Dynamic change in adiposity from fetal to postnatal life is involved in the metabolic syndrome associated with reduced fetal growth

Aims/hypothesis The aims of this study were to establish the role of insulin resistance in the metabolic syndrome associated with restricted fetal growth and to characterise the fetal and postnatal determinants responsible for the long-term metabolic outcome.Methods The study population consisted of adults selected on birth data from a maternity registry and born either small for gestational age (SGA) (n=734, birthweightn=886, 25thp=0.0004). In SGA subjects, the upper tertile of fasting insulinaemia was associated with the highest values of systolic (p=0.001) and diastolic (p=0.02) blood pressure, triglyceridaemia (p=0.005) and glycaemia at fasting (p=0.0001) and during OGTT (p=0.0001). In SGA subjects, insulin resistance was not related to birthweight itself (p=0.26), but correlated negatively with BMI at birth (p=0.03) and positively with the subsequent postnatal catch-up in BMI (p=0.009).Conclusions/interpretation Insulin resistance is the keystone of metabolic syndrome associated with SGA, and its origin should be sought in the fetal development process of adiposity that is responsible for postnatal growth and the later development of insulin resistance.     

Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity

Aims/hypothesis

Fetal programming plays an important role in the pathogenesis of type 2 diabetes. The aim of the present study was to investigate whether maternal metabolic changes during OGTT influence fetal brain activity.

Methods

Thirteen healthy pregnant women underwent an OGTT (75 g). Insulin sensitivity was determined by glucose and insulin measurements at 0, 60 and 120 min. At each time point, fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device and response latencies were determined.

Results

Maternal insulin increased from a fasting level of 67?±?25 pmol/l (mean ± SD) to 918?±?492 pmol/l 60 min after glucose ingestion and glucose levels increased from 4.4?±?0.3 to 7.4?±?1.1 mmol/l. Over the same time period, fetal response latencies decreased from 297?±?99 to 235?±?84 ms (p?=?0.01) and then remained stable until 120 min (235?±?84 vs 251?±?91 ms, p?=?0.39). There was a negative correlation between maternal insulin sensitivity and fetal response latencies 60 min after glucose ingestion (r?=?0.68, p?=?0.02). After a median split of the group based on maternal insulin sensitivity, fetuses of insulin-resistant mothers showed a slower response to auditory stimuli (283?±?79 ms) than those of insulin-sensitive mothers (178?±?46 ms, p?=?0.03).

Conclusions/interpretation

Lower maternal insulin sensitivity is associated with slower fetal brain responses. These findings provide the first evidence of a direct effect of maternal metabolism on fetal brain activity and suggest that central insulin resistance may be programmed during fetal development.     

Maternal and grandmaternal smoking patterns are associated with early childhood asthma

OBJECTIVE: To investigate the associations of maternal and grandmaternal smoking before, during, and after pregnancy with childhood asthma. DESIGN, SETTING, AND PARTICIPANTS: We conducted a case-control study nested within the Children's Health Study in southern California. The case patients consisted of 338 children with asthma that had been diagnosed in the first 5 years of life, and 570 control subjects were countermatched on in utero exposure to maternal smoking within grade, sex, and community of residence. MEASUREMENTS: Detailed maternal and household smoking histories and other asthma risk factor information was obtained by telephone interview. RESULTS: The participation rates were 72.3% and 82.5%, respectively, for control subjects and case patients. In utero exposure to maternal smoking was associated with increased risk for asthma diagnosed in the first 5 years of life (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.0 to 2.3), and for persistent asthma (OR, 1.5; 95% CI, 1.0 to 2.3). The associations did not differ in children with early transient asthma compared to those with early persistent asthma. Relative to never-smokers, children whose mothers smoked throughout the pregnancy had an elevated risk of asthma in the first 5 years of life (OR, 1.6; 95% CI, 1.0 to 2.6). Children of mothers who quit smoking prior to the pregnancy showed no increased risk (OR, 0.9; 95% CI, 0.5 to 1.5). We were unable to assess the association of smoking cessation during pregnancy because very few mothers were reported to have done so (15%). Asthma risk did not increase in a monotonic pattern with smoking intensity during pregnancy. Postnatal secondhand smoke exposure was not independently associated with asthma. Grandmaternal smoking during the mother's fetal period was associated with increased asthma risk in her grandchildren (OR, 2.1; 95% CI, 1.4 to 3.2). CONCLUSIONS: Maternal and grandmaternal smoking during pregnancy may increase the risk of childhood asthma.     

Leukocyte count is associated with reduced endothelial reactivity

BACKGROUND: Leukocyte count has been associated with cardiovascular and cerebrovascular disease in several studies. We hypothesized that white blood cell count is associated with endothelial reactivity. METHODS AND RESULTS: Leukocyte count was measured in a sample of stroke-free community participants undergoing brachial artery testing for endothelial reactivity. Flow-mediated dilation (FMD) during reactive hyperemia was assessed in each subject using high-resolution B-mode ultrasound. Multivariate linear regression was used to calculate the effect of leukocyte count on endothelial reactivity after adjusting for potential confounding factors. Mean age of the 868 participants was 66.7+/-8.8 years; 57% were women. Mean leukocyte count was (6.1+/-1.8)x10(9)/L. Each unit increase in leukocyte count was associated with a mean 0.18% decrease in FMD (p = 0.01). After adjusting for other atherosclerosis risk factors, including age, sex, hypertension, diabetes, hyperlipidemia, and smoking, the relationship persisted (mean decrease in FMD per unit leukocyte count = 0.17%, p = 0.02). There was a linear decrease in FMD by quartile of leukocyte count (p = 0.0014). The effect of leukocyte count on FMD was greater for women, those under age 70, and non-diabetics. CONCLUSIONS: Relative elevations in leukocyte count are associated with a reduction in brachial artery endothelial reactivity. These findings are consistent with current hypotheses regarding the inflammatory or infectious etiology of risk of atherosclerosis and stroke, but also suggest interactions with demographic and other risk factors.     

Coughing during mannitol challenge is associated with asthma

STUDY OBJECTIVES: To define whether coughing during mannitol challenge is a nonspecific side effect of this challenge or is associated with asthma. DESIGN: A prospective study. SETTING: University hospital. PARTICIPANTS: Thirty-seven steroid-naive, asthmatic subjects and 10 healthy subjects. MEASUREMENTS: The participants completed a symptom questionnaire, recorded peak expiratory flows (PEFs), and underwent spirometry, skin tests, and bronchial provocations with mannitol, histamine, and cold air. Seventeen of the asthmatic subjects were treated with budesonide, 800 micro g per day, and the measurements were repeated after 3 and 6 months of treatment. Coughs were recorded during the mannitol challenges, and the cough sensitivity was expressed as the cumulative number of coughs divided by the cumulative dose of mannitol. RESULTS: The asthmatic subjects coughed more during the mannitol challenge than the healthy subjects (8.3 coughs per 100 mg [95% confidence interval (CI), 6.2 to 11.0] vs 1.1 coughs per 100 mg [95% CI, 0.4 to 3.0]; p < 0.0001). Even those asthmatic subjects who did not develop bronchoconstriction after the maximal cumulative dose of mannitol (635 mg) coughed significantly more than the healthy subjects (53 coughs [95% CI, 34 to 72] vs 12 coughs [95% CI, 4 to 21]; p = 0.003). Budesonide treatment decreased the cough sensitivity (p = 0.023), which was significantly associated with improvements in overall symptom frequency, cough frequency, diurnal PEF variation, FEV(1), and bronchial hyperresponsiveness. CONCLUSIONS: Coughing during mannitol challenge is associated with asthma and occurs independently of bronchoconstriction. It can be used to study the mechanisms of asthmatic cough. Furthermore, the measurement of the mannitol-provoked coughing may be useful both in the diagnosis of asthma as well as in the assessment of the effects of an anti-inflammatory therapy on this common disorder.     

Maternal lung growth in surgically reduced litter size pregnancy

In our previous study (Faridy et al., this issue) we observed that pregnant rats with large litter size have larger lungs than rats with small litter size. The present study was conducted to test the hypothesis that in large litter size pregnancy, the maternal lung may not enlarge if, during pregnancy, the large litter size of 11-18 is surgically reduced to a small litter size of 3. A laparotomy was performed in pregnant albino rats at gestation day 7 (R7) or 14 (R14), all fetuses except 3 were removed and the rats were sacrificed at gestation day 21 (term 22 days). Maternal lung growth was assessed by measuring lung weight, lung DNA content and lung air volume, and the fetal lung growth by lung DNA content. The results were then compared with control pregnant rats of large (11-18) and small (1-3) litter size. The findings were: (1) reduction of litter size hindered maternal lung enlargement; (2) the earlier in pregnancy the surgical reduction was performed the smaller was the maternal lung, such that control (11-18) greater than R14 greater than R7 = control (1-3); (3) fetuses of R14 rats had larger lungs per body weight than R7 rats; (4) oxygen consumption of sham-operated rats with large litter size was higher (by 8-12%) than R7 rats. The results suggest that enlargement of maternal lung during pregnancy is related to litter size and perhaps to VO2. The fact that R14 fetal lung is larger than that of R7, supports our previous notion (Faridy et al., this tissue) that factors regulating the maternal lung growth similarly influence the fetal lung.     

Maternal ethanol exposure is associated with decreased plasma zinc and increased fetal abnormalities in normal but not metallothionein-null mice

BACKGROUND: Ethanol profoundly affects fetal development, and this is proposed to be due primarily to a transient fetal zinc (Zn) deficiency that arises from the binding of Zn by metallothionein (MT) in the maternal liver. Zn homeostasis and fetal outcome were investigated in normal (MT+/+) and metallothionein-null (MT-/-) mice in response to ethanol exposure. METHODS/RESULTS: Mice were treated with saline or ethanol (0.015 m/g intraperitoneally at 0 and 4 hr) on day 8 of gestation (Gd8), and the degree of fetal dysmorphology was assessed on Gd18. The incidence of external abnormalities was significantly increased in offspring from MT+/+ dams exposed to ethanol, where 27.4% of fetuses were affected. MT-/- ethanol-, MT+/+ saline-, and MT-/- saline-treated dams had fetuses in which the frequencies of abnormalities were 2.2, 6.4, and 6.9%, respectively. To investigate Zn homeostasis, nonpregnant mice were killed at intervals over 16 hr after ethanol injection. Liver MT concentrations in MT+/+ mice were increased 20-fold by 16 hr, with a significant elevation evident by 4 hr, whereas liver Zn levels were also significantly increased by 2 hr and maintained for 16 hr. In parallel with these changes, plasma Zn concentrations in MT+/+ mice decreased by 65%, with minimum levels of 4.5+/-0.3 micromol/liter at 8 hr. Conversely, MT-/- mice exhibited increased plasma Zn concentrations, with peak values of 20.8+/-0.3 observed at 4 hr. CONCLUSION: These findings link the teratogenic effect of ethanol to the induction of maternal MT and the limitation of fetal Zn supply from the plasma.     

Angiotensin-converting enzyme 2 deficiency is associated with impaired gestational weight gain and fetal growth restriction

Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system that influences the relative expression of angiotensin II (Ang II) and Ang-(1-7). Although ACE2 expression increases in normal pregnancy, the impact of ACE2 deficiency in pregnancy has not been elucidated. We determined the influence of ACE2 deficiency on circulating and tissue renin-angiotensin system components, fetal and maternal growth characteristics, and maternal hemodynamics (mean blood pressure and cardiac output) at day 18 of gestation. Gestational body weight gain was lower in the ACE2 knockout (KO) versus C57BL/6 (wild-type) mice (30.3±4.7 versus 38.2±1.0 g; P<0.001). Fetal weight (0.94±0.1 versus 1.24±0.01 g; P<0.01) and length (19.6±0.2 versus 22.2±0.2 mm; P<0.001) were less in KO. Mean blood pressure was significantly reduced in C57BL/6 with pregnancy; it was elevated (P<0.05) in the KO virgin and pregnant mice, and this was associated with an increased cardiac output in both C57BL/6 and KO pregnant mice (P<0.05). Plasma Ang-(1-7) was reduced in pregnant KO mice (P<0.05). Placenta Ang II levels were higher in KO mice (52.9±6.0 versus 22.0±3.3 fmol/mg of protein; P<0.001). Renal Ang II levels were greater in KO virgin mice (30.0±1.7 versus 23.7±1.1 fmol/mg of protein; P<0.001). There was no change in the Ang-(1-7) levels in the KO placenta and virgin kidney. These results suggest that ACE2 deficiency and associated elevated placenta Ang II levels impact pregnancy by impairing gestational weight gain and restricting fetal growth.     

Increased pulse pressure is associated with reduced baroreflex sensitivity

Although pulse pressure (PP), heart rate variability (HRV) and baroreflex sensitivity (BRS) have been shown to predict cardiovascular events and mortality in various populations, their relationships have not been clarified. We examined these associations in two separate population-based samples of healthy middle-aged subjects. In population 1, data were obtained from 149 subjects (71 men and 78 women) aged 35-64 (mean 47.7) years, and in population 2, from 214 subjects (88 men and 126 women) aged 40-62 (mean 50.5) years. Increased 24-h ambulatory PP was related to decreased cross-spectral BRS independent of age and gender (beta=-0.28, P<0.001 for population 1; beta=-0.22, P=0.003 for population 2). This association remained significant when 24-h ambulatory diastolic blood pressure, body mass index, smoking and alcohol intake were added as covariates in the multivariate analysis. Increased ambulatory PP was also associated with increased beat-to-beat systolic arterial pressure variability. Associations between ambulatory PP and HRV were not significant after controlling for age and gender. Our results suggest that elevated PP does not affect overall HRV, but it interferes with baroreflex-mediated control of the heart rate. This association may be due to a common denominator, such as arterial stiffness, for PP and BRS.     

Menopause is associated with reduced protection from postprandial lipemia

Deficiency of endogenous estrogens has been associated with a higher incidence of coronary heart disease (CHD) in women. We investigated whether natural menopause is associated with reduced protection from postprandial lipemia, which represents a risk indicator of CHD. Twenty-three postmenopausal women (mean age, 50+/-1 [SD] years; body mass index, 24.6+/-2.8 kg/m(2)) and 21 premenopausal women matched for age and body mass index (age, 49+/-1 years; body mass index, 24. 1+/-2.6 kg/m(2)) underwent an oral vitamin A fat-loading test. Vitamin A is a marker of the metabolism of chylomicrons and chylomicron remnants. All women were normolipidemic, were in good health, were nonsmokers, and used no medication. Postprandial lipids and vitamin A were measured at hourly intervals up to 12 hours. In postmenopausal women, plasma total cholesterol and LDL cholesterol concentrations were significantly higher. Fasting plasma triglyceride (TG) concentrations were 1.14+/-0.57 mmol/L in postmenopausal women and 0.88+/-0.33 mmol/L in premenopausal women (P=NS). In the postprandial phase, postmenopausal women had higher plasma TG (13.0+/-6.1 versus 9.5+/-3.3 mmol x L(-1) x h(-1); P=0.024) and vitamin A (54.1+/-22.9 versus 35.9+/-9.6 mg x L(-1) x h(-1); P=0. 001) responses. To correct for the possible confounding effect of fasting TG, 13 postmenopausal women were carefully matched with 19 premenopausal women. Although fasting TG levels were identical (0. 72+/-0.20 versus 0.73+/-0.21 mmol/L), differences in postprandial vitamin A (45.3+/-14.5 versus 33.0+/-7.7 mg x L(-1) x h(-1); P=0.006) and incremental TG (ie, after subtraction of baseline TG) (3.2+/-1.8 versus 2.3+/-1.0 mmol x L(-1) x h(-1); P=0.023) persisted between postmenopausal and premenopausal women. Natural menopause is associated with aggravated postprandial lipemia in women matched for age and body mass index. Higher postprandial lipemia potentially explains the relation of TGs and CHD mortality risk in postmenopausal women.     

Healthy ageing is associated with reduced and delayed disability

OBJECTIVE: to identify subgroups within the population with reduced or delayed disability during healthy ageing. DESIGN: a longitudinal, community-based study. SETTING: Dubbo, New South Wales, Australia. PARTICIPANTS: 2805 men and women 60 years and older, first examined in 1988-89. OUTCOME MEASURES: activities of daily living assessed serially every 2 years over 8 years (scored in the range 0-6, least to most impaired); scores related to subsequent hospital admissions and to demographic, clinical and psychosocial characteristics at baseline. RESULTS: 1973 men and women provided complete follow-up data. Mean disability score at entry was low at 0.18 and increased to 0.69 by the final survey. Those having three or more hospital admissions (40% of the sample) had minimum disability (disability score approximately 0.3) around 5 years earlier than those with fewer admissions. Those with dementia or other mental illness had the most severe disability (mean disability scores of 3.15 and 2.13 respectively), but their numbers were very small. Those with a stroke or respiratory illness were more numerous and they had major physical disability (mean disability scores of 1.44 and 1.32 respectively). In a regression model, the statistically significant baseline predictors of disability at the final survey were age, body mass index, use of anti-hypertensive medication, history of stroke, depression score, peak expiratory flow and physical disability. CONCLUSIONS: the findings confirm reduced or delayed disability in older citizens requiring little or no hospitalization. Age, impaired peak expiratory flow and physical disability at study entry were most strongly predictive of disability, while stroke and respiratory illness were relatively common causes of severe disability.     

Helicobacter pylori colonization is inversely associated with childhood asthma

BACKGROUND: Asthma, a serious health problem worldwide, is becoming more common. Colonization with Helicobacter pylori, a major human indigenous (commensal) microbe, during early life may be relevant to the risk of childhood asthma. METHODS: We conducted cross-sectional analyses, using data from 7412 participants in the National Health and Nutrition Examination Survey (NHANES) 1999-2000, to assess the association between H. pylori and childhood asthma. RESULTS: H. pylori seropositivity was inversely associated with onset of asthma before 5 years of age and current asthma in children aged 3-13 years. Among participants 3-19 years of age, the presence of H. pylori was inversely related to ever having had asthma (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.45-1.06), and the inverse association with onset of asthma before 5 years of age was stronger (OR, 0.58; 95% CI, 0.38-0.88). Among participants 3-13 years of age, H. pylori positivity was significantly inversely associated with current asthma (OR, 0.41; 95% CI, 0.24-0.69). H. pylori seropositivity also was inversely related to recent wheezing, allergic rhinitis, and dermatitis, eczema, or rash. CONCLUSIONS: This study is the first to report an inverse association between H. pylori seropositivity and asthma in children. The findings indicate new directions for research and asthma prevention.