Yechiel Friedlander

Associations of Maternal Prepregnancy Body Mass Index and Gestational Weight Gain With Adult Offspring Cardiometabolic Risk Factors The Jerusalem Perinatal Family Follow-Up Study

Background— Accumulating evidence demonstrates that both maternal prepregnancy body mass index (mppBMI) and gestational weight gain (GWG) are associated with adult offspring adiposity. However, whether these maternal attributes are related to other cardiometabolic risk factors in adulthood has not been comprehensively studied. Methods and Results— We used a birth cohort of 1400 young adults born in Jerusalem who had extensive archival data and clinical information at 32 years of age to prospectively examine the associations of mppBMI and GWG with adiposity and related cardiometabolic outcomes. Greater mppBMI, independently of GWG and confounders, was significantly associated with higher offspring BMI, waist circumference, systolic and diastolic blood pressures, insulin, and triglycerides and with lower high-density lipoprotein cholesterol. For example, the effect sizes were translated to nearly 5 kg/m2 higher mean BMI, 8.4 cm higher waist circumference, 0.13 mmol/L (11.4 mg/dL) higher triglycerides, and 0.10 mmol/L (3.8 mg/dL) lower high-density lipoprotein cholesterol among offspring of mothers within the upper mppBMI quartile (mppBMI >26.4 kg/m2) compared with the lower quartile (mppBMI <21.0 kg/m2). GWG, independently of mppBMI, was positively associated with offspring adiposity; differences of 1.6 kg/m2 in BMI and 2.4 cm in waist were observed when offspring of mothers in the upper (GWG >14 kg) and lower (GWG <9 kg) quartiles of GWG were compared. Further adjustment for offspring adiposity attenuated the observed associations to the null. Conclusions— Maternal size both before and during pregnancy is associated with cardiometabolic risk factors in young adult offspring. The associations appear to be driven mainly by offspring adiposity. Future studies that explore mechanisms underlying the intergenerational cycle of obesity are warranted to identify potentially novel targets for cardiometabolic risk-reduction interventions.

Ageing and the mismatch repair system.

Age-related accumulation of mutations has been extensively documented, and it has been proposed as one of the prominent causes of malignancies in old age. The present review is focused on the particular case of DNA mismatch repair system (MMR), that has drawn increased attention for its possible relevance to malignancy. We also report on our own observations on an age-associated genomic instability that develops with age in the MMR system. Our study was performed on DNA samples that were prepared from peripheral blood cells, obtained at a 10-year interval from young and old human subjects. The two DNA samples from each individual were examined comparatively. The older individuals showed a significantly higher rate of microsatellite instability (MSI) in several loci examined, whereas no difference was found between the paired samples of any of the young subjects. We suggest that this increase in MSI with age may indicate an overall genomic instability in the elderly.

Local and systemic immune response in community-dwelling elderly after intranasal or intramuscular immunization with inactivated influenza vaccine.

Intramuscular (IM) influenza vaccines are about 50% effective in preventing clinical illness among the elderly and their effectiveness in eliciting mucosal response may be even lower. The aim of the present study was to evaluate the immunological effect of a novel inactivated intranasal (IN) trivalent whole influenza virus vaccine among community‐dwelling elderly. Sixty‐one subjects were vaccinated with two doses of an IN vaccine and a control group of 31 subjects was vaccinated with a commercial IM vaccine. Viral strains in the 1997/8 vaccine used were A/Nanchang/933/95(H3N2), A/Johannesburg/82/96(H1N1) and B/Harbin/7/94. Serum IgG and nasal IgA were determined by HI and ELISA, respectively. Only a few minor local adverse events were reported after vaccination. Seroconversion for the three antigens tested was higher after IM vaccination, although not statistically significant. Local antibody response to the three antigens tested was detected in 50–53% and 19–26% of IN and IM immunized subjects, respectively. The IN vaccine tested was significantly more effective than the IM vaccine in inducing mucosal IgA response. This may prevent influenza at its early stages and thus contribute to the reduction of complications in the elderly. J. Med. Virol. 61:100–106, 2000.

Association between number of children and mortality of mothers: results of a 37-year follow-up study

PURPOSEnTo examine the association between parity and long-term, all-cause mortality and mortality owing to specific causes in women.nnnMETHODSnThis prospective population-based study included 40,454 mothers who gave birth in Western Jerusalem, Israel, to 125,842 children and were followed for an average of 37 years after the birth of their first child. Cox proportional hazards models were used to evaluate long-term total and specific-cause mortality of women by their parity.nnnRESULTSnWe found a U-shaped relationship between the number of offspring and risk of all-cause mortality in mothers. After adjustment for sociodemographic characteristics and maternal health and obstetric conditions, higher mortality rates were observed for mothers of 1 child (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.04-1.4), mothers of 5 to 9 children (HR, 1.21; 95% CI, 1.09-1.33), and mothers of 10 or more children (HR, 1.49; 95% CI, 1.12-1.99) compared with mothers of 2 to 4 children. Mortality risk from specific causes including coronary disease, circulatory disease, and cancer were increased for multiparous women.nnnCONCLUSIONSnIn this long-term follow-up study, there was an association between number of children and mortality risk for mothers. These findings suggest that maternal pregnancies and postnatal characteristics as reflected by number of children may have consequences for long-term maternal health.

Coronary artery disease is not associated with the E298 → D variant of the constitutive, endothelial nitric oxide synthase gene

To the Editor: Coronary artery disease (CAD) is multifactorial, occurring as a result of polygenic determinants coupled with a number of environmental factors (1). Endothelial nitric oxide is derived from Larginine by the nitric oxide synthase isoform expressed constitutively in endothelial cells (eNOS). In animal models, inhibition of NOS leads to induction of hypertension, abnormal vasoconstriction and tissue hypoxia (2). phenotypes that are among those observed in certain patients with CAD. A strong association has been demonstrated between a point mutation (G8944T) in exon 7 of the eNOS gene (chromosome 12) and CAD (3). This mutation causes substitution of a Glu -, Asp (E294D) at the protein level. The E294D mutation studied falls well outside the functional domains that have been postulated within the eNOS gene sequence (4), so it is thought most likely that the G894T polymorphism represents a marker mutation.

Consanguinity and birth defects in the jerusalem perinatal study cohort.

Background: While parental consanguinity is known to increase the risk of birth defects in offspring, it is hard to quantify this risk in populations where consanguinity is prevalent. Methods: To support ongoing studies of cancer and of psychiatric disease, we studied relationships of consanguinity to 1,053 major birth defects in 29,815 offspring, born in 1964–1976. To adjust for confounding variables (geographic origin, social class and hospital), we constructed logistic regression models, using GEE to take into account correlations between sibs. Odds ratios (ORs) and 95% confidence limits were estimated in comparison to a reference group of offspring with grandfathers born in different countries. Results: With 10.1% of offspring having consanguineous parents, the adjusted OR for major birth defect was 1.41 (1.12–1.74). Offspring of marriages between uncles-nieces, first cousins and more distant relatives showed adjusted ORs of 2.36 (0.98–5.68), 1.59 (1.22–2.07) and 1.20 (0.89–1.59) respectively. For descendents of grandfathers born in the same country, but not known to be related, the OR was 1.05 (0.91–1.21); these showed increased risk associated with ancestries in Western Asia (1.27, 1.04–1.55, p < 0.02) or Europe (1.13, 0.79–1.80). Conclusions: A strong association of consanguinity with poverty and low education points to the need to avoid exposure to environmental hazards in these families.

Parental smoking during pregnancy and offspring cardio-metabolic risk factors at ages 17 and 32

OBJECTIVEnTo examine the association of maternal and/or paternal smoking during pregnancy with offspring cardio-metabolic risk (CMR) factors at adolescence and early adulthood, taking into account socio-demographic, medical and lifestyle characteristics of parents and offspring, as well as offspring common genetic variation.nnnMETHODSnWe used a population-based cohort of all 17 003 births in Jerusalem during 1974-76, with available archival data on parental and birth characteristics. Measurements at age 17 were assessed at military induction examinations for 11 530 offspring. 1440 offspring from the original 1974-1976 birth cohort were sampled using a stratified sampling approach, and were interviewed and examined at age 32. Parental smoking during pregnancy (i.e. maternal, paternal and any parent) was primarily defined dichotomously (any number of cigarettes smoked daily by mother or father during pregnancy vs. non-smokers). Additionally, smoking was assessed by quantity of cigarettes smoked daily. Linear regression models were used to evaluate the associations of parental smoking during pregnancy with various offspring CMR factors, after controlling for potential confounders and for genetic variation in candidate genes.nnnRESULTSnPrevalence of exposure to parental smoking in-utero (i.e. smoking of any parent) was 53.2% and 48.4% among the 17 years old and 32 years old samples, respectively. At age 17, smoking of at least one parent during pregnancy was significantly associated with weight (Bxa0=xa01.39), height (Bxa0=xa00.59), BMI (Bxa0=xa00.32) and pulse rate (Bxa0=xa0-0.78) (p-valuesxa0<xa00.001). At age 32, parental smoking, adjusted for covariates, was associated with 2.22xa0kg higher mean offspring weight, 0.95xa0cm higher mean offspring height, 0.57xa0kg/m(2) higher BMI, and 1.46xa0cm higher waist-circumference (p-valuesxa0≤xa00.02). Similar results, reflecting a dose response, were observed when maternal and paternal smokings were assessed by number of cigarettes smoked daily.nnnCONCLUSIONSnThis prospective study demonstrates a potential long-term adverse effect of parental smoking during pregnancy on offspring health and calls for increasing efforts to promote smoking cessation of both parents before pregnancy.

Factor V Leiden, Prothrombin G20210A, and Risk of Sudden Coronary Death in Apparently Healthy Persons

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Plasma vitamin D is associated with fasting insulin and homeostatic model assessment of insulin resistance in young adult males, but not females, of the Jerusalem Perinatal Study

OBJECTIVEnTo examine cross-sectional relationships between plasma vitamin D and cardiometabolic risk factors in young adults.nnnDESIGNnData were collected from interviews, physical examinations and biomarker measurements. Total plasma 25-hydroxyvitamin D (25(OH)D) was measured using LC-tandem MS. Associations between 25(OH)D and cardiometabolic risk factors were modelled using weighted linear regression with robust estimates of standard errors.nnnSETTINGnIndividuals born in Jerusalem during 1974-1976.nnnSUBJECTSnParticipants of the Jerusalem Perinatal Study (n 1204) interviewed and examined at age 32 years. Participants were oversampled for low and high birth weight and for maternal pre-pregnancy obesity.nnnRESULTSnMean total 25(OH)D concentration among participants was 21·7 (sd 8·9) ng/ml. Among males, 25(OH)D was associated with homeostatic model assessment of insulin resistance (natural log-transformed, β=-0·011, P=0·004) after adjustment for BMI. However, these associations were not present among females (P for sex interaction=0·005).nnnCONCLUSIONSnWe found evidence for inverse associations of 25(OH)D with markers of insulin resistance among males, but not females, in a healthy, young adult Caucasian population. Prospective studies and studies conducted on other populations investigating sex-specific effects of vitamin D on cardiometabolic risk factors are warranted.

Associations of maternal pre‐pregnancy and gestational body size with offspring longitudinal change in BMI

Studies demonstrate associations between changes in obesity‐related phenotypes and cardiovascular risk. Although maternal pre‐pregnancy BMI (mppBMI) and gestational weight gain (GWG) may be associated with adult offspring adiposity, no study has examined associations with obesity changes. Associations of mppBMI and GWG with longitudinal change in offsprings BMI (ΔBMI) were examined, and whether associations are explained by offspring genetics was assessed.