Volume 30, Issue 6

Background: A systematic review and meta-analysis was designed to evaluate the effect of probiotics on diabetes and its associated risk factors. Methods: We systematically searched the Cochrane Library, PubMed, EMBASE and Web of Science to June 2016. We also hand-searched the citation lists of included studies and previously identified systematic reviews to identify further relevant trials. Our primary outcome variables included glucose, glycated hemoglobin (HbA 1c ) and insulin. The pooled standardized mean difference was used to compare the effect between the probiotics and controlled groups, and the pooled standardized mean difference effect size with a 95% confidence interval (CI) was estimated using a random-effect model. Heterogeneity was assessed with Cochran’s Q and Higgins I 2 tests. Two reviewers assessed trial quality and extracted data independently. The analysis and bias for each included study was performed and assessed using Review Manager 5.2. Results: Eighteen randomized, placebo-controlled studies (n=1056 participants, 527 consuming probiotics, 529 not consuming probiotics) were included for analysis. Comparing the probiotics groups with the control groups, there were statistically significant pooled standardized mean differences on the reduction of glucose (−0.61, 95% CI −0.98, −0.24; p=0.001), insulin (−0.49, 95% CI −0.93, −0.04; p=0.03) and HbA 1c (−0.39, 95% CI −0.60, −0.19%; p=0.0001). Subgroup analysis also indicated statistical significance on the reduction of low-density lipoprotein cholesterol (LDL-C) in non-type 2 diabetes (non-T2DM) mellitus patients with diabetes, for the pooled standardized mean difference was −0.29 (95% CI −0.54, −0.04; p=0.02). Conclusions: Probiotics may have beneficial effects on the reduction of glucose, insulin and HbA 1c for diabetes, especially for T2DM mellitus patients.

Background: Neonatal central diabetes insipidus (NCDI) remains a therapeutic challenge, as extremely low doses of enteral desmopressin cannot be titrated with current preparations. The aim of this study was to describe the use of orally administered dilute desmopressin in NCDI. Methods: Nasal desmopressin (100 μg/mL) was diluted in 0.9% saline to 10 μg/mL. Infants were treated with 1–5 μg and doses were titrated to a twice-daily regimen. The feed volume was 150 mL/kg/day and titrated according to weight gain. Results: Five infants aged 6–105 days were included. Stabilizing treatment doses ranged from 2 to 5 μg twice daily in neonates, and 12 μg twice daily in the older infant who was diagnosed at 105 days. Conclusions: Dilution of nasal desmopressin with saline facilitates safe administration and dose titration in NCDI. We recommend considering this therapeutic approach to NCDI, particularly in small infants or where alternative treatment regimens have been unsuccessful.

Background: A correlation between adiposity and post-exercise autonomic regulation has been established in overweight and obese children. However, little information exists about this link in non-obese youth. The main purpose of this cross-sectional study was to describe the relationship between body fat percentage (BFP) and heart rate recovery after exercise [post-exercise heart rate (PEHR)], a marker of autonomic regulation, in normal-weight children and adolescents. Methods: We evaluated the body composition of 183 children and adolescents (age 15.0±2.3 years; 132 boys and 51 girls) who performed a maximal graded exercise test on a treadmill, with the heart rate monitored during and immediately after exercise. Results: A strong positive trend was observed in the association between BFP and PEHR (r=0.14; p=0.06). Hierarchical multiple regression revealed that our model explained 18.3% of the variance in PEHR (p=0.00), yet BFP accounted for only 0.9% of the variability in PEHR (p=0.16). The evaluation of the contribution of each independent variable revealed that only two variables made a unique statistically significant contribution to our model (p<0.01), with age contributing 38.7% to our model (p=0.00) while gender accounted for an additional 25.5% (p=0.01). Neither BFP (14.4%; p=0.16) nor cardiorespiratory endurance (5.0%, p=0.60) made a significant unique contribution to the model. Conclusions: Body fatness seems to poorly predict PEHR in our sample of non-obese children and adolescents, while non-modifiable variables (age and gender) were demonstrated as strong predictors of heart rate recovery. The low amount of body fat reported in non-obese young participants was perhaps too small to cause disturbances in autonomic nervous system regulation.

Background: Insulin resistance and endothelial dysfunction share a reciprocal relationship that links the metabolic and cardiovascular sequelae of obesity. We characterized the brachial artery reactivity testing (BART) and carotid artery-intima media thickness (CIMT) in adolescents categorized as obese insulin resistant (OIR) and obese not insulin resistant (ONIR). Lipoprotein particle (p) analysis and inflammatory cytokines in OIR and ONIR groups were also analyzed. Methods: Obese adolescents (n=40; mean body mass index [BMI] 35.6) were categorized as ONIR and OIR based on their homeostatic model assessment of insulin resistance (HOMA-IR) calculation (≤or> than 3.4). Ultrasound measured conduit arterial function BART, microvascular function (post-ischemic hyperemia) and conduit artery structure CIMT. Results: BART did not differ according to IR status (mean±SD: 7.0±4.3% vs. 5.9±3.4% in ONIR and OIR, respectively, p=0.3, but post-ischemic hyperemia was significantly greater in the ONIR group (4.5±2.2 vs. 3.5±3, p=0.04). Atherogenic lipoprotein particles; large VLDL particles and small LDL particles were higher in the OIR compared to ONIR group. Conclusions: OIR adolescents demonstrate an inflamed atherogenic milieu compared to the ONIR adolescents. Microvascular function, but not conduit vessel structure or function, was impaired in association with IR.

Background: The objective of the study was to investigate the association of neck circumference (NC) to parameters of glucose homeostasis compared to classical anthropometric parameters of lean and obese children. Methods: Three dimensional (3D)-body scanning quantified anthropometric (height, weight, NC, hip/waist circumference, BMI) and metabolic parameters (fasting plasma glucose [FPG], insulin, HbA 1c , oGTT, HOMA-IR) were determined cross-sectionally in 1542 participants (5–18 years). Results: NC was positively correlated with all metabolic parameters, except for FPG. For HbA 1c there was only a modestly positive correlation. The associations between NC and glucose parameters were rather weak, while the correlation to insulin parameters were stronger. Overall the strongest association to glucose metabolism parameters was found for waist circumference (WC), except for FPG and 2h-postload glucose. In multiple linear regression analyses, NC provided additional benefit beyond classical anthropometric indices to describe impairment of glucose homeostasis. Conclusions: We suggest that NC is comparable or additive to established anthropometric parameters but might not be superior to them. However NC is simple to measure, reproducible and may be considered in clinical practice as an additional measurement tool.

Background: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder. Dietary control of classic PKU needs restriction of natural proteins. The diet results in unbalanced nutrition, which might affect the physical development of the patients. Our aim was to evaluate bone mineral density (BMD) in children with PKU. Methods: To investigate the BMD of children with PKU, 41 children with PKU and 64 healthy controls were recruited (all 3–4 years of age). Body weight and height, BMD, Phe blood levels, thyroid function, calcium, phosphorus, iron metabolism markers, and vitamin D3 were measured. Results: Body height and BMD of patients were lower than in controls. The BMD of controls was positively associated with age, body weight and height. In patients, BMD was positively associated with body weight. There was no correlation between Phe blood levels and BMD in patients. Blood levels of alkaline phosphatase were higher in patients compared to controls. Blood calcium levels were higher in 4-year-old patients, while the body weight was lower compared to controls. Thyroid function, iron metabolism markers, vitamin D3 levels and IGF-1 levels were normal. Conclusions: Reduced BMD was observed in children with phenylketonuria, but the exact reasons for this remain to be elucidated.

Background: The objective of the study was to determine the stress levels of girls with central precocious puberty (CPP) before and during treatment with a long-acting gonadotropin-releasing hormone agonist (GnRHa). Methods: The Child Stress Scale (CSS) was used for 10 unrelated girls with CPP before and after the first year of GnRHa treatment. The CSS is divided into four subscales (physical, psychological, psychological with depressive component and psychophysiological reactions). Through a quantitative analysis, it is possible to classify stress into four stages: alarm, resistance, near-exhaustion and exhaustion. Results: At diagnosis, 90% of the girls showed stress levels scores at the alarm or resistance stage on at least one subscale, mostly in terms of physical and psychological reactions. The mean total stress score was significantly higher before when compared to after GnRHa treatment (43.4±15.6 vs. 28.9±9.7; p<0.05). The mean stress scores obtained in all subscales, except the one on psychophysiological reactions, were significantly higher before GnRHa treatment. Conclusions: Higher stress levels were a common finding in girls with CPP before treatment. The significant stress level reduction after pubertal suppression reinforces the idea that sexual precocity is a stressful condition in children. The CSS might be a useful tool for psychological assessment of patients with CPP.

Background: Central precocious puberty (CPP), predominant in girls, is defined by early development of secondary sexual characteristics driven by the early secretion of hypothalamic gonadotropin releasing hormone (GnRH) and subsequent gonadotropin. Recent studies have shown variation in the LIN28B gene is associated with timing of puberty, but only a few have show it to be associated with CPP. Methods: This study attempted to investigate the relation between single-nucleotide polymorphisms (SNPs) in LIN28B and girls with precocious puberty. Genotype and alleles frequencies of selected SNPs were compared between 116 girls with CPP and 102 controls. Results: We found genotype frequencies in rs314276 and rs221634 were significantly correlated with girls with CPP; while the C allele frequency in rs314276 showed the dominant trait. Standard deviation score (SDS) of weight and body mass index (BMI) were higher in CC homozygotes of rs314276 in girls with CPP. Conclusions: Our results demonstrate that the genotype of rs314276 in LIN28B is associated with girls with CPP, carrying dominant trait in the C allele.

Background: With the paucity of available literature correlating genetic mutation and response to treatment, we aimed to study the genetic makeup of children with growth hormone (GH) deficiency in Western India and correlate the mutation with auxology and response to GH treatment at end of 1 year. Methods: Fifty-three (31 boys and 22 girls) children with severe short stature (height for age z-score <−3) and failed GH stimulation test were studied. Those having concomitant thyroid hormone or cortisol deficiencies were appropriately replaced prior to starting GH treatment. A magnetic resonance imaging (MRI) brain scan was done in all. Genetic mutations were tested for in GH1, GHRH, LHX3, LHX4 and PROP1, POU1F1 and HESX1 genes. Results: Mean age at presentation was 9.7±5.1 years. Thirty-seven children (Group A) had no genetic mutation detected. Six children (Group B) had mutations in the GH releasing hormone receptor ( GHRHR ) gene, while eight children (Group C) had mutation in the GH1 gene. In two children, one each had a mutation in PROP1 and LHX3 . There was no statistically significant difference in baseline height, weight and BMI for age z-score and height velocity for age z-score (HVZ). HVZ was significantly lower, post 1 year GH treatment in the group with homozygous GH1 deletion than in children with no genetic defect. Conclusions: Response to GH at the end of 1 year was poor in children with the homozygous GH1 deletion as compared to those with GHRHR mutation or without a known mutation.

Background: Measurement of 17-hydroxyprogesterone (17-OHP) in dried blood spots has been widely used as a newborn screening tool for congenital adrenal hyperplasia (CAH). Various maternal and neonatal factors can result in falsely high values of 17-OHP. There is a paucity of Indian studies in this regard because routine evaluation of newborn 17-OHP levels as a screening program is not widely practiced in India. Hence, this study was undertaken to evaluate the influence of various maternal and neonatal factors on newborn 17-OHP levels. The aim of the study was to determine the effect of various maternal and neonatal factors on the newborn 17-OHP values. Methods: Retrospective data related to a total of 3080 newborn 17-OHP values and clinical characteristics were collected for 3 years (2013–2015). The data were analyzed to determine the influence of various factors on 17-OHP values. Results: The mean value of 17-OHP in our study was 5.486±3.96 ng/mL. Gender and mode of delivery did not significantly affect the 17-OHP levels. The levels were significantly higher in preterm and low birth weight babies as compared to term babies and babies with normal birth weight. Stress factors like pregnancy induced hypertension (PIH), early onset sepsis (EOS), neonatal seizures and birth asphyxia significantly increase the neonatal 17-OHP levels. Conclusions: The levels of 17-OHP in newborns was measured around day 3 of life are very sensitive to the influence of gestational age, birth weight and presence of stress factors like maternal PIH, birth asphyxia, neonatal sepsis and neonatal seizures and should be interpreted cautiously.

Background: Endocrine organs are highly susceptible to effects of high-dose chemotherapy. The objective of the study was to evaluate endocrine and metabolic complications after hematopoietic stem cell transplantation (HSCT) in children. Methods: The patients who underwent HSCT in our center from April 2010 to October 2014 with at least 1 year follow-up were analyzed retrospectively. Results: One-hundred children (M/F:59/41; mean age 8.9±4.8 years, mean follow-up time 3.4±1.2 years) were included in the study. Female hypogonadism was the most common endocrine dysfunction (35.7%), followed by growth impairment (29.4%), malnutrition (27.4%), dyslipidemia (26%), low bone mineral density (BMD) (25%), hypothyroidism (13%) and insulin resistance (12%). Patients who underwent HSCT >10 years of age were significantly at risk for hypogonadism, metabolic syndrome, growth impairment and malnutrition (p<0.05). Conclusions: Endocrine or metabolic dysfunctions are more prevalent in children who are older than 10 years of age at HSCT. Children who underwent HSCT should be followed-up by a multidisciplinary team during puberty and adolescence.

Hyponatremia can be a complication of opioid therapy, which has been postulated to occur secondary to inappropriate antidiuretic hormone secretion (syndrome of inappropriate antidiuretic hormone secretion [SIADH]). We report severe hyponatremia following wisdom teeth extraction with opioid analgesia in a 19-year-old female with diabetes insipidus (DI) and acquired panhypopituitarism that challenges this theory. As this patient has DI, we believe opioid treatment caused severe hyponatremia by the following mechanisms: (1) Opioids have a direct antidiuretic effect independent of changes in ADH, as demonstrated in Brattleboro rats with central DI. (2) Hydrocodone may have stimulated this patient’s thirst center contributing to hyponatremia, as demonstrated in animal studies. Opioid use can cause hyponatremia in patients independent of ADH. It is important for clinicians to be aware of this so that patients can be appropriately counseled.

Background: Hepatic involvement is a common feature in childhood mitochondrial disorders. Deoxyguanosine kinase (DGUOK) deficiency is one of the mitochondrial DNA depletion syndromes associated with hepatocerebral syndrome. Hepatic disease and neurologic dysfunction occurs within weeks after birth. Low birth weight is one of the common features. This study aims to describe the clinical and laboratory features of four infants carrying four different pathogenic variants in the DGUOK gene. Case presentation: Common clinical findings were progressive cholestatic liver failure, hypoglycemia, hypotonia and rotatory nystagmus in our DGUOK deficiency patients. Lactic acidosis, elevated serum tyrosine and ferritin levels were the striking laboratory features. Cholestasis, iron deposits, microvesicular steatosis and fibrosis were the histopathological findings seen in liver biopsies of two patients. All patients died with multi-organ failure between the ages of 42 days and 6 months. Conclusions: While neurologic findings may occur later in the course of the disease, elevated serum tyrosine levels may alert the physicians to a DGUOK deficiency in a baby with hepatopathy in the presence of the mentioned signs. Early diagnosis is important not only for genetic counseling but also for a possible liver transplantation.

Fructose-1,6-bisphosphatase (FBPase) enzyme deficiency is one of the treatable autosomal recessive inherited metabolic disorders. If diagnosed early, FBPase deficiency has a favorable prognosis. We report the clinical and biochemical findings of a 9.5-year-old female child with FBPase deficiency. FBPase deficiency is caused by a homozygous Arthrobacter luteus (Alu) insertion in the FBP1 gene, reported for the first time.