Growing up: A NOD2 our microbes.

In a recent report in Science, Schwarzer and colleagues demonstrate the growth benefits of treatment with Lactiplantibacillus plantarum strain WJL in a preclinical mouse model of chronic undernutrition. L. plantarum influences the somatotropic axis to promote growth through intestinal epithelial NOD2 sensing.

Microbe-mediated intestinal NOD2 stimulation improves linear growth of undernourished infant mice.

The intestinal microbiota is known to influence postnatal growth. We previously found that a strain of Lactiplantibacillus plantarum (strain LpWJL) buffers the adverse effects of chronic undernutrition on the growth of juvenile germ-free mice. Here, we report that LpWJL sustains the postnatal growth of malnourished conventional animals and supports both insulin-like growth factor-1 (IGF-1) and insulin production and activity. We have identified cell walls isolated from LpWJL, as well as muramyl dipeptide and mifamurtide, as sufficient cues to stimulate animal growth despite undernutrition. Further, we found that NOD2 is necessary in intestinal epithelial cells for LpWJL-mediated IGF-1 production and for postnatal growth promotion in malnourished conventional animals. These findings indicate that, coupled with renutrition, bacteria cell walls or purified NOD2 ligands have the potential to alleviate stunting.

An increase in the developmental tempo affects the secular trend in height in male Austrian conscripts birth cohorts 1951-2002.

OBJECTIVES: Using population-based data on height in Austria from birth cohort 1951 to 2002, we aim to evaluate the secular trends in height and developmental tempo among Austrian young men. METHODS: Data were obtained from the Austrian conscription medical examination. We included 1 205 112 conscripts (18-<20 years) who were born between 1951 and 2002 and 853 645 conscripts (17-<19 years) who were born between 1961 and 2002. Height was measured during the medical examination and was used to evaluate the secular trends of mean height over time. Furthermore, the mean difference in height between conscripts of 17- and 18 years old were compared across birth cohorts. RESULTS: The mean height of conscripts aged 17 years increased by 2.2 cm (p < .0001) in between 1961 and 2002. The mean height of conscripts aged 18 years increased by 4.3 cm (p < .0001) between 1951 and 2002. However, the increase in mean height has slowed down since the 1970 s. The difference in mean height between 17 and 18 years old widened from about 0.1 cm in 1961 to 0.3 cm around 1970 and then steadily narrowed again to 0.1 cm at the end of the study period. CONCLUSIONS: The increasing trend in height slows at the end of the 20th century, the developmental tempo at the population level, however, continued to increase. The difference in mean height between 17 and 18 years old narrowed, which may indicate that young men reached their final height earlier.

Determining the timing of pubertal onset via a multicohort analysis of growth.

OBJECTIVE: Growth-based determination of pubertal onset timing would be cheap and practical. We aimed to determine this timing based on pubertal growth markers. Secondary aims were to estimate the differences in growth between cohorts and identify the role of overweight in onset timing. DESIGN: This multicohort study includes data from three Finnish cohorts-the Type 1 Diabetes Prediction and Prevention (DIPP, N = 2,825) Study, the Special Turku Coronary Risk Factor Intervention Project (STRIP, N = 711), and the Boy cohort (N = 66). Children were monitored for growth and Tanner staging (except in DIPP). METHODS: The growth data were analyzed using a Super-Imposition by Translation And Rotation growth curve model, and pubertal onset analyses were run using a time-to-pubertal onset model. RESULTS: The time-to-pubertal onset model used age at peak height velocity (aPHV), peak height velocity (PHV), and overweight status as covariates, with interaction between aPHV and overweight status for girls, and succeeded in determining the onset timing. Cross-validation showed a good agreement (71.0% for girls, 77.0% for boys) between the observed and predicted onset timings. Children in STRIP were taller overall (girls: 1.7 [95% CI: 0.9, 2.5] cm, boys: 1.0 [0.3, 2.2] cm) and had higher PHV values (girls: 0.13 [0.02, 0.25] cm/year, boys: 0.35 [0.21, 0.49] cm/year) than those in DIPP. Boys in the Boy cohort were taller (2.3 [0.3, 4.2] cm) compared with DIPP. Overweight girls showed pubertal onset at 1.0 [0.7, 1.4] year earlier compared with other girls. In boys, there was no such difference. CONCLUSIONS: The novel modeling approach provides an opportunity to evaluate the Tanner breast/genital stage-based pubertal onset timing in cohort studies including longitudinal data on growth but lacking pubertal follow-up.

Ventilatory responses at submaximal exercise intensities in healthy children and adolescents during the growth spurt period: a semi-longitudinal study.

PURPOSE: To identify the changes of ventilation ([Formula: see text]E), tidal volume (VT) and respiratory frequency (fr) at different incremental step test intensities during maturation of children and adolescents. METHODS: A semi-longitudinal study was conducted on 68 healthy untrained boys and girls aged 11-17 years. The subjects were separated into three distinct age groups. [Formula: see text]E, VT and fr parameters were evaluated annually during 3 years by modifying incremental step test intensities according to ventilatory threshold (VTh) level (30, 60 and 90% of [Formula: see text]O2max). Absolute and relative values of ventilatory responses were analyzed and compared according to age and developmental phase. RESULTS: (1) Height, weight, lean body mass and vital capacity increased significantly from 11 to 17 years of age. (2) [Formula: see text]O2max, [Formula: see text]E, and VT increased during maturation even when exercise intensity changed, especially from 11 to 15 years of age. On the other hand, fr showed a decreasing trend. CONCLUSION: Increases of VT are the main reason for [Formula: see text]E increases during maturation of children. fr decreased independently of total body mass during maturation. [Formula: see text]E.kg-1 was stable despite intensity variations. VT.kg-1 increased significantly from 11 to 15 years then stabilized at 17 years. Lean body mass seems to explain the evolution of VT.kg-1 during maturation.

Rodent studies of developmental programming and ageing mechanisms: Special issue: In utero and early life programming of ageing and disease.

Compelling evidence exists indicating that developmental programming influences ageing. Programming alters life-course phenotype in multiple organs, predisposing to diseases such as diabetes, obesity and cardiovascular disease that shorten lifespan. This review describes studies in rodents, the most commonly studied species, addressing interactions of programming challenges with ageing. We first consider ageing and programming of insulin function that has been clearly shown to decrease with age. It is important to evaluate ageing in pancreatic islets isolated from other systems. Studies discussed show premature pancreatic islet ageing resulting from both maternal under- and overnutrition. New ways to determine programming of adipose tissue and effects on fat storage are explored. Oxidative stress is a major factor that regulates ageing in tissues. Oxidative stress is discussed in relation to reproductive and cardiovascular ageing. Premature ageing is associated with both low and high glucocorticoid function. Both over and undernutrition have offspring sex-specific programming effects on life-course glucocorticoid concentrations. Evidence is provided that maternal age at conception affects offspring endocrine and metabolism ageing. Finally, the importance of matching foetal nutrition and energy availability with composition and energy content in the post-weaning diet is demonstrated. This mismatch can lead to a greatly shortened lifespan. General principles are discussed throughout. For example, sexual dimorphism of age-related outcomes can be marked. Accelerated ageing occurs early in life. Improving knowledge on programming ageing interactions will improve health span as well as lifespan. Finally, there are considerable similarities in outcomes programmed by maternal undernutrition and overnutrition.

Motor performance is not related to injury risk in growing elite-level male youth football players. A causal inference approach to injury risk assessment.

OBJECTIVE: To identify the causal relation between growth velocity and injury in elite-level youth football players, and to assess the mediating effects of motor performance in this causal pathway. DESIGN: Prospective cohort study. METHODS: We measured the body height of 378 male elite-level football players of the U13 to U15 age categories three to four months before and at the start of the competitive season. At the start of the season, players also performed a motor performance test battery, including motor coordination (Körperkoordinationstest für Kinder), muscular performance (standing broad jump, counter movement jump), flexibility (sit and reach), and endurance measures (YoYo intermittent recovery test). Injuries were continuously registered by the academies' medical staff during the first two months of the season. Based on the causal directed acyclic graph (DAG) that identified our assumptions about causal relations between growth velocity (standardized to cm/y), injuries, and motor performance, the causal effect of growth velocity on injury was obtained by conditioning on maturity offset. We determined the natural indirect effects of growth velocity on injury mediated through motor performance. RESULTS: In total, 105 players sustained an injury. Odds ratios (OR) showed a 15% increase in injury risk per centimetre/year of growth velocity (1.15, 95%CI: 1.05-1.26). There was no causal effect of growth on injury through the motor performance mediated pathways (all ORs were close to 1.0 with narrow 95%CIs). CONCLUSIONS: Growth velocity is causally related to injury risk in elite-level youth football players, but motor performance does not mediate this relation.

Early heat exposure effect on the heat shock proteins in broilers under acute heat stress.

The effects of early heat conditioning on the acute heat stress response in broilers were investigated via the growth performance, dopamine, serotonin, and corticosterone and the expression of heat shock proteins (HSP) and heat shock factors. One-day-old chicks (n = 144) were divided into 3 groups in a 35-d experiment (48 chicks per each group). Group 1 (C) was treated with an optimum temperature, group 2 (CH) was treated with 40°C ± 1°C on day 35 (5 h), and group 3 (HH) was treated with 40°C ± 1°C on day 5 (24 h) and day 35 (5 h). On day 7, the body weight gain was lower (P < 0.05) in HH than in C and CH. On day 35, the heat-treated groups (CH and HH) had lower weight gains than the C group (P < 0.05), whereas the feed conversion ratio was lower in HH (P < 0.05). Serum corticosterone was higher in CH than in C, but HH and C did not differ (P < 0.05). Liver HSP70 protein expression was higher in CH than HH and C (P < 0.05), which did not differ, and HSP40 protein expression was higher in CH than C (P < 0.05). These results suggest that early heat conditioning may reduce acute heat stress on broiler.

Long-term growth patterns in children born with cleft lip and/or palate. A systematic review.

INTRODUCTION: Introduction: in children with cleft lip and/or palate nutritional status and growth may be impaired due to early life feeding difficulties. Objective: to review the existing literature on the nutritional prognosis during childhood of patients undergoing surgery for cleft lip and/or palate (CLP), their body composition and growth patterns from 2 to 10 years of age, and the possible effects of their early nutritional status on the long-term onset of overweight. Methods: a systematic search of growth and body composition parameters in 2-10 year-old CLP children, including cross-sectional and longitudinal studies, and using the Pubmed and Scopus databases. From the 2,983 retrieved articles, 6 were finally included. Results: two studies out of 6 were longitudinal and the other 4 were cross-sectional, including very heterogeneous samples. Weight and height were used as growth parameters in 2 studies; 2 studies used body mass index (BMI); and the remaining 2 used indexes of nutritional status derived from anthropometric measures. The studies showed discrepancies among results: 3 of them found growth differences between children with CLP and their counterparts, whereas the other 3 did not. The two longitudinal studies did not show any significant differences between the mean BMI z-scores or growth curves of cleft patients and their counterparts. When differences existed, the most affected group was that under 5 years, syndromic children, and adopted children with CL/P. Conclusions: the literature is scarce comparing growth patterns between children with CLP and controls, and results cannot confirm that children with CLP aged 2-10 years, excluding those with syndromes or belonging to vulnerable populations, have different growth patterns or a worse nutritional status than their counterparts.

INTRODUCCIÓN: Introducción: en niños con fisura labial y/o palatina, el estado nutricional y el crecimiento pueden verse afectados debido a dificultades en la alimentación. Objetivos: revisar el pronóstico nutricional de pacientes sometidos a cirugía de fisura labiopalatina (FLP), su composición corporal y sus patrones de crecimiento de los 2 a los 10 años, así como los posibles efectos del estado nutricional durante la primera infancia sobre la aparición posterior de sobrepeso. Métodos: búsqueda sistemática de parámetros de crecimiento y composición corporal en niños con CLP de 2 a 10 años, incluyendo estudios transversales y longitudinales en las bases de datos Pubmed y Scopus. De los 2983 artículos potencialmente relevantes, 6 fueron finalmente incluidos. Resultados: dos estudios de 6 fueron longitudinales y los otros 4, transversales, con muestras muy heterogéneas. El peso y la altura se utilizaron como parámetros de crecimiento en 2 estudios; 2 estudios utilizaron el índice de masa corporal (IMC), y los otros 2, índices del estado nutricional a partir de medidas antropométricas. Los estudios mostraron discrepancias entre los resultados: 3 de ellos encontraron diferencias de crecimiento entre los niños con CLP y sus coetáneos, mientras que los otros 3, no las encontraron. Los dos estudios longitudinales no mostraron diferencias significativas entre el IMC (z-score) ni entre las curvas de crecimiento de los pacientes con FLP y sus coetáneos. Cuando existían diferencias, el grupo más afectado fue el de los menores de 5 años, niños sindrómicos y niños adoptados con CL/P. Conclusiones: la literatura sobre los patrones de crecimiento de los niños con CLP es escasa y los resultados no pueden confirmar que los niños con CLP de 2 a 10 años, excluyendo aquellos con síndromes o pertenecientes a poblaciones vulnerables, tengan patrones de crecimiento diferentes o un peor estado nutricional que sus coetáneos.

Broiler growth and efficiency in response to relaxed maternal feed restriction.

Broiler growth performance can be influenced by maternal BW, maternal age, and sex. The present study evaluated broiler growth and efficiency in response to increased maternal BW (relaxed level of maternal feed restriction). It was hypothesized that BW and fatness would increase, and efficiency would be reduced as maternal BW increased. Ten BW trajectories were applied to precision-fed Ross 708 female broiler breeders (n = 30) from 2 to 42 wk of age. Trajectories varied in prepubertal and pubertal growth phases from 2.5 to 22.5% above the recommended BW target. Additional unrestricted breeders (n = 6) were not limited to a maximum BW (fed ad libitum). Two 35 d experiments were conducted with precision-fed broilers from these breeders at 35 and 42 wk of age. Two analyses (full and restricted analysis scopes) were performed to evaluate broiler BW, feed conversion ratio (FCR) and carcass traits with maternal BW at photostimulation (22 wk of age) as a continuous effect, and maternal age and sex as discrete effects. The full scope included broilers from all hens (feed restricted and unrestricted). The restricted scope excluded broilers from unrestricted hens. Differences were reported at P ≤ 0.05. For every kilogram increase in maternal BW, cumulative FCR increased by 0.235 and 0.471 g:g for broilers from all and feed restricted hens, respectively. Proportional gut weight of broilers from feed restricted hens decreased by 0.8244% per kilogram increase in maternal BW. Males were heavier than females on day 28 and 35, and broilers from 42-wk-old breeders were heavier than broilers from 35-wk-old breeders on day 0 and 35. Males from all hens were more feed efficient (1.318 g:g) than females (1.335 g:g) from day 29 to 35. Females from all and feed restricted hens had a greater proportional fat pad and breast muscle weight than males, and proportional breast muscle yield of broilers from 42-wk-old breeders was on average 1.04 times greater than that of broilers from 35-wk-old breeders. Maternal BW did not affect offspring BW, reduced cumulative FCR, and reduced gut weight in the restricted analysis scope.

Effect of Vitamin D Supplementation in Early Life on Children's Growth and Body Composition: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Vitamin D deficiency during pregnancy or infancy is associated with adverse growth in children. No systematic review has been conducted to summarize available evidence on the effect of vitamin D supplementation in pregnancy and infancy on growth and body composition in children. OBJECTIVE: We aim to summarize the available evidence on the effect of vitamin D supplementation in pregnancy and infancy on child growth and body composition. METHOD: A systematic review and meta-analysis were performed on the effects of vitamin D supplementation during early life on children's growth and body composition (bone, lean and fat). A literature search of randomized controlled trials (RCTs) was conducted to identify relevant studies on the effects of vitamin D supplementation during pregnancy and infancy on children's body composition (bone, lean and fat) in PubMed, EMBASE and Cochrane Library from inception to 31 December 2020. A Cochrane Risk Assessment Tool was used for quality assessment. The comparison was vitamin D supplementation vs. placebo or standard care. Random-effects and fixed-effect meta-analyses were conducted. The effects are presented as mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: A total of 3960 participants from eleven randomized controlled trials were eligible for inclusion. Vitamin D supplementation during pregnancy was associated with higher triceps skinfold thickness (mm) (MD 0.33, 95% CI, 0.12, 0.54; I2 = 34%) in neonates. Vitamin D supplementation during pregnancy or infancy was associated with significantly increased length for age z-score in infants at 1 year of age (MD 0.29, 95% CI, 0.03, 0.54; I2 = 0%), and was associated with lower body mass index (BMI) (kg/m2) (MD -0.19, 95% CI -0.34, -0.04; I2 = 0%) and body mass index z-score (BMIZ) (MD -0.12, 95% CI -0.21, -0.04; I2 = 0%) in offspring at 3-6 years of age. Vitamin D supplementation during early life was not observed to be associated with children's bone, lean or fat mass. CONCLUSION: Vitamin D supplementation during pregnancy or infancy may be associated with reduced adiposity in childhood. Further large clinical trials of the effects of vitamin D supplementation on childhood body composition are warranted.

Injuries in youth football and the relationship to player maturation: An analysis of time-loss injuries during four seasons in an English elite male football academy.

A better insight into injuries in elite-youth football may inform prevention strategies. The purpose of this prospective cohort study was to investigate the frequency, incidence, and pattern of time-loss injuries in an elite male football academy, exploring injuries in relation to age and maturation status. Across four consecutive playing seasons, playing exposure and injuries to all academy players (U'9 to U'21) were recorded by club medical staff. Maturation status at the time of injury was also calculated for players competing in U'13 to U'16 aged squads. Time-loss injury occurrence and maturation status at time of injury were the main outcome measures. A total of 603 time-loss injuries were recorded, from 190 different players. Playing exposure was 229 317 hours resulting in an overall injury rate of 2.4 p/1000 h, ranging from 0.7 p/1000 h (U'11) to 4.8 p/1000 h (U'21). Most injuries were traumatic in mechanism (73%). The most common injury location was the thigh (23%), and the most common injury type was muscle injury (29%) combining to provide the most common injury diagnosis; thigh muscle injury (17%). In U'13-U'16 players, a higher number of injuries to early-maturing players were observed in U'13-U'14 players, while more injuries to U'15-U'16 players occurred when classed as "on-time" in maturity status. Maturation status did not statistically relate to injury pattern; however, knee bone (not-fracture) injuries peaked in U'13 players while hip/groin muscle injuries peaked in U'15 players.

Protective effects of Bacillus subtilis ASAG 216 on growth performance, antioxidant capacity, gut microbiota and tissues residues of weaned piglets fed deoxynivalenol contaminated diets.

Deoxynivalenol (DON) poses a serious health threat to animals and humans consuming DON-contaminated food and feed. Biological means of detoxification of DON are considered as one of the effective strategies. The aim of the work was to study ameliorative effects of Bacillus subtilis ASAG 216 on DON-induced toxicosis in piglets. A decrease in average daily gain and average daily feed intake was observed in piglets fed DON-contaminated feed. In addition, DON exposure increased the serum concentrations of aspartate aminotransferase, immunoglobulin A, diamine oxidase, endotoxin, and peptide YY. Moreover, DON exposure caused oxidative stress in the serum, liver and jejunum, induced intestinal inflammation, impaired the intestinal barrier, and disturbed the gut microbiota homeostasis. Supplementation of B. subtilis ASAG 216 effectively attenuated the aforementioned effects of DON on piglets. Moreover, DON and de-epoxy-DON (DOM-1) in the serum, liver and kidney were significantly decreased when B. subtilis ASAG 216 was added to DON-contaminated diet. Our results imply that B. subtilis ASAG 216 can protect against DON-induced toxicosis in piglets, and thus this strain has a potential to be used as an animal feed ingredient to counteract harmful effects of DON in animals.

Physical fitness is associated with better technical performance in adolescent alpine ski racers after controlling for practice time: A retrospective regression analysis.

In an effort to evaluate the mechanisms underpinning performance in alpine ski racing, researchers have focused on the predictive validity of measures derived from fitness assessments. However, a limitation of this literature is the absence of practice time, since prolonged training may naturally develop specific fitness capacities, making some tests of physical ability less predictive of performance. We examine the relationship between fitness tests, practice, and performance using linear regressions with fitness test data, practice history data, and performance results from adolescent alpine ski racers attending professional development academies in the United States (N = 82). Only aerobic capacity (i.e. 20 m shuttle run) was significantly associated with more practice time. After controlling for practice hours, 5.5-6.5% of variance in ski performance was significantly explained by assessments of lower body power (i.e. standing long jump, triple jump), anaerobic capacity (i.e. 60 s box jump), and upper body strength/endurance (i.e. push-ups). Findings highlight the important role of anaerobic power on alpine ski racing performance, which may be developed outside of regular practice, possibly through weight training or physical maturation. The small variance explained by physical/physiological measures suggests that superior ski performance is likely a product of various skills and characteristics (e.g. technical, tactical, perceptual-cognitive, psychosocial).

Association between adenotonsillar hypertrophy and leptin, ghrelin and IGF-1 levels in children.

OBJECTIVE: Developmental and growth retardation is a condition that is often encountered among children with adenotonsillar hypertrophy (ATH). Leptin, ghrelin and IGF-1 are important factors in growth and development for children. The aim of the study was to investigate serum leptin, ghrelin and IGF-1 levels in children with ATH compare with healthy controls. MATERIAL METHOD: 82 children between ages 6-12 were included in this study, divided into two groups. The first group being the study-group consisted of 42 children with obstructive adenotonsillar hypertrophy and the second group being the control-group consisted of 40 healthy children. At 08:30 a.m., peripheral blood samples were extracted from children from both groups to examine the serum levels, and kept in -40 °C until the Elisa test. RESULTS: Leptin serum level of the control-group was found to be statistically significantly higher than the serum leptin level of the ATH group (p = 0,049; p < 0.05). Body mass indexes of the children with ATH were found to be statistically significantly lower than the body mass index (BMI) of the control group (p = 0,001; p < 0.05). In contrast, there was no statistically significant difference between ghrelin and IGF-1 levels between the ATH and control group (p = 0.193, p > 0.05 and p = 0.478, p > 0.05, respectively). CONCLUSION: Upper airway infections are common in children with ATH. Increased airway infections and obstructive enlarged adenotonsillar lymphoid tissue which are caused swallowing difficulties can lead to reduced oral intake and fat tissue. It has led us to think that, ghrelin levels may be increasing secondary to these problems in children with ATH. Furthermore, BMI and leptin would be lower in children with ATH, considering adipose tissue was lesser and leptin was being synthesized and oscillated out of the fat cells of the tissue in these children.

The role of growth, maturation and sporting environment on the development of performance and technical and tactical skills in youth basketball players: The INEX study.

In this paper, we outline a systematic testing programme developed to help identify excellence in youth basketball players. We examine the links between biological maturation and training experience with anthropometry, body composition, physical performance, technical and tactical skills from five age-cohorts, and characterize, in detail, facets of their environment. In total, 238 young basketball players aged 11-15 years, clustered into five age-cohorts (11, 12, 13, 14, 15 years) were recruited. We assessed measures across three domains: (1) biological [anthropometry, body composition, biological maturation and physical performance]; (2) skill/game proficiency [technical skills and tactical skills]; and (3) contextual [family support, coach knowledge and competence and club context]. The data were analysed using one-way ANOVAs and multivariate analysis of covariance adjusting for biological maturation and training experience. We report significant differences favouring older basketball players on most biological and skill/game proficiency variables. However, differences between age-cohorts in physical performance and technical skills were mitigated after controlling for the effects of both covariates. In conclusion, our findings highlight the important role of both biological maturation and training experience on youth basketball players' performance and development. We discuss the implications of these findings for research as well as for athletes, parents, coaches and clubs.

Effects of trichostatin A on FHIT and WWOX genes expression, cell growth inhibition and apoptosis induction in hepatocellular carcinoma WCH 17 cell line

Previously, we evaluated the effect of trichostatin A (TSA) on the expression of DNA methyltransferase 1 (DNMT1) in Hepatocellular Carcinoma (HCC). Fragile histidine triad (FHIT) and WW domain-containing oxidoreductase (WWOX) are two of the most common down-regulated genes in many cancers located on chromosome 3p14.2 and 16q23.3-24.1 respectively. The aim of the current study was to assess the effect of TSA on these genes expression, cell growth, and apoptosis in HCC WCH 17 cell. The cells were seeded and treated with TSA at different times. Then, MTT assay, flow cytometry, and qRT-PCR were achieved to determine viability, apoptosis and gene expression respectively. Cell growth was significantly inhibited, 92 to 36% after 24 h, 86 to 28% after 48 h, and 78 to 24% after 72 h. The results of flow cytometry confirmed that TSA increased apoptosis compared to the control group, the apoptosis percentage increased to 12%, 16%, and 18% in comparison to control groups (2%). Significant up-regulation of the genes was observed in all treated groups. We concluded that re-expression of silenced WWOX and FHIT genes could be achieved by TSA resulting in cell growth inhibition and apoptosis induction in WCH 17 cell.

ERα Signaling in GHRH/Kiss1 Dual-Phenotype Neurons Plays Sex-Specific Roles in Growth and Puberty.

Gonadal steroids modulate growth hormone (GH) secretion and the pubertal growth spurt via undefined central pathways. GH-releasing hormone (GHRH) neurons express estrogen receptor α (ERα) and androgen receptor (AR), suggesting changing levels of gonadal steroids during puberty directly modulate the somatotropic axis. We generated mice with deletion of ERα in GHRH cells (GHRHΔERα), which displayed reduced body length in both sexes. Timing of puberty onset was similar in both groups, but puberty completion was delayed in GHRHΔERα females. Lack of AR in GHRH cells (GHRHΔAR mice) induced no changes in body length, but puberty completion was also delayed in females. Using a mouse model with two reporter genes, we observed that, while GHRHtdTom neurons minimally colocalize with Kiss1hrGFP in prepubertal mice, ∼30% of GHRH neurons coexpressed both reporter genes in adult females, but not in males. Developmental analysis of Ghrh and Kiss1 expression suggested that a subpopulation of ERα neurons in the arcuate nucleus of female mice undergoes a shift in phenotype, from GHRH to Kiss1, during pubertal transition. Our findings demonstrate that direct actions of gonadal steroids in GHRH neurons modulate growth and puberty and indicate that GHRH/Kiss1 dual-phenotype neurons play a sex-specific role in the crosstalk between the somatotropic and gonadotropic axes during pubertal transition.SIGNIFICANCE STATEMENT Late maturing adolescents usually show delayed growth and bone age. At puberty, gonadal steroids have stimulatory effects on the activation of growth and reproductive axes, but the existence of gonadal steroid-sensitive neuronal crosstalk remains undefined. Moreover, the neural basis for the sex differences observed in the clinical arena is unknown. Lack of ERα in GHRH neurons disrupts growth in both sexes and causes pubertal delay in females. Deletion of androgen receptor in GHRH neurons only delayed female puberty. In adult females, not males, a subset of GHRH neurons shift phenotype to start producing Kiss1. Thus, direct estrogen action in GHRH/Kiss1 dual-phenotype neurons modulates growth and puberty and may orchestrate the sex differences in endocrine function observed during pubertal transition.

A new approach to the diagnosis of short stature.

Growth is the task of children. We review the normal process of linear growth from the fetus through adolescence and note that growth is the result of age- and gender-dependent interactions among key genetic, environmental, dietary, socioeconomic, developmental, behavioral, nutritional, metabolic, biochemical, and hormonal factors. We then define the wide range of normative data at each stage of growth and note that a pattern within this range is generally indicative of good general health and that growth significantly slower than this range may lead to growth faltering and subsequent short stature. Although not often emphasized, we detail how to properly measure infants and children because height velocity is usually determined from two height measurements (both relatively large values) to calculate the actual height velocity (a relatively much smaller number in comparison). Traditionally the physiology of growth has been taught from an endocrine-centric point-of-view. Here we review the hypothalamic-pituitary-end organ axes for the GH/IGF-1 and gonadal steroid hormones (hypothalamic-pituitary-gonadal axis), both during "mini"-puberty as well as at puberty. However, over the past few decades much more emphasis has been placed on the growth plate and its many interactions with the endocrine system but also with its own intrinsic physiology and gene mutations. These latter, whether individually (large effect size) or in combination with many others including endocrine system-based, may account in toto for meaningful differences in adult height. The clinical assessment of children with short stature includes medical, social and family history, physical exam and importantly proper interpretation of the growth curve. This analysis should lead to judicious use of screening laboratory and imaging tests depending on the pre-test probability (Bayesian inference) of a particular diagnosis in that child. In particular for those with no pathological features in the history and physical exam and a low, but normal height velocity, may lead only to a bone age exam and reevaluation (re-measurement), perhaps 6 months later. he next step depends on the comfort level of the primary care physician, the patient, and the parent; that is, whether to continue with the evaluation with more directed, more sophisticated testing, again based on Bayesian inference or to seek consultation with a subspecialist pediatrician based on the data obtained. This is not necessarily an endocrinologist. The newest area and the one most in flux is the role for genetic testing, given that growth is a complex process with large effect size for single genes but smaller effect sizes for multiple other genes which in the aggregate may be relevant to attained adult height. Genetics is a discipline that is rapidly changing, especially as the cost of exome or whole gene sequencing diminishes sharply. Within a decade it is quite likely that a genetic approach to the evaluation of children with short stature will become the standard, truncating the diagnostic odyssey and be cost effective as fewer biochemical and imaging studies are required to make a proper diagnosis.

Vascular endothelial growth factor B promotes transendothelial fatty acid transport into skeletal muscle via histone modifications during catch-up growth.

Caloric restriction (CR) followed by refeeding, a phenomenon known as catch-up growth (CUG), results in excessive lipid deposition and insulin resistance in skeletal muscle, but the underlying mechanisms remain elusive. Recent reports have suggested that vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation by regulating endothelial fatty acid transport. Here, we found continuous activation of VEGF-B signaling and increased lipid uptake in skeletal muscle from CR to refeeding, as well as increased lipid deposition and impaired insulin sensitivity after refeeding in the skeletal muscle of CUG rodents. Inhibiting VEGF-B signaling reduced fatty acid uptake in and transport across endothelial cells. Knockdown of Vegfb in the tibialis anterior (TA) muscle of CUG mice significantly attenuated muscle lipid accumulation and ameliorated muscle insulin sensitivity by decreasing lipid uptake. Furthermore, we showed that aberrant histone methylation (H3K9me1) and acetylation (H3K14ac and H3K18ac) at the Vegfb promoter might be the main cause of persistent VEGF-B upregulation in skeletal muscle during CUG. Modifying these aberrant loci using their related enzymes [PHD finger protein 2 (PHF2) or E1A binding protein p300 (p300)] could regulate VEGF-B expression in vitro. Collectively, our findings indicate that VEGF-B can promote transendothelial lipid transport and lead to lipid overaccumulation and insulin resistance in skeletal muscle during CUG, which might be mediated by histone methylation and acetylation.