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Hyperhomocysteinemia is an independent risk factor for arteriosclerotic vascular disease. It can result from deficiencies of co-factors required for homocysteine metabolism and/or from genetic disorders of its metabolism. The association between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and vascular disease is controversial, and may be affected by ethnic origin. A unique feature of the Israeli population is its ethnic diversity. The aim of this study was to study the frequency of the C677T MTHFR mutation in healthy Israeli ethnic groups. The frequency of the mutation was determined in 897 young healthy Jewish and Muslim Arab Israelis of eight different ethnic groups. Marked ethnic differences in the frequency of mutant homozygotes were found, ranging from 2% in Yemenite Jews, 4% in Sephardic Jews, 9% in Oriental Jews, 10% in Muslim Arabs, 16% in North African Jews, and 19% in Ashkenazi Jews. The frequency of mutant homozygotes was significantly higher in Ashkenazi Jews compared to Yemenites Oriental Jews, Sephardic Jews, and Muslim Arabs (chi2 = 12.35p0.001, chi2 = 8.17p = 0.004, chi2 = 6.04p = 0.01, chi2 = 6.54 p = 0.01, respectively). Our findings demonstrate the need for matching ethnic background in patients and controls when studying the association between the C677T MTHFR mutation and any disease.

Alzheimer's disease (AD) and vascular dementia (VaD) are the main causes of dementia. Postmenopausal estrogen deficiency was suggested as a contributor to cognitive decline; however, replacement therapy failed to prove beneficial in its prevention or therapy. Sequence variants in the estrogen receptor alpha gene (ESR1) and beta gene (ESR2) may alter the effects of estrogen.This is a case-control association study of sporadic AD, VaD, and single-nucleotide polymorphisms in ESR1 (rs2234693 and rs9340799), the TA dinucleotide repeat in the ESR1 promoter, and the rs4986938 single-nucleotide polymorphism in ESR2. Two hundred forty-six women (118 AD, age 83 +/- 7; 60 VaD, age 82 +/- 6; and 68 cognitively intact, age 81 +/- 7) residing in nursing homes were studied. The association of genotypes and AD or VaD was determined by logistic regression analysis adjusted for age and ethnic origin.An association of VaD and ESR2 rs4986938 was found. Carriers of each A allele had a 1.7 increased risk compared to carriers of the G allele (odds ratio 1.71, 95% confidence interval 1-2.95). The ApoE epsilon 4 allele was associated with AD (odds ratio 3.35, confidence interval 1.44-7.82), but not with VaD. No association of AD or VaD with ESR1 genotypes or haplotypes was detected.The ESR2 rs4986938 polymorphism is associated with susceptibility for VaD in elderly Jewish women. These results need to be confirmed in replicate studies in other populations.

We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations1, 2, 3, 4 (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10-3). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.

A prospective study of elderly Australians commenced in 1988 in Dubbo, NSW. Its goals are to identify predictors of mortality, hospitalisation and placement in long-term care, with special focus on risk factors for cardiovascular disease. The study population were non-institutionalised subjects, comprising 1237 males and 1568 females 60 years and over. This report describes the baseline findings: demographic, educational and economic data; tobacco and alcohol usage, self-medication and other habits; medical contacts and past diagnosis; prescribed medication and in study diagnosis; psychosocial variables, functional health and social support; blood lipid and lipoprotein data; blood pressure, spirometry and glucose data; heights and weights. Where comparison has been feasible, the findings in Dubbo closely resemble those obtained from the rest of Australia. The findings presented provide the basis for aetiological studies of future outcomes.

HDL cholesterol and apolipoprotein A-I are associated with the development of coronary artery disease (CAD). The presence of a PstI site polymorphism adjacent to the gene encoding apo A-I (known as P2) has also been shown to be associated with CAD but this relationship is controversial. A case control study was conducted in an Australian population to re-examine whether the rare P2 allele is associated with CAD. Data were derived from 159 cases of angiographically confirmed CAD and 99 healthy controls. The proportion of CAD cases carrying the P2 allele did not differ significantly from controls (11% versus 9%). In a multiple logistic regression model controlling for the effects of age, country of birth, hypertension and hypotensive drugs, body mass index and lipid variables, the P2 allele failed to predict significantly the presence of CAD (odds ratio 1.83; 95% confidence interval 0.65-5.19).

Twenty-six Yeshiva students were randomly assigned to a 24-wk crossover study of monounsaturated fatty acid (MUFA) vs polyunsaturated fatty acid (PUFA) diets (50% carbohydrate, 32% fat, 18% protein) fed alternately during two 12-wk periods. Total plasma cholesterol (TC) decreased significantly by approximately 10% and approximately 16% on the MUFA and PUFA diets, respectively. Plasma triglyceride response was variable. Low-density-lipoprotein cholesterol (LDL-C) decreased in both groups with an additional significant effect between periods. Concentrations of high-density-lipoprotein cholesterol did not change significantly. LDL-receptor status in fresh monocytes, affinity of LDL towards the LDL receptor in cultured fibroblasts, zonal-centrifugation profiles, and lipoprotein composition were not significantly different between the diets. There was a significantly higher tendency toward lipid peroxidation on the PUFA diet, as ascertained by more thiobarbituric acid-reactive-substances formation on that diet. Dietary PUFA results in somewhat lower TC and LDL-C concentrations whereas with MUFA the susceptibility of LDL to oxidative stress is lower.

Background Conventional risk factors for coronary heart disease (CHD) and ischaemic stroke (IS) have been well documented. This study examines whether there is a unique pattern of risk factors for each disease. Methods This is a prospective cohort study in Dubbo NSW which has followed 2805 men and women 60 years and older for 16 years since 1988–1989. CHD and IS events were identified by hospital record linkage. The independent contributions of risk factors to these events were evaluated in proportional hazards regression models. Results CHD events (without stroke) occurred in 853 subjects (30.4/100). IS events (without CHD) occurred in 185 subjects (6.6/100). Some risk factors produced broadly similar prediction of CHD and IS events (male sex, current smoking, diabetes, LDL cholesterol, reduced peak expiratory flow, physical disability). Other factors potentially produced unique prediction of CHD (CHD at baseline, family history of CHD, HDL cholesterol, ApoB/ApoA1 ratio) or IS (stroke at baseline), or stronger prediction of IS compared with CHD (age, hypertension, atrial fibrillation). Conclusions CHD and IS may each have some unique predictors, but treatable risk factors have been demonstrated for both cardiovascular outcomes.

In order to capture the "longevity dividend," modifiable risk factors for a diagnosis of dementia and nursing home placement were examined in a longitudinal study of an elderly cohort living in Dubbo, New South Wales, Australia. One thousand two-hundred thirty-three men and 1572 women 60 years and older living in the community were examined in 1988 and followed to 2002 for diagnosis of dementia and nursing home placement. There were 244 (8.7%) nursing home placements and 44% of these placements were primarily due to dementia, but dementia was a secondary diagnosis in another 20% of cases. In a proportional hazards model for dementia, any intake of alcohol predicted a 34% lower risk, and daily gardening a 36% lower risk. Daily walking predicted a 38% lower risk of dementia in men, but there was no significant prediction in women. The lowest tertile of peak expiratory flow predicted an 84% higher risk of dementia, the upper tertile of depression score predicted a 50% higher risk. The Cox proportional hazards model for nursing home placement, showed placement increased significantly with age, urinary incontinence, impaired peak expiratory flow, physical disability, and depression. The hazard of placement was significantly reduced by alcohol intake and female gender. Socioeconomic factors were not significant. Similar risk factors for dementia and nursing home placement indicate that the continuation of moderate alcohol intake, the maintenance of physical activity, especially daily gardening, and improvement of respiratory function, and the treatment of depression are recommended targets for interventions to delay or prevent major negative late-life experiences.

Purpose We sought to examine the association between birthweight in offspring and mortality in their parents. Distinguishing between risks of outcomes in mothers from fathers potentially provides clues as to the relative roles of genetic versus nongenetic mechanisms underlying these associations. Methods We studied total and cause-specific mortality in a population-based cohort of 37,718 mothers and 38,002 fathers whose offspring were delivered in West Jerusalem during 1964–1976, after an average follow-up of 34.12 years. Results Hazard models controlling for sociodemographic and lifestyle characteristics indicated a U-shaped relationship between offspring's birthweight and overall mortality, deaths from coronary heart disease, circulatory and other non-neoplastic causes in their mothers. Greater rates of mortality from coronary heart disease were observed among mothers who gave birth to babies with low (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.40–3.25) and high birthweight (HR, 1.98; 95% CI, 1.36–2.88), as compared with mothers whose offspring weighed 2500–3999 g at birth. Adjustment for maternal pre-eclampsia slightly attenuated these results. Multivariate models indicated a negative linear relationship (HR, 0.95; 95% CI, 0.91–0.99) between offspring's birthweight and overall mortality in their fathers. Unlike the association in mothers, the relation was noted primarily with deaths from “other causes.” Conclusions Birthweight of offspring is associated with parental mortality although the relation differs for fathers and mothers. These findings broaden previous observations that intra-uterine events have long-term consequences for adult health and support the need to explore genetic and/or environmental mechanisms underlying these associations.

Background Diabetes is known to be associated with cancer of the pancreas, though there is some debate as to whether it is a cause or a consequence of the disease. We investigated the incidence of pancreatic cancer in a cohort of 37926 Israeli women followed for 28–40 years for whom information on diabetes had been collected at the time they gave birth, in 1964–1976, in Jerusalem. There were 54 cases of pancreatic cancer ascertained from the Israel Cancer Registry during follow-up. Methods We used Cox proportional hazards models to adjust for age at baseline and explore effects of other risk factors, including ethnic groups, preeclampsia, birth order and birth weight of offspring. Results We observed no cases of pancreatic cancer in the women with insulin dependent diabetes; however, there were five cases in the women with gestational diabetes. The interval between the record of diabetes in pregnancy and the diagnosis of pancreatic cancer ranged from 14–35 years. Women with a history of gestational diabetes showed a relative risk of pancreatic cancer of 7.1 (95% confidence interval, 2.8–18.0). Conclusion We conclude that gestational diabetes is strongly related to the risk of cancer of the pancreas in women in this population, and that gestational diabetes can precede cancer diagnosis by many years.

Summary The Jerusalem Perinatal Study recorded information on population-based cohorts of 92 408 live- and stillbirths in 1964–76, and their parents, with active surveillance of infant deaths and birth defects. Data on maternal conditions, obstetric complications and interventions during labour and delivery were recorded for 92% of the births. Subsets were surveyed with antenatal interviews in 1965–68 (n = 11 467), paediatric admissions to hospital (n = 17 782) and postpartum interviews in 1975–76 (n = 16 912). Data from some offspring were linked to records of a health examination at age 17. The offspring, mothers and fathers have been traced recently, their vital status assessed, and the data linked to Israel's Cancer Registry and Psychiatric Registry. This paper describes the different types of data available, their sources, and some potential biases. Characteristics of this unique population are shown. Findings from the study are reviewed and a list of references is provided. The cohorts provide a unique source of data for a wide variety of studies.

Objective Recent studies have shown increased maternal mortality rates after hypertensive disorders of pregnancy (HDP), but the reasons for this increase remain unclear. This study examines the relationship between elevated prepregnancy body mass index (BMI), HDP, and postpregnancy mortality. Study Design Data came from a 1975-1976 subset (n = 13,722 women) of a population-based cohort. Multiple logistic regression was used to examine the risk of HDP by BMI; age-adjusted Cox proportional hazards models were used to examine survival rates. Results Overweight (BMI, 25-29.9 kg/m 2 ) and obesity (BMI, ≥30 kg/m 2 ) were associated with increased HDP (odds ratio [OR], 2.82; 95% confidence interval [CI], 2.40-3.31 and OR, 5.51; 95% CI, 4.15-7.31]) and decreased survival (hazard ratio [HR], 1.42; 95% CI, 1.10-1.83 and HR, 2.43; 95% CI, 1.61-3.68), compared with normal weight (BMI, 18.5-24.9 kg/m 2 ). HDP was significantly associated with increased mortality rates for women who survived >15 years (HR, 1.94; 95% CI, 1.42-2.67]; HR adjusted for BMI, 1.65; 95% CI, 1.19-2.79]). A greater increase in risk of death after HDP was seen in the overweight women (HR, 1.86; 95% CI, 1.07-3.20) and obese women (HR, 2.90; 95% CI, 1.28-6.58), compared with normal weight women (HR, 1.26; 95% CI, 0.74-2.14). Conclusion Elevated prepregnancy BMI is associated with increased risk of HDP, which are in turn is associated with increased long-term maternal mortality rates. This association between HDP and mortality rates increases with elevated prepregnancy BMI.

Background and aim Hypercholesterolaemia is a major risk factor for atherosclerosis. Cholesterol is modulated by genetic and environmental factors. An important regulatory pathway is controlled by the sterol-regulatory element-binding proteins (SREBPs) and the SREBP cleavage-activating protein (SCAP). Both SREBP-2 and SCAP are candidates to contribute to the development of atherosclerosis. We investigated the possible effects of the variability of proteins involved in this regulatory pathway on plasma lipids among familial hypercholesterolaemia patients. Methods and results Single nucleotide polymorphisms (SNPs) in the genes encoding SREBP-2 and SCAP causing amino acid changes at positions 595 (595G/A) and 796 (796I/V), respectively, were genotyped in 801 FH individuals originating from Israel, The Netherlands, and Switzerland. A linear regression model to examine the associations between SREBP-2 and SCAP isoforms and lipid and lipoprotein levels was used. In females, homozygosity either for the SREBP-2-595A or for the SCAP-796I isoform was associated with higher LDL-cholesterol plasma concentrations (14.7mg/dl and 20.3mg/dl, respectively). Surprisingly, heterozygosity for the combination SREBP-2-595A/SCAP-796I was associated with a decrease of 30.28mg/dl in LDL-C ( p -value for gene–gene interaction=0.09). No such effect was observed among FH males. Subgroup analysis considering the most frequent ( N ≥24) LDL receptor mutations (del191−2, ins313+1−2, C660X, E207K, S285L) revealed further gene-dosage- and gender-dependent effects of the SCAP mutations on LDL-cholesterol concentrations ( p =0.0345). These effects were, however, not present when less frequent LDL receptor mutations were investigated. Conclusions These results suggest a possible gene–gene interaction between the genes encoding SREBP-2 and SCAP that modulate plasma lipids in a strictly gender-specific fashion. Further investigation is needed to confirm this effect. A study in a larger FH group or in non-FH hypercholesterolaemic subjects may further define the role of this regulatory mechanism in determining plasma lipid concentration.

Summary QT interval prolongation is associated with increased risk of sudden and non-sudden cardiac death. Potassium channel gene variants are associated with inherited long QT syndromes. Using linkage and association analyses, we investigated whether variants in the potassium channel subunit KCNE1 are associated with QTc intervals in an unselected population sample of 80 kindreds living in kibbutz settlements in Israel. Variance-component linkage analysis revealed weak evidence of linkage of KCNE1 polymorphisms with QTc intervals. Family-based association analysis showed a significant association between the G38S polymorphism and QTc interval. Further quantitative trait association analysis demonstrated a significant residual heritability component (h2= 0.33), and that the effect of the G38S variant allele is modified by gender. Estimated maximum likelihood parameters from these models indicated that male gender, age, hypertension, diabetes, hypercholesterolemia, fibrinogen and BMI were positively associated with QTc interval; level of education and cigarette smoking showed an inverse association. Both erythrocyte membrane n-6 and n-3 fatty acids showed a significant inverse association with QTc interval. While more than 15.8% of QTc variability was contributed by covariates, another 4.7% was explained by dietary factors, the G38S polymorphism explained 2.2%, and approximately 36% was explained by polygenes. An in silico analysis showed also that the novel V80 SNP, another KCNE1 synonymous variant, abolishes the recognition for a splicing enhancer, which may lead to an increased effect of the G38S mutation. These results demonstrate that, in addition to polygenic background, dietary factors and other covariables, the KCNE1 G38S variant is involved in determining QTc levels in this population-based sample of families.

Objective To estimate the genetic and environmental determinants of plasma fibrinogen and C-reactive protein (CRP). Methods and results A complex segregation analysis was undertaken in a sample of 142 kindreds residing in Kibbutz settlements in Israel. In addition, included in this analysis were family members who were examined 10 years earlier in the framework of this study. Analysis indicated a major locus in addition to polygenic effect that explained the sex- and age-adjusted levels and longitudinal changes in plasma fibrinogen. A non-transmitted environmental major factor with no polygenic effect explained the adjusted variation in levels and change of CRP. Both the particular genotypes determined by the major genetic factor associated with fibrinogen levels and the particular ousiotypes determined by the major environmental factor associated with CRP levels were sex- and age-dependent. In addition, our results demonstrated significant interactions between polygenotype and gender, age and environmental factors such as smoking and BMI on fibrinogen and CRP levels. Conclusions Our models that consider interactions between genotypes and gender, age and environmental exposures have the potential to improve our understanding of the genetics of fibrinogen and CRP levels.

Whereas current evidence attests to a genetic component in the etiology of dyslexia and attention-deficit/hyperactivity disorder (ADHD), little is known about the role of genetics in developmental dyscalculia (DC). The objective of this study was to determine the familial aggregation of DC. Siblings and parents of children with DC were assessed for arithmetic, reading and attention disorders. The criteria for DC were an IQ higher than 85, poor performance in arithmetic, and a significant discrepancy between arithmetic achievement and IQ. The study group was composed of 39 children with DC, 21 mothers, 22 fathers, 90 siblings, and 16 second-degree relatives. We found that 66% of mothers, 40% of fathers, 53% of siblings, and 44% of second-degree relatives had DC. The intraclass correlation between the sib pairs was .27. A 95% confidential interval (CI) for the prevalence of DC among siblings of DC probands (see Note 1) ranged from 40% to 64%, indicating a familial prevalence almost tenfold higher than expected for the general population. IQ and attention problems were not risk factors for DC. We conclude that DC, like other learning disabilities, has a significant familial aggregation, suggesting a role for genetics in the evolution of this disorder.

Objective To study the impact of various risk factors on survival time in a cohort of elderly Australians. Design, setting and participants A longitudinal, prospective cohort study conducted in Dubbo, NSW. Participants were men and women aged 60 years or over living in the community, first assessed in 1988-1989 and followed for 15 years. Main outcome measures Mortality rates; risk factors; survival times. Results There were 668 deaths in 1233 men (54%) and 625 deaths in 1572 women (40%). Coronary heart disease was the major cause of death, rates being higher in men than women until age group 80+ years; stroke death rates were similar in both sexes; cancer and respiratory death rates were higher in men than women across all ages. In a proportional hazards model, the independent predictors of mortality were cigarette smoking, diabetes, very high blood pressure (BP), impaired peak expiratory flow (PEF), physical disability, and zero intake of alcohol. Over 15 years, the average reductions in survival time associated with various risk factors, in men and women respectively, were smoking, 22 and 15 months; diabetes, 18 and 18 months; very high BP, 16 and 9 months; impaired PEF, 14 and 17 months; physical disability, 16 and 12 months; zero alcohol intake, 9 and 5 months. Combinations of selected risk factors were associated with a multiplier effect. Conclusion The reduction in survival time in elderly citizens demonstrated in the presence of smoking, diabetes and hypertension highlights a potential benefit to healthy ageing to be gained from prevention and intervention.

Changes in the marriage patterns of Israeli Jews have been associated with the mass immigration of Jews from many countries over a relatively short period of time.This study seeks to document consanguineous, intracommunity and intercommunity marriage patterns, and to observe the changes that have occurred over time, and in relation to the level of education and religiousness.During 1990-1992, 4388 Jewish women were interviewed after delivery in maternity wards throughout Israel. Demographic information was received, with special emphasis on country of origin, community and consanguinity of the couples and their parents.The consanguinity rate among the couples was 2.3%, including 0.8% first cousin marriages, with the highest consanguinity rate among Eastern Jews (7.1%). The rate of intracommunity marriages was 64% (25% Ashkenazim, 22% Sephardim and 17% Eastern Jews). The rate of intercommunity marriages was lowest among Ashkenazim. It rose with the level of education and inversely to the degree of religiousness.Over the past decades there has been a decline in consanguineous and intracommunity marriage rates and an increase in intercommunity marriages. Immigrant and ultraorthodox women tended to marry within the community as opposed to Israeli-born women and those with higher educational level who tended to intermarry with other communities as well.

Sound decision-making and practice in public health, as in other disciplines, is contingent upon information that is properly collected, analyzed, and interpreted. We describe the content and teaching methods of a graduate course in investigative methods in public health taught within the framework of a Master of Public Health (MPH) program. Following the progressive steps of carrying out research, we highlight the main concepts and skills that a student of public health should be exposed to. This includes the formulation of the study purpose and objectives, basic study designs, definition and selection of the study population and study variables, issues related to the actual collection of data in the field including the reliability and validity of the information, and preparing the data for analysis. We describe the teaching methods that are employed including frontal lectures, individual and group-based exercises, and the use of simulated data to develop skills in the critical reading of published literature and data analysis. The integration of the learned concepts and tools into course workshops and dissertation work is also addressed. Together with training in epidemiology, statistics and other quantitative and qualitative methodologies, this course provides a solid basis for MPH graduates to tackle the public health challenges that await them.

Australian lipid management guidelines published in 2001 highlighted the need to assess absolute coronary risk before prescribing lipid-modifying drugs.1 Patients already manifesting coronary or other arterial disease, or those with diabetes or certain other conditions, were deemed to be at “higher absolute risk” and would merit intervention with lipid-lowering medication. Others at lesser risk would merit intervention if their absolute risk of cardiovascular disease (CVD) exceeded 10%–15% over the ensuing 5 years — as assessed by a CVD risk calculator2 derived from the Framingham Study.3 US and European guidelines advocate a generally similar approach, but target risk over 10 years rather than 5 years.4,5 A recent UK lipid intervention trial confirmed that lipid therapy reduces the incidence of stroke as well as coronary heart disease (CHD) in high risk patients.6 Hence, it is important that risk calculation relates to CVD risk, not just CHD risk. The Framingham risk function has been validated in middle-aged men and women in Northern Europe7 and Busselton, WA,8 but has not been similarly validated in elderly populations outside Framingham. The Australian Dubbo Study of the elderly has previously reported on risk factors for myocardial infarction,9 CHD10 and stroke.11 In this report (i) we evaluate the Framingham risk function for CHD in this elderly Australian cohort and (ii) we derive an Australian CVD risk function for subjects 60 years and older.

Paternal aging is associated with premeiotic damage to spermatogonia, a mechanism by which new point mutations are introduced into the gene pool. We hypothesized that paternal age might contribute to preeclampsia.We studied the incidence of preeclampsia in 81,213 deliveries surveyed in 1964-1976 in the Jerusalem Perinatal Study. We controlled for maternal age, parity and other risk factors using logistic regression.Preeclampsia was reported in 1303 deliveries (1.6%). Compared with fathers age 25-34 years, the odds ratios (ORs) for preeclampsia were 1.24 (95% confidence interval = 1.05-1.46) for age 35-44 and 1.80 (1.40-2.31) for age 45+. For fathers age25, the OR was 1.25 (1.04-1.51). Although weaker than maternal age effects, paternal effects were consistent within subgroups of other variables.These findings support the hypothesis that a modest proportion of preeclampsia might be explained by new mutations acquired from fathers and add to a growing body of evidence for paternal age effects in birth defects, neuropsychiatric disease and neoplasia.

Various studies support the concept of an inherited vulnerability to drug dependency, while emphasizing the importance of social and environmental influences and their interactions.To compare the characteristics of heroin-dependent Jewish men in Israel with those of the general population, focusing on the nature of family history of substance abuse.This case-control study compares 64 heroin-dependent Jewish male residents of Jerusalem with a community sample of 131 randomly selected Jerusalem residents with no drug use disorder. Univariate and multivariate models were employed to appraise the independent associations between heroin dependence and exposure variables such as family history of substance misuse and exposure to legal psychoactive substances.The case group is characterized by heavy tobacco and alcohol involvement. Nearly 70% of the cases report an alcohol and/or drug problem in at least one first-degree relative compared with 10% of controls (odds ratio 14.5, adjusted for sociodemographic and other potential confounders). Cases with a positive family history have, on average, higher alcohol consumption levels and higher heroin-use severity scores, as compared with cases with no such history.Familial aggregation of drug and alcohol problems, along with smoking at a young age, is the strongest predictor of heroin dependence in this population. Better understanding of the components underlying this familial aggregation can lead to improved prevention and treatment strategies.

In Israel lives a heterogeneous population; most of the inhabitants are Jews, and about a fifth of the population is made up of other religions, mainly Muslim Arabs including Bedouins, Christian Arabs and Druze.A national survey was performed on consanguineous marriages in Israeli Arabs and Druze in order to identify population groups that are at highest risk for autosomal recessive and for multifactorial disorders.During 1990-1992, women were interviewed after delivery in maternity wards all over Israel. Data on consanguinity between the couples, their parents, and other demographic information were received from 1303 Muslim Arabs including 278 Bedouins, from 107 Christian Arabs and 115 Druze.The results showed high consanguinity rates in Muslim Arabs (42%), Christian Arabs (22%) and in Druze (47%). Rates of first cousin and closer matings in Muslim Arabs and Druze were stable over time in contrast with a significant decrease in the rates of distant consanguineous matings. Muslim Arab husbands (not Bedouins) who were sons of first cousins were more frequently (31%) married to a cousin than were other husbands (22%), and in Bedouins these rates were 53% and 33%, respectively. The rate of first cousin matings was predominantly associated with the level of education. The rate was highest in those Bedouins (37%) and Druze (37%) with low educational level, and lowest in highly educated Christian Arabs (14%) and non-Bedouin Muslim Arabs (10%). The association with education has implications for developing strategies for reducing consanguinity rates.

Proton pump inhibitors have been proven to have a major role in the management of peptic diseases, especially the long-term control of reflux esophagitis. The potent inhibitory effect of omeprazole on gastric acid secretion is frequently associated with hypergastrinemia, and gastrin and its intermediates have been reported to promote gastrointestinal cellular functions and cell growth. Experimental data suggest that gastrin may affect the proliferation of colon cells and some other cancer cells. However, so far the direct role of gastrin in tumorigenesis is unclear. Although most clinical studies on long-term treatment with omeprazole or other proton pump inhibitors do not report serious adverse effects, the issue of prolonged hypergastrinemia and tissue growth is unsettled, and many clinicians are reluctant to recommend long-term use of omeprazole or of other proton pump inhibitors.We examined the effect of long-term omeprazole treatment on serum gastrin levels in patients with reflux esophagitis when given either 20 mg daily (group 1) or on alternate days (group 2). During the follow-up period, clinical remission was monitored and maintained in all patients in group 1 and in the majority of patients in group 2.The mean serum gastrin level was significantly elevated in group 1 (mean +/- SE, 159 +/- 23.6 pg/mL; range, 45-620 pg/mL; n = 31) as compared with the alternate-day treatment group (group 2) (66 +/- 4.8 pg/mL; range, 37-115 pg/mL; n = 21) (p0.005). In controls, serum gastrin levels showed similar values to those found in group 2 (54 +/- 4.3 pg/mL; range, 27-94 pg/mL; n = 20). Fourteen patients (45%) in group 1 had serum gastric ranging from 140 to 620 pg/mL, and 8 (25%) had a 6-fold or greater increase in serum gastrin. The follow-up treatment period ranged between 3 and 60 months (mean +/- SE, 16.1 +/- 2.1 months) for group 1 and 3-36 months (9.7 +/- 1.4 months) for group 2. Upon multivariate adjustment for age and duration of treatment, a significantly lower mean serum gastrin level was observed in the alternate-day group as compared with the daily treated group.Alternate-day, long-term treatment with omeprazole may be adequate to maintain remission in patients with reflux esophagitis. This regimen can assure serum gastrin levels within the normal range, thus reducing the potential risk of prolonged, sustained hypergastrinemia and profound hypochlorhydria.

Background : The relation between a family history of heart attack and the occurrence of early myocardial infarction (MI) has not been studied extensively in women. In addition, whether recognized and newly-identified coronary heart disease (CHD) risk factors account for the familial aggregation of these events remains unknown. We therefore examined these questions in a population-based case–control study among female 18- to 44-year-old residents of western Washington State. Methods and results : The patients consisted of 107 women with first acute MI, and the control subjects comprised 526 women similar in age identified from the community and without a history of recognized clinical coronary heart disease or stroke. Trained interviewers used a structured questionnaire to elicit a detailed history of heart attack in first-degree relatives. Information about other known MI risk factors was collected and biochemical measurements performed, and common polymorphisms in various candidate genes were determined. The rate of MI among first-degree relatives of MI cases was twice as high as among first-degree relatives of controls (relative risk, 1.96; 95% confidence interval (CI), 1.46–2.48); this association was present for each familial relationship. Sibling history of MI but not parental history was associated with MI, after controlling for established CHD risk factors. In a subsample of subjects with blood measurements, further adjustment for lipids, lipoproteins and specific genetic risk factors slightly reduced the association with sibling MI history (from odds ratio (OR), 5.17; 95% CI, 1.93–13.85 to OR, 3.97; 95% CI, 0.92–17.17). Conclusion : Family history of MI is positively associated with the risk of early MI in women. While the association with parental history of MI is mediated through the clustering of other common risk factors, the association of sibling history of MI with early-onset MI in young women is only partially explained by the clustering of established and newly-identified risk factors.

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.

Objective: To examine the relationship between alcohol intake and survival in elderly people. Design and setting: A prospective study over 116 months of non-institutionalised subjects living in Dubbo, a rural town (population, 34000) in New South Wales. Participants: 1235 men and 1570 women aged 60 years and over who were first examined in 1988-89. Main outcome measures: All-causes mortality; gross cost of alcohol per life-year gained. Results: Death occurred in 450 men and 392 women. Intake of alcohol was generally moderate (ie, less than 14 drinks/week). Any intake of alcohol was associated with reduced mortality in men up to 75 years and in women over 64 years. In a proportional hazards model, the hazard ratio for mortality in men taking any alcohol was 0.63 (95% Cl, 0.47-0.84) and in women was 0.75 (95% Cl, 0.60-0.94). Cardiovascular deaths in men were reduced from 20/100 (95% Cl, 14-26) to 11/100 (95% Cl, 9-13) and in women from 16/100 (95% Cl, 13-19) to 8/100 (95% Cl, 6-10). The reduction in mortality occurred in men and women taking only 1-7 drinks/week - hazard ratios, 0.68 (95% Cl, 0.49-0.94) and 0.78 (95% Cl, 0.61-0.99), respectively, with a similar protective effect from intake of beer or other forms of alcohol. After almost 10 years' follow-up, men taking any alcohol lived on average 7.6 months longer, and women on average 2.7 months longer, compared with non-drinkers. The gross cost for alcohol per life-year gained if consuming 1-7 drinks/week was $5700 in men, and $19000 in women. Conclusions: Moderate alcohol intake in the elderly appears to be associated with significantly longer survival in men 60-74 years and in all elderly women.

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. © 2000 Wiley-Liss, Inc.

Objectives. Hyperhomocysteinemia as well as insulin resistance are considered to be risk factors for the development of coronary artery disease. This study was aimed at determining whether any relationship between plasma insulin and glucose levels and total plasma homocysteine (tHcy) concentrations exists in a population based survey performed 10 years apart. Design and Setting. A cross-sectional study was undertaken during the years 1986–87 to examine risk factors for diabetes and for coronary artery disease (CAD) in the Jewish population of Jerusalem. Ten years later two groups of individuals were invited for re-examination. Subjects. Two groups of individuals were examined: the first one consisted of nondiabetic subjects (n = 86), who had hyperinsulinemia 10 years previously (at the first visit), the second group consisted of normoinsulinemic nondiabetic individuals (n = 265) who had initially normal glucose and insulin levels. Main outcome measures. Metabolic, biochemical and anthropomorphic features were determined. Fasting and post load glucose, as well as insulin concentrations on fasting and 2 h post glucose load were measured at the first and second visits. Plasma tHcy and folic acid were determined only at the second visit. Results. The results demonstrated a significant negative correlation between plasma tHcy levels and insulin levels at the second visit. No difference was found in folic acid levels between these two groups. Conclusions. In general, hyperinsulinemia and hyperhomocysteinemia are both related to an increased incidence of CAD. In our population most of the subjects examined had tHcy levels within the normal range and only a few demonstrated very high levels. However, negative association between insulin levels and tHcy concentrations was found. Possible explanations for this finding are discussed.

OBJECTIVES: This study examined differentials in mortality among adult Israeli men with respect to ethnic origin, marital status, and several measures of social status. METHODS: Data were based on a linkage of records from a 20% sample of the 1983 census to records of deaths occurring before the end of 1992. The study population included 72,527 men, and the number of deaths was 17,378. RESULTS: Differentials is mortality by origin show that mortality was higher among individuals of North African origin than among those of Asian and European origin. After allowance for several socioeconomic indicators, the excess mortality among North African Jews was eliminated. Substantial and consistent differences in mortality were found according to education, occupation, income, possession of a car, housing, and household amenities. Differentials among the elderly were markedly narrower than those among men younger than 70 years. CONCLUSIONS: Some sectors of Israeli society have higher risks of death than others, including, among the male population, these who are poor, less educated, unmarried, unskilled, out of the labor force, and of North African origin.

OBJECTIVES: To analyze the clinical characteristics, associated risk factors, and outcome of hypoglycemia in nondiabetic hospitalized older patients. DESIGN: A retrospective case control study. PARTICIPANTS: Sixty patients, aged 65 years and older, in the acute medical and geriatric wards who developed hypoglycemia. A control group was composed of 83 older patients, sex and age matched, in orthopedic and surgery wards who were undergoing corrective surgery for hip fracture or hernioplasty. MEASUREMENTS: For all patients, data for the following variables were abstracted from the charts: age, sex, degree of hypoglycemia, clinical presentation of hypoglycemia, number and duration of hypoglycemia episodes, nutritional state, and blood chemistry analysis. Risk factors were defined as nutritional state, heart failure, renal or liver disease, malignancy, and infection or sepsis. RESULTS: Mean blood glucose in hypoglycemic cases was 38.9 ± 7 mg/dL. Symptoms and signs of hypoglycemia were noted in only 38.4% (23/60) of patients. All identified risk factors except cachexia were found significantly more frequently in the hypoglycemic patients than in the control group. Mean total number of risk factors was greater in the hypoglycemic group than in the control group, 2.97 ± 1.1 versus 1.64 ±.8, respectively (P

This study provides preliminary evidence on the associations between alcohol consumption patterns and polymorphisms of the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzymes in a Jewish population.Two groups of Jewish men were studied--one group (n = 92) representative of the free-living population of Jerusalem and generally light consumers of ethanol and the other group (n = 53) composed of treatment-enrolled heroin dependent individuals in the same city, most with a history of heavy daily drinking. All participants were interviewed regarding sociodemographic background, present and past alcohol consumption patterns, and familial characteristics including alcohol problems among first-degree relatives. Polymorphisms of the ADH2, ADH3 and ALDH loci were determined for all participants.The less common allele of the ADH2 locus (ADH2*2 allele frequency approximately 20% in Ashkenazic and non-Ashkenazic members of both groups) was related to a reduced mean level of peak weekly alcohol intake in the two groups. In multiple regression models adjusting for family history of alcohol problems and other factors, the ADH2*2 allele accounted for 20% and 30% of the explained alcohol intake variance in these two groups, respectively. Results from a logistic regression indicated that the ADH2*2 allele was also related to infrequent drinking in both groups. Evidence for an independent association between the ADH3 polymorphism and alcohol consumption patterns was not found. The ALDH gene was not polymorphic in this population.This report describes for the first time an association between alcohol consumption patterns and a polymorphism at the ADH2 locus in a Jewish population. The relatively high frequency of the ADH2*2 allele may contribute to the seemingly lower levels of alcohol consumption and heightened sensitivity to alcohol observed among Jews.

AUSTIN, MELISSA A, YECHIEL FRIEDLANDER, BETH NEWMAN, KAREN EDWARDS, ELIZABETH J MAYER-DAVIS, MARY-CLAIRE KING. Genetic influences on changes in body mass index: a longitudinal analysis of women twins. Numerous studies have demonstrated genetic influences on body fat, but there also may be genetic effects on its intraindividual variation over time. This study examined changes in body mass index (BMI) using longitudinal data from two examinations of the Kaiser Permanente Women Twins Study, performed a decade apart. The analysis included 630 women, 185 monozygotic and 130 dizygotic twin pairs, with average ages of 41 years and 51 years at the two examinations, respectively. Age adjusted heritability estimates for the change in BMI over the decade ranged from 0.57 to 0.86 (all ρ≤0.001) using three different statistical analysis approaches, indicating that at least half, and possibly as much as 85%, of the variance in the change in BMI is attributable to genetic influences under a polygenic model. These estimates remained statistically significant after adjusting for environmental factors (ranging from 0.57 to 0.78) and with additional adjustment for BMI at baseline (ranging from 0.41 to 0.79), although dizygotic intraclass correlations were low after these adjustments. Thus, in addition to known environmental and behavioral influences, these results provide evidence for genetic influences on changes in BMI over a decade in women.

The aim of this study was to compare some aspects of lipid metabolism in monocyte-derived macrophages isolated from young males, aged 18-24 years, and old males, aged 74-90 years, who were found healthy in accordance with the Senieur protocol. The parameters tested were metabolism of 125I-acetylated low-density lipoproteins (LDL) and oxidized LDL, incorporation of [3H]cholesterol into cholesteryl ester and expression of apolipoprotein E (apo E) mRNA. Cell association and degradation of 125I-acetylated LDL by macrophages of old and young subjects, respectively, was 15,978 +/- 2492 and 9300 +/- 1416 ng/mg cell protein per 24 h. Incorporation of [3H]cholesterol into cellular [3H]cholesteryl ester in the presence of acetylated LDL in cells isolated from old subjects was twice that in cells from young subjects. The macrophages from both age groups metabolized less 125I-oxidized LDL than 125I-acetylated LDL. Cell association and degradation of 125I-oxidized LDL in cells from old and young subjects, respectively, was 6779 +/- 1398 and 3219 +/- 643 ng/mg cell protein per 24 h. Expression of apo E mRNA was determined by reverse transcriptase polymerase chain reaction. In the basal state, it was 5.8 +/- 0.4 and 2.4 +/- 0.2 photo-stimulated luminescence (PSL) units in cells from the old and young subjects, respectively, and increased after exposure to acetylated LDL. In conclusion, these findings suggest that a combination of higher scavenger receptor activity and increased expression of apo E mRNA in macrophages could contribute to (a) enhanced metabolism of modified LDL and (b) more efficient removal of cholesterol from arteries, thus leading to healthy old age.

Summary Numerous studies have demonstrated genetic influences on levels of coronary heart disease (CHD) risk factors, but there also may be genetic effects on the intraindivid-ual variation in these risk factors over time. Changes in risk factors are likely to reflect genetic-environmental interactions and may have important implications for understanding CHD risk. The present study examines the heritability of changes in CHD risk factors, using data from the two examinations by the Kaiser Perma-nente Women Twins Study, performed a decade apart. The sample consisted of 348 pairs of women twins who participated in both examinations, including 203 MZ pairs and 145 DZ pairs. Average ages at the two examinations were 41 and 51 years, respectively. By means of three different statistical analytic approaches, moderate heritability estimates were demonstrated for changes in LDL cholesterol (h 2 = .25-36) and in HDL cholesterol (h 2 = .23-.58), some of which were statistically significant. Although small to moderate heritability estimates were found for systolic blood pressure (.18-37; P > .05 for some estimates), no genetic influence on changes in diastolic blood pressure was detected. Based on longitudinal twin data in women, this study demonstrates a genetic influence on changes in both lipoprotein risk factors and systolic blood pressure over a decade. In addition to environmental factors, which clearly are operating, the effect of various "variability genes" may be acting independently of the genetic influences on the absolute levels of these risk factors. Both mapping the gene(s) underlying intraindividual variations in these CHD risk factors and understanding their function(s) could lead to targeted intervention strategies to reduce CHD risk among genetically susceptible individuals.

Background : A prospective study in non-institutionalised Australian elderly 60 years and over commenced in Dubbo, NSW in 1988. Aim : To examine clinical and socio-demographic predictors of all-causes mortality. Methods : The data were derived from a community-based sample comprising 1236 men and 1569 women followed for a median period of 62 months. Results : Two hundred and thirty five men (19%) and 184 women (12%) died, 46% of male and 53% of female deaths respectively related to cardiovascular disease. In a proportional hazards model, the significant predictors of mortality were : older age, being married (relative risk [RR]=0.71 for men, 0.74 for women), current smoking for men (RR=3.11), taking more than three alcoholic drinks per day for men (RR=0.37), prior coronary heart disease for men (RR=1.36), severe hypertension for women (RR=1.99), use of anti-hypertensive medication for men (RR=1.74), diabetes for men (RR=1.62), poor-fair self-rated health for women (RR=1.74) and physical disability for men (RR=1.72). Serum cholesterol was associated with mortality in a 'J-shaped' relationship in men and in a reciprocal relationship in women. Blood pressure predicted mortality in an incremental fashion below 75 years, but in older subjects lower pressure was associated with excess mortality. Conclusion : Some predictors of mortality in the well elderly have been identified and a more extended period of follow-up will possibly resolve contradictory findings in some areas.

The possible role of four candidate genes in lipid and lipoprotein response to diet was examined in 63 male students. Four site polymorphisms (signal peptide insertion/deletion, XbaI, MspI and EcoRI) of the apo B gene, three RFLPs (AvaII, StuI, and HincII) of the LDL receptor gene, two SSCPs of the cholesterol 7 alpha-hydroxylase gene and the common apo E genotypes were determined. The average reductions induced by diet in participants homozygous for the absence of the XbaI restriction site (X-X-) of the apo B gene compared to those harboring this site (X+) were: 14.5 mg/dl and 9.4 mg/dl for total cholesterol (TC) (p < 0.09) and 15.5 mg/dl and 7.9 mg/dl for LDL-C (p < 0.003), respectively. Differences in dietary responsiveness among the apo E, LDL receptor and the cholesterol 7 alpha-hydroxylase genotypes were largely insignificant. Using the four apo B polymorphic sites, six unambiguous haplotypes were constructed and a model for their possible evolutionary relationship is presented. Genetic variation in the apo B gene region, as defined by haplotypes, accounted for 8.7% and 24.3% of the phenotypic variance in TC and LDL-C response to diet, respectively. Sequence analysis of a candidate locus, the putative LDL receptor binding region of apo B and its flanking sequences, was performed in two individuals, one homozygous for an apo B "hyper-responding" and another for the "lower-responding" haplotype, and no differences were found. In conclusion, haplotypes at the apo B gene locus are associated with dietary response of TC and LDL-C in young males. Yet, the sequence variation responsible for these differences is possibly located outside the putative LDL receptor binding domain.

Background Studies indicate that Socio Economic Position (SEP) might be an important predictor of cardiometabolic disease mortality and morbidity; yet the importance of timing of the effect of SEP on cardiometabolic risk factors has not been fully established. Our aim was to assess the independent effect of SEP in both childhood and adulthood on cardiometabolic risk factors in young adults and to examine potential interactive effects of SEP at both time points on these risk factors. Methods This is a prospective follow-up of 1132 individuals, born in Jerusalem between the years 1974–76, to young adulthood with bio-medical data at mean age 32. Outcomes include Body Mass Index (BMI), Waist to Hip Ratio (WHR), blood pressure, waist circumference (WC), pelvis circumference, body fat percentage, fasting levels of Triglyceride (TG), HDL-C, LDL-C, glucose, insulin, and lifestyle characteristics, including smoking and physical activity. SEP in childhood was based on father’s occupation (scale 1–6) and in adulthood, on subject’s occupation (scale 1–5). Additional analyses used maternal and subject’s years of education. GLM and logistic regression models were used with mutual adjustment for SEP at both time points and further adjustment for gender, ethnic origin and fasting duration. Log transformation was used for TG and insulin levels. Results Independently of current SEP, lower childhood SEP was significantly associated with higher logTG (β=0.013, p=0.042), higher LDL (β=1.979, p=0.023), higher body fat percentage (β=0.476, p=0.025) and higher odds of physical inactivity (OR=1.13, p=0.043). Independently of childhood SEP, lower adulthood SEP was significantly associated with lower HDL level (β=–0.934, p=0.026), higher WHR (β=0.006, p=0.002), and higher odds of smoking (OR=1.31, p=0.001) and physical inactivity (OR=1.34, p Conclusion Adverse SEP at both childhood and adulthood has an independent influence on physiological and behavioral risk factors. The interaction between SEP in childhood and adulthood in their effect on cardiometabolic risk factors points to the important role played by social mobility in affecting adult poorer health.

Objective: To assess the attitude and factors affecting decision-making by offspring for life-sustaining measures toward their elderly terminally ill parents. Design: Survey Setting: Acute geriatric department of a university-affiliated teaching hospital. Patients and Participants: 108 offspring of 48 terminally ill elderly patients were interviewed. Measurements: The attitude of offspring regarding life-sustaining measures based on a comprehensive questionnaire, administered by face-to-face interview, that included clinical, social, and religious information for each patient and social, religious, demographic, and educational information for each family member. Results: A significant majority requested the continuation of fluid, nutrition, and medication (78%, 66%, 73%, respectively). A minority of 25%–29% requested the initiation of resuscitation, mechanical ventilation, and dialysis. Active euthanasia was requested by seven offspring. Factors that significantly affected offspring's decisions were the degree of religious observance and close relationship. Approximately 50% of offspring believed they knew their parents' wishes, but most of them did not comply with the parents' wishes. The offspring's preferences for themselves differed in important aspects from the requests for their parents. The great majority stated that a family member and/or the responsible physician should be involved in the decision-making process (76% and 79%, respectively). Only 2.0% suggested the participation of an ethics committee, and the court was rejected by all. Conclusions: Basic life-sustaining measures are requested for the terminally ill parents by most of the offspring. A significant minority even requested aggressive life-sustaining measures. The degree of religiosity and closeness of relationship influenced offspring's request most strongly.

A dietary trial was carried out on a group of offspring whose parents were hospitalized for an acute myocardial infarction. The XbaI Restriction Fragment Length Polymorphism (RFLP) was used to examine the genetic contribution of variation at this apo B locus to the response of lipids and lipoproteins to dietary manipulations. Twenty participants were homozygotes for the 8.0 kb fragment (X1X1), two were homozygotes for the 5.0 kb fragment (X2X2), and 15 were heterozygotes (X1X2). Subjects were randomized to a 5-week crossover study. Half began on a low SFA--cholesterol (LSC) diet for 5 weeks and, after a washout period of 4 weeks, they were placed on a high SFA--cholesterol (HSC) diet for a second period of 5 weeks. This order was reversed in the second group of participants. Significant changes in total cholesterol, LDL-C, and apo B were observed when subjects were moved from the LSC to the HSF diet. The corresponding average change induced by the dietary manipulations in X1X1 subjects compared with subjects with X2 allele were: 18.1 +/- 17.6 mg/dl and 9.5 +/- 19.6 mg/dl for total cholesterol and 15.8 +/- 15.3 mg/dl and 4.8 +/- 20.9 mg/dl for LDL-C, respectively. Our observation indicated that variation at the apo B XbaI locus may interact with baseline levels to determine individual dietary response in LDL-C level. However, the differences between the genotypic classes were not statistically significant, suggesting that the apo B XbaI locus is not a major determinant of interindividual differences in lipid and lipoprotein response to diet in this population.

Objective The purpose of this study was to examine the association between preeclampsia and cancer incidence. Study Design The Jerusalem Perinatal Study is a population-based cohort of all births to 41,206 residents of Western Jerusalem from 1964-76. Cancer incidence to 2004 was assessed by linkage of the cohort with the Israel Cancer Registry. Cox's proportional hazards models were constructed to estimate the hazard ratio for cancer among women who had had preeclampsia. Results Preeclampsia was associated with a 1.23-fold increased risk of cancer at all sites, a 37% increased risk of breast cancer, and more than a doubling of ovarian cancer risk. Analysis by morphologic condition yielded significantly increased risks for malignancies that were classed as cystic mucinous and serous (relative risk, 1.96; 95% CI, 1.00-3.83) and for ductal, lobular, and medullary carcinomas (relative risk, 1.40; 95% CI, 1.07-1.83). No differential association was observed by sex of offspring. Conclusion Our study suggests that the previously described protective effect of preeclampsia on cancer is not universal.

Deafness occurs in about 1 per thousand live births, and at least 50% of congenital deafness is hereditary. The aim of this study was to examine the number of loci for recessively in herited severe nerve deafness of early onset within the Israeli population and to compare the results to those obtained in other populations. The Jewish population in Israel originates from many countries and may be divided into Sephardi, Eastern and Ashkenazi Jews, and the matings will be intraethnic or interethnic. Data were obtained on 133 deaf couples who lived in the Tel Aviv area, through the files of the Helen Keller Center. Causes of deafness in the spouses were studied and data on their children were obtained. Among 111 couples who had recessive or possibly recessive deafness and had at least 1 child, there were 12 with only deaf children and 5 with both deaf and hearing children. The number of loci for recessive deafness in the whole group was estimated at 8–9. Intraethnic and interethnic matings gave an estimate of 6.7 and 22.0 loci, respectively, which indicates that within populations fewer loci exist with recessive mutations for deafness than between populations. it could be shown that the sharing of loci between spouses decreased with increasing geographical distance of their origin. The results provide data for genetic counseling in Israel for deaf couples who have no children or have one hearing or one deaf child.

Segregation analyses were performed for plasma low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) in five Christian Arab kindreds identified through probands with familial hypercholesterolemia. In this subset of the Christian Arab community, the results were consistent with major gene determination of LDL-C with allele frequency (q) of 0.042 (95% confidence interval 0.008–0.079) in addition to polygenic transmission (h 2= 0.34). The “Lebanese” allele was identified directly by polymerase chain reaction and HinfI restriction analysis. Analysis of this mutation permits direct diagnosis of familial hypercholesterolemia in most affected individuals although our results indicated the possible existence of an additional independent factor leading to elevated LDL-C levels. The segregation results for TG indicated the presence of a major effect, although the existence of a major gene could not be demonstrated. There was also no evidence of a major locus effect on HDL-C levels.

Plasma lipids, lipoproteins, and lipoprotein[a] (Lp[a]) levels were determined in 216 members of 14 families with familial hypercholesterolemia (FH). Ninety-nine subjects harbored a mutant low density lipoprotein (LDL) receptor allele as confirmed by molecular genetic analysis. Four different mutant alleles were identified, each in a defined genetic group, Druze, Christian-Arabs, and Ashkenazi and Sephardic Jews. The findings in FH subjects (cases) were compared with their nonaffected family members (controls). Plasma Lp[a] levels increased with age in the controls but not in cases and were different among the four genetic groups. Mean plasma Lp[a] levels were significantly higher in cases (33 mg/dl) than in controls (22 mg/dl). Plasma LDL cholesterol levels were raised in cases of the four genetic groups to a similar extent, in contrast to the mean plasma Lp[a] that varied. The Lp[a] level was higher by 30-33% in cases from the Druze, Christian-Arabs, and Jewish-Ashkenazi groups but by 110% in the Jewish-Sephardic group. Apo[a] isoform distribution was similar in cases and controls within each genetic group. Lp[a] levels were highest in subjects with LpS1 isoform, in particular in cases from the Jewish-Sephardic group. These data indicate that the higher Lp[a] levels in FH heterozygotes cannot be attributed solely to lack of functional LDL receptor molecules but possibly reflect multiple gene interactions.

A prospective study of the health of elderly Australians recently commenced in Dubbo, NSW, the study population comprising 1,237 males and 1,568 females 60 years and older. The prevalence rates of coronary heart disease (CHD) and its associated risk factors have been examined in the baseline data. The age-standardized rate of CHD was 23.8/100 in males and 18.1/100 in females. The prevalence rate increased with age until 79 years in males, thereafter declining. The rate increased steadily with age in females. In a multiple logistic model, the following possible predictors of CHD were included: age, cigarette smoking, use of alcohol, exercise, religiosity, years of education, hypertension, diabetes, family history of CHD, body mass index, lipid and lipoprotein variables. The presence of CHD in males was significantly predicted by age, hypertension (odds ratio, OR = 1.40), family history (OR = 2.05), and high density lipoprotein (HDL) cholesterol (OR = 0.78). The significant predictors in females were age, years of education (OR = 0.82), hypertension (OR = 1.45), family history (OR = 1.77), serum triglycerides (OR = 1.30), and HDL cholesterol (OR = 0.73). Hypertension was found to be a stronger predictor of CHD in the younger age group (60-69 years), while diabetes was a predictor of CHD in older males (70-79 years). Our findings require confirmation in the prospective study now in progress.

1. Using a nested case-control study of 661 non-institutionalized elderly (> or = 60 years) residents of Dubbo, New South Wales, Australia, the aim of this study is to determine whether the A1166C polymorphism of the angiotensin II type I (AT1) receptor gene is associated with hypertension in the elderly. 2. Individuals were classified as isolated systolic hypertension (ISH, n = 146), systolic diastolic hypertension (SDH, n = 188), or normotensive, age- and sex-matched controls (n = 327). AA, CC and AC genotypes were determined using restriction fragment length polymorphism analysis of DNA generated by nested polymerase chain reaction. 3. A univariate analysis (chi 2) was complemented by a logistic regression analysis, facilitating adjustment for potential confounders. The unadjusted genotype and allele frequencies in ISH or SDH subjects did not differ significantly from the control subjects (chi 2 = 3.0, P = 0.55, 4 d.f.; chi 2 = 3.0, P = 0.23, 2 d.f., respectively). After adjustment for potential confounders neither genotype nor allele predicted ISH or SDH in this cohort. 4. From this study we conclude that the A1166C polymorphism of the AT1 receptor gene is not a marker for ISH nor for SDH in this large, elderly community sample.