Perinatal Outcomes by Mode of Assisted Conception and Sub-Fertility in an Australian Data Linkage Cohort

Background

Fertility treatment is associated with increased risk of major birth defects, which varies between in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), and is significantly reduced by embryo freezing. We therefore examined a range of additional perinatal outcomes for these exposures.

Methods

All patients in South Australia receiving assisted conception between Jan 1986–Dec 2002 were linked to the state-wide perinatal collection (all births/stillbirths ≥20 weeks gestation or 400 g birth weight, n = 306 995). We examined stillbirth, mean birth weight, low birth weight (<2500 g, <1500 g), small size for gestational age (<10th percentile, <3rd percentile), large size for gestational age (>90th percentile), preterm birth (32–<37 weeks, <32 weeks gestation), postterm birth (≥41 weeks gestation), Apgar <7 at 5 minutes and neonatal death.

Results

Relative to spontaneous conceptions, singletons from assisted conception were more likely to be stillborn (OR = 1.82, 95% Confidence Interval (CI) 1.34–2.48), while survivors as a group were comprehensively disadvantaged at birth, including lower birth weight (−109 g, CI −129–−89), very low birth weight (OR = 2.74, CI 2.19–3.43), very preterm birth (OR = 2.30, CI 1.82–2.90) and neonatal death (OR = 2.04, CI 1.27–3.26). Outcomes varied by type of assisted conception. Very low and low birth weight, very preterm and preterm birth, and neonatal death were markedly more common in singleton births from IVF and to a lesser degree, in births from ICSI. Using frozen-embryos eliminated all significant adverse outcomes associated with ICSI but not with IVF. However, frozen-embryo cycles were also associated with increased risk of macrosomia for IVF and ICSI singletons (OR = 1.36, CI 1.02–1.82; OR = 1.55, CI 1.05–2.28). Infertility status without treatment was also associated with adverse outcomes.

Conclusions

Births after assisted conception show an extensive range of compromised outcomes that vary by treatment modality, that are substantially reduced after embryo freezing, but which co-occur with an increased risk of macrosomia.     

Maternal Glomerular Filtration Rate in Pregnancy and Fetal Size

BackgroundThe relationship of maternal glomerular filtration rate (GFR) in pregnancy to fetal size needs to be better characterized as it impacts an ongoing debate about confounding effect of maternal GFR in investigations of important environmental contaminants. We aimed to characterize the size of the association between maternal GFR and infant birth weight.ResultsMaternal GFR-CG (β: 0.73 g/ml/min, p = 0.04) and GFR-MDRD (β: 0.83 g/ml/min, p = 0.04) were associated with infant birth weight in models adjusted for maternal weight in kilograms, preeclampsia, and gestational age at delivery (days). Partial correlation coefficients for the association between infant birth weight and GFR were 0.07 for both formulas. Although the birth weight-GFR association was stronger among the women with preeclampsia, the difference from women without preeclampsia was not statistically significant.ConclusionThese data support an association between GFR during pregnancy and infant birth weight, and indicate that GFR may confound selected epidemiologic associations.     

Perinatal Lead (Pb) Exposure Results in Sex-Specific Effects on Food Intake,Fat, Weight,and Insulin Response across the Murine Life-Course

Developmental lead (Pb) exposure has been associated with lower body weight in human infants and late onset obesity in mice. We determined the association of perinatal Pb exposure in mice with changes in obesity-related phenotypes into adulthood. Mice underwent exposure via maternal drinking water supplemented with 0 (control), 2.1 (low), 16 (medium), or 32 (high) ppm Pb-acetate two weeks prior to mating through lactation. Offspring were phenotyped at ages 3, 6, and 9 months for energy expenditure, spontaneous activity, food intake, body weight, body composition, and at age 10 months for glucose tolerance. Data analyses were stratified by sex and adjusted for litter effects. Exposed females and males exhibited increased energy expenditure as compared to controls (p<0.0001 for both). In females, horizontal activity differed significantly from controls (p = 0.02) over the life-course. Overall, food intake increased in exposed females and males (p<0.0008 and p<0.0001, respectively) with significant linear trends at 9 months in females (p = 0.01) and 6 months in males (p<0.01). Body weight was significantly increased in males at the medium and high exposures (p = 0.001 and p = 0.006). Total body fat differed among exposed females and males (p<0.0001 and p<0.0001, respectively). Insulin response was significantly increased in medium exposure males (p<0.05). Perinatal Pb exposure at blood lead levels between 4.1 µg/dL and 32 µg/dL is associated with increased food intake, body weight, total body fat, energy expenditure, activity, and insulin response in mice. Physiological effects of developmental Pb exposure persist and vary according to sex and age.     

Pulmonary and Cardiac Function in Asymptomatic Obese Subjects and Changes following a Structured Weight Reduction Program: A Prospective Observational Study

Background

The prevalence of obesity is rising. Obesity can lead to cardiovascular and ventilatory complications through multiple mechanisms. Cardiac and pulmonary function in asymptomatic subjects and the effect of structured dietary programs on cardiac and pulmonary function is unclear.

Objective

To determine lung and cardiac function in asymptomatic obese adults and to evaluate whether weight loss positively affects functional parameters.

Methods

We prospectively evaluated bodyplethysmographic and echocardiographic data in asymptomatic subjects undergoing a structured one-year weight reduction program.

Results

74 subjects (32 male, 42 female; mean age 42±12 years) with an average BMI 42.5±7.9, body weight 123.7±24.9 kg were enrolled. Body weight correlated negatively with vital capacity (R = −0.42, p<0.001), FEV1 (R = −0.497, p<0.001) and positively with P 0.1 (R = 0.32, p = 0.02) and myocardial mass (R = 0.419, p = 0.002). After 4 months the study subjects had significantly reduced their body weight (−26.0±11.8 kg) and BMI (−8.9±3.8) associated with a significant improvement of lung function (absolute changes: vital capacity +5.5±7.5% pred., p<0.001; FEV1+9.8±8.3% pred., p<0.001, ITGV+16.4±16.0% pred., p<0.001, SR tot −17.4±41.5% pred., p<0.01). Moreover, P0.1/Pimax decreased to 47.7% (p<0.01) indicating a decreased respiratory load. The change of FEV1 correlated significantly with the change of body weight (R = −0.31, p = 0.03). Echocardiography demonstrated reduced myocardial wall thickness (−0.08±0.2 cm, p = 0.02) and improved left ventricular myocardial performance index (−0.16±0.35, p = 0.02). Mitral annular plane systolic excursion (+0.14, p = 0.03) and pulmonary outflow acceleration time (AT +26.65±41.3 ms, p = 0.001) increased.

Conclusion

Even in asymptomatic individuals obesity is associated with abnormalities in pulmonary and cardiac function and increased myocardial mass. All the abnormalities can be reversed by a weight reduction program.     

The Vitamin D Status in Inflammatory Bowel Disease

Context

There is no consensus on the vitamin D status of children and adolescents with inflammatory bowel disease (IBD).

Aim

To determine the vitamin D status of patients with IBD by comparing their serum 25(OH)D concentration to that of healthy controls.

Hypothesis

Serum 25(OH)D concentration will be lower in patients with IBD compared to controls.

Subjects and Methods

A case-controlled retrospective study of subjects with IBD (n = 58) of 2–20 years (male n = 31, age 16.38±2.21 years; female n = 27, age16.56±2.08 years) and healthy controls (n = 116; male n = 49, age 13.90±4.59 years; female n = 67, age 15.04±4.12years). Study subject inclusion criteria: diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC). Vitamin D deficiency was defined as 25(OH)D of (<20 ng/mL) (<50 nmol/L), overweight as BMI of ≥85^th but <95^th percentile, and obesity as BMI ≥95^th percentile. Data were expressed as mean ± SD.

Results

Patients with CD, UC, and their controls had mean serum 25(OH)D concentrations of 61.69±24.43 nmol/L, 53.26±25.51, and 65.32±27.97 respectively (ANOVA, p = 0.196). The overweight/obese controls had significantly lower 25(OH)D concentration compared to the normal-weight controls (p = 0.031); whereas 25(OH)D concentration was similar between the normal-weight and overweight/obese IBD patients (p = 0.883). There was no difference in 25(OH)D between patients with UC and CD, or between subjects with active IBD and controls. However, IBD subjects with elevated ESR had significantly lower 25(OH)D than IBD subjects with normal ESR (p = 0.025), as well as controls (65.3±28.0 nmol/L vs. 49.5±25.23, p = 0.045).

Conclusion

There is no difference in mean serum 25(OH)D concentration between children and adolescents with IBD and controls. However, IBD subjects with elevated ESR have significantly lower 25(OH)D than controls. Therefore, IBD subjects with elevated ESR should be monitored for vitamin D deficiency.     

DNA Methyltransferase Candidate Polymorphisms,Imprinting Methylation,and Birth Outcome

Background

Birth weight and prematurity are important obstetric outcomes linked to lifelong health. We studied a large birth cohort to look for evidence of epigenetic involvement in birth outcomes.

Methods

We investigated the association between birth weight, length, placental weight and duration of gestation and four candidate variants in 1,236 mothers and 1,073 newborns; DNMT1 (rs2162560), DNMT3A (rs734693), DNMT3B (rs2424913) and DNMT3L (rs7354779). We measured methylation of LINE1 and the imprinted genes, PEG3, SNRPN, and IGF2, in cord blood.

Results

The minor DNMT3L allele in the baby was associated with higher birth weight (+54 95% CI 10,99 g; p = 0.016), birth length (+0.23 95% CI 0.04,0.42 cm; p = 0.017), placental weight, (+18 95% CI 3,33 g; p = 0.017), and reduced risk of being in the lowest birth weight decile (p = 0.018) or requiring neonatal care (p = 0.039). The DNMT3B minor allele in the mother was associated with an increased risk of prematurity (p = 0.001). Placental size was related to PEG3 (p<0.001) and IGF2 (p<0.001) methylation. Birth weight was related to LINE1 and IGF2 methylation but only at p = 0.052. The risk of requiring neonatal treatment was related to LINE1 (p = 0.010) and SNRPN (p = 0.001) methylation. PEG3 methylation was influenced by baby DNMT3A genotype (p = 0.012) and LINE1 by baby 3B genotype (p = 0.044). Maternal DNMT3L genotype was related to IGF2 methylation in the cord blood but this effect was only seen in carriers of the minor frequency allele (p = 0.050).

Conclusions

The results here suggest that epigenetic processes are linked birth outcome and health in early life. Our emerging understanding of the role of epigenetics in health and biological function across the lifecourse suggests that these early epigenetic events could have longer term implications.     

Pericardial Fat Is Associated with Coronary Artery Calcification in Non-Dialysis Dependent Chronic Kidney Disease Patients

Pericardial fat (PF) a component of visceral adipose tissue has been consistently related to coronary atherosclerosis in the general population. This study evaluated the association between PF and coronary artery calcification (CAC) in non-dialysis dependent chronic kidney disease (CKD) patients. This is a post-hoc cross sectional analysis of the baseline of a prospective cohort of 117 outward CKD patients without manifest coronary artery disease (age, 56.9±11.0 years, 64.1% males, 95.1% hypertensives, 25.2% diabetics, 15.5% ever smokers, CKD stage 2 to 5 with estimated glomerular filtration rate 36.8±18.1 ml/min). CAC scores, PF volume and abdominal visceral fat (AVF) areas were measured by computed tomography. The association of PF as a continuous variable with the presence of CAC was analyzed by multivariate logistic regression. CAC (calcium score >0) was present in 59.2% patients. Those presenting CAC were on average 10 years older, had a higher proportion of male gender (78.7% vs. 42.9%, p<0.001), and had higher values of waist circumference (95.9±10.7 vs. 90.2±13.2 cm, p = 0.02), PF volumes (224.8±107.6 vs. 139.1±85.0 cm³, p<0.01) and AVF areas (109.2±81.5 vs. 70.2±62.9 cm², p = 0.01). In the multivariate analysis, adjusting for age, gender, diabetes, smoking and, left ventricular concentric hypertrophy, PF was significantly associated with the presence of CAC (OR: 1.88 95% CI: 1.03–3.43 per standard deviation). PF remained associated with CAC even with additional adjustments for estimated glomerular filtration rate or serum phosphorus (OR: 1.85 95% CI: 1.00–3.42, p = 0.05). PF is independently associated with CAC in non-dialysis dependent CKD patients.     

IgM-Antibodies against Phosphorylcholine in Mothers and Normal or Low Birth Weight Term Newborn Infants

Objective

To determine levels of athero-protective IgM antibodies against phosphorylcholine in mothers and term-born normal or low birth weight infants.

Approach

Twenty three mother-infant pairs were studied, of whom 16 infants were within the normal weight range for gestational age (NGA; 3652[504] g) and 7 were small for gestational age (SGA; birth weight: 2715[255] g), the latter <2SD below the Swedish reference data mean for normal fetal growth. All infants were born at term (mean±SD 40.5±1.1 weeks). Serum was available from 6 mothers with SGA and 14 with NGA infants. Participating mothers were aged 34.0±3.9 years (no difference between groups). Fourteen neonates were boys and seven were girls. Levels of anti-PC IgM were determined by ELISA.

Results

Neonatal IgM anti-PC levels were low (undetectable in 8 infants out of which 3 were SGA) with a median of 76[range 0–2.51] U/ml. Maternal IgM anti-PC levels were significantly higher (median 7198[range: 25.32–656.0]) U/ml) and the proportion of mothers in highest quartile (>75th percentile) was larger in mothers of NGA-infants (43%) vs. those of SGA-infants (0%, p = 0.032).

Conclusions

IgM anti-PC levels are low at birth, which suggests that these antibodies do not play a “housekeeping” role in immune function during fetal life/development, but arise predominately on exposure to external antigens after birth. Furthermore, low maternal IgM anti-PC levels may play a role in placental insufficiency, contributing to poor fetal growth and a small-for-date baby. This preliminary observation may have implications for the future risk of atherosclerosis/cardiovascular disease development in pregnant women and their offspring.     

Female Sexual Function of Overweight Women with Gestational Diabetes Mellitus – A Cross-Sectional Study

Obesity and gestational diabetes mellitus (GDM) are increasing worldwide and may compromise female sexual function. We hypothesize that among GDM patients in the third trimester of pregnancy, those with excess body fat would have worse female sexual function scores than normal weight women. Our aim was to assess the sexual function of overweight compared to normal weight women with GDM. This was a cross-sectional survey involving 143 Brazilian women with GDM in the third trimester of pregnancy: 76 were overweight (pre-pregnancy body mass index-BMI≥25.0 Kg/m²) and 67 were normal weight (BMI 18.5–24.9 Kg/m²). Participants were recruited from March 2010 to April 2013 at the antenatal clinic of a single public tertiary teaching institution. The Female Sexual Function Index (FSFI) questionnaire was used to assess sexual function. Overall, 51.7% of the 143 participants were at risk for sexual dysfunction symptoms (FSFI scores ≤26); this rate was significantly higher among overweight compared to normal weight women (60.5% versus 41.8%, p = 0.038). Mean total FSFI scores were significantly lower in overweight compared to normal weight women (21.7±9.2 versus 24.9±8.0, p = 0.029). Compared to normal weight women, overweight participants had lower mean scores in desire (3.4±1.2 versus 4.0±1.4, p = 0.007) and lubrication (3.8±2.0 versus 4.5±1.6, p = 0.023). According to these results, overweight women with GDM in the third trimester of pregnancy have lower female sexual function scores than normal weight women with the same disorder.     

Alcohol consumption in Dundee primigravidas and its effects on outcome of pregnancy

In a population based cohort study information on the consumption of alcohol was obtained from 95% of the 952 consecutive primigravidas who lived in the Dundee district and attended for antenatal care between May 1985 and April 1986. Before realising that they were pregnant more than 90% drank alcohol and 53% were cigarette smokers. During the first four months of pregnancy, however, the proportion of women drinking and smoking fell to 56% and 44%, respectively. Alcohol consumption of more than 120 g absolute alcohol/week (12 or more standard drinks) during pregnancy was related to shorter gestational age (-2·6 weeks), smaller head circumference (-18 mm), shorter (-21 mm) and lighter (-499 g) babies, and lower Apgar scores at five minutes (-0·4, all p<0·01). After adjustment for the effect of smoking, social class, mother''s size, and other confounding factors, however, an alcohol intake of more than 120 g/week was significantly related only to shorter gestational age (-2·0 weeks, p<0·001) and lower Apgar score at five minutes (-0·2, p<0·05). Alcohol intake in the region of 100-119 g/week was significantly related to smaller head circumference (-12 mm, p<0·05). Analysis by type of beverage consumed suggested that beer rather than wine or spirits was associated with a poorer outcome.As there was no detectable effect on pregnancy of alcohol consumption below 100 g/week, it is suggested that health education should be directed towards mothers who drink more than this amount.     

Increasing Maternal Age Is Associated with Taller Stature and Reduced Abdominal Fat in Their Children

Background

Maternal age at childbirth continues to increase worldwide. We aimed to assess whether increasing maternal age is associated with changes in childhood height, body composition, and metabolism.

Methods

277 healthy pre-pubertal children, born 37–41 weeks gestation were studied. Assessments included: height and weight corrected for parental measurements, DEXA-derived body composition, fasting lipids, glucose, insulin, and hormonal profiles. Subjects were separated according to maternal age at childbirth: <30, 30–35, and >35 years.

Results

Our cohort consisted of 126 girls and 151 boys, aged 7.4±2.2 years (range 3–10); maternal age at childbirth was 33.3±4.7 years (range 19–44). Children of mothers aged >35 and 30–35 years at childbirth were taller than children of mothers aged <30 years by 0.26 (p = 0.002) and 0.23 (p = 0.042) SDS, respectively. There was a reduction in childhood BMISDS with increasing maternal age at childbirth, and children of mothers aged >35 years at childbirth were 0.61 SDS slimmer than those of mothers <30 years (p = 0.049). Children of mothers aged 30–35 (p = 0.022) and >35 (p = 0.036) years at childbirth had abdominal adiposity reduced by 10% and 13%, respectively, compared to those in the <30 group. Children of mothers aged 30–35 years at childbirth displayed a 19% increase in IGF-I concentrations compared to offspring in <30 group (p = 0.042). Conversely, IGF-II concentrations were lower among the children born to mothers aged 30–35 (6.5%; p = 0.004) and >35 (8.1%; p = 0.005) compared to those of mothers aged <30 years. Girls of mothers aged 30–35 years at childbirth also displayed improved HOMA-IR insulin sensitivity (p = 0.010) compared to girls born to mothers aged <30 years.

Conclusions

Increasing maternal age at childbirth is associated with a more favourable phenotype (taller stature and reduced abdominal fat) in their children, as well as improved insulin sensitivity in girls.     

Estimation of Newborn Risk for Child or Adolescent Obesity: Lessons from Longitudinal Birth Cohorts

Objectives

Prevention of obesity should start as early as possible after birth. We aimed to build clinically useful equations estimating the risk of later obesity in newborns, as a first step towards focused early prevention against the global obesity epidemic.

Methods

We analyzed the lifetime Northern Finland Birth Cohort 1986 (NFBC1986) (N = 4,032) to draw predictive equations for childhood and adolescent obesity from traditional risk factors (parental BMI, birth weight, maternal gestational weight gain, behaviour and social indicators), and a genetic score built from 39 BMI/obesity-associated polymorphisms. We performed validation analyses in a retrospective cohort of 1,503 Italian children and in a prospective cohort of 1,032 U.S. children.

Results

In the NFBC1986, the cumulative accuracy of traditional risk factors predicting childhood obesity, adolescent obesity, and childhood obesity persistent into adolescence was good: AUROC = 0·78[0·74–0.82], 0·75[0·71–0·79] and 0·85[0·80–0·90] respectively (all p<0·001). Adding the genetic score produced discrimination improvements ≤1%. The NFBC1986 equation for childhood obesity remained acceptably accurate when applied to the Italian and the U.S. cohort (AUROC = 0·70[0·63–0·77] and 0·73[0·67–0·80] respectively) and the two additional equations for childhood obesity newly drawn from the Italian and the U.S. datasets showed good accuracy in respective cohorts (AUROC = 0·74[0·69–0·79] and 0·79[0·73–0·84]) (all p<0·001). The three equations for childhood obesity were converted into simple Excel risk calculators for potential clinical use.

Conclusion

This study provides the first example of handy tools for predicting childhood obesity in newborns by means of easily recorded information, while it shows that currently known genetic variants have very little usefulness for such prediction.     

Association between Body Water Status and Acute Mountain Sickness

Purpose

The present study determined the association between body fluid variation and the development of acute mountain sickness (AMS) in adults.

Methods

Forty-three healthy participants (26 males and 17 females, age: 26±6 yr, height: 174±9 cm, weight: 68±12 kg) were passively exposed at a FiO₂ of 12.6% (simulated altitude hypoxia of 4500 m, PiO₂ = 83.9 mmHg) for 12-h. AMS severity was assessed using the Lake Louise Score (LLS). Food and drink intakes were consumed ad libitum and measured; all urine was collected. Before and after the 12-h exposure, body weight and plasma osmolality were measured and whole-body bioimpedance analysis was performed.

Results

The overall AMS incidence was 43% (38% males, 50% females). Participants who developed AMS showed lower fluid losses (3.0±0.9 vs. 4.5±2.0 ml/kg/h, p = 0.002), a higher fluid retention (1.9±1.5 vs. 0.6±0.8 ml/kg/h, p = 0.022), greater plasma osmolality decreases (−7±7 vs. −2±5 mOsm/kg, p = 0.028) and a larger plasma volume expansion (11±10 vs. 1±15%, p = 0.041) compared to participants not developing AMS. Net water balance (fluid intake – fluid loss) and the amount of fluid loss were strong predictors whether getting sick or not (Nagelkerkes r² = 0.532). The LLS score was related to net water balance (r = 0.358, p = 0.018), changes in plasma osmolality (r = −0.325, p = 0.033) and sodium concentration (r = −0.305, p = 0.047). Changes in the impedance vector length were related to weight changes (r = −0.550, p<0.001), fluid intake (r = −0.533, p<0.001) and net water balance (r = −0.590, p<0.001).

Conclusions

Participants developing AMS within 12 hours showed a positive net water balance due to low fluid loss. Thus measures to avoid excess fluid retention are likely to reduce AMS symptoms.     

Magnesium Sulfate Treatment Reverses Seizure Susceptibility and Decreases Neuroinflammation in a Rat Model of Severe Preeclampsia

Eclampsia, defined as unexplained seizure in a woman with preeclampsia, is a life-threatening complication of pregnancy with unclear etiology. Magnesium sulfate (MgSO₄) is the leading eclamptic seizure prophylactic, yet its mechanism of action remains unclear. Here, we hypothesized severe preeclampsia is a state of increased seizure susceptibility due to blood-brain barrier (BBB) disruption and neuroinflammation that lowers seizure threshold. Further, MgSO₄ decreases seizure susceptibility by protecting the BBB and preventing neuroinflammation. To model severe preeclampsia, placental ischemia (reduced uteroplacental perfusion pressure; RUPP) was combined with a high cholesterol diet (HC) to cause maternal endothelial dysfunction. RUPP+HC rats developed symptoms associated with severe preeclampsia, including hypertension, oxidative stress, endothelial dysfunction and fetal and placental growth restriction. Seizure threshold was determined by quantifying the amount of pentylenetetrazole (PTZ; mg/kg) required to elicit seizure in RUPP+HC±MgSO₄ and compared to normal pregnant controls (n = 6/group; gestational day 20). RUPP+HC rats were more sensitive to PTZ with seizure threshold being ∼65% lower vs. control (12.4±1.7 vs. 36.7±3.9 mg/kg PTZ; p<0.05) that was reversed by MgSO₄ (45.7±8.7 mg/kg PTZ; p<0.05 vs. RUPP+HC). BBB permeability to sodium fluorescein, measured in-vivo (n = 5–7/group), was increased in RUPP+HC vs. control rats, with more tracer passing into the brain (15.9±1.0 vs. 12.2±0.3 counts/gram ×1000; p<0.05) and was unaffected by MgSO₄ (15.6±1.0 counts/gram ×1000; p<0.05 vs. controls). In addition, RUPP+HC rats were in a state of neuroinflammation, indicated by 35±2% of microglia being active compared to 9±2% in normal pregnancy (p<0.01; n = 3–8/group). MgSO₄ treatment reversed neuroinflammation, reducing microglial activation to 6±2% (p<0.01 vs. RUPP+HC). Overall, RUPP+HC rats were in a state of augmented seizure susceptibility potentially due to increased BBB permeability and neuroinflammation. MgSO₄ treatment reversed this, increasing seizure threshold and decreasing neuroinflammation, without affecting BBB permeability. Thus, reducing neuroinflammation may be one mechanism by which MgSO₄ prevents eclampsia during severe preeclampsia.     

Interaction between PNPLA3 I148M Variant and Age at Infection in Determining Fibrosis Progression in Chronic Hepatitis C

Background and Aims

The PNPLA3 I148M sequence variant favors hepatic lipid accumulation and confers susceptibility to hepatic fibrosis and hepatocellular carcinoma. The aim of this study was to estimate the effect size of homozygosity for the PNPLA3 I148M variant (148M/M) on the fibrosis progression rate (FPR) and the interaction with age at infection in chronic hepatitis C (CHC).

Methods

FPR was estimated in a prospective cohort of 247 CHC patients without alcohol intake and diabetes, with careful estimation of age at infection and determination of fibrosis stage by Ishak score.

Results

Older age at infection was the strongest determinant of FPR (p<0.0001). PNPLA3 148M/M was associated with faster FPR in individuals infected at older age (above the median, 21 years; −0.64±0.2, n = 8 vs. −0.95±0.3, n = 166 log₁₀ FPR respectively; p = 0.001; confirmed for lower age thresholds, p<0.05), but not in those infected at younger age (p = ns). The negative impact of PNPLA3 148M/M on fibrosis progression was more marked in subjects at risk of altered hepatic lipid metabolism (those with grade 2–3 steatosis, genotype 3, and overweight; p<0.05). At multivariate analysis, PNPLA3 148M/M was associated with FPR (incremental effect 0.08±0.03 log₁₀ fibrosis unit per year; p = 0.022), independently of several confounders, and there was a significant interaction between 148M/M and older age at infection (p = 0.025). The association between 148M/M and FPR remained significant even after adjustment for steatosis severity (p = 0.032).

Conclusions

We observed an interaction between homozygosity for the PNPLA3 I148M variant and age at infection in determining fibrosis progression in CHC patients.     

Insulin Sensitivity from Preschool to School Age in Patients with Severe Obesity

Background

Insulin sensitivity decreases at puberty transition, but little information has been provided on its earlier time-course. Aim of the present study was to describe the time-course of insulin sensitivity in severely obese children at the transition from preschool to school age.

Research design and methods

Retrospective study of a cohort of 47 severely obese [Body Mass Index (BMI) ≥99° percentile] preschoolers evaluated twice, once between 2 and 6 years of age, and once before age 8. Glucose tolerance, Whole Body Insulin Sensitivity Index (WBISI), Insulinogenic Index (IGI); β-cell demand index (BCDI) and Insulin Secretion-Sensitivity Index 2 (ISSI-2) were longitudinally estimated during the oral glucose tolerance test.

Results

After a median follow-up of 2.23 (1–4.52) y, obese patients showed significant decrease in WBISI (p<0.0001), and increase in fasting (p = 0.005) and 2 h glucose (2HG, p = 0.001). One child in preschool age and 4 school age children presented with 2HG between 7.8–11.1 mmol/l. Best predictors of WBISI, 2HG and BCDI in the school age were changes in BMI z-score (R² = 0.309; p = 0.002; β = −0.556), ISSI-2 (R² = 0.465; p<0.0001; β = −0.682), and BMI z-score (R² = 0.246; p = 0.008; 0.496), respectively.

Conclusions

In morbidly obese children, insulin sensitivity seems to decline even before pubertal transition, but changes in total adiposity can only partially explain this variation.     

High Blood Pressure and Its Association with Body Weight among Children and Adolescents in the United Arab Emirates

Objectives

To estimate the prevalence of high blood pressure (BP) and its relationship with obesity among children and adolescents.

Methodology/Principal Findings

In this cross-sectional population (Emirati) representative study, we invited a random sample of 1600 students (grades 1–12) attending 23 out of all 246 schools in the Emirate of Abu Dhabi, United Arab Emirates. But analysis was restricted to Emirati nationals aged 6–17 years. We measured BP, height, weight, waist circumferences (WC), and calculated body mass index (BMI) by standard methods. BP levels ≥90^th percentile but <95^th percentile and ≥ 95^th for age, sex, and height (CDC percentiles) were classified as pre-hypertension (pre-HTN) and hypertension (HTN), respectively. Associations between BP, age, BMI, WC, and sex, were investigated by (multiple) linear regression methods. A total of 999 (47% girls) students provided complete results. The prevalence of pre-HTN was 10.5% and 11.4% and the prevalence of HTN was 15.4% and 17.8% among boys and girls, respectively. The prevalence of systolic/diastolic HTN was 14.4%/2.5% and 14.8/7.4% among boys and girls, respectively. BMI CDC percentile was positively correlated with WC percentile (r = 0.734, p<0.01), and both systolic (r = 0.34, p<0.001) and diastolic (r = 0.21, p<0.001) standardized BP. WC percentile was less strongly correlated with standardized SBP (r = 0.255, p<0.01) and DBP (r = 0.175, p<0.01) than BMI.

Conclusions/Significance

The prevalence of elevated BP, notably systolic was significantly high among the Emirati children and adolescents in Abu Dhabi. High BP was strongly related to body weight, and appears more strongly associated with BMI than WC. Further studies are required to investigate the impact of childhood obesity on HTN.     

Elevated Soluble VEGF Receptor sFlt-1 Correlates with Endothelial Injury in IgA Nephropathy

Background

Endothelial injury, which may present clinically as hypertension, proteinuria and increased von Willebrand Factor (vWF) level, is a common manifestation in IgA nephropathy (IgAN). However, causal factors for endothelial injury in IgAN are not completely understood. An imbalance of vascular endothelial growth factor/Soluble fms-like tyrosine kinase-1 (VEGF/sFlt-1) has been observed in many diseases with endothelial dysfunction, including pre-eclampsia and diabetic retinopathy, but whether it contributes to endothelial injury in IgAN requires further exploration.

Methods

Initially, 96 IgAN patients and 22 healthy volunteers were enrolled as a discovery cohort. VEGF/sFlt-1, sFlt-1 and VEGF levels were compared between patients with IgAN and healthy volunteers to explore the underlying factors that contribute to endothelial injury in IgAN. The identified contributor (sFlt-1) was further confirmed in a replication cohort, which included 109 IgAN patients and 30 healthy volunteers. Correlations of sFlt-1 with hypertension, proteinuria, Oxford-E score and plasma vWF were further evaluated in the combined 205 patients with IgAN.

Results

VEGF/sFlt-1 levels were significantly lower in IgAN patients than healthy volunteers (0.33±0.27 vs. 0.43±0.22, p = 0.02) in the discovery cohort. Within the ratio, plasma sFlt-1 levels were significantly elevated (101.18±25.19 vs. 79.73±18.85 pg/ml, p<0.001), but plasma VEGF levels showed no significant differences. Elevated sFlt-1 levels in the replication cohort were confirmed in IgAN patients (93.40±39.78 vs. 71.92±15.78 pg/ml, p<0.001). Plasma sFlt-1 levels in IgAN patients correlated with proteinuria (severe (>3.5 g/d) vs. moderate (1–3.5 g/d) vs. mild (<1 g/d) proteinuria: 115.95±39.09 vs. 99.89±28.55 vs. 83.24±33.92 pg/ml; severe vs. mild: p<0.001, moderate vs. mild p = 0.001, severe vs. moderate: p = 0.014), hypertension (with vs. without hypertension: 107.87±31.94 vs. 87.32±32.76 pg/ml, p = 0.015) and vWF levels (r = 0.161, p = 0.021).

Conclusions

The present study found elevated sFlt-1 in IgAN patients and further identified its correlation with proteinuria, hypertension and vWF levels. These results suggested that elevated sFlt-1 contributes to endothelial injury in IgAN.     

Plasma Selenium Biomarkers in Low Income Black and White Americans from the Southeastern United States

Biomarkers of selenium are necessary for assessing selenium status in humans, since soil variation hinders estimation of selenium intake from foods. In this study, we measured the concentration of plasma selenium, selenoprotein P (SEPP1), and glutathione peroxidase (GPX3) activity and their interindividual differences in 383 low-income blacks and whites selected from a stratified random sample of adults aged 40–79 years, who were participating in a long-term cohort study in the southeastern United States (US). We assessed the utility of these biomarkers to determine differences in selenium status and their association with demographic, socio-economic, dietary, and other indicators. Dietary selenium intake was assessed using a validated food frequency questionnaire designed for the cohort, matched with region-specific food selenium content, and compared with the US Recommended Dietary Allowances (RDA) set at 55 µg/day. We found that SEPP1, a sensitive biomarker of selenium nutritional status, was significantly lower among blacks than whites (mean 4.4±1.1 vs. 4.7±1.0 mg/L, p = 0.006), with blacks less than half as likely to have highest vs. lowest quartile SEPP1 concentration (Odds Ratio (OR) 0.4, 95% Confidence Interval (CI) 0.2–0.8). The trend in a similar direction was observed for plasma selenium among blacks and whites, (mean 115±15.1 vs. 118±17.7 µg/L, p = 0.08), while GPX3 activity did not differ between blacks and whites (136±33.3 vs. 132±33.5 U/L, p = 0.320). Levels of the three biomarkers were not correlated with estimated dietary selenium intake, except for SEPP1 among 10% of participants with the lowest selenium intake (≤57 µg/day). The findings suggest that SEPP1 may be an effective biomarker of selenium status and disease risk in adults and that low selenium status may disproportionately affect black and white cohort participants.     

Calprotectin and Lactoferrin Faecal Levels in Patients with Clostridium difficile Infection (CDI): A Prospective Cohort Study

Measurement of both calprotectin and lactoferrin in faeces has successfully been used to discriminate between functional and inflammatory bowel conditions, but evidence is limited for Clostridium difficile infection (CDI). We prospectively recruited a cohort of 164 CDI cases and 52 controls with antibiotic-associated diarrhoea (AAD). Information on disease severity, duration of symptoms, 30-day mortality and 90-day recurrence as markers of complicated CDI were recorded. Specimens were subject to microbiological culture and PCR-ribotyping. Levels of faecal calprotectin (FC) and lactoferrin (FL) were measured by ELISA. Statistical analysis was conducted using percentile categorisation. ROC curve analysis was employed to determine optimal cut-off values. Both markers were highly correlated with each other (r² = 0.74) and elevated in cases compared to controls (p<0.0001; ROC>0.85), although we observed a large amount of variability across both groups. The optimal case-control cut-off point was 148 mg/kg for FC and 8.1 ng/µl for FL. Median values for FL in CDI cases were significantly greater in patients suffering from severe disease compared to non-severe disease (104.6 vs. 40.1 ng/µl, p = 0.02), but were not significant for FC (969.3 vs. 512.7 mg/kg, p = 0.09). Neither marker was associated with 90-day recurrence, prolonged CDI symptoms, positive culture results and colonisation by ribotype 027. Both FC and FL distinguished between CDI cases and AAD controls. Although FL was associated with disease severity in CDI patients, this showed high inter-individual variability and was an isolated finding. Thus, FC and FL are unlikely to be useful as biomarkers of complicated CDI disease.