Age-related changes in Egr1 transcription and DNA methylation within the hippocampus.

Aged animals show functional alterations in hippocampal neurons that lead to deficits in synaptic plasticity and changes in cognitive function. Transcription of immediate-early genes (IEGs), including Egr1, is necessary for processes such as long-term potentiation and memory consolidation. Here, we show an age-related reduction in the transcription of Egr1 in the dentate gyrus following spatial behavior, whereas in the area CA1, Egr1 is reduced at rest, but its transcription can be effectively driven by spatial behavior to levels equivalent to those observed in adult animals. One mechanism possibly contributing to these aging-related changes is an age-associated, CpG site-specific change in methylation in DNA associated with the promoter region of the Egr1 gene. Our results add to a growing body of work demonstrating that complex transcriptional and epigenetic changes in the hippocampus significantly contribute to brain and cognitive aging. © 2016 Wiley Periodicals, Inc.

Adult-onset diabetes among Arabs and Jews in Israel: a population-based study.

AIMS: To study the age at presentation and factors associated with adult-onset diabetes (≥ 20 years) among Arabs and Jews in Israel. METHODS: Participants (n = 1100) were randomly selected from the urban population of the Hadera District in Israel. The study sample was stratified into equal groups according to sex, ethnicity (Arabs and Jews) and age. Information on age at diabetes presentation, family history of diabetes, history of gestational diabetes, socio-demographic and lifestyle characteristics was obtained through personal interviews. Self reports of diabetes were compared with medical records and were found reliable (κ = 0.87). The risk for diabetes was calculated using Kaplan-Meier survival analysis. Factors associated with diabetes in both ethnic groups were studied using Cox proportional hazard model. RESULTS: The prevalence of adult-onset diabetes was 21% among Arabs and 12% among Jews. Arab participants were younger than Jews at diabetes presentation. By the age of 57 years, 25% of Arabs had diagnosed diabetes; the corresponding age among Jews was 68 years, a difference of 11 years (P < 0.001). The greater risk for diabetes among Arabs was independent of lifestyle factors, family history of diabetes and, among women, history of gestational diabetes; adjusted hazard ratio 1.70; 95% confidence interval 1.19-2.43. CONCLUSIONS: Arabs in Israel are at greater risk for adult-onset diabetes than Jews and are younger at diabetes presentation. Culturally sensitive interventions aimed at maintaining normal body weight and active lifestyle should be targeted at this population. Possible genetic factors and gene-environmental interactions underlying the high risk for diabetes among Arabs should be investigated.

Role of fat, animal protein, and dietary fiber in breast cancer etiology: a case-control study.

A case-control study of 818 breast cancer (BC) patients and 2 matched control groups, surgical controls (SCs) and neighborhood controls (NCs), was undertaken in Israel between 1975 and 1978. The interview schedule included a detailed dietary history based on the frequency of consumption of 250 food items, which were grouped according to their principal nutrient component. The average frequency of consumption of each food item in each nutrient group was computed. Medical, demographic, hormonal, and parity histories were also obtained. Risks associated with fat, animal protein, and fiber consumption were evaluated. Two types of analysis were performed [in 2 age groups (less than 50 yr and greater than or equal to 50 yr)], using the conditional logistic method: evaluating the risk attributable to nutrition only and controlling for nondietary confounding factors as well. When no adjustment for nondietary confounding factors was made, the risk increased with fat intake in both age groups [one-tailed P-value for linear trend = .08 and .07 in age less than 50 and .01 and .10 for the greater than or equal to 50 age category for the BC case (BCC)-SC and BCC-NC comparisons, respectively]. Increased fiber intake decreased the risk in the younger age group (one-tailed P-value for linear trend = .06 and .07 for the BCC-SC and BCC-NC comparisons, respectively), while in the 50-or-over age category the trend was inconsistent. The risk associated with animal protein was much less clear. For women in the highest quartiles of fat and animal protein intake and the lowest quartiles of fiber intake, risk was about twice as high as that for women in the lowest quartiles of fat and animal protein intake and in the highest quartile of fiber intake (one-tailed P-value for linear trend = .04 and .08 for age less than 50 and .08 and .09 for the age category greater than or equal to 50 BCC-SC and BCC-NC comparisons, respectively). When hormonal and demographic confounding factors were controlled for, this pattern persisted but it remained significant for 1 control only. Power increased when cases were analyzed against both controls simultaneously (one-tailed P-value for linear trend = .10 for age less than 50 and .02 for age greater than or equal to 50). Thus a higher fat-animal protein and lower fiber diet is associated with increased cancer risk, but this relationship needs to be studied further.

Coffee and methylxanthines and breast cancer: a case-control study.

A dietary case-control study based on 818 newly diagnosed breast cancer (BC) patients was conducted in Israel between 1975 and 1978. The role of coffee and total methylxanthine intake from coffee, tea, cola, chocolate, and cocoa drinks was evaluated in the BC patients as compared to that in two matched control populations [surgical controls (SC) and neighborhood controls (NC)]. Because it has been suggested that caffeine enhances mammary carcinogenesis in rats fed high polyunsaturated fat diets, analysis was done also in relation to fat consumption. When comparison was done to both matched control groups, a nonsignificant negative association was found between consumption of cups of coffee and BC (odds ratios of greater than or equal to 4 cups of coffee/day vs. less than or equal to 1 per week = 0.6 for BC/NC and 0.7 for BC/SC). This association was observed in all 3 ethnic subgroups studied. The pattern was stronger among the high-fat consumers after controlling for several hormonal confounding factors (two-tailed P-value for linear trend = 0.06 for SC and P = 0.05 for NC). In addition, when the consumption of methylxanthine of BC patients was compared to that of benign breast patients, adjusted by age and ethnic group, a diminished risk was found (odds ratio for BC of the highest level of methylxanthine vs. lowest level = 0.59).

Low-fiber intake as an etiologic factor in cancer of the colon.

A case-control dietary study of 198 patients with cancer of the colon and two matched control groups demonstrated a significantly lower fiber consumption frequency among the cancer patients. This difference was not confined to a few items. Of the 73 items on the fiber list, 61 were eaten less often by the cancer patient than by a neighborhood control, and 57 were consumed less frequently than by a surgical control. These findings support the hypothesis that low-residue foods play an etiologic role in colon carcinogenesis. A mechanism related to the possible potential carcinogenic properties of degraded biliary compounds may be implicated.

Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies.

We conducted a combined analysis of the original data to evaluate the consistency of 12 case-control studies of diet and breast cancer. Our analysis shows a consistent, statistically significant, positive association between breast cancer risk and saturated fat intake in postmenopausal women (relative risk for highest vs. lowest quintile, 1.46; P less than .0001). A consistent protective effect for a number of markers of fruit and vegetable intake was demonstrated; vitamin C intake had the most consistent and statistically significant inverse association with breast cancer risk (relative risk for highest vs. lowest quintile, 0.69; P less than .0001). If these dietary associations represent causality, the attributable risk (i.e., the percentage of breast cancers that might be prevented by dietary modification) in the North American population is estimated to be 24% for postmenopausal women and 16% for premenopausal women.

Dietary factors and cancer in Israel.

The risk of developing cancer is relatively higher in the European-born Israeli population than in those originating from the Middle Eastern or North African countries. The majority of cancer sites with a higher risk in the European groups involve the gastrointestinal and reproductive systems. Certain leads suggest that at least some of these differences may be attributed to diet. Data based on case-control studies are provided; they indicate a high consomption of starches among gastric cancer patients and a lower fiber consumption in patients with cancer of the colon. The latter observations may be extended to cancer of the breast, ovary, and corpus uteri, assuming an interplay between the concentration of bile degradation products and hormone metabolism. Although a low fiber consumption seems a more likely mechanism, a higher fat consumption is also compatible with this model. However, due to the complexity of human nutrition, it seems unwarranted to incriminate any single dietary factor in carcinogenesis. A better understanding of the metabolic pathways, coupled with consistent observations from distinct populations, should be looked for.

Increased expression of BDNF transcript with exon VI in hippocampi of patients with pharmaco-resistant temporal lobe epilepsy.

A putative role of the brain-derived neurotrophic factor (BDNF) in epilepsy has emerged from in vitro and animal models, but few studies have analyzed human samples. We assessed the BDNF expression of transcripts with exons I (BDNFI), II (BDNFII), IV (BDNFIV) and VI (BDNFVI) and methylation levels of promoters 4 and 6 in the hippocampi of patients with pharmaco-resistant temporal lobe epilepsy (TLE) (n=24). Hippocampal sclerosis (HS) and pre-surgical pharmacological treatment were considered as clinical independent variables. A statistical significant increase for the BDNFVI (p<0.05) was observed in TLE patients compared to the autopsy control group (n=8). BDNFVI was also increased in anxiety/depression TLE (N=4) when compared to autopsies or to the remaining group of patients (p<0.05). In contrast, the use of the antiepileptic drug Topiramate (TPM) (N=3) was associated to a decrease in BDNFVI expression (p<0.05) when compared to the remaining group of patients. Methylation levels at the BDNF promoters 4 and 6 were similar between TLE and autopsies and in relation to the use of either Sertraline (SRT) or TPM. These results suggest an up-regulated expression of a specific BDNF transcript in patients with TLE, an effect that seems to be dependent on the use of specific drugs.

Effect of BRCA mutations on the length of survival in epithelial ovarian tumors.

PURPOSE: To study the role of BRCA mutations in ovarian cancer survival. PATIENTS AND METHODS: Blood samples and specimens of ovarian tumors (whenever blood samples were not available) at the time of the primary surgery were obtained in the course of a nationwide case-control study of women with ovarian cancer in Israel. The three common BRCA mutations in Israel (185delAG, 5382insC, and 6174delT) were analyzed with a multiplex polymerase chain reaction to amplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms. Patients were followed for up to 5 years (range, 20 to 64 months). Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. Stepwise Cox regression analysis was used for determination of independent prognostic factors. RESULTS: This report is based on 896 blood or tumor specimens analyzed for the presence of the BRCA mutations. Of these, 234 women (26.1%) were found to be positive. A significant difference in survival pattern was found between BRCA1/BRCA2 carriers and noncarriers among the women with invasive ovarian cancer (median survival, 53.4 months v. 37.8 months; 3-year survival, 65.8% v. 51.9%, respectively). These differences were independent of age at diagnosis or stage of the disease. CONCLUSION: Our data indicate that the survival of patients with ovarian cancer is affected by BRCA germline mutation, at least in the early years after diagnosis.

Kainate mediates nuclear factor-kappa B activation in hippocampus via phosphatidylinositol-3 kinase and extracellular signal-regulated protein kinase.

The transcription factor nuclear factor-kappa B (NF-kappaB) is an inducible regulator of genes that plays a crucial role in the nervous system. Glutamate receptor stimulation is one well-described mechanism for NF-kappaB activation. In the studies presented here we used the glutamate analog, kainate to investigate the signaling mechanisms that couple to NF-kappaB activation in hippocampus. Kainate (250 nM) application to hippocampal slices elicited a time-dependent increase in nuclear NF-kappaB levels in areas CA3 and CA1, but not dentate, compared with controls. Further analysis focused on hippocampal area CA3, revealed increased NF-kappaB DNA binding activity in response to kainate stimulation. Supershift electrophoretic mobility shift assay indicated that the kainate-mediated NF-kappaB complex binding DNA was composed of p65, p50, and c-Rel subunits. Through inhibition studies we found that extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol-3 kinase (PI3K) couple to basal and kainate-mediated NF-kappaB DNA binding activity in area CA3. Kainate elicited decreased total and increased phospho-inhibitor kappa B alpha (IkappaBalpha), suggesting that kainate-mediated activation of NF-kappaB is via the classical IkappaB kinase pathway. Interestingly, inhibition of ERK but not PI3K blocked the kainate-mediated increase in phospho-IkappaBalpha. Thus, our findings support a role for the ERK and PI3K pathways in kainate-mediated NF-kappaB activation in hippocampal area CA3, but these kinases may target the NF-kappaB pathway at different loci.

Nutritional factors associated with benign breast disease etiology: a case-control study.

Between 1977 and 1980, 854 biopsied cases of benign breast disease (BBD) and 755 matched surgical and 723 matched neighborhood controls subjects were interviewed in Israel by using a detailed food frequency questionnaire. Cases were classified according to degree of ductal atypia (Black-Chablon grading system). Women with atypic lesions (grades greater than or equal to 3) reported a higher intake of all types of foods compared with both control series. Further analyses indicated that the increased consumption was due primarily to foods containing greater than or equal to 10% fat. Odds ratios associated with the highest fat consumption quartile were close to 3.0. There was a trend for increasing saturated fatty acid consumption with increasing ductal atypica. After adjusting for hormonal and demographic confounders, the association with fat intake was strengthened. Because atypic BBD has been reported to be a precursor of breast cancer, our findings lend support to the hypothesis that dietary fat is a risk factor for breast cancer.

Nutritional and lifestyle habits and water-fiber interaction in colorectal adenoma etiology.

Adenomatous polyps are neoplasms that may progress to colorectal cancer. The role of diet and other lifestyle habits in their etiology is now being elucidated. The aim of this study was to evaluate effects of nutritional habits, weight and weight gain, tobacco smoking, and physical activity in adenoma etiology. A quantified dietary history questionnaire was designed to evaluate long-term dietary habits in addition to more recent ones. The study population comprised 196 adenoma patients and matched asymptomatic, screened controls. Statistical analysis used multivariate conditional logistic models, adjusting for total energy intake and physical activity. Odds ratios (ORs) and 95% confidence intervals (CIs) for adenoma associated with highest versus lowest tertiles of mean daily intake were as follows: for energy, OR 3.7 and CI 2.1-6.7; for animal fat, OR 2.4 and CI 1.2-4.7; for tobacco smoking, OR 3.1 and CI 1.1-2.8; and for weight gain, OR 2.2 and CI 1.2-4.1 (P for linear trend for all, < or = 0.01). Significant negative associations were found with intake of total carbohydrates (OR, 0.3; CI, 0.1-0.7) and fluids (OR, 0.4; CI, 0.2-0.8) (P for both < 0.01) as well as for physical activity (OR, 0.6; CI, 0.3-0.9; P = 0.03). Increased risk for adenoma was observed with decreased intake of carotene (OR, 0.6; CI, 0.3-1.0; P = 0.06), vitamin E (OR, 0.6; CI, 0.3-1.0; P = 0.07), and dietary fiber (OR, 0.6; CI, 0.3-1.3; not significant). The OR of interaction between water and dietary fiber was significant (OR, 0.7; CI, 0.6-0.9; P = 0.01), suggesting a synergistic protective effect. Specific dietary and lifestyle habits were identified as independent factors associated with colorectal adenomas; of special interest is the interaction between water and fiber intake. Avoiding these factors might delay or prevent neoplasia.

Vitamin K intake and sensitivity to warfarin in patients consuming regular diets.

The effect of dietary vitamin K intake on warfarin sensitivity is known only from case reports and few small clinical studies. We followed 50 patients commencing warfarin and consuming their regular diets (for 8 weeks) to study this relationship. A one-week recall dietary questionnaire was completed at weeks 2 and 8. Daily intake of nutrients and vitamin K was calculated from standard tables. Warfarin sensitivity index (WSI) was defined as final INR/final warfarin dose (mg/day/m2 of body surface area) (week 8). Vitamin K intake was 17-974 (median: 179) microg/day. Median WSI was 0.82 (0.31-4.47). A WSI value of 1.1 significantly separated excess (>250 microg/day) from normal (<250 microg/day) vitamin K consumers (16/18 vs. 15/32, respectively, p <0.01). The former had lower day 5 INR (median: 1.9 vs. 3.0, p <0.001), needed more warfarin to achieve INR > or =2.0 (32.0+/-9.2 mg vs. 25.4+/-6.4 mg, p = 0.009) and required a higher maintenance steady state warfarin dose (5.7+/-1.7 mg/day vs. 3.5+/-1.0 mg/day, p <0.001). We conclude that in 32% (16/50) of anticoagulated patients under usual dietary conditions sensitivity to warfarin is decreased by vitamin K intake > or =250 microg/day.

Consumption of methylxanthine-containing beverages and the risk of breast cancer.

The idea that caffeine might be involved in the etiology of breast disease was first proposed by Minton et al. in 1979. Since that time, numerous experimental and epidemiologic studies evaluating the relationship between methylxanthines and breast disease have been conducted. Results from studies on benign breast disease have been inconsistent, with some investigators observing a positive association and others no association. However, all but one of the studies which have examined methylxanthine intake and malignant breast disease have concluded that methylxanthines do not play a role in the development of this cancer. Although various methodologies were employed and different populations were evaluated, results were consistently negative. Thus, there appears to be no evidence of an association between coffee and other methylxanthine-containing beverages and breast cancer.

Rectal epithelial proliferation characteristics of first degree relatives of sporadic colon cancer patients.

Hyperproliferation of rectal epithelium is characteristic of families at high genetic risk for large bowel neoplasia, but has not been well-documented in families of sporadic colorectal cancer patients. This was studied in 119 such first degree relatives and 44 comparison subjects without this family history. All screened negative for large bowel neoplasia. Within the family group proliferation was significantly higher in the men and those aged less than 45 years, also higher (insignificantly) in non-Europeans and those having greater than 1 first degree colorectal cancer relative. In comparison to the nonfamily group the labelling index (LI) of the relatives showed a significant negative correlation with age (R = -0.20, P = 0.03). Within this family group the probability of having an elevated LI (greater than 6.0%) was greatest in the young (less than 50 years old) men (odds ratio = 2.0). Measurements of rectal epithelial proliferation (REP) in these first degree relatives, at a young age, might help delineate a high risk subgroup for prospective primary and secondary intervention.

Results from an international case-control study of childhood brain tumors: the role of prenatal vitamin supplementation.

An international case-control study of primary pediatric brain tumors included interviews with mothers of cases diagnosed from 1976 to 1994 and mothers of population controls. Data are available on maternal vitamin use during pregnancy for 1051 cases and 1919 controls from eight geographic areas in North America, Europe, and Israel. Although risk estimates varied by study center, combined results suggest that maternal supplementation for two trimesters may decrease risk of brain tumor (odds ratio [OR] 0.7, 95% confidence interval [CI] 0.5-0.9), with a trend of less risk with longer duration of use (p trend = 0.0007). The greatest risk reduction was among children diagnosed under 5 years of age whose mothers used supplements during all three trimesters (OR 0.5, CI 0.3-0.8). This effect did not vary by histology and was seen for supplementation during pregnancy rather than during the month before pregnancy or while breast feeding. These findings are largely driven by data from the United States, where most mothers took vitamins. The proportion of control mothers who took vitamins during pregnancy varied tremendously: from 3% in Israel and France, 21% in Italy, 33% in Canada, 52% in Spain and 86 to 92% at the three U.S. centers. The composition of the various multivitamin compounds taken also varied: the daily dose of vitamin C ranged from 0 to 600 mg, vitamin E ranged from 0 to 70 mg, vitamin A ranged from 0 to 30,000 IU, and folate ranged from 0 to 2000 micrograms. Mothers also took individual micronutrient supplements (e.g., vitamin C tablets), but most mothers who took these also took multivitamins, making it impossible to determine potential independent effects of these micronutrients.

Relationship between morbidity and extreme values of body mass index in adolescents.

BACKGROUND: Although the association between overweight and cardiovascular risk factors is well documented in cross-sectional and longitudinal studies, reports of adolescent morbidity associated with underweight in industrialized countries are rare. METHODS: This population-based study includes approximately 110,000 17 year old Israeli Jewish males who underwent routine physical examination at army induction centres. Computerized data tapes include overall health profiles, specification of physical and mental conditions, and height and weight measurements. Medically significant conditions are those with sufficient severity to preclude service in a combat unit. RESULTS: Functional limitation is more prevalent at both extremes of the body mass index (BMI) distribution: 149.5/1000 among severely underweight individuals and 164.3/1000 among severely overweight subjects. Overweight was associated with hypertension (14.9/1000 among the severely overweight), as well as joint conditions of the lower extremities, mainly hip, ankle and knee disorders. Functional disorders associated with underweight are bronchial and lung conditions, including asthma (14.2 and 18.9/1000 in the mildly and severely underweight), scoliosis, intestinal conditions and emotional disorders (mainly neurosis). CONCLUSIONS: Both under- and overweight are associated with morbidity at age 17. Intervention programmes should begin at an early age.

Comprehensive individualised nonpharmacological treatment programme for hypertension in physician-nurse clinics: two year follow-up.

A comprehensive programme of nonpharmacological control of hypertension (balanced nutrition, satisfactory weight, enhanced physical activity, relaxation technique, smoking cessation) by primary care physician-nurse (PN) teams who were instructed and routinely advised by a paramedical professional (PP) team (psychologist, nutritionist and physical activity instructor) was developed with the aim of increasing long-term compliance. To evaluate effectiveness, 52 mild and moderate hypertensives without target organ damage were randomly allocated to six weekly meetings of individual intensive instruction by PN teams alone, or direct group instructions by PP teams (24 and 28 patients, respectively). The respective results at 11 months and 24 months follow-up compared with baseline were: (1) 56.9% and 58.8% showed minimal satisfactory reduction of weight, (2) 49% and 58.8% showed minimal satisfactory increase in physical activity, (3) the reported increase in physical activity at 11 months follow-up was validated by significantly correlated improved performance in ergometry, (4) 75% and 40% of the patients performed relaxation vs. 2% at baseline and (5) 71% and 59% needed no medication or reduced dose to control BP, and these changes were significantly (P < 0.02) correlated with weight reduction and increased physical activity. As no differences were found between the two modes of treatment, we conclude that our programme can be successfully applied by the PN primary care teams to increase adherence to nonpharmacological measures in the control of hypertension.

Partial cost-benefit analysis of two different modes of nonpharmacological control of hypertension in the community.

In the Dan and Ashkelon areas of Israel, 28 male and 24 female mild to moderate hypertensives without target organ damage aged 35-65 years were randomly assigned to treatment programmes (based on nutritional management, exercise and stress management techniques) either on an individual basis administered by physician-nurse teams (PN) or on a group basis from a team of paramedical professionals (PP) consisting of a psychologist, nutritionist and physical activity instructor. At 11 and 24 months follow-up, there were similar significant improvements in both treatment modes for such risk factors as body mass index, caloric intake and physical activity levels. There was a significant decrease in drug use from $36.28 a month at baseline to $18.94 a month at 11 month follow-up (P = 0.01) and to an estimated $20.48 at 24 months. Mean BP remained unchanged, despite the reduction in drug use, indicating a reduction in the underlying BP. The net present value (NPV) of the reduction in drug utilisation totalled $740 per person over a five year time horizon and a 7.5% discount rate. The total extra costs of treatment, training, case-note writing, travelling and follow-up booster sessions, amounted to $95 per patient for the PN mode and $234 per patient for the PP mode, yielding benefit to cost ratios of 7.79/1 and 3.16/l, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoprotein profile changes during intense training of Israeli military recruits.

The effect of prolonged strenuous military training on serum lipoproteins was studied in 73 new recruits. Dietary intake, body weight, and average energy expenditure were recorded, and blood samples collected at three time periods before training began (time 0), and after 6 and 12 wk of intense physical activity (times I and II, respectively). There was a significant increase in high density lipoprotein (HDL) cholesterol and a decrease in low density lipoprotein (LDL) cholesterol accompanying an increase of duration and intensity of exercise. HDL increased from 40.5 +/- 7.7 mg.dl-1 at time 0 to 44.5 +/- 9.4 mg.dl-1 at time I and to 52.8 +/- 8.7 mg.dl-1 at time II, and each mean P-value for increases in HDL from time 0-I, I-II, and 0-II were P < 0.0001). For LDL cholesterol, the mean decreases were -1.1, -6.1, and -7.3 mg.dl-1, respectively (P = 0.003 from I-II, and 0.01 from 0-II). These changes did not correlate with weight loss, reduced energy, or fat intake. We conclude that intense physical activity is associated with beneficial changes in the lipoprotein profile in new military recruits during a training period extending over 12 wk.