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Biomedical subjects

Y Friedlander

Publications and source records attributed to Y Friedlander.

At least 37 records · Page 2Linked to original sources
PubMed2000

A cholesterol-lowering gene maps to chromosome 13q.

A cholesterol-lowering gene has been postulated from familial hypercholesterolemia (FH) families having heterozygous persons with normal LDL levels and homozygous individuals with LDL levels similar to those in persons with heterozygous FH. We studied such a family with FH that also had members without FH and with lower-than-normal LDL levels. We performed linkage analyses and identified a locus at 13q, defined by markers D13S156 and D13S158. FASTLINK and GENEHUNTER yielded LOD scores >5 and >4, respectively, whereas an affected-sib-pair analysis gave a peak multipoint LOD score of 4.8, corresponding to a P value of 1.26x10-6. A multipoint quantitative-trait-locus (QTL) linkage analysis with maximum-likelihood binomial QTL verified this locus as a QTL for LDL levels. To test the relevance of this QTL in an independent normal population, we studied MZ and DZ twin subjects. An MZ-DZ comparison confirmed genetic variance with regard to lipid concentrations. We then performed an identity-by-descent linkage analysis on the DZ twins, with markers at the 13q locus. We found strong evidence for linkage at this locus with LDL (P<.0002), HDL (P<.004), total cholesterol (P<.0002), and body-mass index (P<.0001). These data provide support for the existence of a new gene influencing lipid concentrations in humans.

Adult↗
PubMed2000

Ethnic differences in the frequency of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in healthy Israeli populations.

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 = 12.35p < 0.001, 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.

Adolescent↗
PubMed2000

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.

Aged↗
PubMed2000

Apolipoprotein B gene polymorphisms and serum lipids: meta-analysis of the role of genetic variation in responsiveness to diet.

BACKGROUND: The genetic variance determining plasma lipid and lipoprotein concentrations may modify individual responsiveness to alterations in dietary fat and cholesterol content. OBJECTIVE: The aim was to examine the role of apolipoprotein (apo) B DNA polymorphisms in responsiveness of plasma lipids and lipoproteins to diet. DESIGN: A controlled dietary intervention study was conducted in 44 healthy, middle-aged subjects with a 3-mo baseline, a 1-mo fat-controlled, a 1-mo high-fat, and a 1-mo habitual diet period. We also conducted a meta-analysis of all published dietary trials, including our own. RESULTS: In our own dietary study, the apo B XbaI restriction-site polymorphism affected the responsiveness to diet of the plasma LDL-cholesterol concentration (P < 0.05, repeated-measures analysis of variance). Especially during the high-fat diet, homozygous absence of the XbaI restriction site (X(-)/X(-)) was associated with a greater increase in LDL cholesterol (44 +/- 5%) than was X(+)/X(+) (27 +/- 7%) or X(+)/X(-) (40 +/- 5%). The high-fat diet also induced a larger increase in plasma LDL cholesterol in subjects with the R(-)/R(-) genotype (homozygous absence of the EcoRI restriction site) (59 +/- 10%) than in those with the R(+)/R(-) (39 +/- 6%) or R(+)/R(+) (36 +/- 4%) genotype. The M(+)/M(+) genotype (homozygous presence of the MspI restriction site) was also more responsive (41 +/- 3% increase in LDL cholesterol) than the M(+)/M(-) genotype (27 +/- 10% increase). The meta-analysis supported the finding of the significant role of the EcoRI and MspI polymorphisms, but not that of the XbaI polymorphism. CONCLUSIONS: The present study indicated that the apo B EcoRI and MspI polymorphisms are associated with responsiveness to diet.

Apolipoproteins B↗
PubMed2000

The association between two common mutations C677T and A1298C in human methylenetetrahydrofolate reductase gene and the risk for diabetic nephropathy in type II diabetic patients.

Mutations of the methylenetetrahydrofolate reductase (MTHFR) gene have been shown to be associated with a predisposition to developing diabetic nephropathy (DN) in specific populations. The frequency of two MTHFR mutations, a recently described mutation in the human MTHFR gene A1298C and C677T, whose association with DN is already known, was determined in an Israeli Jewish population with type 2 diabetes mellitus (DM). Both A1298C and C677T are highly prevalent in the diabetic population with allele frequencies of 0.35 and 0.36, respectively. The genotype frequency and allele frequency for these two polymorphisms in patients who are normoalbuminuric (n = 55) were compared with those of patients who had either micro- or macroalbuminuria (n = 43). For both polymorphisms, there were no significant differences in either the genotype distribution or allele frequency in patients with or without DN. However, in patients with serum folate <15.4 nmol/L, there was a greater incidence of DN in those patients who were homozygous or heterozygous for the C677T mutation. For the A1298C mutation, there is evidence suggesting that the homozygous state may be protective in patients with low-normal serum folate. Folate supplementation in diabetic patients with the C677T mutation and low-normal serum folate may prevent the onset or retard the progression of DN.

Aged↗
PubMed2000

Fasting plasma glucose in non-diabetic elderly women predicts increased all-causes mortality and coronary heart disease risk.

AIM: To confirm the hypothesis that upper normal plasma glucose levels in non-diabetic subjects are independently predictive of mortality and cardiovascular disease (CVD). METHODS: The study reports on 113 months' follow-up in a prospective study of CVD in the Australian elderly, The Dubbo Study. The cohort, first examined in 1988-89, consisted of 2805 men and women 60 years and older. Of the cohort, 2419 (86%) were defined as non-diabetic. The prediction of outcomes by quartile of fasting plasma glucose was examined in a Cox proportional hazards model, after linkage to hospital and death records. RESULTS: All-causes mortality increased progressively across quartile of fasting plasma glucose in both sexes, reaching statistical significance only in women. Coronary heart disease (CHD) incidence increased similarly, the increases being proportionately greater in women. Ischaemic stroke did not show a consistent gradient with fasting plasma glucose. After adjustment for age and other risk factors, all-causes mortality, CHD and ischaemic stroke incidence were not significantly related to plasma glucose in men. In women, all-causes mortality and CHD incidence showed a significant gradient with glucose quartile. Hazard Ratio (95% confidence intervals) for death in glucose Quartile IV (5.3-6.0 mmol/L) was 1.49 (1.03-2.14) and for CHD incidence was 1.52 (1.08-2.15). Subjects in the upper quartiles of fasting plasma glucose showed a clustering of overweight, hypertension, elevated serum triglycerides, reduced high density lipoprotein cholesterol and excess of small dense low density lipoprotein, suggestive of the Insulin Resistance Syndrome. CONCLUSION: Fasting plasma glucose levels in the upper normal range in non-diabetic elderly subjects appear to be associated with increased all-causes mortality and CHD, especially in women.

Blood Glucose↗
PubMed2000

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.

Administration, Intranasal↗
PubMed2000

Sib-pair linkage analysis of longitudinal changes in lipoprotein risk factors and lipase genes in women twins.

Based on longitudinal twin data in women, we have previously demonstrated a genetic influence on changes in lipoprotein risk factors, blood pressure measurements, and body mass index over a decade. The present study examined the linkage between changes in lipoprotein variables and candidate genes encoding the hormone-sensitive lipase (HSL), hepatic lipase (HL), and lipoprotein lipase (LPL). The sample consisted of 126 dizygotic (DZ) pairs of women twins who participated in the two examinations of the Kaiser Permanente Women Twins Study, performed a decade apart. Using quantitative sib-pair linkage analysis, a linkage was demonstrated between the locus for hormone-sensitive lipase and age-adjusted changes in plasma triglyceride (P = 0.015), which became more significant after adjustment for environmental factors and the exam-1 level (P = 0.005). There was also evidence suggesting linkage between the locus for hepatic lipase and changes in triglyceride (P = 0.023), but no linkage was detected for lipoprotein lipase and changes of lipid levels with time. These findings suggest that variation at these candidate gene loci may underlie a portion of the intraindividual variations in these coronary heart disease (CHD) risk factors, and that studies to identify the functional variants could provide new insights into genetic susceptibility to cardiovascular disease.

Adult↗
PubMed1999

Inheritance of LDL peak particle diameter: results from a segregation analysis in Israeli families.

Genetic and environmental determinants of LDL peak particle diameter (LDL-PPD) were investigated in a sample of 80 kindreds residing in kibbutz settlements in Israel. The sample included 182 males and 191 females ages 15-93 years. LDL-PPD levels were first adjusted for variability in sex and age. Commingling analysis demonstrated that a mixture of two normal distributions fit the adjusted LDL-PPD levels better than did a single normal distribution. Complex segregation analysis was first applied to these sex and age adjusted data but was not conclusive. However, when the regression model for sex and age allowed coefficients to be ousiotype (class) specific, the mixed environmental model was rejected while a major Mendelian model was not. These results suggest that the particular genotypes determined by the major gene, which are associated with different phenotypic variances, are likely to be more realistic, and that this analytic approach can contribute to improving our understanding of the genetics of LDL particle size.

Adolescent↗
PubMed1999

Inheritance of heart rate variability: the kibbutzim family study.

Heart rate variability (HRV) measures are associated with coronary heart disease incidence and mortality. Therefore insight into the genetic and environmental determinants of these measures may have clinical relevance. We assessed the role of genetic and environmental factors of time domain and frequency domain HRV indices. Participants were 451 kibbutz members, aged 15 and up, belonging to 80 families. HRV indices were calculated from Holter recordings measured over 5 min. Our data indicate that for the two time- and four frequency domain indices, a mixture of two normal distributions fit the data significantly better than a single normal distribution (P<0.05). We used complex segregation analysis to infer the modes of inheritance of these HRV measures. We found evidence for possible involvement of a recessive major gene in the inheritance of the root mean square of successive differences in RR intervals (RMSSD), which is predominantly vagally mediated. A putative major gene explains 28%-34% of the adjusted inter-individual variability. The SD, determined by a mixture of mechanisms, is influenced by environmental and polygenic effects, but not by a major gene. The findings regarding the heritability of the frequency domain indices were not conclusive. However, the involvement of genetic factors was not rejected. Additional studies in extended families are needed to confirm the involvement of major genes in the determination of the autonomic activity.

Adolescent↗
PubMed1999

Genetic and environmental sources of QT interval variability in Israeli families: the kibbutz settlements family study.

QT interval prolongation not attributed to long QT syndromes is reported to be associated with increased risk of sudden and nonsudden cardiac death. Genetic and environmental determinants of QTc interval were investigated in an unselected free living population sample of 80 kindreds residing in kibbutz settlements in Israel. The sample included 214 males and 227 females aged 15-97 years. There was a significant familial aggregation of adjusted QT interval levels, as indicated by inter- and intraclass correlation coefficients significantly different from zero. Complex segregation analysis applied to the sex- and age-adjusted data was not conclusive and heterogeneous etiologies for individual differences were suggested. There was evidence for a single recessive locus (q = 0.173) with a major effect in addition to polygenic effects (h2 = 0.41) that explained the mixture of distributions. In parallel, a nontransmitted environmental major factor in addition to polygenic effects that explained the adjusted variation in QTc could not be rejected. Similar results were obtained upon the adjustment for sex, age, and environmental covariables. The major factor, either genetic or environmental, and polygenic-loci accounted for about 20 and 33% of the adjusted QTc variation, respectively. Furthermore, sex, age, measured environmental covariables, the unmeasured major factor, and the unmeasured polygenes could account for 63% of the variation of QTc in these families. Our data provide evidence for a major factor, either genetic or environmental, in addition to a polygenic background, influencing QT interval levels in a population-based sample of pedigrees.

Adolescent↗
PubMed1999

The A1166C mutation in the angiotensin II type I receptor and hypertension in the elderly.

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.

Angiotensin II↗
PubMed1999

A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations.

Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocysteine metabolism. Previous studies revealed that a common mutation in MTHFR gene C677T is related to hyperhomocysteinemia and occlusive vascular pathology. In the current study, we determined the prevalence of a newly described mutation in the human MTHFR gene A1298C, and the already known C677T mutation, and related them to plasma total homocysteine and folate concentrations. We studied 377 Jewish subjects, including 190 men and 186 women aged 56.8 +/- 13 y (range 32-95 y). The frequency of the homozygotes for the A1298C and the C677T MTHFR mutations was common in the Jewish Israeli population (0.34 and 0.37, respectively). Subjects homozygous (TT) for the C677T mutation had significantly greater plasma total homocysteine concentrations (P < 0.01) than subjects without the mutation (CC). Homozygotes (CC) for the A1298C mutation did not have elevated plasma total homocysteine concentrations. Our study indicated that subjects with the 677CC/1298CC genotype had significantly lower concentrations (P < 0. 05) than those with a 677CC/1298AA genotype. Neither mutation (the A1298C and the C677T) was associated with established cardiovascular risk factors such as hypertension, elevated total cholesterol or body mass index.

Adult↗
PubMed1999

Longitudinal changes in attitudes of offspring concerning life-sustaining measures for their terminally ill parents.

OBJECTIVES: To define longitudinal changes in the attitudes of offspring concerning life-sustaining measures for their older, terminally ill parents and to determine whether experience of a "life event" influences such decisions. DESIGN: An attitudinal survey of three groups. SETTING: The geriatric department of a university-affiliated general hospital. PARTICIPANTS: Fifty-one subjects who had been interviewed regarding life-sustaining treatment for their terminally ill parents were reinterviewed 6 years later. In addition, a control group composed of 116 participants was generated from patients visiting hospital outpatient clinics. The control group had no prior experience involving hospitalization of a first-degree relative as a result of a life-threatening situation. INTERVENTIONS: Each subject took part in a personal interview. MAIN OUTCOME MEASURES: Attitudes regarding life-sustaining measures were assessed, and the subjects' sociodemographic and religious characteristics were noted. RESULTS: The attitudes of offspring in the acute phase situation and after the passage of 6 years were strikingly consistent. Twenty-one percent had requested the initiation of resuscitation in the acute phase ("real time"), and 27.4% said the same 6 years later. The provision of nutrition and medication was requested by approximately 70% of participants both at the acute phase and 6 years later. When comparing each individual's personal views at the interviews with all others, consistency in attitude was found among answers to most questions. When comparing the acute phase group with the control group, a significantly higher percentage of the former requested the initiation of resuscitation (48.3% vs 25%), whereas a smaller percentage preferred that the decision be made by the physician (3.5% vs 21.3%). Active euthanasia was requested by 6.5% of the acute phase group and 12.9% of the control group. CONCLUSIONS: The decisions made by offspring regarding life-sustaining measures for their terminally ill parent at real time remain unchanged 6 years after the event. Exposure to a life event significantly affects the decision-making of the offspring of a terminally ill parent. However, the subject's attitude toward extreme solutions--opposing active euthanasia and requesting the administration of nutrition and medication--was not influenced by the fact that the subject had undergone a life event.

Adult Children↗
PubMed1999

Mortality differentials among Israeli men.

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.

Adult↗
PubMed1998

Family history as a risk factor for primary cardiac arrest.

BACKGROUND: The hypothesis that a family history of myocardial infarction (MI) or primary cardiac arrest (PCA) is an independent risk factor for primary cardiac arrest was examined in a population-based case-control study. In addition, we investigated whether recognized risk factors account for the familial aggregation of these cardiovascular events. METHODS AND RESULTS: PCA cases, 25 to 74 years old, attended by paramedics during the period 1988 to 1994 and population-based control subjects matched for age and sex were identified from the community by random digit dialing. All subjects were free of recognized clinical heart disease and major comorbidity. A detailed history of MI and PCA in first-degree relatives was collected in interviews with the spouses of case and control subjects by trained interviewers using a standardized questionnaire. For each familial relationship, there was a higher rate of MI or primary cardiac arrest (MI/PCA) in relatives of case compared with relatives of control subjects. Overall, the rate of MI/PCA among first-degree relatives of cardiac arrest patients was almost 50% higher than that in first-degree relatives of control subjects (rate ratio [RR]=1.46; 95% CI=1.23 to 1.72). In a multivariate logistic model, family history of MI/PCA was associated with PCA (RR=1.57; 95% CI=1.27 to 1.95) even after adjustment for other common risk factors. CONCLUSIONS: Family history of MI or PCA is positively associated with the risk of primary cardiac arrest. This association is mostly independent of familial aggregation of other common risk factors.

Aged↗
PubMed1998

Familial aggregation of heart rate variability based on short recordings--the kibbutzim family study.

The objective of this study was to assess the familial aggregation of heart rate variability (HRV), a readily measurable noninvasive reflection of cardiac autonomic function. Familial correlations were analyzed in 451 kibbutz members aged 15-97 years belonging to 80 kindreds. Five-minute duration Holter recordings made during silent supine spontaneous breathing and metronomic breathing were analyzed in the time and frequency domains. The present analysis considers the familial correlations and the heritability estimates of two time-domain indices, the standard deviation (SD) of the R-R interval (RR), reflecting total variability, and the root mean square of successive differences in RR intervals (RMSSD), reflecting vagal (parasympathetic) tone. During free breathing, age- and sex-adjusted correlations between parents and their children (r=0.24 for both indices) and between adult siblings above 30 years of age (r=0.24 and t=0.34 for SD and RMSSD, respectively) were statistically significant, whereas spouse correlations (r=-0.04, r=-0.02 for SD and RMSSD, respectively) and correlations in younger siblings (r=-0.22 and r=0.01, respectively) were not. Significant heritability estimates were demonstrated for the two indices (h2=0.41 for SD and h2=0.39 for RMSSD). These findings suggest that familial aggregation of HRV characteristics is determined mostly by genetic factors and less so by environmental factors and provide a basis for continuing the investigation into the underlying genetic influences on HRV.

Adolescent↗