Shlomo Segev

Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2

Significance Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose to very high risks of breast and ovarian cancer. For carriers of these mutations, risk-reducing surgery significantly reduces morbidity and mortality. General population screening for BRCA1 and BRCA2 mutations in young adult women could be feasible if accurate estimates of cancer risk for mutation carriers could be obtained. We determined that risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained from the general population are as high as for mutation carriers ascertained through personal or family history of cancer. General screening of BRCA1 and BRCA2 would identify many carriers who are currently not evaluated and could serve as a model for population screening for genetic predisposition to cancer. In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.

Association of Serum Uric Acid and Cardiovascular Disease in Healthy Adults

Studies in different populations with high risk for cardiovascular disease (CVD) have shown an association between serum uric acid (SUA) and CVD. However, only a few studies have demonstrated such an association in healthy populations. The aim of this study was to investigate the association between SUA and CVD in a cohort of men and women without diabetes or CVD. A retrospective study was conducted, with a mean 4.8-year follow-up. The outcome was the occurrence of a cardiovascular event, defined as the diagnosis of ischemic heart disease, acute coronary syndrome, acute myocardial infarction, or ischemic stroke. Mean SUA levels were 6.2 ± 1.1 mg/dl for men (n = 6,580) and 4.4 ± 1.1 mg/dl for women (n = 2,559). For women, the rate of CVD occurrence was 11.6% for the highest quartile of SUA level, compared with 5.0% to 6.5% for the lower 3 quartiles. For men, the rate of CVD occurrence was 14.0% for the highest quartile of SUA level, compared with 10.8% for the lowest quartile. The hazard ratio for CVD, adjusted for age, serum creatinine level, body mass index, systolic blood pressure, low-density lipoprotein cholesterol level, triglyceride level, plasma fasting glucose, physical activity, cardiovascular family history, use of diuretics, and current smoking, was 1.24 (95% confidence interval 1.08 to 1.41) for women and 1.06 (95% confidence interval 1.00 to 1.13) for men (p for interaction = 0.04). In conclusion, the strong association of SUA levels with CVD in women, compared with the much lesser degree in men, highlights the necessity of stratifying by gender in investigations of cardiovascular risk factors and supports exploration of SUA as a marker of CVD risk in healthy populations.

Footshock-induced analgesia: Its opioid nature depends on the strain of rat

Previous studies have indicated that stressful footshock can induce both opioid, naloxone-sensitive, and non-opioid, naloxone-insensitive forms of analgesia, depending on stimulation parameters used with 30 min of intermittent footshock (3 mA, 1 s on, 5 s off) producing opioid analgesia and 3 min of continuous shock (3 mA) producing non-opioid analgesia. Using a local strain of Charles River (CR)-derived rats we conducted a parametric investigation of footshock-induced analgesia applying both AC and DC scrambled shock ranging from 1 to 4 mA, continuous shock of 1, 3 and 5 min in duration and intermittent shock lasting 1, 3, 5, 10, 20, 30 and 80 min. All shock parameters produced potent analgesia. In no case did 10 mg/kg of naloxone block this analgesia. Varying the dose of the antagonist (0.1-10 mg/kg) and testing the animals at different points in the diurnal cycle did not result in the emergence of naloxone-sensitive anangesia. Based on the assumption that non-opioid systems may mask the activity of opioid analgesia systems, we attempted to either enhance opioid analgesia by: preventing enkephalin degradation by the use of D-phenylalanine; increasing the entry of blood-borne opioids into the brain by the use of DMSO; and the attenuation of non-opioid analgesia by the use of reserpine. In no case did a naloxone-sensitive component of analgesia emerge. To test whether the animals possess an intact opioid analgesia system, both electrical stimulation of, and injection of opiates into the periaqueductal gray (PAG) were examined. Both procedures produced analgesia which was reversed by naloxone.(ABSTRACT TRUNCATED AT 250 WORDS)

Waist circumference vs body mass index in association with cardiorespiratory fitness in healthy men and women: a cross sectional analysis of 403 subjects

ObjectiveBody mass index (BMI) is more commonly used than waist circumference as a measure of adiposity in clinical and research settings. The purpose of this study was to compare the associations of BMI and waist circumference with cardiorespiratory fitness.MethodsIn a cross-sectional study of 403 healthy men and women aged 50 ± 8.8 years, BMI and waist circumference were measured. Cardiorespiratory fitness was assessed from estimated maximal O2 uptake (VO2max), as calculated from a maximal fitness test.ResultsMean BMI (kg/m2) was 27.8 ± 3.7 and 25.5 ± 4.6; and mean waist circumference (cm) 94.1 ± 9.7 and 84.3 ± 10.4 for men and women, respectively. Both men and women reported an average of 2.5 hours of weekly sports related physical activity, and 18% were current smokers. Correlation coefficients between both BMI and waist circumference, and VO2max were statistically significant in men (r = −0.280 and r = −0.377, respectively, p > 0.05 for both) and in women (r = −0.514 and r = −0.491, respectively, p > 0.05 for both). In women, the contribution of BMI to the level of VO2max in a regression model was greater, while in men waist circumference contributed more to the final model. In these models, age, hours of training per week, and weekly caloric expenditure in sport activity, significantly associated with VO2max, while smoking did not.ConclusionThe differences observed between the sexes in the associations of BMI and waist circumference with VO2max support the clinical use of both obesity measures for assessment of cardiorespiratory fitness.

Obesity, Metabolic Syndrome and the Risk of Development of Colonic Diverticulosis

Introduction: Colonic diverticulosis is a common condition with obscure pathogenesis. Obesity, hyperlipidemia and hypertension have been demonstrated to increase the risk of complicated diverticular disease, but the impact of metabolic risk factors on the prevalence of uncomplicated diverticulosis has not been clearly determined. Aims: The aim of the study was to examine the impact of obesity and metabolic syndrome on the prevalence of colonic diverticulosis. Methods: This retrospective case-control study included patients aged 40–85 years who were followed up by the Institute of Medical Screening in Israel and underwent colonoscopy in 2006–2011 for indication of colorectal cancer screening. Patients with diverticulosis as detected by colonoscopy were compared to patients without diverticulosis. The comparison parameters included medical history, biometric parameters, biochemical and lipid profile. Results: The study included 3,175 patients. Diverticulosis was diagnosed in 17.4% of the cohort. On univariate analysis, age, male gender, BMI (continuous variable), obesity, systolic blood pressure, low-density lipoprotein cholesterol level, history of hypertension, ischemic heart disease, hypothyroidism, and absence of diabetes mellitus were associated with an increased risk of colonic diverticulosis. On multivariate analysis, advanced age, male gender, obesity (BMI >30), history of hypothyroidism and absence of diabetes mellitus were associated with an increased risk of diverticulosis. Prevalence of colonic polyps was similar in patients with and without diverticulosis. Conclusion: Colonic diverticulosis was associated with age, male gender, obesity and hypothyroidism. Diabetes mellitus was associated with a decreased risk of colonic diverticulosis.

Indices related to apo CII and CIII serum concentrations and coronary heart disease: a case-control study.

BACKGROUND Triglycerides (TG) are carried in the circulation by diverse lipoprotein particles, which vary in their lipid and protein content, metabolism, and atherogenicity. Several indices related to apolipoproteins (apo) CII and CIII blood concentration have been proposed to reflect TG metabolism more accurately than the blood level of TG. In the present study we compared the distribution of those indices in coronary heart disease (CHD) patients and controls.. METHODS Ninety consecutively discharged patients with CHD and 209 healthy controls were included in the analysis. Demographic, clinical, and laboratory characteristics were obtained. RESULTS The CHD patients differed appreciably from controls in several TG-related variables. After adjusting for cardiovascular risk factors, significant associations were found between CHD and the following: TG, VLDL-C, apo CIII, apo CIII in HDL, apo CIII in VLDL + LDL, apo CII- to- TG ratio, and apo CIII ratio (CIII in HDL/CIII in VLDL + LDL). Further adjustment for HDL-C substantially attenuated the above associations, except for those regarding apo CIII in VLDL + LDL (odds ratio (OR): 1.69 per 1 SD increment, 95%CI: 1.03-2.77) and apo CIII ratio (OR: 0.40 per 1 SD increment, 95%CI: 0.15-1.00). CONCLUSION Our results add to the growing evidence which links apo CIII concentration in VLDL + LDL to CHD. Further confirmation in prospective studies would be required before considering this measurement as a screening tool.

The association between cardiorespiratory fitness and cardiovascular risk may be modulated by known cardiovascular risk factors

BACKGROUND We aimed to evaluate whether reduced cardiovascular fitness has a direct or indirect effect for the development of cardiovascular disease. METHODS We investigated 15,595 men and women who were annually screened in a tertiary medical center. All subjects were free of ischemic heart disease and had completed maximal exercise stress test according to the Bruce protocol at their first visit. Fitness was categorized into age- and sex-specific quintiles (Q) according to Bruce protocol treadmill time with Q1 as lowest fitness. Subjects were categorized at baseline into 3 groups: low fitness (Q1), moderate fitness (Q2-Q4), and high fitness (Q5). The primary end point of the current analysis was the development of a first cardiovascular event during follow-up. RESULTS Mean age of study patients was 48 ± 10 years, and 73% were men. A total of 679 events occurred during 92,092 person-years of follow-up. Kaplan-Meier survival analysis showed that the cumulative probability of cardiovascular events at 6 years was significantly higher among subjects with low fitness (P < .001). Low fitness was associated with known cardiovascular risk factors, including hypercholesterolemia (odds ratio [OR] 1.58, 95% CI 1.31-1.89), diabetes mellitus (OR 2.32, 95% CI 1.58-3.41), and obesity (OR 10.46, 95% CI 8.43-12.98). The effect of low fitness on cardiovascular events was no longer significant when including diabetes mellitus, hypercholesterolemia, and obesity as mediators (hazard ratio 0.99, 95% CI 0.82-1.19). CONCLUSIONS The association between cardiovascular fitness and adverse cardiovascular outcomes may be modulated through traditional cardiovascular risk factors. These findings need to be further validated in prospective clinical trials.

Exercise blood pressure and the risk for future hypertension among normotensive middle-aged adults.

Background The aim of the present study was to examine whether exercise blood pressure can be used to predict the development of hypertension in normotensive middle‐aged adults. Methods and Results We investigated 7082 normotensive subjects who were annually screened in a tertiary medical center and completed maximal treadmill exercise tests at each visit. After the initial 3 years, subjects were divided into approximate quartiles according to their average exercise systolic and diastolic blood pressure responses (≤158; 158 to 170; 170 to 183; ≥183 mm Hg for systolic blood pressure and ≤73; 73 to 77; 77 to 82; ≥82 mm Hg for diastolic blood pressure). Mean age of the study population was 48±9 years and 73% were men. Average baseline resting blood pressure was 120/77±12/7 mm Hg. During a follow‐up of 5±3 years, 1036 (14.6%) subjects developed hypertension. The cumulative probability of new‐onset hypertension at 5 years was significantly increased with increasing quartiles of exercise systolic blood pressure (5%, 9%, 17%, and 35%, respectively; P<0.001), with a similar association shown for diastolic blood pressure. After adjustment for baseline resting blood pressure and clinical parameters, each 5‐mm Hg increments in exercise either systolic or diastolic blood pressures were independently associated with respective 11% (P<0.001) and 30% (P<0.001) increased risk for the development of hypertension. Conclusions In normotensive middle‐aged individuals, blood pressure response to exercise is associated with future development of hypertension.

Low ALT blood levels predict long-term all-cause mortality among adults. A historical prospective cohort study

BACKGROUND Increased blood levels of alanine amino transferase (ALT, also known as SGPT; serum glutamic pyruvic transaminase) serve as a marker of liver injury by various mechanisms. Less is known about the clinical implications associated with low-normal ALT levels. Previous studies showed low ALT levels to be associated with poor long-term outcomes among elderlies, serving as a biomarker for increased incidence of frailty and subsequent risk of mortality. However, it has not been determined yet whether low-normal ALT values might be predictive of frailty and mortality in younger, middle-aged adults. METHODS We conducted a historical prospective cohort analysis. RESULTS A total of 23,506 adults with ALT levels within the normal range, at the mean age of 48 ± 11 years, participating in an annual screening program for preventive medicine, were followed-up for a median period of 8.5 years during which 638 died. Low-normal ALT values (serum ALT activity <17IU/L) were found to be predictive for increased risk of all-cause mortality (HR=1.6; 95% CI 1.34-1.92; p<0.001). Statistically significant correlation was demonstrated even after applying a multifactorial model correction for age, gender, eGFR, low albumin, arterial hypertension, diabetes mellitus and ischemic heart disease. CONCLUSIONS We suggest that low-normal ALT values may serve as an independent predictive marker for increased long-term mortality in middle-aged adults.

Association of retinal microvascular caliber with blood pressure levels

Abstract Background. The most common ophthalmologic manifestation of hypertension is hypertensive retinopathy. Our study was designed to evaluate the factors that determine retinal vessel caliber in hypertensive subjects. Methods. During a 6-month period, retinal photographs were taken of participants during a routine yearly check-up. The photographs were evaluated by an ophthalmologist and the diameters of the individual retinal vessels were measured and summarized by a computer program. Data including patients medical history, physical examination and laboratory evaluations were collected. The findings of the ophthalmologic examinations were analyzed with respect to the relevant systemic data. Results. We evaluated 285 subjects (43 women) with an average age of 62 ± 9 years (range 33–87). Hypertension was reported in 204 (71.6%) subjects and diabetes mellitus in 60 subjects (21%). The arteriolar calibers were inversely related to age (R = − 017; p = 0.01). Retinal arteriolar and venular calibers were wider in smokers and in subjects with dyslipidemia. History of hypertension was not associated with any vascular changes. However, retinal arteriolar caliber was inversely related to blood pressure levels. Diuretic treatment was associated with narrow retinal venular caliber. Conclusion. The association between different cardiovascular risk factors and hypertensive retinopathy is complex. Effective blood pressure control has a beneficial effect on the vascular changes in the retina.