Developmental programming of the metabolic syndrome critical windows for intervention

Metabolic disease results from a complex interaction of many factors,including genetic,physiological,behavioral and environmental influences.The recent rate at which these diseases have increased suggests that environmental and behavioral influences,rather than genetic causes,are fuelling the present epidemic.In this context,the developmental origins of health and disease hypothesis has highlighted the link between the periconceptual,fetal and early infant phases of life and the subsequent development of adult obesity and the metabolic syndrome.Although the mechanisms are yet to be fully elucidated,this programming was generally considered an irreversible change in developmental trajectory.Recent work in animal models suggests that developmental programming of metabolic disorders is potentially reversible by nutritional or targeted therapeutic interventions during the period of developmental plasticity.This review will discuss critical windows of developmental plasticity and possible avenues to ameliorate the development of postnatal metabolic disorders following an adverse early life environment.

Urinary metabolic insights into host-gut microbial interactions in healthy and IBD children

AIMTo identify metabolic signatures in urine samples from healthy and inflammatory bowel disease(IBD)children.METHODSWe applied liquid chromatography and gas chromatography coupled to targeted mass spectrometry(MS)-based metabolite profiling to identify and quantify bile acids and host-gut microbial metabolites in urine samples collected from 21 pediatric IBD patients monitored three times over one year(baseline,6 and 12 mo),and 27age-and gender-matched healthy children.RESULTSurinary metabolic profiles of IBD children differ significantly from healthy controls.Such metabolic differences encompass central energy metabolism,amino acids,bile acids and gut microbial metabolites.In particular,levels of pyroglutamic acid,glutamic acid,glycine and cysteine,were significantly higher in IBD children in the course of the study.This suggests that glutathione cannot be optimally synthesized and replenished.Whilst alterations of the enterohepatic circulation of bile acids in pediatric IBD patients is known,we show here that non-invasive urinary bile acid profiling can assess those altered hepatic and intestinal barrier dysfunctions.CONCLUSIONThe present study shows how non-invasive sampling of urine followed by targeted MS-based metabonomic analysis can elucidate and monitor the metabolic status of children with different GI health/disease status.

Modulation of mitochondrial respiration underpins neuronal differentiation enhanced by lutein

Lutein is a dietary carotenoid of particular nutritional interest as it is preferentially taken up by neural tissues. Often linked with beneficial effects on vision, a broader role for lutein in neuronal differentiation has emerged recently, although the underlying mechanisms for these effects are not yet clear. The purpose of this study was to investigate the effect of lutein on neuronal differentiation and explore the associated underpinning mechanisms. We found that lutein treatment enhanced the differentiation of SH-SY5Y cells, specifically increasing neuronal arborization and expression of the neuronal process filament protein microtubule-associated protein 2. This effect was mediated by the intracellular phosphoinositide-3-kinase(PI3K) signaling pathway. While PI3K activity is a known trigger of neuronal differentiation, more recently it has also been shown to modulate the metabolic state of cells. Our analysis of bioenergetics found that lutein treatment increased glucose consumption, rates of glycolysis and enhanced respiratory activity of mitochondrial complexes. Concomitantly, the generation of reactive oxygen species was increased(consistent with previous reports that reactive oxygen species promote neuronal differentiation), as well as the production of the key metabolic intermediate acetyl-CoA, an essential determinant of epigenetic status in the cell. We suggest that lutein-stimulated neuronal differentiation is mediated by PI3K-dependent modulation of mitochondrial respiration and signaling, and that the consequential metabolic shifts initiate epigenetically dependent transcriptomic reprogramming in support of this morphogenesis. These observations support the potential importance of micronutrients supplementation to neurogenesis, both during normal development and in regenerative repair.

出生前接受倍他米松治疗后心血管病危险因素的变化:一项随机化对照试验的30年随访调查研究

Background: Antenatal betamethasone treatment is widely used for the prevention of neonatal respiratory distress syndrome in preterm infants and substantially reduces neonatal mortality and morbidity. Fetal exposure to excess glucocorticoids has been proposed as one of the core mechanisms of the fetal origins of adult disease hypothesis. We assessed whether antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome affects cardiovascular risk factors at 30 years of age. Methods: We followed up at age 30 years 534 individuals whose mothers participated in a doubleblind, placebo-controlled, randomised trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. Mothers received two doses of betamethasone or placebo given by intramuscular injection 24 h apart. Follow-up assessments included anthropometry; measurement of blood pressure, blood lipids (after overnight fasting), and early morning cortisol levels; and a 75 g oral glucose tolerance test. Findings: There were no differences between those exposed to betamethasone and to placebo in body size, blood lipids, blood pressure, plasma cortisol, prevalence of diabetes, or history of cardiovascular disease. After a 75 g oral glucose tolerance test, participants exposed to betamethasone had higher plasma insulin concentrations at 30 min (60.5 vs 52.0 mIU/L; ratio of geometric means 1.16 95%CI 1.03 to 1.31 , p=0.02) and lower glucose concentrations at 120 min (4.8 vs 5.1 mmol/L; difference -0.26 mmol/L -0.53 to 0.00 , p=0.05) than did those exposed to placebo. Interpretation: Antenatal exposure to betamethasone might result in insulin resistance in adult offspring, but has no clinical effect on cardiovascular risk factors at 30 years of age. Thus, obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.

Asymptomatic Bacteriuria and Urinary Tract Infection in Pregnant Women with and without Diabetes Mellitus and Gestational Diabetes Mellitus—A Case-Control Study

Background: Asymptomatic bacteriuria (ASB) and urinary tract infections (UTI) during pregnancy may contribute to adverse pregnancy outcomes. Diabetes mellitus (DM) and gestational diabetes mellitus (GDM) are considered to be important additional risk factor for ASB and UTI during pregnancy. Aims: To investigate differences in prevalence of ASB and incidence of UTI in pregnant women with and without DM and GDM to inform ASB screening and treatment policies. Methods: Data from 214 pregnant women who gave birth during 2010 at the Women’s and Children’s Hospital, Adelaide, Australia where cases were women with a clinical diagnosis of (G)DM and controls were matched on date of birth. ASB was defined as the growth of at least 10e5 colony forming units/ml of one organism or any presence of group B streptococcus (GBS) at the first urine culture collected during pregnancy without complaints of a UTI. A clinical UTI was diagnosed by the treating physician, in combination with a positive urine culture it was defined as culture-confirmed UTI. Results: No significant differences in prevalence of ASB (5.6% and 3.7%;relative risk (RR) 1.50;95% confidence intervals (CI) 0.44 - 5.17), incidence of clinical UTI (4.7% and 11.2%;RR 0.42;95% CI 0.15 - 1.14) or culture-confirmed UTI (2.8% and 3.7%;RR 0.75;95% CI 0.17 - 3.27) between pregnant women with and without (G)DM were present. No association was found between ASB and UTI. GBS was the most common causative organism of ASB in women with and without DM (66.7% and 50.0%). Conclusion: In contrast with earlier research, no significant differences in prevalence of ASB or incidence of UTI was found between pregnant women with and without (G)DM.

出生前使用倍他米松:纳入随机对照试验31年后的心理功能和健康相关生活质量

Objectives: To determine if antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome alters psychological functioning and health related quality of life in adulthood. Design: Followup of the first and largest double blind, placebo controlled, randomised trial of a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. Setting: Tertiary obstetric hospital in Auckland, New Zealand. Participants: 192 adult offspring, mean age 31 years, of mothers who took part in a randomised controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (87 exposed to betamethasone and 105 exposed to placebo). Interventions: Mothers received two doses of betamethasone or placebo 24 hours apart. Main outcome measures: Cognitive functioning assessed with Wechsler abbreviated scale of intelligence; working memory and attention assessed with Benton visual retention test, paced auditory serial addition test, and Brown attention deficit disorder scale; psychiatric morbidity assessed with Beck depression inventory II, statetrait anxiety inventory, and schizotypy traits questionnaire; handedness assessed with Edinburgh handedness inventory; health related quality of life assessed with short form 36 health survey. Results: No differ ences were found between groups exposed to betamethasone and placebo in cognitiv e functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life. Conclusions: Prenatal exposure to a single course of betamethasone does not alter cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life in adulthood. Obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.

出生前暴露于倍他米松是否对成年后的心理功能和健康相关生活质量产生不良影响

Objectives: To determine if antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome alters psychological functioning and health related quality of life in adulthood. Design: Follow-up of the first and largest double blind, placebo controlled, randomised trial of a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. Setting: Tertiary obstetric hospital in Auckland, New Zealand. Participants: 192 adult offspring, mean age 31 years, of mothers who took part in a randomised controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (87 exposed to betamethasone and 105 exposed to placebo). Interventions: Mothers received two doses of betamethasone or placebo 24 hours apart. Main outcome measures: Cognitive functioning assessed with Wechsler abbreviated scale of intelligence; working memory and attention assessed with Benton visual retention test, paced auditory serial addition test, and Brown attention deficit disorder scale; psychiatric morbidity assessed with Beck depression inventory II, state-trait anxiety inventory, and schizotypy traits questionnaire; handedness assessed with Edinburgh handedness inventory; health related quality of life assessed with short form 36 health survey. Results: No differences were found between groups exposed to betamethasone and placebo in cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life. Conclusions: Prenatal exposure to a single course of betamethasone does not alter cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life in adulthood. Obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.

早产儿与迟发性胰岛素抵抗

研究背景:小于胎龄儿的足月儿易于在儿童期出现胰岛素抵抗。本文预测,无论适宜胎龄儿还是小于胎龄儿,如出生体重与胎龄应有体重不符,则在儿童期均比较常见以2型糖尿病为标志的胰岛素抵抗。方法:研究72名处于青春前期的4-10岁健康儿童,其中50例早产出生个体(胎龄≤32周),包括38例出生体重与胎龄应有体重相符个体(高于第十百分位数)。

乙基酰胺兴奋试验对诊断青春期发育延迟男性促性腺激素缺乏症的评价

Objective: To assess the efficacy of the gonadotropin-relea- sing hormone (GnRH) agonist buserelin in a stimulated gonadotropin test for the investigation of delayed puberty in males. Study design: Prepubertal males (n=31; age range, 10.3 to 17.2 years) were studied; buserelin (100 μg) was administered subcutaneously, with blood sampling at 0 and 4 hours for serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH). At follow-up (mean, 4.2 years), 8/31 (26%) failed to progress into puberty, constituting hypogonadotropic hypogonadism (HH), but 23/31 (74%) had testicular enlargement (≥8 mL) consistent with a normal hypothalamic-pituitary-gonadal (HPG) axis. Results: Stimulated serum LH response to buserelin was lower in males with HH (mean ±standard error under the mean for HH, 1.4 ±0.5 U/L, compared with a normal HPG axis of 17.4±2.0 U/L; P < .0001). Stimulated serum FSH response was nondiscriminatory (HH, 7.7±2.2 U/L; normal HPG axis, 11.5±1.6 U/L; P = .27). All males with HH had a stimulated serum LH level < 5 U/L, whereas only 1/23 with a normal HPG axis had a stimulated serum LH below this level. Using this value as the criterion for diagnosing HH, the buserelin stimulation test yielded a sensitivity of 100%, specificity of 96%, and positive predictive value of 89%. Conclusions: The buserelin stimulation test is a highly specific and sensitive GnRH agonist test for the investigation of males with delayed puberty.

对超声图像不同解释可能使所报告的新西兰新生儿重症监护病房中的白质损害的发生率有所不同

Background: The incidence of cerebral white matter damage reported to the Aust ralian and New Zealand Neonatal Network (ANZNN) varies between neonatal intensiv e care units (NICUs). Hypothesis: Differences in the capture, storage, and inter pretation of the cerebral ultrasound scans could account for some of this variation. Methods: A total of 255 infants of birth weight < 1500 g and gestation < 32 weeks born between 1997 and 2002 and drawn equally from each of the six NICUs i n New Zealand were randomly selected from the ANZNN database. Half had early cerebral ultrasound scans previously reported to ANZNN as normal, and half had scan s reported as abnormal. The original scans were copied, anonymised, and independ ently read by a panel of three experts using a standardised method of reviewing and reporting. Results: There was considerable variation between NICUs in method s of image capture, quality, and completeness of the scans. There was only moder ate agreement between the reviewers’reports and the original reports to the ANZ NN (κ0.45-0.51) and between the reviewers (κ0.54-0.64). The reviewers report ed three to six times more white matter damage than had been reported to the ANZ NN. Conclusion: Some of the reported variation in white matter damage between NI CUs may be due to differences in capture and interpretation of cerebral ultrasou nd scans.

出生前母亲暴露于重复剂量的糖皮质激素与出生后新生儿心血管状态的改变有关

Objective: To determine if exposure to more than one course of antenatal gluco cortlcoids is associated with changes in infant blood pressure and myocardial wa ll thickness in the first month after birth. Design: Prospective cohort study. S etting: Tertiary neonatal intensive care unit. Participants: Mothers who were el igible for but declined to enter a randomised trial of repeated doses of antenat al glucocorticoids (ACTORDS)-that is, who had a singleton, twin, or triplet pre gnancy at < 32 weeks gestation, had received an initial course of glucocorticoid s seven or more days previously, and were considered to be at continued risk of preterm birth. Main outcome measures: Blood pressure daily for the first week th en weekly until 4 weeks of age. End diastolic interventricular septal and left v entricular posterior wall (EDIVS and EDLVPW) thickness at 48-72 hours after bir th. Results: Thirty seven women were enrolled and delivered 50 infants. Thirty m others (39 infants) were exposed to one course of glucocorticoids, and seven mot hers (11 infants) to more than one course. Blood pressures were higher in the fi rst week after birth in infants exposed to multiple courses of glucocorticoids, and in infants with a latency between last exposure and delivery of less than se ven days. Systolic blood pressure on day 1 was > 2SD above published normal rang es in 67%of babies exposed to multiple courses and 24%of babies exposed to a s ingle course of glucocorticoids (p = 0.04). There was no difference between grou ps in thickness of the EDIVS or EDLVPW. However, 44/50 (88%) babies had EDIVS a nd 49/50 (98%) babies had EDLVPW thickness > 2 SD above the expected mean for b irth weight and gestation. EDIVS but not EDLVPW thickness increased with increas ing latency (mean 0.02 mm/day, P=0.03). Conclusion: Future randomised trials sho uld assess the long term effects of exposure to antenatal glucocorticoids, particularly multiple courses, on the cardiovascular status of the infant.

青少年囊性纤维化的连续性葡萄糖监测

The presence of cystic fibrosis (CF)-related diabetes was evaluated in 19 adolescents with CF by continuous glucose monitoring system (CGMS) and oral glucose tolerance testing. CGMS confirmed diabetic glucose excursions in 7/19 subjects deemed diabetic on oral glucose tolerance testing. CGMS is a useful tool for detecting hyperglycemia in CF.

新西兰新生儿重症监护室之间是否因对超声检查结果的解释不同而造成所诊断出的早产儿脑/脑室内出血发病率不同

Background: The incidence of germinal matrix/intraventricular haemorrhage (GM/IVH) reported to the Australian and New Zealand Neonatal Network (ANZNN) varies between neonatal intensive care units (NICUs). Hypothesis: Differences in the capture, storage, and interpretation of the cerebral ultrasound scans may account for some of this variation. Methods: A total of 255 infants with birth weight < 1500 g and gestation < 32 weeks born between 1997 and 2002 were randomly selected from the ANZNN database, 44 from each of the six NICUs in New Zealand. Twenty two infants from each NICU had cerebral ultrasound scans previously reported to ANZNN as normal; another 22 had scans reported as abnormal. The original scans were copied using digital photography and anonymised and independently read by a panel of three experts using a standardised method of reviewing and reporting. Results: There was considerable variation between NICUs in methods of image capture and quality and completeness of the scans. However, there was little variation in the reporting of scans between the reviewers and the reports to ANZNN (weighted κ 0.75- 0.91). Grade 1 GM/IVH was generally over-reported and grade 4 under- reported to the ANZNN. Conclusion: For all NICUs, a high level of agreement was found between the reviewers’ reports and the reports to the ANZNN. Thus the variation between NICUs in the incidence of GM/IVH reported to the ANZNN is unlikely to be due to differences in capture, storage, and interpretation of the cerebral ultrasound scans. Further investigation is warranted into the reasons for the variation in incidence of GM/IVH between NICUs.

The metabolic role of LncZBTB39-1:2 in the trophoblast mobility of preeclampsia

Preeclampsia is characterized by new onset of hypertension and proteinuria after 20 weeks’gestation and is a leading cause of maternal and neonatal morbidity and mortality.The pathogenesis of preeclampsia is often associated with aberrant trophoblast function that leads to shallow placental implantation.However,the exact underlying mechanisms remain unclear.Placental LncZBTB39-1:2 expression level was investigated in 20 healthy placentae and 20 placentae with preeclampsia using qRT-PCR,and the metabolic profile of trophoblasts overexpressing LncZBTB39-1:2 in vitro was analysed using gas chromatography-mass spectrometry(GCeMS).In this study,we found that the expression of LncZBTB39-1:2 was significantly higher in preeclamptic placentae than in healthy placentae.Our metabolomics results have shown that tricarboxylic acid cycle intermediates and metabolites related to carbohydrate metabolism were decreased with the overexpression of LncZBTB39-1:2 in HTR8/SVneo cells.These findings were validated by detecting a lower level of intracellular ATP in HTR8/Vneo cells.Furthermore,the migration of HTR8/SVneo cells was compromised when cells were transfected with a plasmid encompassing LncZBTB39-1:2 overexpression.From these results,we conclude that abnormal levels of LncZBTB39-1:2 expression might lead to aberrant conditions in HTR-8/SVneo trophoblast cells.Aberrant conditions might be associated with dysregulated trophoblast migration and subsequent failure of uterine spiral artery remodelling,a pathogenesis recognised as a contributing factor in the aetiology of preeclampsia.

Childhood obesity in New Zealand

Background Paediatric obesity has reached epidemic proportions globally,resulting in significant adverse effects on health and wellbeing.Early life events,including those that happen before,during,and after pregnancy can predispose children to later obesity.The purpose of this review is to examine the magnitude of obesity among New Zealand children and adolescents,and to determine their underlying risk factors and associated comorbidities.Data sources PubMed,Web of Science,and Google Scholar searches were performed using the key terms 'obesity','overweight','children','adolescents',and 'New Zealand'.Results Obesity is a major public health concern in New Zealand,with more than 33% of children and adolescents aged 2-14 years being overweight or obese.Obesity disproportionately affects Māori (New Zealand's indigenous population) and Pacific children and adolescents,as well as those of lower socioeconomic status.New Zealand's obesity epidemic is associated with numerous health issues,including cardiometabolic,gastrointestinal,and psychological problems,which also disproportionately affect Māori and Pacific children and adolescents.Notably,a number of factors may be useful to identify those at increased risk (such as demographic and anthropometric characteristics) and inform possible interventions.Conclusions The prevalence of overweight and obese children and adolescents in New Zealand is markedly high,with a greater impact on particular ethnicities and those of lower socioeconomic status.Alleviating the current burden of pediatric obesity should be a key priority for New Zealand,for the benefit of both current and subsequent generations.Future strategies should focus on obesity prevention,particularly starting at a young age and targeting those at greatest risk.

Targeting growth hormone function: strategies and therapeutic applications

Human growth hormone(GH)is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has pleiotropic effects across multiple physiological systems.GH is also expressed in extrapituitary tissues and has localized autocrine/paracrine effects at these sites.In adults,hypersecretion of GH causes acromegaly,and strategies that block the release of GH or that inhibit GH receptor(GHR)activation are the primary forms of medical therapy for this disease.Overproduction of GH has also been linked to cancer and the microvascular complications that are associated with diabetes.However,studies to investigate the therapeutic potential of GHR antagonism in these diseases have been limited,most likely due to difficulty in accessing therapeutic tools to study the pharmacology of the receptor in vivo.This review will discuss current and emerging strategies for antagonizing GH function and the potential disease indications.

Surrogate markers and predictors of endogenous insulin secretion in children and adolescents with type 1 diabetes

Background No studies have examined endogenous insulin secretion in pediatric patients with type 1 diabetes in China using the gold-standard mixed-meal tolerance test.Because the latter is labor-intensive,we examined simpler surrogate markers of endogenous insulin secretion in Chinese youth,as previously reported for a European population.Methods Participants were 57 children and adolescents with type 1 diabetes aged 4.4-16.8 years(56% females).We per-formed 120-minute mixed-meal tolerance tests with serum C-peptide(CP)measurements every 30 minutes.Severe insulin deficiency(SID)was defined as CP peak<0.2 nmol/L.Urine CP and creatinine levels were measured at 0 and 120 minutes.Results Twenty-five(44%)patients had SID.Fasting CP levels missed one case(96% sensitivity)with no false posi-tives(100% specificity).While the 120-minute urine CP/creatinine had 100% sensitivity,it yielded markedly lower speci-ficity(63%).Every 1-year increase in diabetes duration and 1-year decrease in age at diagnosis were associated with 37%(P<0.001)and 20%(P=0.005)reductions in serum CP area-under-the-curve,respectively.Thus,86% of children aged<5 years had SID compared to none among patients aged ≥11 years.Conclusions Simple fasting CP measurements could be used to detect most SID cases in Chinese youth with type 1 diabe-tes.Fasting CP is a far more reliable measure of endogenous insulin secretion than the more commonly used insulin dose.Therefore,it could more precisely determine insulin secretory capacity to target those who could benefit,if treatments to preserve residual insulin secretion are developed.