Epithelial-Fibroblast Crosstalk Protects against Acidosis-Induced Inflammatory and Fibrotic Alterations.

Pathogenesis of chronic kidney disease (CKD) is accompanied by extracellular acidosis inflammation, fibrosis and epithelial-to-mesenchymal transition (EMT). The aim of this study was to assess the influence of acidosis on tubule epithelial cells (NRK-52E) and fibroblasts (NRK-49F) in dependence of cellular crosstalk. NRK-52E and NRK-49F were used in mono- and co-cultures, and were treated with acidic media (pH 6.0) for 48 h. The intracellular proteins were measured by Western blot. Secreted proteins were measured by ELISA. Distribution of E-cadherin was assessed by immunofluorescence and epithelial barrier function by FITC-dextran diffusion. Inflammation: Acidosis led to an increase in COX-2 in NRK-52E and TNF in NRK-49F in monoculture. In co-culture, this effect was reversed. EMT: Acidosis led to an increase in vimentin protein in both cell lines, whereas in co-culture, the effect was abolished. In NRK-52E, the E-cadherin expression was unchanged, but subcellular E-cadherin showed a disturbed distribution, and cellular barrier function was decreased. Fibrosis: Monoculture acidosis led to an increased secretion of collagen I and fibronectin in NRK-52E and collagen I in NRK-49F. In co-culture, the total collagen I secretion was unchanged, and fibronectin secretion was decreased. Intercellular crosstalk between epithelial cells and fibroblasts has a protective function regarding the development of acidosis-induced damage.

Pitavastatin Is a Highly Potent Inhibitor of T-Cell Proliferation.

Repositioning of approved drugs is an alternative time- and cost-saving strategy to classical drug development. Statins are 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase inhibitors that are usually used as cholesterol-lowering medication, and they also exhibit anti-inflammatory effects. In the present study, we observed that the addition of Pitavastatin at nanomolar concentrations inhibits the proliferation of CD3/CD28 antibody-stimulated human T cells of healthy donors in a dose-dependent fashion. The 50% inhibition of proliferation (IC50) were 3.6 and 48.5 nM for freshly stimulated and pre-activated T cells, respectively. In addition, Pitavastatin suppressed the IL-10 and IL-17 production of stimulated T cells. Mechanistically, we found that treatment of T cells with doses <1 µM of Pitavastatin induced hyperphosphorylation of ERK1/2, and activation of caspase-9, -3 and -7, thus leading to apoptosis. Mevalonic acid, cholesterol and the MEK1/2 inhibitor U0126 reversed this Pitavastatin-mediated ERK1/2 activation and apoptosis of T cells. In summary, our results suggest that Pitavastatin is a highly potent inhibitor of T-cell proliferation, which induces apoptosis via pro-apoptotic ERK1/2 activation, thus representing a potential repositioning candidate for the treatment of T-cell-mediated autoimmune diseases.

Zinc Aspartate Induces IL-16 Secretion and Apoptosis in Human T Cells.

T cell activation mediates immunity to pathogens. On the flipside, T cells are also involved in pathological immune responses during chronic autoimmune diseases. We recently reported that zinc aspartate, a registered drug with high bioavailability, dose-dependently inhibits T cell activation and Th1/Th2/Th17 cytokine production of stimulated human and mouse T cells. To understand the suppressive effect of zinc on T cell function, we here investigated the influence of zinc aspartate on human T cells focusing on the secretion of immunosuppressive cytokines, induction of apoptosis, and caspase 3/7 activity. To this end, we monitored either freshly stimulated or pre-activated human T cells in the presence of zinc aspartate from 40-140 µM over a period of 72 h. Under both experimental conditions, we observed a dose-dependent suppression of human T cell proliferation. While IL-1ra, latent TGF-ß1, and IL-10 were dose-dependently reduced, we, unexpectedly, detected elevated levels of IL-16 upon zinc supplementation. In addition, the number of cells with active caspase 3/7 and, consecutively, the amount of cells undergoing apoptosis, steadily increased at zinc aspartate concentrations exceeding 100 µM. Taken together, our findings suggest that zinc aspartate impairs T cell fitness and might be beneficial for the treatment of T cell-mediated autoimmune diseases.

Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage.

Janus kinase inhibitors (JAKis) represent a new strategy in rheumatoid arthritis (RA) therapy. Still, data directly comparing different JAKis are rare. In the present in vitro study, we investigated the immunomodulatory potential of four JAKis (tofacitinib, baricitinib, upadacitinib, and filgotinib) currently approved for RA treatment by the European Medicines Agency. Increasing concentrations of JAKi or methotrexate, conventionally used in RA therapy, were either added to freshly mitogen-stimulated or preactivated peripheral blood mononuclear cells (PBMC), isolated from healthy volunteers. A comparable, dose-dependent inhibition of lymphocyte proliferation was observed in samples treated with tofacitinib, baricitinib, and upadacitinib, while dosage of filgotinib had to be two orders of magnitude higher. In contrast, antiproliferative effects were strongly attenuated when JAKi were added to preactivated PBMCs. High dosage of upadacitinib and filgotinib also affected cell viability. Further, analyses of DNA double-strand break markers γH2AX and 53BP1 indicated an enhanced level of DNA damage in cells incubated with high concentrations of filgotinib and a dose-dependent reduction in clearance of radiation-induced γH2AX foci in the presence of tofacitinib or baricitinib. Thereby, our study demonstrated a broad comparability of immunomodulatory effects induced by different JAKi and provided first indications, that (pan)JAKi may impair DNA damage repair in irradiated PBMCs.

Methods for Testing the Subjective Visual Vertical during the Chronic Phase of Menière's Disease.

The subjective visual vertical (SVV) evaluates the function of the utricle, which, in patients with Menière's disease (MD), can be affected by endolymphatic hydrops. This study aimed to determine the SVV in MD patients during the chronic phase of illness compared to healthy participants. The second aim was to compare the SVV measurement tools: the analog bucket test, digital bucket test, and C-SVV© goggles. The SVV scores differed significantly between MD patients and the control group for the analog bucket test (p < 0.001) and the C-SVV® goggles (p = 0.028), but no significance was shown when using the digital bucket test (p = 0.062). When comparing the analog bucket test and the C-SVV® goggles applying the calculated threshold (1.125° in analog bucket test, 2.5° in C-SVV® goggles), the bucket test showed higher accuracy (bucket test 73.84%, C-SVV® goggles 69.23%). When examining the influence of betahistine on SVV scores, there were no statistically significant differences in both the analog bucket test and C-SVV© goggles. We conclude that SVV test can be used as an additional tool to evaluate utricle function during the chronic phase of MD and that the analog bucket test produces the most reliable results. The intake of betahistine does not influence the perception of SVV.

Screening of FDA-Approved Drug Library Identifies Adefovir Dipivoxil as Highly Potent Inhibitor of T Cell Proliferation.

Repositioning of approved drugs for identifying new therapeutic purposes is an alternative, time and cost saving strategy to classical drug development. Here, we screened a library of 786 FDA-approved drugs to find compounds, which can potentially be repurposed for treatment of T cell-mediated autoimmune diseases. Investigating the effect of these diverse substances on mitogen-stimulated proliferation of both, freshly stimulated and pre-activated (48 h) peripheral blood mononuclear cells (PBMCs), we discovered Adefovir Dipivoxil (ADV) as very potent compound, which inhibits T cell proliferation in a nanomolar range. We further analyzed the influence of ADV on proliferation, activation, cytokine production, viability and apoptosis of freshly stimulated as well as pre-activated human T cells stimulated with anti-CD3/CD28 antibodies. We observed that ADV was capable of suppressing the proliferation in both T cell stimulation systems in a dose-dependent manner (50% inhibition [IC50]: 63.12 and 364.8 nM for freshly stimulated T cells and pre-activated T cells, respectively). Moreover, the drug impaired T cell activation and inhibited Th1 (IFN-γ), Th2 (IL-5), and Th17 (IL-17) cytokine production dose-dependently. Furthermore, ADV treatment induced DNA double-strand breaks (γH2AX foci expression), which led to an increase of p53-phospho-Ser15 expression. In response to DNA damage p21 and PUMA are transactivated by p53. Subsequently, this caused cell cycle arrest at G0/G1 phase and activation of the intrinsic apoptosis pathway. Our results indicate that ADV could be a new potential candidate for treatment of T cell-mediated autoimmune diseases. Prospective studies should be performed to verify this possible therapeutic application of ADV for such disorders.

Comorbid Symptoms Occurring During Acute Low-Tone Hearing Loss (AHLH) as Potential Predictors of Menière's Disease.

Acute low-tone sensorineural hearing loss (ALHL) is a type of idiopathic sudden sensorineural hearing loss. ALHL is rarely a solitary condition but rather co-occurs with vertigo and tinnitus, being an element of contemporary diagnostic criteria for Menière's disease (MD). The goal of our present study was to determine the value of ALHL for the early diagnosis of MD in patients presenting in the emergency room with ALHL as a main complaint. The files of 106 patients with ALHL who were admitted to the emergency room over the period of 7 years and 104 patients with acute high- tone sensorineural hearing loss (AHHL) from the same period were included in this retrospective study. Forty ALHL patients presented with recurrent episode of hearing loss and 66 remaining patients presented with ALHL for the first time. Of the latter group, 25 patients gave consent for the follow-up. First, we analyzed the difference in the occurrence of tinnitus and vertigo between the ALHL and AHHL groups. In patients with ALHL, the incidence of vertigo with tinnitus and the number of recurrent episodes were statistically higher than in patients with AHHL. Next, we focused on the ALHL follow-up group (25 patients). In that group, two patients had all MD symptoms at presentation, 18 had ALHL and tinnitus and five ALHL only. Of 18 patients with ALHL and tinnitus at admission, five developed vertigo and thus the triad of Menière's disease. None of the five patients with AHLH as a sole symptom developed MD during the follow-up time but four of them have developed tinnitus. Patients with recurrent ALHL had significantly higher incidence of MD than the patients with first episode. We conclude that some patients who present with ALHL and concomitant tinnitus or have recurrent episodes of ALHL are more likely to develop Menière's disease than these patients, who present with ALHL as a sole symptom. Nonetheless, we recommend otological follow-up for all patients presenting with ALHL.

Insulin resistance is higher in prepubertal girls but switches to become higher in boys at age 16: A Cohort Study (EarlyBird 57).

BACKGROUND: The risk of type 2 diabetes is increasing in teenage girls, and is associated with their greater insulin resistance (IR). HYPOTHESIS: We hypothesized that the adverse metabolic profile of girls (compared with boys) would persist from childhood through adolescence. PATIENTS AND METHODS: Community-based longitudinal cohort of 292 children (147 boys) studied annually from 9 to 16 years. MEASURES: IR (homeostasis-model-assessment-2), high-density lipoprotein-cholesterol (HDL-C), triglycerides, % body-fat (dual-energy x-ray absorptiometry), pubertal stage (age at peak height velocity), physical activity (accelerometry). Multi-level modelling established the age-related trends in IR and lipids and the influence of covariates. RESULTS: Each year from 9 to 15 years, girls had 21% to 63% higher IR than boys (girls mean IR 0.73-1.33, boys 0.51-0.89, P < .005). At 16 years the gender difference was not significant (girls IR 0.60, boys 0.56, P = .45). Girls had lower HDL-C from 9 to 12 years, higher triglycerides from 9 to 14 years, greater adiposity throughout, and earlier puberty, but boys were more active than girls (all P < .05). After adjustment for %-fat, puberty and activity, the gender difference in IR between girls and boys aged 9 to 15 years became non-significant (IR girls 0.66-1.01, boys 0.65-1.04, P > .07). However, after adjustment at 16 years, girls' IR was 25% lower than boys' (girls 0.44, boys 0.63, P = .001), and they had 22% higher HDL-C (P < .001) and 20% lower triglycerides (P = .003). CONCLUSIONS: The higher IR of prepubertal and early pubertal girls diminishes during late puberty, and boys begin to exhibit greater metabolic risk. Despite being leaner and more active, boys at 16 years have higher IR than girls, suggesting future higher risk for diabetes, thus we reject our hypothesis.

Generational change in fasting glucose and insulin among children at ages 5-16y: Modelled on the EarlyBird study (2015) and UK growth standards (1990) (EarlyBird 69).

AIM: Pre-diabetes is a state of beta-cell stress caused by excess demand for insulin. Body mass is an important determinant of insulin demand, and BMI has risen substantially over recent time. We sought to model changes in the parameters of glucose control against rising BMI over the past 25years. METHODS: Using random coefficient mixed models, we established the correlations between HbA1C, fasting glucose, fasting insulin, HOMA2-IR and BMI in contemporary (2015) children (N=307) at ages 5-16y from the EarlyBird study, and modelled their corresponding values 25years ago according to the distribution of BMI in the UK Growth Standards (1990). RESULTS: There was little change in HbA1C or fasting glucose over the 25y period at any age or in either gender. On the other hand, the estimates for fasting insulin and HOMA2-IR were substantially higher in both genders in 2015 compared with 1990. CONCLUSION: Insofar as it is determined by body mass, there has been a substantial rise in beta cell demand among children over the past 25years. The change could be detected by fasting insulin and HOMA2-IR, but not by fasting glucose or HbA1C.

Physical activity attenuates the mid-adolescent peak in insulin resistance but by late adolescence the effect is lost: a longitudinal study with annual measures from 9-16 years (EarlyBird 66).

AIMS/HYPOTHESIS: The aim of this work was to test whether the mid-adolescent peak in insulin resistance (IR) and trends in other metabolic markers are influenced by long-term exposure to physical activity. METHODS: Physical activity (7 day ActiGraph accelerometry), HOMA-IR and other metabolic markers (glucose, fasting insulin, HbA1c, lipids and BP) were measured annually from age 9 years to 16 years in 300 children (151 boys) from the EarlyBird study in Plymouth, UK. The activity level of each child was characterised, with 95% reliability, by averaging their eight annual physical activity measures. Age-related trends in IR and metabolic health were analysed by multi-level modelling, with physical activity as the exposure measure (categorical and continuous) and body fat percentage (assessed by dual-energy X-ray absorptiometry) and pubertal status (according to age at peak height velocity and Tanner stage) as covariates. RESULTS: The peak in IR at age 12-13 years was 17% lower (p < 0.001) in the more active adolescents independently of body fat percentage and pubertal status. However, this difference diminished progressively over the next 3 years and had disappeared completely by the age of 16 years (e.g. difference was -14% at 14 years, -8% at 15 years and +1% at 16 years; 'physical activity × age(2), interaction, p < 0.01). Triacylglycerol levels in girls (-9.7%, p = 0.05) and diastolic blood pressure in boys (-1.20 mmHg, p = 0.03) tended to be lower throughout adolescence in the more active group. CONCLUSIONS/INTERPRETATION: Our finding that physical activity attenuates IR during mid-adolescence may be clinically important. It remains to be established whether the temporary attenuation in IR during this period has implications for the development of diabetes in adolescence and for future metabolic health generally.

Metabolic risk in contemporary children is unrelated to socio-economic status: longitudinal study of a UK urban population (EarlyBird 42).

Lifestyle interventions to improve health in young children tend to target areas of relative deprivation, but the evidence for so doing is largely historical. Accordingly, we have re-examined the link between deprivation, obesity and metabolic risk in contemporary UK children. Using a postcode-based index of multiple deprivation (IMD), we assessed 269 children from the community-based EarlyBird Study, attending 53 schools representing a wide socio-economic range. Annual measures of fatness from 5 to 8 yr included body mass index (BMI), waist circumference (WC), and sum of five skinfolds (SSF). A metabolic risk score, based on blood pressure, lipids and insulin resistance, was derived from annual fasting blood samples. There were no significant associations between deprivation and any measure of adiposity in girls (all p > 0.37). In boys, there was a weak but consistently inverse relationship between deprivation and WC (r = -0.19, p = 0.03) and BMI (r = -0.14, p = 0.09) at 8 yr. Changes in adiposity over 3 yr were unrelated to deprivation in boys. In girls there was a slight but significant increase in SSF only (1 mm/yr per 20 IMD units, p = 0.001). Importantly, in both genders, metabolic risk score was unrelated to deprivation throughout (r values -0.05 to -0.13, all p > 0.12), as was change in metabolic risk (all p > 0.30). Our data do not support the assumption that obesity, metabolic disturbance and thus risk of type 2 diabetes are more prevalent among poorer children. In today's increasingly obesogenic environment, youngsters from all backgrounds appear to be vulnerable, with population-wide implications for public health spending, and the prevention of diabetes in contemporary youth.

PGC1α promoter methylation in blood at 5-7 years predicts adiposity from 9 to 14 years (EarlyBird 50).

The early environment, acting via epigenetic processes, is associated with differential risk of cardiometabolic disease (CMD), which can be predicted by epigenetic marks in proxy tissues. However, such measurements at time points disparate from the health outcome or the environmental exposure may be confounded by intervening stochastic and environmental variation. To address this, we analyzed DNA methylation in the peroxisome proliferator-activated receptor γ coactivator 1α promoter in blood from 40 children (20 boys) collected annually between 5 and 14 years of age by pyrosequencing. Body composition was measured annually by dual X-ray absorptiometry, physical activity by accelerometry, and pubertal timing by age at peak high velocity. The effect of methylation on transcription factor binding was investigated by electrophoretic mobility shift assays. Seven cytosine guanine dinucleotide (CpG) loci were identified that showed no significant temporal change or association with leukocyte populations. Modeling using generalized estimating equations showed that methylation of four loci predicted adiposity up to 14 years independent of sex, age, pubertal timing, and activity. Methylation of one predictive locus modified binding of the proadipogenic pre-B-cell leukemia homeobox-1/homeobox 9 complex. These findings suggest that temporally stable CpG loci measured in childhood may have utility in predicting CMD risk.

Divergence between HbA1c and fasting glucose through childhood: implications for diagnosis of impaired fasting glucose (Early Bird 52).

OBJECTIVE: An HbA1c threshold of ≥ 6.5% has recently been adopted for the diagnosis of diabetes in adults, and of ≥ 5.7% to identify adults at risk. Little,however, is known of HbA1c's behaviour or diagnostic value in youth. Our aim was to describe the course of HbA1c during childhood, and its association with fasting glucose. RESEARCH DESIGN AND METHODS: HbA1c and glucose were measured every year in a cohort of 326 healthy children (162 boys) from 5 to 15 years. Mixed effects modelling was used to establish the determinants of HbA1c and its development over time. ROC analysis was used to determine the diagnostic value of HbA1c in the 55 individuals who showed impaired fasting glucose(IFG ­ glucose ≥ 5.6 mmol/L). RESULTS: Glucose rose progressively from 4.3 mmol/L at 5 years to 5.1 mmol/Lat 15 years, and although there were positive associations between HbA1c and glucose, from 10 to 13 years, HbA1c fell while glucose continued to rise. IFG developed in 55 children, but HbA1c exceeded 5.7% in only 16 of them. The maximum area under the ROC curve was 0.71 at the age of 14 (p<0.001), and the sensitivity and specificity were optimal at 50 and 80% respectively,corresponding to HbA1c of 5.4%. CONCLUSIONS: Although HbA1c retains a positive association with glucose throughout childhood, it is weak, and their trends diverge from 10 years,suggesting that factors other than glycaemia systematically influence the variance of HbA1c in youth. These findings therefore limit the interpretation of HbA1c for the diagnosis of IFG during childhood.

Evidence of early beta-cell deficiency among children who show impaired fasting glucose: 10-yr cohort study (EarlyBird 56).

OBJECTIVE: Impaired fasting glucose (IFG) is a predictor of future diabetes and is increasingly common in children, but the extent to which it results from excess insulin demand or failure of supply is unclear. Our aim was to compare the behaviour of insulin sensitivity and beta-cell function in children who developed IFG with those whose glucose levels remained within the normal range. METHODS: We examined trends in fasting glucose, insulin sensitivity (HOMA-S) and beta-cell function (HOMA-B) in 327 healthy children annually from 5 to 15 yr, and the parents at baseline. RESULTS: Fifty-five children showed IFG, mostly after age 11 yr. Fasting glucose rose progressively and was higher throughout in those who developed IFG compared with those who did not (p < 0.001). Beta-cell function was lower from the age of 5 yr in those who developed IFG (p = 0.006), but there was no difference in BMI (p = 0.71). A difference in insulin sensitivity was revealed on adjustment for covariates (p = 0.03). Glucose was higher (p < 0.001), beta-cell function lower (p = 0.01), and insulin sensitivity the same (p = 0.86) in the mothers of children who showed IFG, compared with those who did not. CONCLUSIONS: IFG is common in contemporary children, and appears to be related to a defect in beta-cell function already present at 5 yr. Similar findings in the mothers of IFG children suggest that the beta-cell defect may be transmissible.

Age before stage: insulin resistance rises before the onset of puberty: a 9-year longitudinal study (EarlyBird 26).

OBJECTIVE: Insulin resistance (IR) is associated with diabetes. IR is higher during puberty in both sexes, with some studies showing the increase to be independent of changes in adiposity. Few longitudinal studies have reported on children, and it remains unclear when the rise in IR that is often attributed to puberty really begins. We sought to establish from longitudinal data its relationship to pubertal onset, and interactions with age, sex, adiposity, and IGF-1. RESEARCH DESIGN AND METHODS: The EarlyBird Diabetes study is a longitudinal prospective cohort study of healthy children aged 5-14 years. Homeostasis model assessment (HOMA-IR), skinfolds (SSF), adiposity (percent fat, measured by dual-energy X-ray absorptiometry), serum leptin, and IGF-1 were measured annually in 235 children (134 boys). Pubertal onset was adduced from Tanner stage (TS) and from the age at which luteinizing hormone (LH) first became serially detectable (≥0.2 international units/L). RESULTS: IR rose progressively from age 7 years, 3-4 years before TS2 was reached or LH became detectable. Rising adiposity and IGF-1 together explained 34% of the variance in IR in boys and 35% in girls (both P < 0.001) over the 3 years preceding pubertal onset. The contribution of IGF-1 to IR was greater in boys, despite their comparatively lower IGF-1 levels. CONCLUSIONS: IR starts to rise in mid-childhood, some years before puberty. Its emergence relates more to the age of the child than to pubertal onset. More than 60% of the variation in IR prior to puberty was unexplained. The demography of childhood diabetes is changing, and prepubertal IR may be important.

Direction of causality between body fat and insulin resistance in children--a longitudinal study (EarlyBird 51).

OBJECTIVE: To investigate the direction of causality in the association between adiposity and insulin resistance in children. METHODS: Body composition by DEXA, and insulin resistance by HOMA-2 IR were measured annually in 238 children aged from 7-13 years. Longitudinal modelling was used to establish whether baseline and/or trends in adiposity were associated with change in IR or whether, conversely, baseline and/or trends in IR were associated with change in adiposity. RESULTS: Baseline adiposity was associated with change in IR in the short-term (p < 0.001) but less so in the long-term (p < 0.09) in both genders. Baseline IR was not associated with short-term change in adiposity in either gender (p > 0.42). In the long-term, baseline IR appeared to be positively associated with change in adiposity in boys (p = 0.02) but inversely associated with change in adiposity (the higher the baseline IR, the lower the gain in %fat) in girls (p < 0.001). CONCLUSIONS: The dominant direction of causality appears to be from adiposity to insulin resistance. In boys, adiposity appears to be both a cause and an effect of IR in the long term. In girls, however, higher insulin resistance appeared to limit further gain in body fat in the long term, an observation consistent with insulin desensitization as an adaptive response to weight gain.

Consistency of children's dietary choices: annual repeat measures from 5 to 13 years (EarlyBird 49).

The objective of the present study was to explore the consistency of dietary choices made by children as they grow up. The dietary habits of 342 healthy children were reported annually from 5 to 13 years on a forty-five-item FFQ and analysed by factor analysis. The same two principal dietary patterns--'Healthy' and 'Unhealthy'--emerged each year, and their consistency was assessed using Tucker's congruence coefficient (φ). Individual dietary z-scores for both of these patterns were then calculated every year for each child, and their consistency was measured by Pearson's correlation coefficient (r). Linear mixed-effects modelling was used to investigate individual trends and to quantify reliability of the individual dietary z-scores. Dietary patterns were moderately consistent and systematic over time (0·65 ≤ φHealthy ≤ 0·76; 0·62 ≤ φUnhealthy ≤ 0·78). Individual choices were also consistent year-on-year (0·64 ≤ rHealthy ≤ 0·71; 0·57 ≤ rUnhealthy ≤ 0·68). Reliability rose from 70 % with a single measure to over 90 % with four consecutive measures. The quality of diet diminished over time in 29 % of the children and improved in only 14 %. Dietary habits appear to be set early and seldom improve spontaneously.

The relationship of height and body fat to gender-assortative weight gain in children. A longitudinal cohort study (EarlyBird 44).

OBJECTIVE: Height, body fat and body mass index (BMI) are correlated in children, so we hypothesized that the gender-assortative associations in BMI recently reported in contemporary children might extend to their height and body fat. DESIGN: Prospective longitudinal cohort study. SUBJECTS: A total of 226 healthy trios (mother, father and child) from a 1995?1996 birth cohort randomly recruited in the city of Plymouth, UK. MEASUREMENTS: Height, weight, and BMI (kg/m(2)) were measured in each of the parents and, in addition, sum of five skin-folds (SF) in their children at 5, 6, 7 and 8 y. RESULTS: BMI and SF were strongly height-dependent in the children by 8 y (r = 0.41-0.56). SF was gender-assortative insofar as the mean SF was significantly greater in the daughters (but not the sons) of obese mothers (obese vs. normal weight: +2.5 cm p < 0.001) and in the sons (but not the daughters) of obese fathers (obese vs. normal: +1.3 cm p < 0.001). As expected, offspring height correlated with that of their parents, but overweight/obese children were systematically taller than normal weight children (boys: +1.02 SDS, girls: +1.14 SDS, p < 0.01), and this difference was independent of parental height or BMI. CONCLUSIONS: Height is transmitted by both parents, and the body fat of overweight/obese children largely by the same-sex parent, but the extra height associated with more fat in the child is unrelated to the height or weight of either parent. The secular trend in height among contemporary children may simply reflect their rising body fat. Excess fat is unhealthy, so the trend in height may not be healthy either.

Little impact of resting energy expenditure on childhood weight and body composition: a longitudinal study (EarlyBird 47).

The role of resting energy expenditure (REE) in the development of obesity in children is controversial. Our aim was to test the hypothesis that REE has a meaningful impact on change in weight or body composition in healthy children. Resting energy expenditure by indirect calorimetry and body composition by dual-energy x-ray absorptiometry were measured in 236 children (131 boys) on 7 annual occasions (7-13 years). The effect of REE at 7 years on change in weight and body composition was analyzed using linear mixed effects models. In neither sex was there an interaction between REE at 7 years and change in weight (P > .9). There were weak associations between REE at 7 years and change in body composition in boys but not in girls: for a 418 kJ (100 kcal) lower REE at 7 years, an increase in rate of change in fat mass of approximately 0.1 kg/y and in percentage of fat of 0.2% per year and a decrease in fat-free mass of 0.1 kg/y. Change in REE during follow-up was not significantly associated with body composition changes in either sex (P > .06). Thus, REE has little impact on the wide variation in weight gain at this age; although in boys, some fat was simply exchanged for lean, the effect was small. Resting energy expenditure does not appear to provide an explanation for childhood obesity.