Children with idiopathic short stature have significantly different gut microbiota than their normal height siblings: a case-control study

ObjectivesTo investigate the role of gut microbiota (GM) in pathogenesis of idiopathic short stature (ISS) by comparing GM of ISS children to their normal-height siblings.MethodsThis case-control study, conducted at the Schneider Children’s Medical Center’s Institute for Endocrinology and Diabetes between 4/2018-11/2020, involved 30 pairs of healthy pre-pubertal siblings aged 3-10 years, each comprising one sibling with ISS and one with normal height. Outcome measures from fecal analysis of both siblings included GM composition analyzed by 16S rRNA sequencing, fecal metabolomics, and monitoring the growth of germ-free (GF) mice after fecal transplantation.ResultsFecal analysis of ISS children identified higher predicted levels of genes encoding enzymes for pyrimidine, purine, flavin, coenzyme B, and thiamine biosynthesis, lower levels of several amino acids, and a significantly higher prevalence of the phylum Euryarchaeota compared to their normal-height siblings (p<0.001). ISS children with higher levels of Methanobrevibacter, the dominant species in the archaeal gut community, were significantly shorter in stature than those with lower levels (p=0.022). Mice receiving fecal transplants from ISS children did not experience stunted growth, probably due to the eradication of Methanobrevibacter caused by exposure to oxygen during fecal collection.DiscussionOur findings suggest that different characteristics in the GM may explain variations in linear growth. The varying levels of Methanobrevibacter demonstrated within the ISS group reflect the multifactorial nature of ISS and the potential ability of the GM to partially explain growth variations. The targeting of specific microbiota could provide personalized therapies to improve growth in children with ISS

Quantitative Proteomic of Rat Livers Shows a Major Reprogramming of Mitochondrial Enzymes in Food-Restriction and Increased Stress Hallmarks in Ad Libitum Feeding

Introduction: In the pediatric age group, the incidence of theadrenocortical cancer (ACC) is 0.2%. The effective treatment issurgical resection. The only medical option is mitotane but it hasnegative effects on steroidogenesis. The difficulty in the managementof mitotane therapy is discussed in this case. Case report:An 1110/12 years-old boy was referred with A 5 cm diameter solidhypoecoicmass observed by sonography in the left surrenalregion. The physical examination was all normal at presentation.His pubertal stage was Tanner grade 3. His clinical findings werenormal. In the adrenal hormone profile, DHEA, androstenedion,total testesterone (TT) elevated while the others (11-deoxycortisole,17-OH progesterone, cortizole) were normal. His plasmarenin activity and aldesterone were normal. Analysis of 24-h urinespecimen revealed high cortisole levels. The case was diagnosed asgrade 3 ACC and treated via surgical resection. Postoperativelychemotherapy, mitotane and hydrocortisone treatments werestarted. In the first month of the treatment hormonal profile wasall normal but TT levels started to increase (O1500 ng/dl) atsecond month. In the follow-up, height growth stopped andbilateral gynecomasty developed. Magnetic resonance imaging andpozitron emission tomography scans and scrotal US were negativefor recurrance or metastases at 6 months. The clinic was diagnosedas hypergonadotropic hypogonadism (HH) due to mitotanetreatment. The follow-up of the case is continuing. Discussion:Mitotane treatment leads to HH via reducing the gonadalsteroidogenesis. Additionally, treatment increases the levels ofsex-hormone binding globuline and decreases the activity of 5-alfareductase that results with high levels of testesteron. In our case thetestosterone levels were high but free androgen index was normal.The high levels of testesterone can be the result of metastase,recurrance or mitotane treatment adverse effect. This is astruggling problem in the management of mitotane therapy.</p

The association between adipocytokines and glycemic control in women with gestational diabetes mellitus

<p><b>Objective:</b> To evaluate the relationship between adipocytokines and glycemic control.</p> <p><b>Study design:</b> Prospective observational trial of gestations with gestational diabetes mellitus (GDM). Fasting glucose (FG), insulin, adiponectin, leptin, chemerin, retinol-binding protein 4 (RBP-4), osteocalcin, and resistin were measured. HomeOstasis model assessment of insulin resistance (HOMA-IR) and QUantitative insulin sensitivity ChecK Index (QUICKI) were calculated. Women who required medications for glycemic control were compared to women using nutritional therapy only.</p> <p><b>Results:</b> Overall, 75 women were included −26 (34.7%) required medications to achieve good glycemic control. Factors associated with poor control are as follows: low resistin (aOR 0.84), HOMA-IR (aOR 1.96), QUICKI (aOR 0.62), first trimester FG (aOR 1.43), and maternal age (aOR 1.26). HOMA-IR and QUICKI performed highest for prediction. Resistin, first trimester FG, maternal age, and QUICKI had an AUC of 0.878, sensitivity and specificity of 87.5% for the prediction of the need for medications.</p> <p><b>Conclusions:</b> Low resistin is associated with poor control. A model utilizing maternal age, first trimester fasting glucose, and first visit QUICKI yields good predictability.</p

A Whey-Based Diet Can Ameliorate the Effects of LPS-Induced Growth Attenuation in Young Rats

Chronic inflammation in childhood is associated with impaired growth. In the current study, a lipopolysaccharide (LPS) model of inflammation in young rats was used to study the efficacy of whey-based as compared to soy-based diets to ameliorate growth attenuation. Young rats were injected with LPS and fed normal chow or diets containing whey or soy as the sole protein source during treatment, or during the recovery period in a separate set of experiments. The body and spleen weight, food consumption, humerus length, and EGP height and structure were evaluated. Inflammatory markers in the spleen and markers of differentiation in the EGP were assessed using qPCR. The LPS led to a significant increase in the spleen weight and a decrease in the EGP height. Whey, but not soy, protected the animals from both effects. In the recovery model, whey led to increased EGP height at both 3 and 16 d post treatment. The most affected region in the EGP was the hypertrophic zone (HZ), which was significantly shortened by the LPS treatment but enlarged by whey. In conclusion, LPS affected the spleen weight and EGP height and had a specific effect on the HZ. Nutrition with whey protein appeared to protect the rats from the LPS-induced growth attenuation

Beta Palmitate Improves Bone Length and Quality during Catch-Up Growth in Young Rats

Palmitic acid (PA) is the most abundant saturated fatty acid in human milk, where it is heavily concentrated in the sn-2-position (termed beta palmitate, BPA) and as such is conserved in all women, regardless of their diet or ethnicity, indicating its physiological and metabolic importance. We hypothesized that BPA improves the efficiency of nutrition-induced catch up growth as compared to sn-1,3 PA, which is present in vegetable oil. Pre-pubertal male rats were subjected to a 17 days food restriction followed by re-feeding for nine days with 1,3 PA or BPA-containing diets. We measured bone length, epiphyseal growth plate height (EGP, histology), bone quality (micro-CT and 3-point bending assay), and gene expression (Affymetrix). The BPA-containing diet improved most growth parameters: humeri length and EGP height were greater in the BPA-fed animals. Further analysis of the EGP revealed that the hypertrophic zone was significantly higher in the BPA group. In addition, Affymetrix analysis revealed that the diet affected the expression of several genes in the liver and EGP. Despite the very subtle difference between the diets and the short re-feeding period, we found a small but significant improvement in most growth parameters in the BPA-fed rats. This pre-clinical study may have important implications, especially for children with growth disorders and children with special nutritional needs

Growth hormone therapy in children with idiopathic short stature – the effect on appetite and appetite-regulating hormones: a pilot study

<p><b>Aim</b>: To investigate the effect of growth hormone (GH) therapy on appetite-regulating hormones and to examine the association between these hormones and the response to GH, body composition, and resting energy expenditure (REE).</p> <p><b>Methods</b>: Nine pre-pubertal children with idiopathic short stature underwent a standard meal test before and 4 months following initiation of GH treatment. Ghrelin, GLP-1, leptin, and insulin levels were measured; area under the curve (AUC) was calculated. Height, weight, body composition, REE, and insulin-like growth factor levels were recorded at baseline and after 4 and 12 months.</p> <p><b>Results</b>: Following 4 months of GH therapy, food intake increased, with increased height-standard deviation score (SDS), weight-SDS, and REE (<i>p </i>< .05). Significant changes in appetite-regulating hormones included a decrease in postprandial AUC ghrelin levels (<i>p </i>= .045) and fasting GLP-1 (<i>p </i>= .038), and an increase in fasting insulin (<i>p </i>= .043). Ghrelin levels before GH treatment were positively correlated with the changes in weight-SDS (fasting: <i>r</i> = .667, <i>p </i>= .05; AUC: <i>r</i> = .788, <i>p </i>= .012) and REE (fasting: <i>r</i> = .866, <i>p </i>= .005; AUC: <i>r</i> = .847, <i>p </i>= .008) following 4 months of GH therapy. Ghrelin AUC at 4 months was positively correlated with the changes in height-SDS (<i>r</i> = .741, <i>p </i>= .022) and fat-free-mass (<i>r</i> = .890, <i>p </i>= .001) at 12 months of GH treatment.</p> <p><b>Conclusions</b>: The reduction in ghrelin and GLP-1 following GH treatment suggests a role for GH in appetite regulation. Fasting and meal-AUC ghrelin levels may serve as biomarkers for predicting short-term (4 months) changes in weight and longer term (12 months) changes in height following GH treatment. The mechanisms linking GH with changes in appetite-regulating hormones remain to be elucidated.</p> <p><b>Abbreviations:</b> SDS: standard deviation score; REE: resting energy expenditure; SMT: standard meal test; AUC: area under the curve; ISS: idiopathic short stature; SGA: small for gestational age; FFM: fat-free-mass; FM: fat mass; EER: estimated energy requirements; DRI: dietary reference intakes; IQR: inter-quartile range</p