), and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. RESULTS: Thirty-nine children (9.70 ± 1.71 years, 18 females) with obesity and 29 normal weight children (8.98 ± 1.98 years, 16 females) were assessed. The levels of INS, HOMA-IR and GLP2 of the obesity group were significantly higher than the controls (P < 0.05). Pearson correlation analysis showed that serum GLP2 was positively associated with WHR, FPG, and OGTT2hPG, and adropin was negatively associated with BMI, BMI-Z, WHR, INS, and HOMA-IR (all P < 0.05). Furthermore, GLP2 were negatively associated with adropin and ANGPTL4 (both P < 0.05). By binary logistic regression, adropin and GLP2 were found to be independent markers of obesity. Multiple linear regression showed that GLP2 was associated with OGTT2hPG, and adropin was associated with INS and HOMA-IR (all P < 0.05). CONCLUSIONS: Obese children had elevated GLP2 concentrations, and adropin and GLP2 associated with both childhood obesity and glucose homeostasis. Furthermore, there may be a physiologic interplay between adropin and GLP2 in obese children.

The correlation between serum adipokines levels and metabolic indicators in girls with Turner syndrome.

OBJECTIVE: The following study investigated the serum adiponectin, chemerin and vaspin levels and their relationship with body mass index (BMI), glucose and lipid metabolism in girls with Turner Syndrome (TS). METHODS: A total of 64 girls with TS (mean age, 12.22 ±â€¯3.98 years; mean BMI, 18.90 ±â€¯3.45 kg/m2) were ascertained by chromosome analysis. Height, weight, waist circumference, hip circumference and blood pressure were measured, as well as the levels of fasting plasma glucose (FPG), fasting plasma insulin, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG). The BMI, BMI standard deviation score (SDS), waist to hip ratio, waist to height ratio and insulin resistance index (HOMA-IR) were calculated. The TS group and the control group were subdivided into non-puberty or puberty subgroup. RESULTS: The TS group had higher waist to hip ratio and waist to height ratio compared to the control group. There was no significant difference in FPG, fasting plasma insulin, HOMA-IR, blood lipid and blood pressure between the two groups. Significantly higher serum levels of adioponectin (12.51 ±â€¯4.58 µg/ml) and chemerin (173.71 ±â€¯37.88 ng/ml) and significantly lower levels of vaspin (0.67 ±â€¯0.47 ng/ml) were found in the TS group compared to the control group (9.30 ±â€¯3.17 µg/ml, 159.43 ±â€¯23.19 ng/ml and 1.06 ±â€¯0.49 ng/ml, respectively) (all P < 0.05). In the TS group, adiponectin levels were negatively correlated with age, BMI and TG (r = -0.251, -0.247, -0.294, P < 0.05 for all). In the control group, adiponectin levels were negatively correlated with BMI and BMI SDS (r = -0.416 and -0.315, P < 0.05 for both), while vaspin levels were positively correlated with age, fasting plasma insulin and HOMA-IR (r = 0.257, 0.273 and 0.282, P < 0.05 for all). In addition, significantly higher levels of adiponectin were found in the non-puberty subgroup (13.88 ±â€¯4.49) µg/ml compared to puberty subgroup (9.72 ±â€¯3.39) µg/ml (P < 0.05), while no significant differences in chemerin and vaspin were found between the two TS subgroups. CONCLUSIONS: Elevated adiponectin and chemerin levels and significantly reduced vaspin were found in girls with TS. Puberty or estrogen replacement therapy may reduce adiponectin in girls with TS.

Determination and pharmacokinetic study of pirfenidone in rat plasma by UPLC-MS/MS.

A rapid, sensitive and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of pirfenidone in rat plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2 mL of acetonitrile to a 0.1 mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile-0.1% formic acid in water with gradient elution. The total run time was 3.0 min and the elution of pirfenidone was at 1.39 min. The detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction-monitoring (MRM) mode using the respective transitions m/z 186.2→92.1 for pirfenidone and m/z 237.1→194.2 for carbamazepine (IS), respectively. The calibration curve was linear over the range of 5-2000 ng/mL with a lower limit of quantitation (LLOQ) of 5 ng/mL. Mean recovery of pirfenidone in plasma was in the range of 80.4-84.3%. Intra-day and inter-day precision were both <12.1%. This method was successfully applied in pharmacokinetic study after oral administration of 10.0mg/kg pirfenidone in rats.

Thyroid disease in Chinese girls with Turner syndrome.

AIM: The aim of this study was to determine the prevalence of autoimmune thyroid disease in Turner syndrome (TS) and the association between thyroid autoantibodies (TAA), thyroid dysfunction, age, and karyotype. METHODS: Sixty-nine girls with TS were divided into two groups according to being TAA-positive or TAA-negative. TAA and thyroid hormone concentrations were determined by immunochemiluminescence. RESULTS: One third (23/69) of the girls were TAA positive, with antibody prevalence increasing with age. Of the TAA-positive girls, seven were hypothyroid and three hyperthyroid. Compared with the TAA-negative group, the girls in the TAA-positive group were significantly older (p<0.05). For those who were TAA positive, 26.3% of patients were 5-10 years old, 37.1% 10-15 years old, and 62.5% above the age of 15 years. CONCLUSION: Chinese girls with TS are prone to Hashimoto's thyroiditis, especially those older than 5 years, and routine thyroid testing is advocated thereafter on a yearly basis. There was no specific association between the incidence of autoimmune thyroid disease and TS karyotypes.

[Effects of gonadotropin releasing hormone analog and growth hormone on height in girls with idiopathic central precocious puberty].

OBJECTIVE: To determine the effect of gonadotropin releasing hormone agonist (GnRHa), by itself alone or in combination with recombinant human growth hormone (rhGH), on height in young girls (bone age≥10 years) with idiopathic central precocious puberty (ICPP). METHODS: Eighty girls with ICPP (9.0±0.7 years old) from six medical centers across Southeast and Southwest China participated in this study. They were allocated to treatment with GnRHa+rhGH (n=31) and GnRHa (n=49) respectively. Girls in the GnRHa+rhGH group (bone age 11.18 ±0.53 years) were treated with GnRHa for 25.29±6.92 months and rhGH for 12.87±7.02 months. Girls in the GnRHa group (bone age 11.03 ±0.50 years) were treated with GnRHa for 25.96±8.95 months. The height standard deviation for bone age (HtSDS-BA), predicted adult height, near-adult height and net height increase before and after treatment were recorded for girls in both groups. RESULTS: HtSDS-BA was significantly improved after treatment for both groups (P<0.01) and the HtSDS-BA value was superior in the GnRHa+rhGH group over the GnRHa group (P<0.01). Values in near adult height (157±6 cm vs 157±4 cm), net height increase after treatment (4.68 cm vs 3.89 cm), and predicted adult height after drug withdrawal (161±5 cm vs 158±5 cm) were higher in the GnRHa+rhGH group than the GnRHa group, but the differences were not significant. CONCLUSIONS: Both GnRHa plus rhGH and GnRHa alone can improve the near adult height in girls with ICPP with a bone age ≥10 years to a similar extent. Adult height predicted based on bone age in ICPP girls following drug withdrawal is usually overestimated and precautions should be taken when this parameter is used.

[Analysis of a family affected with familial male-limited precocious puberty due to a Ala568Val mutation in LHCGR gene].

OBJECTIVE: Familial male-limited precocious puberty (FMPP) is due to constitutive activation of a mutant luteinizing hormone/choriogonadotropin receptor (LH/CGR) leading to elevated testosterone synthesis in testicular Leydig cells. In the present study, we have analyzed the LHCGR gene for members of a Chinese FMPP family. METHODS: Physical examinations have included assessment of penile length, testicular volume and pubic hair. Bone age assessment, levels of testosterone and gonadotropin-releasing hormone (GnRH) stimulations tests were measured. DNA was extracted from blood samples of the proband and his parents using an QIAGEN Blood DNA Mini Kit. The 11 exons of LHCGR gene were amplified using an AmpliTaq PCR system, and the PCR products were sequenced using an ABI3130xl Genetic Analyzer. RESULTS: The affected boy was 3 year and 1 month old and showed typical clinical manifestation of peripheral precocious puberty. His height was 116.8cm (+5.1s) and Tanner stages were PH 2. Testicular volume was 8 mL bilaterally, penile was 8.5 cm × 2.5 cm. Basal testosterone was 2310 ng/L and bone age was 9 years. GnRH stimulation test revealed a prepubertal response to gonadotropin. The peak of LH was 2.66 IU/L, and the peak of FSH was 1.03 IU/L. Upon sequencing exon 11 of the LHCGR, a heterozygous point mutation of nucleotide 1703 from C to T was detected, which resulted in an amino acid transition from Ala (GCC) to Val (GTC) at position 568. Thus the mutation of LHCGR gene was confirmed to be constitutively active. After treating with aromatase inhibitors for half a year, the patient showed an increase in bone age and height by half a year and 4 cm, respectively. The same point mutation was detected in the patient's father, but did not have any influence on his puberty development. CONCLUSION: A novel point mutation of the LHCGR gene has been identified in a family affected with FMPP. The c.1703C>T mutant LHCGR was confirmed to be constitutively active, which has led to maturation and proliferation of Leydig cells. The variable phenotype within the family suggested variable expressivity of the disease.

[Etiology and prognosis of peripheral precocious puberty in children].

OBJECTIVE: To study the causes and prognosis of peripheral precocious puberty. METHODS: The levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) were detected by a simplified gonadotrophin-releasing hormone (GnRH) stimulation test. The etiologies of 125 children with peripheral precocious puberty were explored by ultrasound scans and bone age assessment. A total of 102 cases were followed up for 3 months to 7.5 years. RESULTS: The etiological distribution of these children was as follows: exogenous hormones intake (n=80), ovarian cyst (n=11), McCune-Albright syndrome (n=11), congenital adrenal hyperplasia (CAH) (n=5), ovarian teratoma (n=1), masculine adrenal tumor (n=1), feminine adrenal tumor (n=1), and handle pituitary tumor (n=1). The causes in 14 cases were unknown. Follow-up showed that the sexual characteristics of 72 cases due to exogenous hormones intake subsided after 1-6 months. Of 11 cases with ovarian cysts, the sexual characteristics subsided spontaneously in 8 cases after 1 to 4 months, but one case was transformed to central precocious puberty after 2 years and three months. One child with ovarian cysts underwent an operation and than the sexual characteristics subsided. The sexual characteristics of the patient who had an ovarian teratoma subsided after operation. The clinical symptoms of children with McCune-Albright syndrome or CAH were alliaviated partly after treatment, and 7 cases were transformed to central precocious puberty. The clinical symptoms of 2 cases of adrenal tumors subsided after operation. One child with handle pituitary tumor died one year after operation. CONCLUSIONS: Varied causes may contribute to peripheral precocious puberty and therefore must be carefully identified through history taking, physical examination, and auxiliary examinations. The prognosis may differ for patients with different etiologies of peripheral precocious puberty.

Onset of breast and pubic hair development and menses in urban chinese girls.

OBJECTIVES: To determine the current prevalence and mean ages of onset of pubertal characteristics in healthy urban Chinese girls. METHODS: A cross-sectional study of sexual maturation of healthy Chinese girls was conducted in 9 representative cities of the eastern, western, southern, and northern parts and central region of China between 2003 and 2005. At examination, stages of breast and pubic hair development were rated on girls 3 through 19.83 years of age, and height and weight were also recorded. Data on menses were collected by the status quo method. Probit analysis was used to calculate the median age and 95% confidence interval (CI) for onset of breast and pubic hair development and menarche. RESULTS: Data were analyzed for 20654 apparently healthy girls. At age 8 years, 19.57% of these girls had evidence of breast development. The median ages of onset of Tanner stages 2 and 3 for breast development were 9.20 (95% CI: 9.06-9.32) years and 10.37 (95% CI: 10.28-10.45) years, respectively. The median ages of onset of Tanner stages 2 and 3 for pubic hair development were 11.16 (95% CI: 11.03-11.29) years and 12.40 (95% CI: 12.25-12.55) years, respectively. Menses occurred at 12.27 years (95% CI: 12.16-12.39). CONCLUSIONS: These data suggest that urban Chinese girls are actually experiencing earlier breast development than currently used norms. The up-to-date reference for normal pubertal development in urban Chinese girls needs to be established for the purpose of determining precocious puberty or pubertal delay.