Dermatological changes in a prospective cohort of acutely ill, hospitalised Malawian children, stratified according to nutritional status.

RATIONALE: Since the first documentation of skin changes in malnutrition in the early 18th century, various hair and skin changes have been reported in severely malnourished children globally. We aimed to describe the frequency and types of skin conditions in children admitted with acute illness to Queen Elizabeth Central Hospital, Blantyre, Malawi across a spectrum of nutritional status and validate an existing skin assessment tool. METHODS: Children between 1 week and 23 months of age with acute illness were enrolled and stratified by anthropometry. Standardised photographs were taken, and three dermatologists assessed skin changes and scored each child according to the SCORDoK tool. RESULTS: Among 103 children, median age of 12 months, 31 (30%) had severe wasting, 11 (11%) kwashiorkor (nutritional oedema), 20 (19%) had moderate wasting, 41 (40%) had no nutritional wasting and 18 (17%) a positive HIV antibody test. Six (5.8%) of the included patients died. 51 (50%) of children presented with at least one skin change. Pigmentary changes were the most common, observed in 35 (34%), with hair loss and bullae, erosions and desquamation the second most prevalent skin condition. Common diagnoses were congenital dermal melanocytosis, diaper dermatitis, eczema and postinflammatory hyperpigmentation. Severe skin changes like flaky paint dermatosis were rarely identified. Inter-rater variability calculations showed only fair agreement (overall Fleiss' kappa 0.25) while intrarater variability had a fair-moderate agreement (Cohen's kappa score of 0.47-0.58). DISCUSSION: Skin changes in hospitalised children with an acute illness and stratified according to nutritional status were not as prevalent as historically reported. Dermatological assessment by means of the SKORDoK tool using photographs is less reliable than expected.

Weight gain during nutritional rehabilitation post-childhood malnutrition may influence the associations between adulthood desaturases activity and anthro-cardiometabolic risk factors.

BACKGROUNDS & AIMS: Childhood malnutrition is a major global health problem with long-term sequelae, including non-communicable diseases (NCDs). Mechanisms are unknown but may involve metabolic programming, resulting from "short-term" solutions to optimise survival by compromising non-priority organs. As key players in lipid metabolism, desaturases have been shown to be predictive of NCDs. We hypothesised that the association between specific desaturase activities and NCD risk determinants (including body composition, serum glucose, insulin levels, and blood pressure) are influenced by childhood post-malnutrition weight gain. METHODS: 278 Afro-Caribbean adults with well-documented clinical history of severe malnutrition in childhood were studied. Extensive metabolic analyses including body composition (DXA), fasting serum glucose and lipidomics (n = 101), and fasting serum insulin (n = 83) were performed in malnutrition survivors and matched community controls (n = 90). Established lipid ratios were used as proxies of desaturase activities: CE 16:1/CE 16:0 for stearoyl-CoA desaturase (SCD1), LysoPC 20:4/20:3 for fatty acid desaturase 1 (FADS1), and LysoPC 20:3/18:2 for FADS2. RESULTS: Compared to community controls, adult malnutrition survivors (mean ± SD) age 28.3 ± 7.8 and BMI 23.6 ± 5.2 had higher SCD1 and FADS1 activity, (B ± SE) 0.07 ± 0.02 and 0.7 ± 0.08, respectively, but lower FADS2 activities (B ± SE) -0.05 ± 0.01, adjusted for sex and age (p < 0.0005). SCD1 was positively associated with adult BMI and body fat percentage, and negatively associated with lean mass and height. Stratification based on weight gain during nutritional rehabilitation among malnutrition survivors might signal the potential associations between weight gain during that critical period, desaturase activities, and some of adult metabolic parameters, with the lowest tertiles (slowest catch-up weight gain) performing more similarly to controls. CONCLUSIONS: In adult survivors of early-life severe acute malnutrition, desaturase activity is associated with markers of NCD risk, especially adiposity. These associations seem to be strengthened by faster weight gain during nutritional rehabilitation.

Faster rehabilitation weight gain during childhood is associated with risk of non-communicable disease in adult survivors of severe acute malnutrition.

Nutritional rehabilitation during severe acute malnutrition (SAM) aims to quickly restore body size and minimize poor short-term outcomes. We hypothesized that faster weight gain during treatment is associated with greater cardiometabolic risk in adult life. Anthropometry, body composition (DEXA), blood pressure, blood glucose, insulin and lipids were measured in a cohort of adults who were hospitalized as children for SAM between 1963 and 1993. Weight and height measured during hospitalization and at one year post-recovery were abstracted from hospital records. Childhood weight gain during nutritional rehabilitation and weight and height gain one year post-recovery were analysed as continuous variables, quintiles and latent classes in age, sex and minimum weight-for-age z-scores-adjusted regression models against adult measurements. Data for 278 adult SAM survivors who had childhood admission records were analysed. Of these adults, 85 also had data collected 1 year post-hospitalisation. Sixty percent of participants were male, mean (SD) age was 28.2 (7.7) years, mean (SD) BMI was 23.6 (5.2) kg/m2. Mean admission age for SAM was 10.9 months (range 0.3-36.3 months), 77% were wasted (weight-for-height z-scores<-2). Mean rehabilitation weight gain (SD) was 10.1 (3.8) g/kg/day and 61.6 (25.3) g/day. Rehabilitation weight gain > 12.9 g/kg/day was associated with higher adult BMI (difference = 0.5 kg/m2, 95% CI: 0.1-0.9, p = 0.02), waist circumference (difference = 1.4 cm, 95% CI: 0.4-2.4, p = 0.005), fat mass (difference = 1.1 kg, 95% CI: 0.2-2, p = 0.02), fat mass index (difference = 0.32kg/m2, 95% CI: -0.0001-0.6, p = 0.05), and android fat mass (difference = 0.09 kg, 95% CI: 0.01-0.2, p = 0.03). Post-recovery weight gain (g/kg/month) was associated with lean mass (difference = 1.3 kg, 95% CI: 0.3-2.4, p = 0.015) and inversely associated with android-gynoid fat ratio (difference = -0.03, 95% CI: -0.07to-0.001 p = 0.045). Rehabilitation weight gain exceeding 13g/kg/day was associated with adult adiposity in young, normal-weight adult SAM survivors. This challenges existing guidelines for treating malnutrition and warrants further studies aiming at optimising these targets.

Post-malnutrition growth and its associations with child survival and non-communicable disease risk: a secondary analysis of the Malawi 'ChroSAM' cohort.

OBJECTIVE: To explore patterns of post-malnutrition growth (PMGr) during and after treatment for severe malnutrition and describe associations with survival and non-communicable disease (NCD) risk 7 years post-treatment. DESIGN: Six indicators of PMGr were derived based on a variety of timepoints, weight, weight-for-age z-score and height-for-age z-score (HAZ). Three categorisation methods included no categorisation, quintiles and latent class analysis (LCA). Associations with mortality risk and seven NCD indicators were analysed. SETTING: Secondary data from Blantyre, Malawi between 2006 and 2014. PARTICIPANTS: A cohort of 1024 children treated for severe malnutrition (weight-for-length z-score < 70 % median and/or MUAC (mid-upper arm circumference) < 110 mm and/or bilateral oedema) at ages 5-168 months. RESULTS: Faster weight gain during treatment (g/d) and after treatment (g/kg/day) was associated with lower risk of death (adjusted OR 0·99, 95 % CI 0·99, 1·00; and adjusted OR 0·91, 95 % CI 0·87, 0·94, respectively). In survivors (mean age 9 years), it was associated with greater hand grip strength (0·02, 95 % CI 0·00, 0·03) and larger HAZ (6·62, 95 % CI 1·31, 11·9), both indicators of better health. However, faster weight gain was also associated with increased waist:hip ratio (0·02, 95 % CI 0·01, 0·03), an indicator of later-life NCD risk. The clearest patterns of association were seen when defining PMGr based on weight gain in g/d during treatment and using the LCA method to describe growth patterns. Weight deficit at admission was a major confounder. CONCLUSIONS: A complex pattern of benefits and risks is associated with faster PMGr. Both initial weight deficit and rate of weight gain have important implications for future health.

Ursids evolved early and continuously to be low-protein macronutrient omnivores.

The eight species of bears world-wide consume a wide variety of diets. Some are specialists with extensive anatomical and physiological adaptations necessary to exploit specific foods or environments [e.g., polar bears (Ursus maritimus), giant pandas (Ailuropoda melanoleuca), and sloth bears (Melursus ursinus)], while the rest are generalists. Even though ursids evolved from a high-protein carnivore, we hypothesized that all have become low-protein macronutrient omnivores. While this dietary strategy has already been described for polar bears and brown bears (Ursus arctos), a recent study on giant pandas suggested their macronutrient selection was that of the ancestral high-protein carnivore. Consumption of diets with inappropriate macronutrient profiles has been associated with increased energy expenditure, ill health, failed reproduction, and premature death. Consequently, we conducted feeding and preference trials with giant pandas and sloth bears, a termite and ant-feeding specialist. Both giant pandas and sloth bears branched off from the ursid lineage a million or more years before polar bears and brown bears. We found that giant pandas are low-protein, high-carbohydrate omnivores, whereas sloth bears are low-protein, high-fat omnivores. The preference for low protein diets apparently occurred early in the evolution of ursids and may have been critical to their world-wide spread.

Liver fat in adult survivors of severe acute malnutrition.

The association between severe acute malnutrition (SAM) in early childhood and liver fat in adults is unknown. We hypothesized that exposure to SAM, especially severe wasting, is associated with fatty liver later in life. In this observational study, abdominal CT was used to quantify mean liver attenuation (MLA) and liver:spleen attenuation ratio (L/S). Birth weight (BW), serum lipids, insulin resistance (homeostatic model assessment), anthropometry and intrabdominal fat were collected. Mean differences between diagnostic groups were tested and hierarchical regression analysis determined the best predictors of liver fat. We studied 88 adult SAM survivors and 84 community participants (CPs); age 29.0 ± 8.4 years, BMI 23.5 ± 5.0 kg/m2 (mean ± SDs). SAM survivors had less liver fat than CPs (using L/S) (p = 0.025). Severe wasting survivors (SWs) had lower BW (-0.51 kg; p = 0.02), were younger, thinner and had smaller waist circumference than oedematous malnutrition survivors (OMs). In the final regression model adjusting for age, sex, birth weight and SAM phenotype (i.e., oedematous malnutrition or severe wasting), SWs had more liver fat than OMs (using MLA) (B = 2.6 ± 1.3; p = 0.04) but similar liver fat using L/S (p = 0.07) and lower BW infants had less liver fat (MLA) (B = -1.8 ± 0.8; p = 0.03). Greater liver fat in SWs than OMs, despite having less body fat, supports our hypothesis of greater cardiometabolic risk in SWs. Other postnatal factors might influence greater liver fat in survivors of severe wasting, suggesting the need to monitor infants exposed to SAM beyond the acute episode.

The effect of wasting and stunting during severe acute malnutrition in infancy on insulin sensitivity and insulin clearance in adult life.

Adults who had non-edematous severe acute malnutrition (SAM) during infancy (i.e., marasmus) have worse glucose tolerance and beta-cell function than survivors of edematous SAM (i.e., kwashiorkor). We hypothesized that wasting and/or stunting in SAM is associated with lower glucose disposal rate (M) and insulin clearance (MCR) in adulthood.We recruited 40 nondiabetic adult SAM survivors (20 marasmus survivors (MS) and 20 kwashiorkor survivors (KS)) and 13 matched community controls. We performed 150-minute hyperinsulinaemic, euglycaemic clamps to estimate M and MCR. We also measured serum adiponectin, anthropometry, and body composition. Data on wasting (weight-for-height) and stunting (height-for-age) were abstracted from the hospital records.Children with marasmus had lower weight-for-height z-scores (WHZ) (-3.8 ± 0.9 vs. -2.2 ± 1.4; P < 0.001) and lower height-for-age z-scores (HAZ) (-4.6 ± 1.1 vs. -3.4 ± 1.5; P = 0.0092) than those with kwashiorkor. As adults, mean age (SD) of participants was 27.2 (8.1) years; BMI was 23.6 (5.0) kg/m2. SAM survivors and controls had similar body composition. MS and KS and controls had similar M (9.1 ± 3.2; 8.7 ± 4.6; 6.9 ± 2.5 mg.kg-1.min-1 respectively; P = 0.3) and MCR. WHZ and HAZ were not associated with M, MCR or adiponectin even after adjusting for body composition.Wasting and stunting during infancy are not associated with insulin sensitivity and insulin clearance in lean, young, adult survivors of SAM. These data are consistent with the finding that glucose intolerance in malnutrition survivors is mostly due to beta-cell dysfunction.

Severe malnutrition or famine exposure in childhood and cardiometabolic non-communicable disease later in life: a systematic review.

INTRODUCTION: Child malnutrition (undernutrition) and adult non-communicable diseases (NCDs) are major global public health problems. While convincing evidence links prenatal malnutrition with increased risk of NCDs, less is known about the long-term sequelae of malnutrition in childhood. We therefore examined evidence of associations between postnatal malnutrition, encompassing documented severe childhood malnutrition in low/middle-income countries (LMICs) or famine exposure, and later-life cardiometabolic NCDs. METHODS: Our peer-reviewed search strategy focused on 'severe childhood malnutrition', 'LMICs', 'famine', and 'cardiometabolic NCDs' to identify studies in Medline, Embase, Global Health, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. We synthesised results narratively and assessed study quality with the UK National Institute for Health and Care Excellence checklist. RESULTS: We identified 57 studies of cardiometabolic NCD outcomes in survivors of documented severe childhood malnutrition in LMICs (n=14) and historical famines (n=43). Exposure to severe malnutrition or famine in childhood was consistently associated with increased risk of cardiovascular disease (7/8 studies), hypertension (8/11), impaired glucose metabolism (15/24) and metabolic syndrome (6/6) in later life. Evidence for effects on lipid metabolism (6/11 null, 5/11 mixed findings), obesity (3/13 null, 5/13 increased risk, 5/13 decreased risk) and other outcomes was less consistent. Sex-specific differences were observed in some cohorts, with women consistently at higher risk of glucose metabolism disorders and metabolic syndrome. CONCLUSION: Severe malnutrition or famine during childhood is associated with increased risk of cardiometabolic NCDs, suggesting that developmental plasticity extends beyond prenatal life. Severe malnutrition in childhood thus has serious implications not only for acute morbidity and mortality but also for survivors' long-term health. Heterogeneity across studies, confounding by prenatal malnutrition, and age effects in famine studies preclude firm conclusions on causality. Research to improve understanding of mechanisms linking postnatal malnutrition and NCDs is needed to inform policy and programming to improve the lifelong health of severe malnutrition survivors.

Childhood severe acute malnutrition is associated with metabolic changes in adulthood.

BACKGROUNDSevere acute malnutrition (SAM) is a major contributor to global mortality in children under 5 years. Mortality has decreased; however, the long-term cardiometabolic consequences of SAM and its subtypes, severe wasting (SW) and edematous malnutrition (EM), are not well understood. We evaluated the metabolic profiles of adult SAM survivors using targeted metabolomic analyses.METHODSThis cohort study of 122 adult SAM survivors (SW = 69, EM = 53) and 90 age-, sex-, and BMI-matched community participants (CPs) quantified serum metabolites using direct flow injection mass spectrometry combined with reverse-phase liquid chromatography. Univariate and sparse partial least square discriminant analyses (sPLS-DAs) assessed differences in metabolic profiles and identified the most discriminative metabolites.RESULTSSeventy-seven metabolite variables were significant in distinguishing between SAM survivors (28.4 ± 8.8 years, 24.0 ± 6.1 kg/m2) and CPs (28.4 ± 8.9 years, 23.3 ± 4.4 kg/m2) (mean ± SDs) in univariate and sPLS-DA models. Compared with CPs, SAM survivors had less liver fat; higher branched-chain amino acids (BCAAs), urea cycle metabolites, and kynurenine/tryptophan (KT) ratio (P < 0.001); and lower ß-hydroxybutyric acid and acylcarnitine/free carnitine ratio (P < 0.001), which were both associated with hepatic steatosis (P < 0.001). SW and EM survivors had similar metabolic profiles as did stunted and nonstunted SAM survivors.CONCLUSIONAdult SAM survivors have distinct metabolic profiles that suggest reduced ß-oxidation and greater risk of type 2 diabetes (BCAAs, KT ratio, urea cycle metabolites) compared with CPs. This indicates that early childhood SAM exposure has long-term metabolic consequences that may worsen with age and require targeted clinical management.FUNDINGHealth Research Council of New Zealand, Caribbean Public Health Agency, Centre for Global Child Health at the Hospital for Sick Children. DST is an Academic Fellow and a Restracomp Fellow at the Centre for Global Child Health. GBG is a postdoctoral fellow of the Research Foundation Flanders.

Nonalcoholic Fatty Liver Disease in Nonobese Subjects of African Origin Has Atypical Metabolic Characteristics.

BACKGROUND: Nonobese nonalcoholic fatty liver disease is reported in several populations. However, because persons of African origin display unique fat accumulation, insulin resistance, and lipid profiles, we investigated fatty liver in nonobese persons of African origin. METHOD: We recruited 78 urban Jamaican volunteers. CT was used to estimate liver and abdominal fat and dual-energy X-ray absorptiometry to measure body composition. Fasting blood was collected for lipids, alanine aminotransferase (ALT), adiponectin, and fetuin-A. Homeostatic model assessment of insulin resistance (HOMA-IR), whole-body insulin sensitivity index (WBISI), insulinogenic index (IGI), and oral disposition index (oDI) were calculated after a 75-g oral glucose tolerance test. RESULTS: Fifty-two percent of participants were male; mean (±SD) age was 28.5 ± 7.8 years, and body mass index was 22.4 ± 3.0 kg/m2. Mean liver attenuation (MLA) and liver/spleen (LS) ratio, both inversely correlated to liver fat, were 62.8 ± 4.3 HU and 1.2 ± 0.1, respectively; 3.8% of participants had liver fat >30% (LS ratio < 1). In age, sex, and BMI-adjusted correlations, MLA was negatively associated with weight (r = -0.30; P = 0.009) and height (r = -0.28; P = 0.017) and was associated with fasting glucose (r = 0.23; P = 0.05), fasting insulin (r = 0.42; P ≤ 0.001) and HOMA-IR (r = 0.35; P = 0.004). Serum lipids, ALT, adiponectin, fetuin-A, WBISI, IGI, and oDI were not associated with liver fat. CONCLUSIONS: In nonobese Afro-Caribbean participants, greater liver fat was associated with weight and height and lower fasting insulin and hyperinsulinemia appears to be influential in the reduction of NAFLD. These findings may be influenced by ethnicity, body size, and method of estimating liver fat.

Metabolomics in plasma of Malawian children 7 years after surviving severe acute malnutrition: "ChroSAM" a cohort study.

BACKGROUND: More children are now surviving severe acute malnutrition (SAM), but evidence suggests that early-life malnutrition is associated with increased risk of long-term cardio-metabolic disorders. To better understand potential mechanisms, we studied the metabolite profiles of children seven years after treatment for SAM. METHODS: We followed-up children (n = 352) treated for SAM in 2006-2007, at Queen Elizabeth Central Hospital, in Malawi. Using nuclear magnetic resonance spectroscopy, tandem mass spectrometry and enzyme-linked immunosorbent assay, we measured circulating metabolites in fasting blood in a subset of SAM survivors (n = 69, 9·6 ±â€¯1·6 years), siblings (n = 44, 10·5 ±â€¯2·7 years), and age and sex-matched community controls (n = 37, 9·4 ±â€¯1·8 years). Data were analysed using univariate and sparse partial least square (sPLS) methods. Differences associated with SAM survival, oedema status, and anthropometry were tested, adjusting for age, sex, HIV, and wealth index. FINDINGS: Based on 194 measured metabolites, the profiles of SAM survivors were similar to those of siblings and community controls. IGF1, creatinine, and FGF21, had loading values >0·3 and ranked stably in the top 10 distinguishing metabolites, but did not differ between SAM survivors and controls with univariate analysis. Current stunting was associated with IGF1 (ß = 15·2, SE = 3·5, partial R2 = 12%, p < 0·0001) and this relationship could be influenced by early childhood SAM (ß = 17·4, SE = 7·7, partial R2 = 2·8%, p = 0·025). No metabolites were associated with oedema status, duration of hospital stay, anthropometry measured during hospitalization, nor with changes in anthropometry since hospitalization. INTERPRETATION: In this group of survivors, SAM was not associated with longer-term global metabolic changes 7 years after treatment. However, SAM may influence the relationship between current stunting and IGF1. Further risk markers for NCDs in SAM survivors may only be revealed by direct metabolic challenge or later in life.

Socioeconomic factors associated with severe acute malnutrition in Jamaica.

OBJECTIVES: Severe acute malnutrition (SAM) is an important risk factor for illness and death globally, contributing to more than half of deaths in children worldwide. We hypothesized that SAM is positively correlated to poverty, low educational attainment, major crime and higher mean soil concentrations of lead, cadmium and arsenic. METHODS: We reviewed admission records of infants admitted with a diagnosis of SAM over 14 years (2000-2013) in Jamaica. Poverty index, educational attainment, major crime and environmental heavy metal exposure were represented in a Geographic Information System (GIS). Cases of SAM were grouped by community and the number of cases per community/year correlated to socioeconomic variables and geochemistry data for the relevant year. RESULTS: 375 cases of SAM were mapped across 204 urban and rural communities in Jamaica. The mean age at admission was 9 months (range 1-45 months) and 57% were male. SAM had a positive correlation with major crime (r = 0.53; P < 0.001), but not with educational attainment or the poverty index. For every one unit increase in the number of crimes reported, the rate of occurrence of SAM cases increased by 1.01% [Incidence rate ratio (IRR) = 1.01 (95% CI = 1.006-1.014); P P<0.001]. The geochemistry data yielded no correlation between levels of heavy metals and the prevalence of malnutrition. CONCLUSION: Major crime has an independent positive association with severe acute malnutrition in Jamaican infants. This could suggest that SAM and major crime might have similar sociological origins or that criminality at the community level may be indicative of reduced income opportunities with the attendant increase in poor nutrition in the home.

Molecular Evidence for Differential Long-term Outcomes of Early Life Severe Acute Malnutrition.

BACKGROUND: Severe acute malnutrition (SAM) in infants may present as one of two distinct syndromic forms: non-edematous (marasmus), with severe wasting and no nutritional edema; or edematous (kwashiorkor) with moderately severe wasting. These differences may be related to developmental changes prior to the exposure to SAM and phenotypic changes appear to persist into adulthood with differences between the two groups. We examined whether the different response to SAM and subsequent trajectories may be explained by developmentally-induced epigenetic differences. METHODS: We extracted genomic DNA from muscle biopsies obtained from adult survivors of kwashiorkor (n=21) or marasmus (n=23) and compared epigenetic profiles (CpG methylation) between the two groups using the Infinium® 450K BeadChip array. FINDINGS: We found significant differences in methylation of CpG sites from 63 genes in skeletal muscle DNA. Gene ontology studies showed significant differential methylation of genes in immune, body composition, metabolic, musculoskeletal growth, neuronal function and cardiovascular pathways, pathways compatible with the differences in the pathophysiology of adult survivors of SAM. INTERPRETATION: These findings suggest persistent developmental influences on adult physiology in survivors of SAM. Since children who develop marasmus have lower birth weights and after rehabilitation have different intermediary metabolism, these studies provide further support for persistent developmentally-induced phenomena mediated by epigenetic processes affecting both the infant response to acute malnutrition and later life consequences. FUNDING: Supported by a Grant from the Bill and Melinda Gates Foundation (Global Health OPP1066846), Grand Challenge "Discover New Ways to Achieve Healthy Growth." EVIDENCE BEFORE THIS STUDY: Previous research has shown that infants who develop either kwashiorkor or marasmus in response to SAM differ in birth weight and subsequently have different metabolic patterns in both infancy and adulthood. ADDED VALUE OF THIS STUDY: This study demonstrates epigenetic differences in the skeletal muscle of adult survivors of marasmus versus kwashiorkor and these differences are in genes that may underlie the longer-term consequences. IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE: These data are compatible with the different clinical responses to SAM arising from developmentally-induced epigenetic changes laid down largely before birth and provide evidence for the predictive adaptive response model operating in human development.

Early-life factors are associated with nocturnal cortisol and glucose effectiveness in Afro-Caribbean young adults.

CONTEXT: Early-life factors (including intrauterine growth retardation) may influence the development of type 2 diabetes. We postulated that birth size is associated with cortisol levels, which itself could alter serum adipomyokines (i.e. adiponectin, IGF-I, myostatin) and glucose metabolism. DESIGN: An observational study with 60 Afro-Caribbean young adults from a birth cohort. MEASUREMENTS: Fasting blood was drawn for serum adiponectin, IGF-I and myostatin. A frequently sampled intravenous glucose tolerance test measured insulin sensitivity (SI), acute insulin response (AIRg), disposition index (DI) and glucose effectiveness (Sg). Body composition was assessed by dual-energy X-ray absorptiometry. Salivary cortisol was collected at home at 0800 and 2300 h. Sex-adjusted correlations were used to explore the relationships between birth size, cortisol and the metabolic variables. RESULTS: The participants were 55% male, mean age 23·1 ± 0·5 years. Birth weight correlated positively with 2300-h cortisol (P = 0·04), although not after adjusting for gestational age. Gestational age was correlated with 2300 h cortisol (r = 0·38, P = 0·03), even after adjusting for birth weight (P = 0·02). 2300 h cortisol was not associated with adiponectin, IGF-I, myostatin, SI, AIRg or DI, but was negatively correlated with Sg (r = -0·30, P = 0·05) even after adjusting for birth and adult anthropometry. Adiponectin, IGF-I and myostatin were unrelated to glucose metabolism. CONCLUSIONS: Gestational age is associated with higher nocturnal cortisol, which in turn is associated with lower glucose effectiveness in adulthood. Higher glucose effectiveness could therefore be a compensatory mechanism to improve glucose uptake.

Impaired cardiovascular structure and function in adult survivors of severe acute malnutrition.

Malnutrition below 5 years remains a global health issue. Severe acute malnutrition (SAM) presents in childhood as oedematous (kwashiorkor) or nonoedematous (marasmic) forms, with unknown long-term cardiovascular consequences. We hypothesized that cardiovascular structure and function would be poorer in SAM survivors than unexposed controls. We studied 116 adult SAM survivors, 54 after marasmus, 62 kwashiorkor, and 45 age/sex/body mass index-matched community controls who had standardized anthropometry, blood pressure, echocardiography, and arterial tonometry performed. Left ventricular indices and outflow tract diameter, carotid parameters, and pulse wave velocity were measured, with systemic vascular resistance calculated. All were expressed as SD scores. Mean (SD) age was 28.8±7.8 years (55% men). Adjusting for age, sex, height, and weight, SAM survivors had mean (SE) reductions for left ventricular outflow tract diameter of 0.67 (0.16; P<0.001), stroke volume 0.44 (0.17; P=0.009), cardiac output 0.5 (0.16; P=0.001), and pulse wave velocity 0.32 (0.15; P=0.03) compared with controls but higher diastolic blood pressures (by 4.3; 1.2-7.3 mm Hg; P=0.007). Systemic vascular resistance was higher in marasmus and kwashiorkor survivors (30.2 [1.2] and 30.8 [1.1], respectively) than controls 25.3 (0.8), overall difference 5.5 (95% confidence interval, 2.8-8.4 mm Hg min/L; P<0.0001). No evidence of large vessel or cardiac remodeling was found, except closer relationships between these indices in former marasmic survivors. Other parameters did not differ between SAM survivor groups. We conclude that adult SAM survivors had smaller outflow tracts and cardiac output when compared with controls, yet markedly elevated peripheral resistance. Malnutrition survivors are thus likely to develop excess hypertension in later life, especially when exposed to obesity.

Glucose metabolism in adult survivors of severe acute malnutrition.

CONTEXT AND OBJECTIVES: The clinical syndromes of severe acute malnutrition may have early life origins because children with marasmus have lower birth weight than those with kwashiorkor. We hypothesized that resultant metabolic effects may persist into adulthood. We investigated whether marasmus survivors (MS) are more insulin resistant and glucose intolerant than kwashiorkor survivors (KS). RESEARCH DESIGN AND SETTING: This was a case-control study in Jamaican adults. SUBJECTS: We performed oral glucose tolerance tests on 191 adults (aged 17-50 y; 52% male; body mass index 24.2 ± 5.5 kg/m(2)). There were 43 MS; 38 KS; 70 age-, sex-, and body mass index-matched community controls; and 40 age- and birth weight-matched controls. MEASUREMENTS: We measured insulin sensitivity with the whole-body insulin sensitivity index, and ß-cell function with the insulinogenic index and the oral disposition index. RESULTS: Fasting glucose was comparable across groups, but glucose intolerance was significantly more common in MS (19%) than in KS (3%), community controls (11%), and birth weight-matched controls (10%). The whole-body insulin sensitivity index was lower in MS than KS (P = .06) but similar between MS and controls. The insulinogenic index and oral disposition index were lower in MS compared with all three groups (P < .01). CONCLUSIONS: Marasmus survivors tend to be less insulin sensitive, but have significantly lower insulin secretion and are more glucose intolerant compared with kwashiorkor survivors and controls. This suggests that poor nutrition in early life causes ß-cell dysfunction, which may predispose to the development of diabetes.

Limitations of fasting indices in the measurement of insulin sensitivity in Afro-Caribbean adults.

BACKGROUND: Insulin sensitivity can be estimated using glucose disposal rate (M) measured during a hyperinsulinemic euglycemic clamp (HEC) or insulin sensitivity index (SI) derived from a frequently sampled intravenous glucose tolerance test (FSIVGTT). The commonly used homeostatic model assessment of insulin resistance (HOMA-IR) which utilizes fasting glucose and insulin has been validated against M across several populations (r = 0.5-0.8). This study sought to validate HOMA-IR against SI and M in an Afro-Caribbean population. FINDINGS: Sixty participants completed a 180-minute FSIVGTT and another 50 completed a 150-minute hyperinsulinemic euglycemic clamp. In both groups, HOMA-IR was calculated and anthropometry and body composition using dual energy x-ray absorptiometry (DEXA) were measured.FSIVGTT: The participants were 55% male, age 23.1 ± 0.05 years, BMI 24.8 ± 6.3 kg/m2 and % body fat 25.0 ± 15.2 (mean ± SD). HEC: The participants were 44% male, age 27.3 ± 8.1 years, BMI 23.6 ± 5.0 kg/m2 and % body fat 24.7 ± 14.2 (mean ± SD). While HOMA-IR, SI and M correlated with waist, BMI and % body fat (P-values < 0.01) there were no significant correlations between HOMA-IR with either SI or M-value (P-values > 0.2). CONCLUSIONS: In young Afro-Caribbean adults, HOMA-IR compared poorly with other measures of insulin sensitivity. It remains important to determine whether similar findings occur in a more insulin resistant population. However, HOMA-IR correlated with clinical measures of insulin sensitivity (i.e. adiposity), so it may still be useful in epidemiological studies.

Improving management of patients with autism spectrum disorder having scheduled surgery: optimizing practice.

INTRODUCTION: Surgical preparation for children with autism spectrum disorders can be a challenge to perioperative staff because of the unique individual needs and behaviors in this population. Most children with autism function best in predictable, routine environments, and being in the hospital and other health care settings can create a stressful situation. This prospective, descriptive, quality improvement project was conducted to optimize best practices for perioperative staff and better individualize the plan of care for the autistic child and his or her family. METHODS: Forty-three patients with a diagnosis of autism or autistic spectrum disorder were seen over 6 months at a suburban pediatric hospital affiliated with a major urban pediatric hospital and had an upcoming scheduled surgery or procedure requiring anesthesia. Caregivers were interviewed before and after surgery to collect information to better help their child cope with their hospital visit. RESULTS: In an evaluation of project outcomes, data were tabulated and summarized and interview data were qualitatively coded for emerging themes to improve the perioperative process for the child. DISCUSSION: Findings showed that staff members were able to recognize potential and actual stressors and help identify individual needs of surgical patients with autism. The families were pleased and appreciative of the individual attention and focus on their child's special needs. Investigators also found increased staff interest in optimizing the surgical experience for autistic children.

Prenatal factors contribute to the emergence of kwashiorkor or marasmus in severe undernutrition: evidence for the predictive adaptation model.

BACKGROUND: Severe acute malnutrition in childhood manifests as oedematous (kwashiorkor, marasmic kwashiorkor) and non-oedematous (marasmus) syndromes with very different prognoses. Kwashiorkor differs from marasmus in the patterns of protein, amino acid and lipid metabolism when patients are acutely ill as well as after rehabilitation to ideal weight for height. Metabolic patterns among marasmic patients define them as metabolically thrifty, while kwashiorkor patients function as metabolically profligate. Such differences might underlie syndromic presentation and prognosis. However, no fundamental explanation exists for these differences in metabolism, nor clinical pictures, given similar exposures to undernutrition. We hypothesized that different developmental trajectories underlie these clinical-metabolic phenotypes: if so this would be strong evidence in support of predictive adaptation model of developmental plasticity. METHODOLOGY/PRINCIPAL FINDINGS: We reviewed the records of all children admitted with severe acute malnutrition to the Tropical Metabolism Research Unit Ward of the University Hospital of the West Indies, Kingston, Jamaica during 1962-1992. We used Wellcome criteria to establish the diagnoses of kwashiorkor (n = 391), marasmus (n = 383), and marasmic-kwashiorkor (n = 375). We recorded participants' birth weights, as determined from maternal recall at the time of admission. Those who developed kwashiorkor had 333 g (95% confidence interval 217 to 449, p<0.001) higher mean birthweight than those who developed marasmus. CONCLUSIONS/SIGNIFICANCE: These data are consistent with a model suggesting that plastic mechanisms operative in utero induce potential marasmics to develop with a metabolic physiology more able to adapt to postnatal undernutrition than those of higher birthweight. Given the different mortality risks of these different syndromes, this observation is supportive of the predictive adaptive response hypothesis and is the first empirical demonstration of the advantageous effects of such a response in humans. The study has implications for understanding pathways to obesity and its cardio-metabolic co-morbidities in poor countries and for famine intervention programs.