High-methionine diet in skeletal muscle remodeling: epigenetic mechanism of homocysteine-mediated growth retardation.

Epigenetic DNA methylation (1-carbon metabolism) is crucial for gene imprinting/off-printing that ensures epigenetic memory but also generates a copious amount of homocysteine (Hcy), unequivocally. That is why during pregnancy, expectant mothers are recommended "folic acid" preemptively to avoid birth defects in the young ones because of elevated Hcy levels (i.e., hyperhomocysteinemia (HHcy)). As we know, children born with HHcy have several musculoskeletal abnormalities, including growth retardation. Here, we focus on the gut-dysbiotic microbiome implication(s) that we believe instigates the "1-carbon metabolism" and HHcy causing growth retardation along with skeletal muscle abnormalities. We test our hypothesis whether high-methionine diet (HMD) (an amino acid that is high in red meat), a substrate for Hcy, can cause skeletal muscle and growth retardation, and treatment with probiotics (PB) to mitigate skeletal muscle dysfunction. To test this, we employed cystathionine ß-synthase, CBS deficient mouse (CBS+/-) fed with/without HMD and with/without a probiotic (Lactobacillus rhamnosus) in drinking water for 16 weeks. Matrix metalloproteinase (MMP) activity, a hallmark of remodeling, was measured by zymography. Muscle functions were scored via electric stimulation. Our results suggest that compared to the wild-type, CBS+/- mice exhibited reduced growth phenotype. MMP-2 activity was robust in CBS+/- and HMD effects were successfully attenuated by PB intervention. Electrical stimulation magnitude was decreased in CBS+/- and CBS+/- treated with HMD. Interestingly; PB mitigated skeletal muscle growth retardation and atrophy. Collectively, results imply that individuals with mild/moderate HHcy seem more prone to skeletal muscle injury and its dysfunction.

Beyond the growth delay in children with sleep-related breathing disorders: a systematic review.

INTRODUCTION: The availability of high-quality studies on the association between sleep-disordered breathing in children and delayed growth associated with the hormonal profile recorded before surgery and at follow-up is limited. EVIDENCE ACQUISITION: Medline PubMed, Scopus and WebOfScience databases were searched for relevant publications published between January 2008 to January 2020 and a total of 261 potentially eligible studies were identified. EVIDENCE SYNTHESIS: Following review 19 papers were eligible for inclusion: seven reported a significant postsurgical increase in growth regardless of initial weight status, type of surgery, type of study design, and length of follow-up period. The only high-quality study was a randomized controlled trial that found an increased risk of obstructive sleep apnea syndrome relapse in overweight children. Twelve studies reported the significant increase in growth parameters showing that IGF-1, IGFBP-3, and ghrelin may boost growth after surgery. CONCLUSIONS: The current systematic review demonstrates a scarcity of high-quality studies on growth delay in children with sleep-disordered breathing. Significant catch-up growth after surgery in the short term and changes in IGF-1, IGFBP-3, ghrelin, and leptin levels has been reported in most published studies.

Low-molecular-weight chitosan relieves enterotoxigenic Escherichia coli-induced growth retardation in weaned pigs.

The objective of the present study was to evaluate the effects of low-molecular-weight chitosan (LMWC) on the growth performance, immune responses and intestinal health of weaned pigs challenged by enterotoxigenic Escherichia coli (ETEC). A total of 32 weaned pigs were randomly allocated to four treatments: non-challenged (fed with basal diet), ETEC-challenged (fed with basal diet) and ETEC-challenged plus 50 or 100 mg/kg LMWC supplementation, respectively. After 11 days feeding, the non-challenged pigs were infused with sterilised Luria-Bertani culture, while the remaining pigs were infused with 2.6 × 1011 colony-forming units of ETEC. At 3 days post-challenge, all pigs were administered d-xylose at 0.1 g/kg body weight. One hour later, blood samples were obtained, and the pigs then euthanised to collect intestinal samples. Data showed that only 100 mg/kg LMWC supplementation attenuated (P < 0.05) the average daily gain reduction caused by ETEC. Furthermore, besides the decreased (P < 0.05) serum tumour necrosis factor-α and immunoglobulin (Ig) G concentrations detected in ETEC-challenged pigs supplemented with LMWC at 50 or 100 mg/kg, the higher dose (100 mg/kg) also decreased (P < 0.05) the serum IgM concentration and increased (P < 0.05) the villus height and villus height-to-crypt depth ratio in both the jejunum and ileum, and the sucrase activity in the ileal mucosa. Moreover, LMWC supplementation (50 or 100 mg/kg) in ETEC-challenged pigs elevated (P < 0.05) the mRNA levels of jejunal mucosal peptide transporter 1 and ileal mucosal peptide transporter 1, divalent metal transporter 1 and zinc transporter 1, and decreased (P < 0.05) the ileal and caecal E. coli abundances, while 100 mg/kg LMWC additionally elevated (P < 0.05) the ileal Bacillus abundance, and caecal and colonic Bifidobacterium abundances. These results suggest that LMWC helps alleviate ETEC-induced growth retardation in weaned pigs, which could be associated with the inhibition of the immune responses and improved intestinal health.

Interleukine 6 and C-reactive protein predict growth impairment and acute malnutrition in children and adolescents with chronic kidney disease.

INTRODUCTION: Objective: secondary malnutrition and systemic inflammation may impair growth and body composition in children and adolescents with chronic kidney disease (CKD). This association has been scantily studied, particularly in pre-dialytic stages. Our aim was to correlate growth and nutritional status indicators with the serum concentration of interleukine 6 (IL-6) and ultrasensitive C-reactive protein (CRP) in children with CKD. Methods: this was a prospective cross-sectional study in 29 children and adolescents aged 3-16 years with CKD, stages 3 or 4, in two third-level general hospitals. The outcome variables were height for age, body mass index, arm anthropometric indicators, plus lean mass/fat percentage by bioelectrical impedance. The independent variables were IL-6 and CRP. This study was reviewed and approved by the Health Research and Ethics Committees of both hospitals. Results: height for age, body mass index, subscapular skinfold, arm fat area, and lean mass had a significant negative correlation with IL-6. The height-for-age z-score had a negative correlation with CRP. IL-6 explained 15% to 35% of the variance in height for age and nutritional status indicators. CRP predicted 22% of height for age. One fifth of the patients had acute malnutrition, and one third were stunted. Muscle was the most affected compartment. Conclusion: IL-6 and CRP in children and adolescents with CKD in the pre-dialytic stage predicted one fifth and one third of the variance in acute and chronic malnutrition indicators. The frequency of acute malnutrition and impaired growth was clinically significant. Muscular mass deficit was a central component of malnutrition.

INTRODUCCIÓN: Objetivo: correlacionar indicadores de crecimiento y del estado nutricional con la concentración sérica de interleucina 6 (IL-6) y proteína C-reactiva ultrasensible (PCR) en niños con ERC. Métodos: estudio transversal analítico de 29 niños y adolescentes de 3 a 16 años de edad con ERC, estadios 3 o 4, en dos hospitales generales de tercer nivel. Las variables dependientes fueron indicadores antropométricos de crecimiento y del estado nutricional y la composición corporal por impedancia bioeléctrica. Las variables independientes fueron IL-6 y PCR. Este estudio fue revisado y aprobado por los Comités de Ética y de Investigación de ambos hospitales. Resultados: la talla para la edad (T/E), el índice de masa corporal, el pliegue cutáneo subescapular, el área de grasa del brazo y la masa magra obtuvieron una correlación negativa con la IL-6. La T/E obtuvo una correlación negativa con la PCR. La IL-6 explicó el 15% y 35% de la varianza de la T/E y de los indicadores del estado nutricional. La CRP predijo el 22% de la T/E. Una quinta parte de los pacientes tenía desnutrición aguda y una tercera parte desmedro. El compartimento corporal más afectado fue el muscular. Conclusión: la IL-6 y la PCR en niños y adolescentes con ERC en etapa predialítica explicaron una quinta y una tercera parte de la varianza de los indicadores de desnutrición aguda y crónica, respectivamente. La frecuencia de la desnutrición aguda y el desmedro fueron clínicamente significativos. El déficit de masa muscular fue un componente central de la desnutrición.

Plasma midkine concentrations in healthy children, children with increased and decreased adiposity, and children with short stature.

BACKGROUND: Midkine (MDK), one of the heparin-binding growth factors, is highly expressed in multiple organs during embryogenesis. Plasma concentrations have been reported to be elevated in patients with a variety of malignancies, in adults with obesity, and in children with short stature, diabetes, and obesity. However, the concentrations in healthy children and their relationships to age, nutrition, and linear growth have not been well studied. SUBJECTS AND METHODS: Plasma MDK was measured by immunoassay in 222 healthy, normal-weight children (age 0-18 yrs, 101 boys), 206 healthy adults (age 18-91 yrs, 60 males), 61 children with BMI ≥ 95th percentile (age 4-18 yrs, 20 boys), 20 girls and young women with anorexia nervosa (age 14-23 yrs), and 75 children with idiopathic short stature (age 3-18 yrs, 42 boys). Body fat was evaluated by dual-energy X-ray absorptiometry (DXA) in a subset of subjects. The associations of MDK with age, sex, adiposity, race/ethnicity and stature were evaluated. RESULTS: In healthy children, plasma MDK concentrations declined with age (r = -0.54, P < 0.001) with values highest in infants. The decline occurred primarily during the first year of life. Plasma MDK did not significantly differ between males and females or between race/ethnic groups. MDK concentrations were not correlated with BMI SDS, fat mass (kg) or percent total body fat, and no difference in MDK was found between children with anorexia nervosa, healthy weight and obesity. For children with idiopathic short stature, MDK concentrations did not differ significantly from normal height subjects, or according to height SDS or IGF-1 SDS. CONCLUSIONS: In healthy children, plasma MDK concentrations declined with age and were not significantly associated with sex, adiposity, or stature-for-age. These findings provide useful reference data for studies of plasma MDK in children with malignancies and other pathological conditions.

Low DHEAS Concentration in a Girl Presenting with Short Stature and Premature Pubarche: A Novel PAPSS2 Gene Mutation.

OBJECTIVE: Dehydroepiandrosterone (DHEA) sulfotransferase (SULT2A1) converts DHEA to DHEA sulfate (DHEAS) which prevents bioactive androgen excess. This enzymatic reaction requires PAPS (3'-phospho-adenosine-5'-phosphosulfate) biosynthesis mediated by PAPS synthase 2 (PAPSS2). Here, we report a patient presenting with short stature and premature pubarche due to a novel homozygous mutation in the PAPPS2 gene. CASE REPORT: A 7.5-year-old girl was referred for short stature. She was born at term with a birth weight of 2,850 g and her parents were first cousins. At presentation, her height was 113.0 cm (-2.1 SDS) and weight was 28.3 kg (+0.9 SDS), her arm span was 115.0 cm, and upper to lower segment ratio was 1.2. Her pubic hair and breast development were at Tanner stage III and I, respectively. Radiographs revealed mild lumbar scoliosis and platyspondyly and irregular vertebral endplates in the thoracolumbar region. Her serum DHEAS was low (39 ng/mL). The plasma DHEAS/DHEA ratio was significantly decreased on 2 separate measurements (4.4 and 19.8; normal range 31-345). PAPSS2 gene analysis identified a homozygous p.L440Wfs*12 (c.1318_1330 delCTACTACACCCTC) variant. This is the first report of a large deletion leading to a frameshift effect in the PAPSS2 gene and a truncated PAPSS2 protein. CONCLUSION: We describe the third case with PAPSS2 deficiency presenting with premature pubarche, and the first large deletion in the PAPSS2 gene. Although PAPSS2 deficiency is a rare cause of premature pubarche and adrenal androgen excess, it should be considered, especially in cases with disproportionate short stature and clinical hyperandrogenism associated with low plasma DHEAS concentration.

Serum Adipokines, Growth Factors, and Cytokines Are Independently Associated with Stunting in Bangladeshi Children.

Growth in young children is controlled through the release of several hormonal signals, which are affected by diet, infection, and other exposures. Stunting is clearly a growth disorder, yet limited evidence exists documenting the association of different growth biomarkers with child stunting. This study explored the association between different growth biomarkers and stunting in Bangladeshi children. A quasi-experimental study was conducted among 50 stunted (length-for-age Z-score (LAZ) < -2 SD) and 50 control (LAZ ≥ -2 SD) children, aged 12-18 months, residing in a Bangladeshi slum. The enrolled stunted children received an intervention package, which included food supplementation for three months, psychosocial stimulation for six months, and routine clinical care on community nutrition center at the study field site. The controls received routine clinical care only. All children were clinically screened over the study period. Length, weight, fasting blood and fecal biomarkers were measured. All biomarkers levels were similar in both groups except for oxyntomodulin at enrolment. Leptin (adjusted odds ratio, AOR: 4.0, p < 0.01), leptin-adiponectin ratio (AOR 5.07 × 108, p < 0.01), insulin-like growth factor-1 (IGF-1) (AOR 1.02, p < 0.05), and gamma interferon (IFN-γ) (AOR 0.92, p < 0.05) levels were independently associated with stunting at enrolment. Serum leptin, leptin-adiponectin ratio, interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-α), and fecal alpha-1-antitrypsin (AAT) levels increased significantly (p < 0.001), while IFN-γ levels significantly decreased among stunted children after six months of intervention. Leptin, leptin-adiponectin ratio, IGF-1, and IFN-γ are independently associated with stunting in Bangladeshi children. This trial was registered at clinicaltrials.gov as NCT02839148.

[Growth hormone of dried blood spot for the diagnosis of growth hormone deficiency]. / Hormona de crecimiento en sangre de papel filtro para el diagnóstico de deficiencia de hormona de crecimiento.

INTRODUCTION: The diagnosis of growth hormone deficiency (GHD) is difficult to determine, and could be associated with severe complications, especially in the neonatal period. The stimulation test of growth hormone (GH) secretion is considered the gold standard for diagnosis, but it has methodological complications and is associated with adverse effects. Neonates present physiological increased secretion of GH, representing a diagnostic window. OBJECTIVE: To evaluate if the dried blood spot on filter paper obtained in the neonatal period, as part of a neonatal screening for con genital hypothyroidism and phenylketonuria, allows differentiating patients with GHD from those who do not have it. PATIENTS AND METHOD: Study of cases and controls by measuring the GH concen tration in dried blood spot on filter paper obtained in the neonatal period, comparing controls with GHD with cases with discarded deficiency. The sample was extracted from the filter paper, obtaining two 0.125 inch discs per each patient from the center of the blood spot on the paper, for a highly sen sitive ELISA assay for human GH based on the use of polyclonal antibodies against 22 kDa recom binant human GH. RESULTS: Seven cases of GHD and ten controls were obtained. The median GH concentration of the dried blood spot in the cases is 2.0 ng/ml (Interquartile range 3.6 ng/ml) and 2.05 ng/ml (Interquartile range 2.0 ng/ml) in the controls, Mann-Whitney U test 30.5 (p = 0.68). The two cases with multiple pituitary-hormone deficiency (MPHD) present concentrations lower than 1 ng/ml. CONCLUSION: The dried blood spot sample did not differentiate GHD patients from control cases, although MPHD cases present much lower concentrations compared to isolated growth hor mone deficiency (IGHD).

Hormona de crecimiento en sangre de papel filtro para el diagnóstico de deficiencia de hormona de crecimiento / Growth hormone of dried blood spot for the diagnosis of growth hormone deficiency

INTRODUCCIÓN: El diagnóstico de deficiencia de hormona de crecimiento (DHC) es difícil de establecer, y se puede asociar a serias complicaciones, especialmente en el período neonatal. La prueba de estímulo de secreción de hormona de crecimiento (HC) se considera de elección para el diagnóstico, pero presenta complicaciones metodológicas y se asocia a efectos adversos. Los neonatos presentan aumento de la secreción de HC de forma fisiológica, siendo una ventana diagnóstica. OBJETIVO: Evaluar si la muestra de sangre en papel filtro tomada en el período neonatal, en contexto del tamizaje neonatal de hipotiroidismo congénito y fenilcetonuria, permite diferenciar pacientes con DHC, de los que no la presentan. PACIENTES Y MÉTODO: Estudio de casos y controles mediante determinación de concentración de HC en sangre de papel filtro extraída en período neonatal, comparando controles con DHC con casos con deficiencia descartada. Se realizó extracción de la muestra del papel filtro, obteniendo dos discos de 0,125 pulgada por cada uno de los pacientes desde el centro de la mancha de sangre del papel, para un ELISA de HC humana altamente sensible basado en el uso de anticuerpos policlonales dirigidos contra la HC humana recombinante de 22kDa de peso molecular. RESULTADOS: Se obtuvo un total de 7 casos de DHC y 10 controles. La mediana de concentración de HC de papel filtro en los casos es 2,0 ng/ml (Rango intercuartil 3,6 ng/ml) y controles 2,05 ng/mL (RIC 2,0 ng/ml), U de Mann-Withney 30,5 (p = 0,68). Los dos casos con deficiencia de hormonas hipofisarias múltiples (DHHM) presentan concentraciones menores a 1 ng/ml. CONCLUSIÓN: La muestra de papel filtro no permitió diferenciar a los pacientes con DHC de los casos controles, aunque los casos con DHHM presentaron concentraciones mucho menores, en comparación a la deficiencia de hormona de crecimiento aislada (DHCA).

INTRODUCTION: The diagnosis of growth hormone deficiency (GHD) is difficult to determine, and could be associated with severe complications, especially in the neonatal period. The stimulation test of growth hormone (GH) secretion is considered the gold standard for diagnosis, but it has methodological complications and is associated with adverse effects. Neonates present physiological increased secretion of GH, representing a diagnostic window. OBJECTIVE: To evaluate if the dried blood spot on filter paper obtained in the neonatal period, as part of a neonatal screening for con genital hypothyroidism and phenylketonuria, allows differentiating patients with GHD from those who do not have it. PATIENTS AND METHOD: Study of cases and controls by measuring the GH concen tration in dried blood spot on filter paper obtained in the neonatal period, comparing controls with GHD with cases with discarded deficiency. The sample was extracted from the filter paper, obtaining two 0.125 inch discs per each patient from the center of the blood spot on the paper, for a highly sen sitive ELISA assay for human GH based on the use of polyclonal antibodies against 22 kDa recom binant human GH. RESULTS: Seven cases of GHD and ten controls were obtained. The median GH concentration of the dried blood spot in the cases is 2.0 ng/ml (Interquartile range 3.6 ng/ml) and 2.05 ng/ml (Interquartile range 2.0 ng/ml) in the controls, Mann-Whitney U test 30.5 (p = 0.68). The two cases with multiple pituitary-hormone deficiency (MPHD) present concentrations lower than 1 ng/ml. CONCLUSION: The dried blood spot sample did not differentiate GHD patients from control cases, although MPHD cases present much lower concentrations compared to isolated growth hor mone deficiency (IGHD).

Hibiscus sabdariffa Meal Improves Iron Status of Childbearing Age Women and Prevents Stunting in Their Toddlers in Northern Ghana.

Globally, iron deficiency (ID) is the most common form of nutritional deficiency, particularly in young children and childbearing age women. ID can lead to stunting and impaired cognitive development in children, as well as adverse maternal health and birth outcomes. In this study, the efficacy of an alternative food-to-food fortification utilizing indigenous iron-rich food sources was investigated in a quasi-experimental study. Childbearing age women (15⁻49 years, intervention-Kassena Nankana West district: n = 60; control-Builsa North district: n = 60) and their toddlers (6⁻24 months) consumed Hibiscus sabdariffa leaf meals (HSM, 1.71 mg Fe/100 g meal) three times a week for 12 weeks during the dry/lean season in Northern Ghana. We found that feeding the HSM (1.9 kg/day) improved iron status of women of childbearing age with time (p = 0.011), and protected stunting among toddlers during the dry/lean season (p = 0.024), which is the period with the worst food and nutrition insecurity. Compared with the control group, the number of stunted toddlers declined in the intervention group.

The association of malaria morbidity with linear growth, hemoglobin, iron status, and development in young Malawian children: a prospective cohort study.

BACKGROUND: Although poor complementary feeding is associated with poor child growth, nutrition interventions only have modest impact on child growth, due to high burden of infections. We aimed to assess the association of malaria with linear growth, hemoglobin, iron status, and development in children aged 6-18 months in a setting of high malaria and undernutrition prevalence. METHODS: Prospective cohort study, conducted in Mangochi district, Malawi. We enrolled six-months-old infants and collected weekly data for 'presumed' malaria, diarrhea, and acute respiratory infections (ARI) until age 18 months. Change in length-for-age z-scores (LAZ), stunting, hemoglobin, iron status, and development were assessed at age 18 months. We used ordinary least squares regression for continuous outcomes and modified Poisson regression for categorical outcomes. RESULTS: Of the 2723 children enrolled, 2016 (74.0%) had complete measurements. The mean (standard deviation) incidences of 'presumed' malaria, diarrhea, and ARI, respectively were: 1.4 (2.0), 4.6 (10.1), and 8.3 (5.0) episodes/child year. Prevalence of stunting increased from 27.4 to 41.5% from 6 to 18 months. 'Presumed' malaria incidence was associated with higher risk of stunting (risk ratio [RR] = 1.04, 95% confidence interval [CI] = 1.01 to 1.07, p = 0.023), anemia (RR = 1.02, 95%CI = 1.00 to 1.04, p = 0.014) and better socio-emotional scores (B = - 0.21, 95%CI = - 0.39 to - 0.03, p = 0.041), but not with change in LAZ, haemoglobin, iron status or other developmental outcomes. Diarrhea incidence was associated with change in LAZ (B = - 0.02; 95% CI = - 0.03 to - 0.01; p = 0.009), stunting (RR = 1.02; 95% CI = 1.01 to 1.03; p = 0.005), and slower motor development. ARI incidence was not associated with any outcome except for poorer socio-emotional scores. CONCLUSION: In this population of young children living in a malaria-endemic setting, with active surveillance and treatment, 'presumed' malaria is not associated with change in LAZ, hemoglobin, or iron status, but could be associated with stunting and anemia. Diarrhea was more consistently associated with growth than was malaria or ARI. The findings may be different in contexts where active malaria surveillance and treatment is not provided. TRIAL REGISTRATION: NCT00945698 (July 24, 2009) and NCT01239693 (November 11, 2010).

Effectiveness of a Program Intervention with Reduced-Iron Multiple Micronutrient Powders on Iron Status, Morbidity and Growth in Young Children in Ethiopia.

Despite the potential for improving iron status and child growth in low- and middle-income settings, concerns on the safety of high iron dosages of Micronutrient Powders (MNP currently limit their applicability in programs. We examined the effectiveness and risks of an integrated complementary feeding program with low iron dose (6 mg/serving) MNP among 6⁻23-month-old Ethiopian children using a quasi-experimental study design comparing children from five intervention districts (n = 1172) to those from four matched non-intervention districts (n = 1137). Haemoglobin concentrations increased in intervention and decreased in non-intervention children (group-difference +3.17 g/L), but without improvement in iron stores. Intervention children were 2.31 times more likely to have diarrhoea and 2.08 times more likely to have common cold and flu, but these differences decreased towards the end of the intervention. At end line, intervention children had higher mean Height-for-Age Zscore (HAZ) and a 51% reduced odds of being stunted compared to non-intervention children. MNP with low iron dose, when provided combined with other Infant and Young Child Feeding (IYCF) interventions, marginally improved haemoglobin status and resulted in a remarkable improvement in linear growth in 6⁻23-month-old children. These benefits likely outweigh the relatively small increase in the risk of diarrhoea.

Association of Fecal Markers of Environmental Enteric Dysfunction with Zinc and Iron Status among Children at First Two Years of Life in Bangladesh.

Environmental enteric dysfunction (EED) causes gut inflammation and increased intestinal permeability leading to deficiencies in micronutrients such as zinc and iron. Fecal markers such as myeloperoxidase (MPO), neopterin (NEO), and alpha-1-anti-trypsin (AAT) can predict EED. The aim of this study was to examine the association between fecal markers of EED with zinc and iron status among children at first 2 years of life. Malnutrition and Enteric Disease Study Bangladeshi birth cohort data were used to conduct this analysis. Multivariable analyses using generalized estimating equations were performed to test the association between individual fecal markers with zinc or iron status of the children. A total of 265 children were enrolled in the study (male:female = 1:1). Of the 627 stool samples collected (N = 222 children), 535, 511, and 577 were accompanied by zinc, ferritin, and soluble transferrin receptor values, respectively. Median (interquartile range [IQR]) values of AAT, MPO, and NEO were 0.33 (0.18-0.62) mg/g, 3,895.42 (1,563.76-8,432.82) ng/mL, and 890.81 (331.57-2,089.04) nmol/L, respectively. Overall, 60%, 71%, and 97% of samples were above the values considered normal in nontropical settings for AAT, MPO, and NEO, respectively. High AAT levels were significantly associated with low ferritin values after adjusting for age and gender (coefficient = -5.85; 95% confidence interval = -11.23 to -0.47; P value = 0.03). No such association was found between AAT and plasma zinc status. Myeloperoxidase and NEO were not associated with plasma zinc or iron status. The study results imply the importance of enteric protein loss in contributing to reduced ferritin levels at first 2 years of life.

Examining the relationship between blood lead level and stunting, wasting and underweight- A cross-sectional study of children under 2 years-of-age in a Bangladeshi slum.

Elevated blood lead level (BLL) is known to cause cardiac, immune, and cognitive damage but had not been thoroughly studied in relation to stunting among children under two years of age. We primarily aimed to assess the relationship between elevated BLL, the accumulation of concerned amount of the metal lead in blood and stunting and secondarily-wasting and underweight amongst Bangladeshi children less than two years of age. For this cross-sectional study, BLL measurements, anthropometric data, and socioeconomic indicator information were collected and analyzed for 729 children under two years of age upon enrollment in the MAL-ED study conducted in a Bangladeshi slum area. Univariate, bivariate and multivariate analyses were carried out to observe the proportion and mean and contribution of elevated BLL and other relevant variables in explaining the occurrence of stunting. Of the enrolled subjects, 39.0% were stunted [length-for-age z score (LAZ<-2)], 50.3% were male, and 86.6% had an elevated BLL (≥5µg/dL). Mean BLL of stunted children was 8.47 ± 3·37 µg/dL and 8.10 ± 3·80 µg/dL for non-stunted children. Proportion of children with elevated BLL was not significantly different between the stunted and non-stunted groups (p>0.05). When adjusted for other variables, elevated BLL was found to be a significant predictor of stunting and underweight (p<0.05) but not wasting (p>0.05). Elevated BLL (p<0·01), child's gender and weight (p<0·001), maternal body mass index (BMI) (p<0.05) and severe household food insecurity (p<0·05) were all significantly associated with stunting in the multivariate model. Increased odds of stunting was also observed for increased BLL. The findings suggest that chronic lead poisoning is significantly associated with high level of stunting among child slum dwellers in Bangladesh. These findings strengthen the argument for improved lead reduction efforts in Bangladesh, where lead poisoning and stunting are both highly prevalent.

Utility of serum IGF-1 for diagnosis of growth hormone deficiency following traumatic brain injury and sport-related concussion.

BACKGROUND: Growth hormone deficiency (GHD) is a potential consequence of traumatic brain injury (TBI), including sport-related concussion (SRC). GH stimulation testing is required for definitive diagnosis; however, this is resource intensive and can be associated with adverse symptoms or risks. Measurement of serum IGF-1 is more practical and accessible, and pituitary tumour patients with hypopituitarism and low serum IGF-1 have been shown to have a high probability of GHD. We aimed to evaluate IGF-1 measurement for diagnosing GHD in our local TBI population. METHODS: We conducted a retrospective chart review of patients evaluated for GHD at the TBI clinic and referred for GH stimulation testing with insulin tolerance test (ITT) or glucagon stimulation test (GST) since December 2013. We obtained demographics, TBI severity, IGF-1, data pertaining to pituitary function, and GH stimulation results. IGF-1 values were used to calculate z-scores per age and gender specific reference ranges. Receiver operator curve analysis was performed to evaluate diagnostic threshold of IGF-1 z-score for determining GHD by GST or ITT. RESULTS: Sixty four patient charts were reviewed. 48 patients had mild, six had moderate, eight had severe TBI, and two had non-traumatic brain injuries. 47 patients underwent ITT or GST. 27 were confirmed to have GHD (peak hGH < 5 µg/L). IGF-1 level was within the age and gender specific reference range for all patients with confirmed GHD following GH stimulation testing. Only one patient had a baseline IGF-1 level below the age and gender specific reference range; this patient had a normal response to GH stimulation testing. ROC analysis showed IGF-1 z-score AUC f, confirming lack of diagnostic utility. CONCLUSION: Baseline IGF-1 is not a useful predictor of GHD in our local TBI population, and therefore has no value as a screening tool. TBI patients undergoing pituitary evaluation will require a dynamic test of GH reserve.

Metabolic and immunological assessment of small-for-gestational-age children during one-year treatment with growth hormone: the clinical impact of apolipoproteins.

Children born small for gestational age (SGA) are at a higher risk for metabolic disorders later in life. In this study, we aimed to characterize young SGA children without catch-up growth and evaluate the effects of GH treatment on endocrinological, metabolic, and immunological parameters. Study design is a one-year single hospital-based study included prospective observation of SGA patients during 12 months of GH treatment. Clinical and laboratory profiles of SGA children at baseline were compared with controls born appropriate size for age. Twenty-six SGA children (median age, 3.4 years) and 26 control children (median age, 3.8 years) were enrolled. Anthropometric, hematologic, biochemical, immunological, and endocrinological parameters were assessed at baseline and 1, 3, 6, 9, and 12 months after the start of GH treatment. As a result, median height SD score (SDS) of SGA children increased by +0.42 with 12-month GH treatment. Body mass index SDS was lower in SGA children than in controls. Serum apolipoprotein A1 increased, whereas apolipoprotein B decreased during GH treatment. Serum leptin and resistin levels, which were lower in SGA children than in controls at baseline, did not change remarkably with GH treatment. Monocyte counts, which were lower in SGA patients at baseline, increased after GH treatment. Neutrophil counts significantly increased after GH treatment. Natural killer cell ratios, which were higher in SGA patients, decreased after GH treatment. In conclusion, there was no evidence suggesting metabolic abnormalities in SGA children. Serum apolipoprotein changes might predict the beneficial role of GH treatment in lowering cardiometabolic risk.

Infant Development at the Age of 6 Months in Relation to Feeding Practices, Iron Status, and Growth in a Peri-Urban Community of South Africa.

BACKGROUND: Evidence on the association between feeding practices, iron deficiency, anaemia, stunting, and impaired psychomotor development during infancy is limited. This study assessed the association between psychomotor development with early feeding practices, growth, iron status, and anaemia. METHODS: This was cross-sectional baseline data of a randomised controlled trial which included 6-month-old infants and their mothers or primary caregivers (n = 750) in a peri-urban community in the North West province of South Africa. The Kilifi Developmental Inventory and a parent rating scale were used to assess psychomotor development. Feeding practices and anthropometric measurements were based on the World Health Organisation (WHO) guidelines. Anaemia and iron status were determined by blood sample analysis. RESULTS: Prevalence of anaemia and stunting for the infants were 36.4% and 28.5%, respectively. Multiple regression analysis showed that birth weight was related to combined psychomotor scores (ß = -3.427 (-4.603, 1.891), p < 0.001), as well as parent rating scores (ß = -0.843 (-1.507, -0.180), p = 0.013). Length-for-age z-scores were associated with combined psychomotor scores (ß = -1.419 (-2.466, 0.373), p = 0.008), as well as parent rating scores (ß = -0.747 (-1.483, -0.010), p = 0.047). CONCLUSIONS: In this setting, with high prevalence of anaemia and stunting, important associations between lower psychomotor development scores and birthweight as well as length-for-age z-scores in 6-month-old infants were found. These findings warrant further investigation to develop a greater understanding of factors influencing the association between child growth and psychomotor development within the first 1000 days of life.

Plasma C-Type Natriuretic Peptide: Emerging Applications in Disorders of Skeletal Growth.

Although studies in experimental animals show that blood levels of C-type natriuretic peptide (CNP) and its bioinactive aminoterminal propeptide (NTproCNP) are potential biomarkers of long bone growth, a lack of suitable assays and appropriate reference ranges has limited the application of CNP measurements in clinical practice. Plasma concentrations of the processed product of proCNP, NTproCNP - and to a lesser extent CNP itself - correlate with concurrent height velocity throughout all phases of normal skeletal growth, as well as during interventions known to affect skeletal growth in children. Since a change in levels precedes a measurable change in height velocity during interventions, measuring NTproCNP may have predictive value in clinical practice. Findings from a variety of genetic disorders affecting CNP signaling suggest that plasma concentrations of both peptides may be helpful in diagnosis, provided factors such as concurrent height velocity, feedback regulation of CNP, and differential changes in peptide clearance are considered when interpreting values. An improved understanding of factors affecting plasma levels, and the availability of commercial kits enabling accurate measurement using small volumes of plasma, can be expected to facilitate potential applications in growth disorders including genetic causes -affecting the CNP signaling pathway.

Eggs early in complementary feeding increase choline pathway biomarkers and DHA: a randomized controlled trial in Ecuador.

Background: Choline status has been associated with stunting among young children. Findings from this study showed that an egg intervention improved linear growth by a length-for-age z score of 0.63.Objective: We aimed to test the efficacy of eggs introduced early in complementary feeding on plasma concentrations of biomarkers in choline pathways, vitamins B-12 and A, and essential fatty acids.Design: A randomized controlled trial, the Lulun ("egg" in Kichwa) Project, was conducted in a rural indigenous population of Ecuador. Infants aged 6-9 mo were randomly assigned to treatment (1 egg/d for 6 mo; n = 80) and control (no intervention; n = 83) groups. Socioeconomic data, anthropometric measures, and blood samples were collected at baseline and endline. Household visits were made weekly for morbidity surveillance. We tested vitamin B-12 plasma concentrations by using chemiluminescent competitive immunoassay and plasma concentrations of choline, betaine, dimethylglycine, retinol, essential fatty acids, methionine, dimethylamine (DMA), trimethylamine, and trimethylamine-N-oxide (TMAO) with the use of liquid chromatography-tandem mass spectrometry.Results: Socioeconomic factors and biomarker concentrations were comparable at baseline. Of infants, 11.4% were vitamin B-12 deficient and 31.7% marginally deficient at baseline. In adjusted generalized linear regression modeling, the egg intervention increased plasma concentrations compared with control by the following effect sizes: choline, 0.35 (95% CI: 0.12, 0.57); betaine, 0.29 (95% CI: 0.01, 0.58); methionine, 0.31 (95% CI: 0.03, 0.60); docosahexaenoic acid, 0.43 (95% CI: 0.13, 0.73); DMA, 0.37 (95% CI: 0.37, 0.69); and TMAO, 0.33 (95% CI: 0.08, 0.58). No significant group differences were found for vitamin B-12, retinol, linoleic acid (LA), α-linolenic acid (ALA), or ratios of betaine to choline and LA to ALA.Conclusion: The findings supported our hypothesis that early introduction of eggs significantly improved choline and other markers in its methyl group metabolism pathway. This trial was registered at clinicaltrials.gov as NCT02446873.

Low serum ω-3 and ω-6 polyunsaturated fatty acids and other metabolites are associated with poor linear growth in young children from rural Malawi.

Background: Stunting affects ∼25% of children <5 y of age and is associated with impaired cognitive and motor development and increased morbidity and mortality. The pathogenesis of stunting is poorly understood.Objective: The purpose of this study was to identify altered metabolic pathways associated with child stunting.Design: We measured 677 serum metabolites using liquid chromatography-tandem mass spectrometry in a cross-sectional study of 400 Malawian children aged 12-59 mo, of whom 62% were stunted.Results: A low height-for-age z score (HAZ) was associated with lower serum concentrations of 1) ω-3 (n-3) and ω-6 (n-6) polyunsaturated fatty acids (PUFAs), 2) sulfated neurosteroids, which play a role in brain development, 3) carnitine, a conditionally essential nutrient with an important role in the carnitine shuttle for the metabolism of fatty acids and energy production, and 4) γ-glutamyl amino acids, which represent an altered γ-glutamyl cycle of glutathione metabolism. A low HAZ was associated with significantly higher serum concentrations of 5 biomarkers related to cigarette smoke exposure.Conclusions: This metabolomics study shows a cross-sectional association between stunting and low serum ω-3 and ω-6 long-chain PUFAs, which are essential for growth and development; low sulfated neurosteroids, which play a role in brain development; low carnitine, which is essential for ß-oxidation of fatty acids; alterations in glutathione metabolism; and increased serum metabolites that are associated with secondhand tobacco smoke exposure. This trial was registered at www.controlled-trials.com as ISRCTN14597012.