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Over 25 million people are victims of forced labor globally; the vast majority are low-skilled migrant workers who migrated from a different country or region. Evidence so far indicates that much of labor exploitation has roots in the recruitment process. This motivates the question of whether there are characteristics common to low-skilled labor recruitment that can serve as reliable indicators of forced labor risk in the workplace. Leveraging unique data sets from the Myanmar Government and the Issara Institute on weekly demand for Burmese migrant workers in Thailand by Thai companies, and on worker voice hot-line data from 2018-2020, we find that unexpected labor shortages in the workplace significantly increase migrant worker abuse. Using an Instrumental Variable (IV) approach, we find that an increase of one standard deviation in low-skilled labor shortages in the workplace leads to a 34.5% or higher increase in worker-reported labor abuse in the two to four weeks that follow. Shocks of such magnitude occur about 10% of the time. We also find a visible correlation between provinces whose labor markets are more stressed on average and the frequency of unexpected labor shortages in a province, suggesting that stressed labor markets are also more prone to unexpected shortages and abuse. Overall, this research suggests that inefficiencies in matching supply and demand for low-skilled labor play an important role in determining labor abuse outcomes, and that reducing these inefficiencies in the labor recruitment process could help mitigate labor abuse.

Significance Supply chains tied to multinational corporations represent over 80% of global trade and engage over one in five workers. Supply-chain management therefore has a significant impact on key social and environmental challenges. Despite this importance, there is currently no comprehensive, empirically grounded understanding of how companies address sustainability in their supply chains. We develop a global database based on a random sample of publicly listed companies with annual reports in English to provide insight into how the private sector contributes to advancing global sustainability via their supply chains. This study provides a large-scale empirical analysis of corporate sustainable-sourcing practices across multiple sectors and geographies., Global supply chains play a critical role in many of the most pressing environmental stresses and social struggles identified by the United Nations’ Sustainable Development Goals (SDGs). Responding to calls from the global community, companies are adopting a variety of voluntary practices to improve the environmental and/or social management of their suppliers’ activities. We develop a global survey of 449 publicly listed companies in the food, textile, and wood-products sectors with annual reports in English to provide insight into how the private sector contributes to advancing the SDGs via such sustainable-sourcing practices. We find that while 52% of companies use at least one sustainable-sourcing practice, these practices are limited in scope; 71% relates to only one or a few input materials and 60.5% apply to only first-tier suppliers. We also find that sustainable-sourcing practices typically address a small subset of the sustainability challenges laid out by the SDGs, primarily focusing on labor rights and compliance with national laws. Consistent with existing hypotheses, companies that face consumer and civil society pressure are associated with a significantly higher probability of adopting sustainable-sourcing practices. Our findings highlight the opportunities and limitations of corporate sustainable-sourcing practices in addressing the myriad sustainability challenges facing our world today.

Low birth weight followed by rapid postnatal weight gain is associated with increased risks for obesity and diabetes in adulthood. Modulation of glucagon-like-peptide 1 (GLP-1) secretion by (epi)genetic mechanisms or nutrition may influence in part this risk. Formula fed infants born small-for-gestational-age (SGA) have higher circulating GLP-1 at age 4 months than breastfed SGA or appropriate-for-gestational-age (AGA) infants. Here, we assessed GLP-1 concentrations in healthy AGA (n=149) and SGA (n=107) subjects at age 12 months, and their association with endocrine-metabolic and body composition parameters and GLP-1 receptor (GLP-1R) rs6923761 and rs3765467 polymorphisms. At birth, cord GLP-1 concentrations were comparable in AGA and SGA infants. At age 12 months, insulin-like growth factor I (IGF-I) and GLP-1 levels were higher than at birth; SGA infants displayed higher IGF-I and GLP-1 concentrations than AGA infants (both P

Market price information is not widely available to many firms in the developing world. In these settings, information sharing agreements among competing firms can create significant benefits. However, such agreements may be difficult to implement, because a firm might fear that sharing its information will benefit competitors, allowing them to steal its market share. We show that an appropriately designed information-sharing platform can disclose partial information that will benefit all firms. By eliminating business stealing concerns, our information disclosure policy creates a Pareto improvement and is implementable if the information shared by the platform is sufficiently valuable. The model requires minimal assumptions and can account for general market dynamics. The interpretability of our results allows us to propose a heuristic for use in practice by an Indonesia-based information-sharing platform we collaborate with.

SummaryBackground Telomere length at birth is a major determinant of telomere length in late adulthood. However, the prenatal setting of telomere length is poorly understood. Individuals born large from non-diabetic mothers are at lower risk for later-life disorders than those born small, a feature of their longer health span being a higher lean mass that provides more muscle strength and that is already present in infancy. Methods At birth, we studied leukocyte telomere length (by quantitative polymerase chain reaction) in 103 small-for-gestational-age, appropriate-for-gestational-age or large-for-gestational-age (SGA, AGA or LGA) infants born after uncomplicated, term, singleton pregnancies. All infants were breastfed for ≥4 months. At 2 weeks and 12 months, body composition was assessed by dual X-ray absorptiometry. Results Telomere lengths were shorter in SGA newborns and longer in LGA newborns than in AGA newborns (P

Summary Objectives The aim of this paper is to test whether α-defensins and bacterial/permeability-increasing protein were related to obesity and cardiovascular risk factors in prepubertal children. Methods Plasma α-defensins and bacterial/permeability-increasing protein, body mass index (BMI), waist circumference, systolic blood pressure (SBP), carotid intima media thickness (cIMT), HOMA-IR and HMW-adiponectin were assessed. Results In a cross-sectional study (N = 250), higher α-defensins concentrations were positively associated with BMI, waist, SBP, cIMT, HOMA-IR and negative correlated with HMW-adiponectin (all between r = 0.191 and r = 0.377, p ≤ 0.01 and p ≤ 0.0001). Conversely, plasma bacterial/permeability-increasing protein concentrations presented inversed associated with the same parameters (all between r = −0.124 and r = −0.329; p ≤ 0.05 and p ≤ 0.0001). In a longitudinal study (N = 91), α-defensins at age 7 were associated with BMI (β = 0.189, p = 0.002; model R2 = 0.847) and waist (β = 0.241, pthinsp;= 0.001; model R2 = 0.754) at age 10. Conclusions α-Defensins and bacterial/permeability-increasing protein may be the markers of childhood obesity. Increased concentrations of α-defensins may predict BMI and abdominal fat deposition in children.

Summary Objective Macrophages are known to be involved in low-grade inflammatory processes such as obesity. soluble cluster of differentiation 163 (sCD163) is shed from the cell surface as specific macrophage activation marker. In prepubertal children, we studied if circulating sCD163 is associated with metabolic and cardiovascular risk markers. Methods A population of 236 school-aged Caucasian children (111 girls and 125 boys) aged 8 ± 1 year [81 normal weight (body mass index [BMI]-SDS

BACKGROUND: The sequence of prenatal growth restraint and postnatal catch-up growth leads to a thicker intima-media and more pre-peritoneal fat by age 3-6 years. OBJECTIVES: To study whether carotid intima-media thickness (cIMT) and pre-peritoneal fat differ already between catch-up small-for-gestational-age (SGA) infants and appropriate-for-gestational-age (AGA) controls in late infancy (ages 1 and 2 years) and whether such differences - if any - are accompanied by differences in cardiac morphology and function. METHODS: Longitudinal assessments included body height and weight; fasting glucose, insulin, Insulin-like growth factor (IGF-I), high-molecular-weight adiponectin; body composition (by absorptiometry); cIMT, aortic IMT, pre-peritoneal fat partitioning (by ultrasound); cardiac morphometry and function (by echocardiography) in AGA and SGA infants at birth, at age 1 year (N = 87), and again at age 2 years (N = 68). RESULTS: Catch-up SGA infants had already a thicker cIMT than AGA controls at ages 1 and 2 years, and more pre-peritoneal fat by age 2 years (all p values between

To mitigate environmental and social harm, policy-makers often provide incentives or impose sanctions to discourage harmful behavior. Such policies are usually implemented with limited monitoring capabilities, which may cause strategic behavior that leads to unintended consequences. Three related questions for any policy are therefore: do targeted agents comply on elements that are visible (visible compliance), do agents behave strategically to undermine the policy (effectiveness), and are raw material prices affected (economic cost)? We study these questions empirically in the context of a zero-tolerance policy (a ban) on seafood transshipments on the high seas --- a ban imposed because seafood transshipments are associated with illegal fishing and widespread forced labor. Novel satellite-based datasets, available ex-post several years after implementation of the ban, offer a unique opportunity to study the effect of the ban in hindsight. Combining satellite-based and economic datasets, and exploiting variation across regions and over time, we find that a ban reduces the yearly growth in transshipment rates by an estimated 58% despite significant monitoring challenges, and does not cause appreciable strategic behavior. A difference-in-differences analysis of landing prices suggests that this reduction comes at an estimated cost of 3% higher raw material prices.

Summary Background Increased uric acid is an independent biomarker for cardiovascular disease in obese adolescents and adults. Objective We investigated whether uric acid relates to carotid intima-media thickness (cIMT) in prepubertal children, and whether body mass index (BMI) and preperitoneal fat modulate this association. Methods 359 asymptomatic prepubertal Caucasian children were stratified according to BMI categories (171 with BMI-SDS 50th centile). Uric acid levels, insulin resistance (homeostasis model assessment insulin resistance; HOMA-IR), C-reactive protein (CRP), triacylglycerol (TG), systolic blood pressure (SBP), abdominal fat and cIMT (both by ultrasound) were assessed. Results Uric acid was associated with several cardiovascular risk factors, namely higher HOMA-IR, CRP, TG, BMI, waist, SBP, preperitoneal fat and cIMT (all P

BACKGROUND AND OBJECTIVE: The sequence of prenatal growth restraint and postnatal catch-up growth may lead to hepato-visceral adiposity, insulin resistance and low-grade inflammation before the onset of puberty. In prepubertal children born appropriate for gestational age (AGA) or small for gestational age (SGA), we assessed potential relationships between the aforementioned sequence and liver volume. SUBJECTS/METHODS: The study population consisted of 86 children (41 AGA and 45 SGA with catch-up growth; age (mean±s.e.m.), 8.5±0.1 years), recruited into two prospective longitudinal studies. Anthropometry, endocrine-metabolic variables and inflammatory and hepatic markers were assessed, along with liver volume, hepatic adiposity and abdominal fat partitioning (by magnetic resonance imaging). RESULTS: AGA and SGA children differed in hepato-visceral adiposity, but had similar liver volumes. Boys had larger livers than girls, and higher sex hormone binding globulin and inflammation markers. Liver volume correlated with height Z-score, body mass index Z-score, HOMA-IR (homeostasis model assessment-insulin resistance) and with subcutaneous and visceral fat, but not with birth weight Z-score or with hepatic adiposity. Height, visceral fat, gender and HOMA-IR were major determinants of liver volume, together explaining 61% of its variance. CONCLUSIONS: The trajectory from prenatal restraint, via postnatal catch-up, to hepato-visceral adiposity and insulin resistance does not appear to be detectably influenced by prepubertal alterations of liver volume. Further follow-up will disclose the potential role of liver volume in the pubertal segment of this trajectory, and whether the augmented fat content and visceral adiposity in SGA subjects is followed by the development of metabolic syndrome and hepatic dysfunction in adulthood.

Background: KBG syndrome is a rare disorder characterized by intellectual disability and associated with macrodontia of the upper central incisors, specific craniofacial findings, short stature and skeletal anomalies. Genetic corroboration of a clinical diagnosis has been possible since 2011, upon identification of heterozygous mutations in or a deletion of the ANKRD11 gene. Methods: We summarized the height data of 14 adults and 18 children (age range 2-16 years) with a genetically confirmed diagnosis of KBG syndrome. Two of these children were treated with growth hormones. Results: Stature below the 3rd centile or -1.88 standard deviation score (SDS) was observed in 72% of KBG children and in 57% of KBG adults. Height below -2.50 SDS was observed in 62% of KBG children and in 36% of KBG adults. The mean SDS of height in KBG children was -2.56 and in KBG adults -2.17. Two KBG children on growth hormone therapy increased their height by 0.6 and 1 SDS within 1 year, respectively. The former also received a gonadotropin-releasing hormone agonist due to medical necessity. Conclusion: Short stature is prevalent in KBG syndrome, and spontaneous catch-up growth beyond childhood appears limited. Growth hormone intervention in short KBG children is perceived as promising.

BACKGROUND/OBJECTIVES: It is well known that increased abdominal fat is associated with cardiovascular (CV) risk. Perirenal fat has been recently associated with CV risk in adults. However, studies with children are lacking. We investigated the relationship of perirenal fat and other abdominal fat depots (including preperitoneal, intra-abdominal and subcutaneous fat) with carotid intima-media thickness (cIMT-a surrogate marker of CV risk) in prepubertal children, so as to identify novel markers that can be easily assessed and used in the early prevention of cardiovascular disease. SUBJECTS/METHODS: Subjects were 702 asymptomatic prepubertal Caucasian children (418 lean, 142 overweight and 142 obese) who were recruited in a primary care setting. Ultrasound measurements (perirenal, preperitoneal, intra-abdominal and subcutaneous fat and cIMT), clinical (body mass index (BMI) and systolic blood pressure) and metabolic parameters (insulin resistance (HOMA-IR), high molecular weight (HMW) adiponectin and serum lipids) were assessed. RESULTS: Perirenal fat was associated with diverse metabolic and CV risk factors in all the studied subjects. However, in overweight and obese children, perirenal fat was mostly associated with cIMT (P

Very low birth weight (VLBW) infants are at an increased risk of long-term cognitive impairment. Early identification and timely interventions are important. We aimed to validate the Dutch version of the revised Parent Report of Children's Abilities (PARCA-R) questionnaire.The subjects were survivors from the Belgian participating centers to the NIRTURE trial. As part of a study-related follow-up, PARCA-R was sent out at the age of 2 years. As part of a normal hospital follow-up, these infants were assessed by the Bayley Scales of Infant Development - second edition (BSID-II) at the age of 9, 18 and 36 months. MRI was performed at term in the group of VLBW infants of ZOL Genk as standard care.PARCA-R was sent out to 193 surviving infants. BSID-II was performed in 36% (n=70) at 9 months, in 30% (n=58) at 18 months and in 12% (n=23) at 36 months. MRI was available for 32 infants. We received 86 responses to the PARCA-R. Parent report composite (PRC) scores were significantly correlated with the Mental Development Index (MDI) (p0.0001 (9 months); p=0.003 (18 months); p=0.01 (36 months)). PRC scores were significantly lower in those with an abnormal MRI (92 vs.124; p=0.04).We support the use of the PARCA-R as a time and cost efficient alternative for identifying cognitive delay.We suggest that the combination of BSID-II, MRI at term and PARCA-R would be the ideal testing method for identifying VLBW infants at risk for cognitive developmental delay by two years of age.

Prenatal growth restraint associates with the risk for later diabetes, particularly if such restraint is followed by postnatal formula-feeding (FOF) rather than breast-feeding (BRF). Circulating incretins can influence the neonatal programming of hypothalamic setpoints for appetite and energy expenditure, and are thus candidate mediators of the long-term effects exerted by early nutrition. We have tested this concept by measuring (at birth and at age 4 months) the circulating concentrations of glucagon-like peptide-1 (GLP-1) in BRF infants born appropriate-for-gestational-age (AGA; n=63) and in small-for-gestational-age (SGA) infants receiving either BRF (n=28) or FOF (n=26). At birth, concentrations of GLP-1 were similar in AGA and SGA infants. At 4 months, pre-feeding GLP-1 concentrations were higher than at birth; SGA-BRF infants had GLP-1 concentrations similar to those in AGA-BRF infants but SGA-FOF infants had higher concentrations. In conclusion, nutrition appears to influence the circulating GLP-1 concentrations in SGA infants and may thereby modulate long-term diabetes risk.

Summary Background Maternal nutrition is the main source of Poly-Unsaturated Fatty Acids (PUFA) for the fetus. PUFA may influence the accumulation of fat in early life. Objectives & Methods In 33 breastfed infants born appropriate-for-gestational-age, we studied whether body composition (judged by absorptiometry at 2 wk and 4 mo) relates to PUFA levels (assessed by gas chromatography) in the maternal or fetal circulation at birth. Results Abdominal fat at 2 wk associated negatively to umbilical-cord levels of separate PUFA (linoleic, arachidonic, eicosapentanoic and docosahexaenoic acid; all P between 0.001 and 0.015). Collectively, the assessed n-6 PUFA on one hand and the n-3 PUFA on the other hand associated negatively to the absolute amount of abdominal fat (in grams; P = 0.001 and P = 0.002, respectively) and to the relative amount of abdominal fat (fraction of total fat; P = 0.001 and P = 0.006, respectively). No other significant associations were observed. Conclusion In conclusion, newborns with lower levels of circulating PUFA were found to be abdominally more adipose. The mechanisms underpinning these associations remain to be determined.

Summary What is already known about this subject The adaptive immune system has been shown to be a novel modulator of insulin resistance. Increased activation of B lymphocytes has been described in obese mice and in obese and type 2 diabetic patients. B lymphocytes promote insulin resistance by accumulating in adipose tissue and producing pathogenic antibodies. What this study adds Increased serum concentrations of IgG and IgA were found in overweight pre-pubertal children. Increasing concentrations of IgG and IgA were in obese, but not in lean pre-pubertal children, associated with a less favourable metabolic phenotype, consisting of increased insulin resistance and a more adverse lipid profile. Background The adaptive immune system has emerged as an unexpected modulator of insulin resistance. B lymphocytes accumulate in adipose tissue and produce pathogenic antibodies that cause insulin resistance. Objective We studied whether circulating immunoglobulins (IgG, IgA and IgM) were related to metabolic risk markers in pre-pubertal children with and without overweight. Design and methods Subjects were 270 asymptomatic pre-pubertal Caucasian children (145 lean, 125 overweight) recruited in a primary care setting. Assessments included serum IgG, IgA and IgM concentrations (nephelometry), insulin resistance (HOMA-IR) and fasting lipids (triacylglycerol and high-density lipoprotein [HDL]-cholesterol). Results Overweight children had higher IgG and IgA serum levels than lean children (P ≤ 0.01). Increasing serum IgG and IgA, but not IgM, were associated with a less favourable metabolic phenotype, consisting of higher HOMA-IR and triacylglycerol and lower HDL-cholesterol, particularly in obese children, in whom serum IgG and IgA were both independently associated with HOMA-IR (β = 0.308, P = 0.017, r2 = 9.5% and β = 0.361, P = 0.005, r2 = 13.0%, respectively) and triacylglycerol (β = 0.343, P = 0.006, r2 = 11.1% and β = 0.354, P = 0.003, r2 = 12.2%, respectively). Conclusions Increased circulating IgG and IgA in overweight children are associated with a less favourable metabolic phenotype, particularly in obese children. These results suggest a relationship between adaptive immunity and insulin resistance in childhood obesity.

Circulating soluble fatty acid synthase (FASN, a key enzyme in de novo biosynthesis of fatty acids, expressed in both adipocytes and osteoblasts) is clinically related to a less favorable bone profile in healthy prepubertal children. Soluble FASN may participate in the reciprocal regulation between fat and bone metabolism. Fatty acid synthase (FASN), a key enzyme in de novo biosynthesis of fatty acids, is expressed in adipocytes and osteoblasts. We hypothesized that FASN may participate in the crosstalk between fat and bone. To this aim, we studied the relation between circulating soluble FASN (an extracellular FASN that reflects previously intracellular enzymatic activity) and adipose tissue and bone biomarkers in prepubertal children. Circulating soluble FASN, total and high molecular weight (HMW) adiponectin, bone biomarkers [osteocalcin (OC), uncarboxylated osteocalcin (ucOC), C-terminal cross-linked telopeptide of type I collagen (CTX), bone-specific alkaline phosphatase (BSAP)], and a profile of energy metabolism [body fat, insulin resistance and secretion (HOMA), serum lipids] were assessed in 84 asymptomatic prepubertal children (44 girls, 40 boys, age 6.8 ± 0.1 year). Serum 25-OH Vitamin D (Vit D) was additionally measured. Circulating soluble FASN increased with increasing HMW adiponectin (r = 0.29, p = 0.01) and decreasing serum Vit D (r = −0.21, p < 0.05), and was related to a less favorable bone profile, showing negative associations with bone-derived metabolic parameters [total OC (r = −0.33, p = 0.002) and ucOC (r = −0.37, p < 0.0001)] and a positive association with the CTX-to-BSAP ratio (r = 0.31, p < 0.01). These correlations were not explained by age, gender, body fat, insulin resistance or secretion or serum lipids; however, they were predominant in those subjects with Vit D levels below the population median. Circulating soluble FASN relates to both adipose tissue and bone biomarkers in prepubertal children, with associations that are dependent on Vit D concentrations. These findings suggest that FASN may participate in the crosstalk between fat and bone metabolism.

BACKGROUND The sequence of prenatal growth restraint and postnatal catch-up growth leads to a thicker intima-media and more pre-peritoneal fat by age 3-6 years. OBJECTIVES To study whether carotid intima-media thickness (cIMT) and pre-peritoneal fat differ already between catch-up small-for-gestational-age (SGA) infants and appropriate-for-gestational-age (AGA) controls in late infancy (ages 1 and 2 years) and whether such differences - if any - are accompanied by differences in cardiac morphology and function. METHODS Longitudinal assessments included body height and weight; fasting glucose, insulin, Insulin-like growth factor (IGF-I), high-molecular-weight adiponectin; body composition (by absorptiometry); cIMT, aortic IMT, pre-peritoneal fat partitioning (by ultrasound); cardiac morphometry and function (by echocardiography) in AGA and SGA infants at birth, at age 1 year (N = 87), and again at age 2 years (N = 68). RESULTS Catch-up SGA infants had already a thicker cIMT than AGA controls at ages 1 and 2 years, and more pre-peritoneal fat by age 2 years (all p values between

The fat mass and obesity-associated gene (FTO) participates in the control of postnatal weight gain. We assessed whether FTO is expressed in human placenta and whether such expression relates to prenatal weight gain and to the rs9939609 single nucleotide polymorphism (SNP) in FTO. In a birth cohort study, placentas from women (n=147) with an uncomplicated, singleton, term pregnancy were weighed at delivery. Real-time PCR was used to study, in placental tissue, the expression of FTO and of housekeeping genes (TATA box binding protein and succinate dehydrogenase complex, subunit A) and to genotype the rs9939609 SNP in FTO. Weights and lengths of the newborns were measured; circulating insulin and insulin-like growth factor-I (IGF-I) were quantified in cord blood. FTO was highly expressed in placenta and was associated with increased fetal weight and length (P

Macrophages are known to be involved in low-grade inflammatory processes such as obesity. soluble cluster of differentiation 163 (sCD163) is shed from the cell surface as specific macrophage activation marker. In prepubertal children, we studied if circulating sCD163 is associated with metabolic and cardiovascular risk markers.A population of 236 school-aged Caucasian children (111 girls and 125 boys) aged 8 ± 1 year [81 normal weight (body mass index [BMI]-SDS 1); 74 overweight (1 ≤ BMI-standard deviation score [SDS] 2) and 81 with obesity (BMI-SDS ≥ 2)] were studied. BMI, waist circumference, fat mass and visceral fat were measured. Fasting serum sCD163, homeostatic model assessment of insulin resistance, high sensitivity C-reactive protein, gamma-glutamyl transpeptidase and lipids were quantified.Circulating sCD163 concentrations were higher in children with obesity (p 0.0001). Associations were observed between circulating sCD163 and a less favourable metabolic profile as judged by higher waist circumference, fat mass, visceral fat, epicardial fat, homeostatic model assessment of insulin resistance, high sensitivity C-reactive protein, gamma-glutamyl transpeptidase and triglycerides (all between r = 0.173 and r = 0.363; p 0.05 to p 0.0001) and lower high-density lipoprotein-cholesterol (r = -0.285, p 0.0001). In multiple regression analyses, circulating sCD163 was independently associated with HOMA-IR (β = 0.162, p = 0.016; model RChildhood obesity may increase the risk of developing metabolic diseases later in life through chronic macrophage activation having deleterious effects on metabolism.

There is still a lack of data from randomized, controlled, long-term studies of growth hormone (GH) treatment in children born small for gestational age (SGA), but the available evidence indicates consistently that GH therapy is a valid growth-promoting treatment in these children, particularly if started early. Whilst side effects appear uncommon, ongoing surveillance is required and treated children should be monitored for changes in glucose homeostasis, lipid profiles and blood pressure, especially during puberty. We provide an update on the safety and efficacy of GH treatment in short children born SGA.

There is increasing evidence for a link between prenatal growth and pubertal development. Here we highlight a selection of pubertal characteristics in children who were born small for gestational age (SGA). Boys born SGA are at risk of high levels of follicle-stimulating hormone (FSH) and low levels of inhibin B and a small testicular volume during adolescence. In girls born SGA, the age at pubertal onset and the age at menarche are advanced by about 5–10 months; prenatal growth restraint may also be associated with higher FSH levels and smaller internal genitalia in adolescence. The ovulation rate was found to be reduced in adolescent girls born SGA, and an insulin-sensitizing therapy was capable of raising this low ovulation rate. Menarche is definitely advanced in girls born SGA with precocious pubarche and in those with an early-normal onset of puberty. Current evidence suggests that insulin resistance is a key mechanism linking a post-SGA state to early menarche; hence, insulin sensitization may become a valid approach to prevent early menarche and early growth arrest in girls born SGA.

Flutamide is a nonsteroidal antiandrogenic agent that to date has been used chiefly in treating prostate cancer. Hepatotoxicity, although rare, is a potentially fatal side effect that has been documented with doses of 750 to 1500 mg daily. Minor hepatotoxicity has been associated with doses as low as 250 mg daily. This study examined the risk of hepatotoxicity when flutamide was given in ultralow doses for up to 3 years and for periods as long as 54 months. Participants were 190 hyperandrogenic girls and young women, 150 of whom had established and 40 incipient polycystic ovary syndrome (PCOS); none were obese. Flutamide was given alone or in combination with metformin, an insulin sensitizer, and/or an estro-progestagen oral contraceptive containing gestodene or drospirenone. Doses of flutamide ranged from 62.5 to 250 mg daily. Circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) served as markers of hepatic toxicity. All participants had normal levels of ALT and AST at baseline, and concentrations were unchanged during flutamide treatment-both 3 months after the start of treatment and at the last assessment, which took place after a mean of 19 months on treatment. Treatment times ranged up to 54 months. No subject had an AST or ALT level of 45 U/L or higher at any time. These findings suggest that flutamide is a safe treatment when used in low dosage to treat hyperandrogenic, nonobese girls and young women having actual or impending PCOS. It remains possible that hepatic toxicity may, in rare instances, develop in patients taking ultralow doses of flutamide. Nevertheless, the investigators anticipate that such doses may become a part of treating hyperandrogenic girls and young women with PCOS. They do recommend that transaminase levels be monitored during flutamide treatment.

Markers for cardiovascular disease in monozygotic twins discordant for the use of third-generation oral contraceptives.Loos RJ, Verhaeghe J, De Zegher F, Beunen G, Derom C, Fagard R, Mathieu C, Vlietinck R.Department of Sport and Movement Sciences, Faculty of Physical Education and Physiotherapy, Katholieke Universiteit Leuven, 3000 Leuven, Belgium. loosr@pbrc.eduOral contraceptives (OC) modulate the risk for developing cardiovascular (CV) diseases. The aim of this study was to determine whether the use of third-generation OC has an impact on markers of CV disease in genetically identical women. We performed an intrapair comparison in 27 monozygotic twin pairs, one of whom was taking third-generation OC, whereas the other was not using OC. Biometric parameters were ascertained and conventional and 24-h ambulatory blood pressure (BP) was recorded. A fasting blood sample was taken for the measurement of glucose, insulin, proinsulin, lipids, and insulin-like growth factor binding protein-1 (IGFBP-1). Insulin resistance and beta-cell function were calculated by homeostasis model assessment (HOMA). A 24-h urine sample for cortisol was obtained. Third-generation OC use increased 24-h ambulatory systolic and diastolic BP by 5.2 and 3.9 mmHg, respectively (both P=0.0003). There was no effect on glucose, insulin and proinsulin levels, and on HOMA parameters, but the IGFBP-1 levels were markedly raised (P=0.0009). The lipid profile showed a 34% increase in triglyceride levels (P < 0.0001), but also a 7% increase in HDL-cholesterol levels (P=0.037). Use of third-generation OC impacts on CV disease markers in young-adult genetically identical women. Some changes are beneficial (increased HDL-cholesterol), whereas others may be deleterious (increased BP and triglyceride levels) or have unknown effects at this time (increased IGFBP-1 levels).

SummaryBackground Infants born small-for-gestational-age (SGA) who develop post-natal weight catch-up are at risk for insulin resistance, central adiposity and cardiovascular disease in later life, even in the absence of overweight. Objective In young (age 3–6 years) non-obese SGA children, we assessed arterial health (as judged by intima-media thickness [IMT]) and abdominal fat distribution (subcutaneous, visceral, preperitoneal and hepatic components by magnetic resonance imaging [MRI] and/or ultrasound [US]) besides a selection of endocrine markers. Methods Comparisons of measures in SGA (n = 27) vs. appropriate-for-GA (AGA) children (n = 19) of similar height, weight and body mass index. Longitudinal outcomes (age 3–6 years) were carotid IMT (cIMT); fasting glucose, circulating insulin, IGF-I and high-molecular-weight (HMW) adiponectin; abdominal fat partitioning by US. Cross-sectional outcomes (age 6 years) were aortic IMT (aIMT) and abdominal fat partitioning by MRI. Results At 3 and 6 years, cIMT and IGF-I results were higher and HMW adiponectin lower in SGA than AGA children; at 6 years, SGA subjects had also a thicker aIMT and more pre-peritoneal and hepatic fat, and were less insulin sensitive (all P values between

BACKGROUND/OBJECTIVE: Fibroblast growth factor 19 (FGF19) and 21 (FGF21) have been linked to obesity and type 2 diabetes in adults. We assessed the circulating concentrations of these factors in human neonates and infants, and their association with the endocrine-metabolic changes associated to prenatal growth restraint. SUBJECTS/METHODS: Circulating FGF19 and FGF21, selected hormones (insulin, insulin-like growth factor I and high- molecular-weight (HMW) adiponectin) and body composition (absorptiometry) were assessed longitudinally in 44 infants born appropriate( AGA) or small-for-gestational-age (SGA). Measurements were performed at 0, 4 and 12 months in AGA infants; at 0 and 4 months in SGA infants; and cross-sectionally in 11 first-week AGA newborns. RESULTS: Circulating FGF19 and FGF21 surged >10-fold in early infancy from infra- to supra-adult concentrations, the FGF19 surge appearing slower and more pronounced than the FGF21 surge. Whereas the FGF21 surge was of similar magnitude in AGA and SGA infants, FGF19 induction was significantly reduced in SGA infants. In AGA and SGA infants, cord-blood FGF21 and serum FGF19 at 4 months showed a positive correlation with HMW adiponectin (r = 0.49, P = 0.013; r = 0.43, P = 0.019, respectively). CONCLUSIONS: Our results suggest that these early FGF19 and FGF21 surges are of a physiological relevance that warrants further delineation and that may extend beyond infancy.

Craniofacial growth was investigated in boys treated with low-dose testosterone for delayed puberty (> 14 years old; testicular volume < 4 ml; n = 7) and compared with controls (12-14 years; n = 37). Cephalometric radiographs, statural height and pubertal stage were recorded at the start of the study and after 1 year. Craniofacial growth was assessed by nine linear measurements. At the beginning of the study, statural height, mandibular ramus length, upper anterior face height, and total cranial base length were significantly shorter in the delayed puberty boys than in the controls. After 1 year, the growth rate of the statural height, total mandibular length, ramus length, and upper and total anterior face height was significantly higher in the treated boys than in the untreated height-matched controls (n = 7). The craniofacial measurements were similar in the treated boys as compared with the controls. These results show that statural height and craniofacial dimensions are low in boys with delayed puberty. Low doses of testosterone accelerate statural and craniofacial growth, particularly in the delayed components, thus leading towards a normalization of facial dimensions.

To assess whether fetal luteinizing hormone releasing hormone (LH-RH) neurosecretory neurons have the capacity to respond to an exogenous stimulus, a synthetic excitatory amino acid analogue, N-methyl-D-L-aspartate (NMDA; 15 mg/kg), was given rapidly intravenously to 8 chronically catheterized fetuses (130–142 days of gestation; term 147 ± 3 days). All 8 fetuses exhibited a rise in plasma ovine luteinizing hormone (oLH) and ovine follicle-stimulating hormone (oFSH) within 5 min. The mean maximal increments of oLH (2.25 ± 0.36 ng/ml) and oFSH (1.21 ± 0.32 ng/ml) were significantly greater than in 6 normal saline-injected controls (oLH p < 0.0002; oFSH p < 0.03). The secretion of ovine prolactin (oPRL) and ovine growth hormone (oGH) was unaffected. LH-RH (5 μg) evoked a greater oLH response (p < 0.0009) and a greater oFSH response (p < 0.03) than NMDA (n = 6). Desensitization of the fetal gonadotrope by a potent LH-RH agonist, D-Trp6Pro9NEt-LH-RH (10 μg/day i.v. × 4 days), abolished the fetal oLH and the oFSH response to NMDA (n = 5). Moreover, D,L-2-amino-5-phosphonovalerate, a specific competitive antagonist for the NMDA receptor, completely inhibited the fetal oLH and oFSH response to NMDA, whereas D-L-2-amino-5-phosphonovalerate alone did not affect the plasma oLH or oFSH levels, the gonadotropin response to LH-RH, or the release of oGH or oPRL (n = 3). In primary ovine fetal pituitary cell cultures, NMDA (10–10 to 10–6 M) had no effect on oLH, oFSH, oGH, or oPRL secretion, whereas LH-RH stimulated oLH (10–8 M; p < 0.0004) and oFSH (10–8 M; p < 0.0001) release, evidence that NMDA did not have a direct pituitary effect. The results suggest that NMDA induces oLH and oFSH secretion by stimulation of the fetal LH-RH pulse generator and is mediated by central NMDA receptors. Fetal LH and FSH secretion and the response to LH-RH decrease in late gestation in the ovine and human fetus. The relative importance of sex steroid dependent and sex steroid independent central nervous system inhibition in this developmental change is unclear. It appears that central neural inhibition in addition to sex steroid negative feedback contributes to the decrease in fetal gonadotropin concentrations in late gestation. NMDA did not affect fetal oGH or oPRL secretion.

Pronounced adrenarche with precocious pubarche (PP) in girls has been associated with hyperinsulinism and subsequent functional ovarian hyperandrogenism (FOH). Recently, pronounced adrenarche and insulin resistance have each been related to low birth weight. We have now tested the hypothesis that the frequent concurrence of PP with pronounced adrenarche, FOH, and hyperinsulinemia in girls may be secondary to separate relationships between these conditions and low birth weight. A total of 185 girls (aged 5-18 yr) without endocrinopathy or with PP and pronounced adrenarche with or without FOH were studied; mean serum insulin (MSI) concentrations were determined after a standardized oral glucose tolerance test. Birth weight SD scores [mean (SEM)] of control girls (0.38+/-0.08; n = 83) were higher (P < 0.0001) than those of PP girls (-0.81+/-0.13; n = 102). Among postmenarcheal PP girls, birth weight SD scores of girls without FOH (-0.25+/-0.19; n = 25) were higher (P < 0.0001) than those in girls with FOH (-1.51+/-0.28; n = 23). In pubertal girls (n = 145), MSI levels correlated negatively with birth weight SD scores (r = -0.48; P < 0.05), independently of PP. MSI levels in girls with birth weight below 1 SD (93+/-9 mU/L; n = 33) were higher (P < 0.0001) than those in girls with birth weight between -1 and +1 SD (52+/-2 mU/L; n = 94), whereas glycemia profiles were comparable. Integration of the aforementioned data suggests that there may be a sequence in the associations between reduced fetal growth and components of the postnatal endocrine system; minor fetal growth reduction appears to be associated with amplified adrenarche, whereas more pronounced prenatal growth restriction seem to precede FOH and hyperinsulinemia during adolescence. In conclusion, these findings corroborate the hypothesis that the frequent concurrence of PP (with pronounced adrenarche), FOH, and hyperinsulinemia in girls may result from a common early origin (low birth weight serving as a marker), rather than from a direct interrelationship later in life.

SUMMARY Recently, children born small for gestational age (SGA) with a catch-up growth failure, have been selected for high dose growth hormone (GH) treatment. In order to gain greater insight concerning dentofacial growth and maturation of these patients, and to evalu­ ate the possible effects of high dose GH administration on facial structures, craniofacial growth and dental maturation were evaluated in short SGA persons. Seventy-seven cephalo­ grams and orthopantomograms were available from 48 subjects, aged between 2 and 32 years. Craniofacial growth was assessed by calculating age- and gender-specific standard devi­ ation scores (SOS) for eight linear and five angular measurements. Tooth formation was evaluated by means of a dental delay score (i.e. dental age minus chronological age). The SOS for craniofacial growth measurements for the lateral aspect showed a short anterior cranial base (-1.8 SOS), a small retropositioned mandible (~-1.7 SOS) and a small maxilla (-1.5 SOS); a high mandibular plane angle (+ 1.9 SOS) and a wide cranial base angle 1+1 SOS). These findings result in a small retrognathic face with a relatively increased lower anterior face height (+ 1.7 SOS). In contrast to skeletal maturation, dental age was not delayed. The general growth retardation is, apparently, reflected to a differential extent within the craniofacial complex, while dental maturation appears to be a distinct process tightly linked to chronological age, and independent of general growth and bone age.

A minority of children born small for gestational age (SGA) fail to achieve sufficient catch-up growth during infancy and remain short throughout childhood, apparently without being growth hormone (GH) deficient. A previous metanalysis of four trials revealed that GH treatment over a period of 2 years induced a dose-dependent acceleration of linear growth and, to a lesser extent, of the rate of bone maturation in short, prepubertal children born SGA. The rate of bone maturation and the change in height SDS for bone age from the previous 2-year metanalysis have been re-analysed according to chronological age (two prepubertal age groups: group A, 3.0-5.9 years old; group B, 6.0-8.9 years old). The rate of bone maturation was slower in younger than in older prepubertal children; this difference was more marked in children receiving high-dose (0.2 or 0.3 IU/kg/day) GH treatment (p < or = 0.01). Accordingly, the change in height SDS for bone age was increased by high-dose GH treatment in both age groups (p < or = 0.01), and was more pronounced in younger than in older children (1.45 +/- 0.28 versus 0.63 +/- 0.20; p < or = 0.01). Height SDS data from 100 short, prepubertal children born SGA have been analysed over 4 years. The change in height SDS appeared to be related to the average dose of GH. A mean GH dose of 0.1 IU/kg/day over 4 years was administered either as 0.1 IU/kg/day for 4 years (continuous) or as 0.2 IU/kg/day for 2 years, followed by 2 years without GH treatment (discontinuous). After 4 years of treatment, the increase in height SDS for the continuous and discontinuous treatment schedules was similar, being 1.42 +/- 0.10 SDS and 1.58 +/- 0.17 SDS, respectively. In a second regimen, a mean GH dose of 0.2 IU/kg/day over 3 years was administered either as 0.2 IU/kg/day for 3 years (continuous) or as 0.3 IU/kg/day for 2 years, followed by 1 year without GH treatment (discontinuous). After 3 years, the increase in height SDS with the continuous and discontinuous treatment schedules was similar, being 2.01 +/- 0.18 SDS and 2.22 +/- 0.16 SDS, respectively. GH administration was well tolerated in all treatment groups. In conclusion, the rate of bone maturation in short, prepubertal children born SGA treated with GH appeared to depend not only on the dose of GH, but also on the age of the child. GH treatment resulted in a prolonged increase in height SDS, the magnitude of the rise being dependent on the average GH dose rather than on the continuous or discontinuous mode of GH administration.

Maternal nutrition is the main source of Poly-Unsaturated Fatty Acids (PUFA) for the fetus. PUFA may influence the accumulation of fat in early life.In 33 breastfed infants born appropriate-for-gestational-age, we studied whether body composition (judged by absorptiometry at 2 wk and 4 mo) relates to PUFA levels (assessed by gas chromatography) in the maternal or fetal circulation at birth.Abdominal fat at 2 wk associated negatively to umbilical-cord levels of separate PUFA (linoleic, arachidonic, eicosapentanoic and docosahexaenoic acid; all P between 0.001 and 0.015). Collectively, the assessed n-6 PUFA on one hand and the n-3 PUFA on the other hand associated negatively to the absolute amount of abdominal fat (in grams; P = 0.001 and P = 0.002, respectively) and to the relative amount of abdominal fat (fraction of total fat; P = 0.001 and P = 0.006, respectively). No other significant associations were observed.In conclusion, newborns with lower levels of circulating PUFA were found to be abdominally more adipose. The mechanisms underpinning these associations remain to be determined.

The effect of GH administration was evaluated over 2 yr in 50 short, prepubertal, non-GH deficient children born small for gestational age, who had been randomly allocated to a group receiving no treatment or daily sc GH treatment at a dose of 0.2 or 0.3 IU/kg. At the start of the study, mean age was 5.2 yr, bone age was 4.0 yr, height sos was -3.5, height velocity sos was -0.8, weight SDS was -2.7, and body mass index SDS was -1.9. Catch-up growth was observed in none of the untreated and all of the treated children. The response to GH treatment included a near doubling of growth velocity and of weight gain and a mean height increment of more than 2 SDS. GH treatment was associated with a distinct acceleration of bone maturation. The differences between the growth responses evoked by the two GH doses were minor. The prepubertal GH-induced catch-up growth was associated with elevated serum concentrations of insulin, insulin-like growth factor-I, insulin-like growth factor binding protein-3, and osteocalcin, whereas insulin-like growth factor-II levels remained unaltered. GH treatment was well tolerated. In conclusion, high-dose GH administration over 2 yr is emerging as a potential therapy to increase the short stature that results from insufficient catch-up growth in young children born small for gestational age. The long-term impact of this approach remains to be delineated.

A child with the tentative diagnosis of Alagille syndrome is reported. Additional renal abnormalities are unilateral kidney agenesis and a kidney with subcortical cysts with decreased function. At the age of 5 years, insulin-dependent diabetes mellitus developed, with the pancreas being atrophic and negative pancreatic islet cell antibodies. This observation extends the picture of Alagille syndrome and suggests an overlap with renal-hepatic-pancreatic dysplasia (Iyemark syndrome).

Insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and insulin are believed to be important in the regulation of fetal and neonatal growth. We previously reported that the profiles of IGFBPs in fetal cord serum (FCS) were dependent on the growth/metabolic status of the fetus. The goals of the current study were to examine the IGF system in FCS from term fetuses with normal growth, those with intrauterine growth retardation (IUGR), and those who were large for gestational age (LGA) and in FCS from normal weight preterm (25-37 weeks) and term fetuses in the neonatal period from the day of birth (day 0) until 7 days of age (day 7). Western ligand blotting (WLB) of term FCS revealed IGFBPs with mol wt of 43 and 38 kilodaltons (kDa; IGFBP-3), 34 kDa (IGFBP-2), 28 kDa (IGFBP-1 and glycosylated IGFBP-4), and 24 kDa (IGFBP-4). In IUGR FCS, there was a 50% decrease in IGFBP-3 detected by WLB, which was shown not to be due to an IGFBP-3 protease in IUGR sera. In LGA FCS, IGFBP-3 levels were elevated 2-fold by densitometric analysis of ligand blots. In normal term FCS, the following levels (+/- SE) were present: IGF-I, 76 +/- 16; IGF-II, 401 +/- 38; IGFBP-3, 700 +/- 112; IGFBP-1, 77 +/- 10 ng/mL; and insulin, 3.8 +/- 1.6 microU/mL. In IUGR FCS, IGF-I, IGF-II, and IGFBP-3 were significantly reduced, and IGFBP-1 was 7-fold higher than in FCS from normal weight fetuses. In LGA FCS, IGF-I, insulin, and IGFBP-3 were significantly increased, whereas IGFBP-1 was significantly decreased. During the neonatal period, IGF-I levels on day 0 were 4-fold higher in FCS from term (38-40 weeks) compared to preterm (25-31 weeks) newborns. FCS IGF-II levels did not change significantly on day 0 between 25-40 weeks gestation. In the first 7 days of postnatal life, IGF-I levels were unchanged in preterm newborns, whereas in term neonates, IGF-I levels decreased precipitously on day 1, remained low during the first 3 days of life, and returned to birth levels by the end of the first week. In contrast, IGF-II and IGFBP-3 levels did not significantly change during the first week of life in preterm or term newborns.(ABSTRACT TRUNCATED AT 400 WORDS)

The adaptive immune system has emerged as an unexpected modulator of insulin resistance. B lymphocytes accumulate in adipose tissue and produce pathogenic antibodies that cause insulin resistance.We studied whether circulating immunoglobulins (IgG, IgA and IgM) were related to metabolic risk markers in pre-pubertal children with and without overweight.Subjects were 270 asymptomatic pre-pubertal Caucasian children (145 lean, 125 overweight) recruited in a primary care setting. Assessments included serum IgG, IgA and IgM concentrations (nephelometry), insulin resistance (HOMA-IR) and fasting lipids (triacylglycerol and high-density lipoprotein [HDL]-cholesterol).Overweight children had higher IgG and IgA serum levels than lean children (P ≤ 0.01). Increasing serum IgG and IgA, but not IgM, were associated with a less favourable metabolic phenotype, consisting of higher HOMA-IR and triacylglycerol and lower HDL-cholesterol, particularly in obese children, in whom serum IgG and IgA were both independently associated with HOMA-IR (β = 0.308, P = 0.017, r2 = 9.5% and β = 0.361, P = 0.005, r2 = 13.0%, respectively) and triacylglycerol (β = 0.343, P = 0.006, r2 = 11.1% and β = 0.354, P = 0.003, r2 = 12.2%, respectively).Increased circulating IgG and IgA in overweight children are associated with a less favourable metabolic phenotype, particularly in obese children. These results suggest a relationship between adaptive immunity and insulin resistance in childhood obesity.

Objective Recent studies have highlighted the need for improved methods of monitoring glucose control in intensive care to reduce hyperglycaemia, without increasing the risk of hypoglycaemia. Continuous glucose monitoring is increasingly used in children with diabetes, but there are little data regarding its use in the preterm infant, particularly at extremes of glucose levels and over prolonged periods. This study aimed to assess the accuracy of the continuous glucose monitoring sensor (CGMS) across the glucose profile, and to determine whether there was any deterioration over a 7 day period. Design Prospectively collected CGMS data from the NIRTURE Trial was compared with the data obtained simultaneously using point of care glucose monitors. Setting An international multicentre randomised controlled trial. Patients One hundred and eighty-eight very low birth weight control infants. Outcome measures Optimal accuracy, performance goals (American Diabetes Association consensus), Bland Altman, Error Grid analyses and accuracy. Results The mean (SD) duration of CGMS recordings was 156.18 (29) h (6.5 days), with a total of 5207 paired glucose levels. CGMS data correlated well with point of care devices (r=0.94), with minimal bias. It met the Clarke Error Grid and Consensus Grid criteria for clinical significance. Accuracy of single readings to detect set thresholds of hypoglycaemia, or hyperglycaemia was poor. There was no deterioration over time from insertion. Conclusions CGMS can provide information on trends in glucose control, and guidance on the need for blood glucose assessment. This highlights the potential use of CGMS in optimising glucose control in preterm infants.