Ari Shamiss

Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood

BACKGROUND In light of the worldwide increase in childhood obesity, we examined the association between body-mass index (BMI) in late adolescence and death from cardiovascular causes in adulthood. METHODS We grouped data on BMI, as measured from 1967 through 2010 in 2.3 million Israeli adolescents (mean age, 17.3±0.4 years), according to age- and sex-specific percentiles from the U.S. Centers for Disease Control and Prevention. Primary outcomes were the number of deaths attributed to coronary heart disease, stroke, sudden death from an unknown cause, or a combination of all three categories (total cardiovascular causes) by mid-2011. Cox proportional-hazards models were used. RESULTS During 42,297,007 person-years of follow-up, 2918 of 32,127 deaths (9.1%) were from cardiovascular causes, including 1497 from coronary heart disease, 528 from stroke, and 893 from sudden death. On multivariable analysis, there was a graded increase in the risk of death from cardiovascular causes and all causes that started among participants in the group that was in the 50th to 74th percentiles of BMI (i.e., within the accepted normal range). Hazard ratios in the obese group (≥95th percentile for BMI), as compared with the reference group in the 5th to 24th percentiles, were 4.9 (95% confidence interval [CI], 3.9 to 6.1) for death from coronary heart disease, 2.6 (95% CI, 1.7 to 4.1) for death from stroke, 2.1 (95% CI, 1.5 to 2.9) for sudden death, and 3.5 (95% CI, 2.9 to 4.1) for death from total cardiovascular causes, after adjustment for sex, age, birth year, sociodemographic characteristics, and height. Hazard ratios for death from cardiovascular causes in the same percentile groups increased from 2.0 (95% CI, 1.1 to 3.9) during follow-up for 0 to 10 years to 4.1 (95% CI, 3.1 to 5.4) during follow-up for 30 to 40 years; during both periods, hazard ratios were consistently high for death from coronary heart disease. Findings persisted in extensive sensitivity analyses. CONCLUSIONS A BMI in the 50th to 74th percentiles, within the accepted normal range, during adolescence was associated with increased cardiovascular and all-cause mortality during 40 years of follow-up. Overweight and obesity were strongly associated with increased cardiovascular mortality in adulthood. (Funded by the Environment and Health Fund.).

Rapid Detection of blaKPC Carbapenemase Genes by Real-Time PCR

ABSTRACT Carbapenem resistance among Enterobacteriaceae is an emerging problem worldwide. Klebsiella pneumoniae carbapenemase (blaKPC) enzymes are among the most common β-lactamases described. In this study, we report the development and validation of a real-time PCR (q-PCR) assay for the detection of blaKPC genes using TaqMan chemistry. The q-PCR amplification of blaKPC DNA was linear over 7 log dilutions (r2 = 0.999; slope, 3.54), and the amplification efficiency was 91.6%. The q-PCR detection limit was 1 CFU, and there was no cross-reaction with DNA extracted from several multidrug-resistant bacteria. Perianal/rectal swabs (n = 187) collected in duplicate from 128 patients admitted to Sheba Medical Center surgical intensive care units were evaluated for the presence of carbapenem-resistant bacteria by culturing on MacConkey agar-plus-carbapenem disks and for blaKPC genes by q-PCR. Carbapenem-resistant organisms, all K. pneumoniae, were isolated from 47 (25.1%) of the 187 samples collected, while blaKPC genes were detected in 54 (28.9%) of the patient samples extracted by the NucliSENS easyMAG system. Of these, seven samples were positive for blaKPC genes by q-PCR but negative for carbapenem resistance by culture, while all samples in which no carbapenem-resistant bacteria were detected by culture also tested negative by q-PCR. Thus, the sensitivity and specificity of the q-PCR assay after extraction by the NucliSENS easyMAG system were 100% and 95%, respectively. Similar values were obtained after DNA extraction by the Roche MagNA Pure LC instrument: 97.9% sensitivity and 96.4% specificity. Overall, the blaKPC q-PCR assay appears to be highly sensitive and specific. The utilization of q-PCR will shorten the time to blaKPC detection from 24 h to 4 h and will help in rapidly isolating colonized or infected patients and assigning them to cohorts.

Progression of Normotensive Adolescents to Hypertensive Adults. A Study of 26 980 Teenagers

Although prehypertension at adolescence is accepted to indicate increased future risk of hypertension, large-scale/long follow-up studies are required to better understand how adolescent blood pressure (BP) tracks into young adulthood. We studied 23 191 male and 3789 female adolescents from the Metabolic Lifestyle and Nutrition Assessment in Young Adults cohort (mean age: 17.4 years) with BP <140/90 mm Hg at enrollment or categorized by current criteria for pediatric BP and body mass index (BMI) values. Participants were prospectively followed up with repeated BP measurements between ages 25 and 42 years and retrospectively between ages 17 and 25 years for the incidence of hypertension. We identified 3810 new cases of hypertension between ages 17 and 42 years. In survival analyses, the cumulative risk of hypertension between ages 17 and 42 years was 3 to 4 times higher in men than in women. Using Cox regression models adjusted for age, BMI, and stratified by baseline BP, the hazard ratio of hypertension increased gradually across BP groups within the normotensive range at age 17 years, without a discernible threshold effect, reaching a hazard ratio of 2.50 (95% CI: 1.75 to 3.57) for boys and 2.31 (95% CI: 0.71 to 7.60) for girls in the group with BP at 130 to 139/85 to 89 mm Hg. BMI at age 17 years was strongly associated with future risk of hypertension even when adjusted to BP at age 17 years, particularly in boys. Yet, BMI at age 30 years attenuated this association, more evidently in girls. In conclusion, BP at adolescence, even in the low-normotensive range, linearly predicts progression to hypertension in young adulthood. This progression and the apparent interaction between BP at age 17 years and BMI at adolescence and at adulthood are sex dependent.

White Blood Cells Count and Incidence of Type 2 Diabetes in Young Men

OBJECTIVE Association between white blood cell (WBC) count and diabetes risk has been recently suggested. We assessed whether WBC count is an independent risk factor for diabetes incidence among young healthy adults. RESEARCH DESIGN AND METHODS WBC count was measured in 24,897 young (mean age 30.8 ± 5.36 years), normoglycemic men with WBC range of 3,000 to 12,000 cells/mm3. Participants were periodically screened for diabetes during a mean follow-up of 7.5 years. RESULTS During 185,354 person-years of follow-up, diabetes was diagnosed in 447 subjects. A multivariate model adjusted for age, BMI, family history of diabetes, physical activity, and fasting glucose and triglyceride levels revealed a 7.6% increase in incident diabetes for every increment of 1,000 cells/mm3 (P = 0.046). When grouped in quintiles, a baseline WBC count above 6,900 cells/mm3 had an independent 52% increase in diabetes risk (hazard ratio 1.52 [95% CI 1.06–2.18]) compared with the lowest quintile (WBC <5,400 cells/mm3). Men at the lowest WBC quintile were protected from diabetes incidence even in the presence of overweight, family history of diabetes, or elevated triglyceride levels. After simultaneous control for risk factors, BMI was the primary contributor of the variation in multivariate models (P < 0.001), followed by age and WBC count (P < 0.001), and family history of diabetes and triglyceride levels (P = 0.12). CONCLUSIONS WBC count, a commonly used and widely available test, is an independent risk factor for diabetes in young men at values well within the normal range.

Measured Body Mass Index in Adolescence and the Incidence of Colorectal Cancer in a Cohort of 1.1 Million Males

Background and Aims: The increasing prevalence of adolescent obesity affects adult health. We investigated the association of adolescent overweight with colorectal cancer incidence in a large cohort of males. Methods: Body mass index (BMI) was measured in 1.1 million Jewish Israeli males who underwent a general health examination at ages 16 to 19 between 1967 and 2005. Overweight was defined as BMI ≥ 85th percentile of the standard U.S. distribution in adolescence. Colorectal cancer was identified by linkage with the Israel National Cancer Registry up to 2006. The mean follow-up period was 17.6 ± 10.9 years, reflecting 19.5 million person-years. Cox proportional hazards modeling was used. Results: The prevalence of adolescent overweight increased from 9.9% to 16.8% in the first 10 and last 10 annual examination cohorts. Colon (n = 445) and rectal cancer (n = 193) cases were detected. Overweight predicted an increased risk of colon cancer [HR = 1.53; 95% confidence interval (CI), 1.17–2.02, P = 0.002] but not of rectal cancer (HR = 1.09; 95% CI, 0.38–1.73, P = 0.72). The risk was greatest for nonmucinous adenocarcinoma of the colon (HR = 1.68, 95% CI, 1.26–2.23, P = 0.001). The association of BMI ≥ 85th percentile with colon cancer was even more pronounced in analyses that were restricted to men followed until at least 40 years of age [N = 367,478; HR = 1.75 (95% CI, 1.33–2.3, P < 0.001)]. Conclusions: Adolescent overweight is substantially associated with colon cancer incidence in young to middle-aged adults. Impact: These long-term sequelae add to the urgency to seriously address increasing childhood and adolescent obesity with its attendant increasing population impact. Cancer Epidemiol Biomarkers Prev; 20(12); 2524–31. ©2011 AACR.

Diuretic Treatment of Hypertension

Although thiazide and thiazide-like diuretics are indispensable drugs in the treatment of hypertension, their role as first-line or even second-line drugs is a provoking debate. The European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines recommend that thiazide diuretics should be considered as suitable as β-blockers, calcium antagonists, ACE inhibitors, and angiotensin receptor blockers for the initiation and maintenance of antihypertensive treatment (1). Another European position, endorsed by the British Hypertension Society, is that diuretics and calcium channel blockers should be first-line drugs in hypertensive patients aged ≥55 years or black patients of any age, whereas ACE inhibitors (or angiotensin receptor blockers in the case of intolerance to ACE inhibitors) should be first-line drugs in hypertensive patients younger than 55 years of age (http://nice.org.uk/CG034guidance). The Seventh Report of the Joint National Committee (JNC VII) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends that thiazide diuretics should be preferred drugs in “most” hypertensive patients, either alone or combined with drugs from other classes (2). The present review does not intend to negate the important role of diuretics in certain groups of patients (blacks, salt-sensitive patients, concomitant heart failure) or to underestimate their role in multiple-drug combinations in patients with resistant hypertension. The main argument that will be discussed is the place of diuretics as first-line drugs or add-on drugs in the context of the available antihypertensive armamentarium. The pro side of the controversy will argue that diuretics should remain the preferred drugs for initial treatment in many hypertensive patients, whereas the cons side will contend that emerging evidence from outcome-based studies is casting doubt on the role of these drugs as first-line and even second-line antihypertensive treatment. Lowering blood pressure (BP) has been shown to reduce the risk of cardiovascular (CV) morbidity and mortality. The …

The role of melatonin in the pathogenesis of hypertension in rats with metabolic syndrome.

BACKGROUND Melatonin, the primary hormone of the pineal gland, is a known modulator of various physiological processes. The aim of this study was to evaluate the role of melatonin in the pathogenesis of hypertension in rats with metabolic syndrome and to assess whether melatonin supplementation prevents the development of hypertension in this model. METHODS Twenty male Sprague-Dawley (SD) rats were fed either a high fructose diet (n = 10) or a regular diet (control; n = 10) for 5 weeks. Urinary excretion of 6-hydroxymelatoninsulfate (a metabolite of melatonin) was measured at the beginning and the end of the study. An additional 20 SD rats were fed with the same diets but with a supplementation of melatonin (30 mg/kg/day) in their drinking water. Blood pressure (BP) was measured every week. RESULTS BP increased significantly in rats fed with a high fructose diet and remained unchanged in the control group. The BP rise was associated with a significant decrease in melatonin secretion during sleep. Melatonin supplementation prevented the BP rise in fructose fed rats. BP increased by 14.6 +/- 1.0 mm Hg in the fructose fed rats, whereas it increased by only 3 +/- 2.6 mm Hg in rats fed with fructose and melatonin (P < 0.001 between groups). CONCLUSIONS Melatonin secretion decreased in fructose fed rats that developed hypertension. Administration of melatonin blunted this BP rise. These data suggested that melatonin plays a role in the pathogenesis of hypertension in rats with metabolic syndrome.

Adolescent obesity and paternal country of origin predict renal cell carcinoma: a cohort study of 1.1 million 16 to 19-year-old males.

PURPOSE The incidence of renal cell carcinoma has increased in recent decades, particularly among middle-aged adults. Early precursors of renal cancer remain unclear. We evaluated the association of body mass index and height determined in late adolescence, and paternal or grandpaternal country of origin with the risk of renal cell carcinoma. MATERIALS AND METHODS Health related data on 1,110,835 males at ages 16 to 19 years who were examined for fitness for military service between 1967 and 2005 were linked to the Israel National Cancer Registry in this nationwide, population based cohort study. We used Cox proportional hazards modeling to estimate the HR of renal cell carcinoma associated with birth year, body mass index, height, father country of origin and socioeconomic indicators. RESULTS During 19,576,635 person-years of followup renal cancer developed in 274 examinees. Substantial excess risk was conferred by a body mass index of greater than 27.5 kg/m(2) compared to less than 22.5 kg/m(2) (HR 2.43, 95% CI 1.54-3.83, p <0.0001). Asian or African origin was protective compared to European origin (African origin HR 0.67, 95% CI 0.49-0.92). CONCLUSIONS Overweight in late adolescence is a substantial risk factor for renal cell carcinoma. European origin is independently associated with excess risk and it persists among Israeli born males. Preventing childhood obesity may be a promising target for decreasing the burden of renal cancer.

Mortality risk factors associated with familial Mediterranean fever among a cohort of 1.25 million adolescents

Objective There are limited data on long-term comorbidities and mortality among patients with familial Mediterranean fever (FMF). Our objective was to evaluate comorbidities and death rates among individuals with FMF. Methods We studied a nationwide, population-based, retrospective cohort of 1225 individuals with FMF (59% men) in a database of 1 244 350 adolescents (16–20 years of age) medically evaluated for military service between 1973 and 1997. This cohort was linked with the national mortality, cancer and end-stage renal disease (ESRD) registries in Israel. Study outcomes were all-cause mortality, occurrence of ESRD and malignancy by the age of 50 years. Results During 30 years of follow-up, death rates were 8.73/104 versus 4.32/104 person-years in the FMF and control groups, respectively (p=0.002). In a multivariable analysis adjusted for age, birth year, socio-economic status, education, ethnicity and body mass index, FMF was associated with increased mortality in men (HR=1.705 (95% CI 1.059 to 2.745), p=0.028) and women (HR=2.48 (1.032 to 5.992), p=0.042). Renal amyloidosis accounted for 35% and 60% of deaths in men and women, respectively. FMF was not associated with an increased incidence of cancer. Conclusions FMF is associated with increased all-cause mortality that is likely attributed to reduced colchicine compliance or responsiveness. Individuals with FMF do not have an increased incidence of cancer. These results support the awareness among medical community to decrease the higher than average mortality rate among participants with FMF.

White Blood Cell Count and the Risk for Coronary Artery Disease in Young Adults

Background The association between white blood cell (WBC) count and coronary artery disease (CAD) is unknown in young adults. Our objective was to assess the association between WBC count and its changes over time with CAD incidence in the Metabolic, Life-style and Nutrition Assessment in Young adults (MELANY) study, a cohort of Israeli army personnel. Methods and Findings 29,120 apparently healthy young men (mean age; 31.2±5.5 years) with a normal baseline WBC count (3,000–12,000 cells/mm3) were followed during a mean follow up of 7.5±3.8 years for incidence of CAD. Participants were screened every 3–5 years using a stress test, and CAD was confirmed by coronary angiography. In a multivariate model adjusted for age, body mass index (BMI), LDL- and HDL-cholesterol, blood pressure, family history of CAD, physical activity, diabetes, triglycerides and smoking status, WBC levels (divided to quintiles) above 6,900 cells/mm3 (quintile 4) were associated with a 2.17-fold increase (95%CI = 1.18–3.97) in the risk for CAD as compared with men in quintile 1 (WBC≤5,400 cells/mm3). When modeled as a continuous variable, a WBC increment of 1000 cells/mm3 was associated with a 17.4% increase in CAD risk (HR 1.174; 95%CI = 1.067–1.290, p = 0.001). A decrease in the WBC level (within the normal range) during the follow-up period was associated with increased physical activity and decreased triglyceride levels as well as with reduced incidence of CAD. Conclusions WBC count is an independent risk factor for CAD in young adults at values well within the normal range. WBC count may assist in detecting subgroups of young men at either low or high risk for progression to CAD.