Adi Leiba

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.).

Behçet's disease and thrombophilia

Behcets disease (BD), first described in 1973, is characterised by recurrent oral and genital ulcers as well as eye inflammation. Other features of this chronic multisystem inflammatory disease include neurological, cardiovascular, pulmonary, gastrointestinal, musculoskeletal, and dermatological involvement.1 Venous or arterial thrombosis occurs in 25% (10–37%) of patients.2 Venous thrombosis is more common than arterial thrombosis (88% v 12%).3 Deep and superficial venous thrombosis of the legs predominates.4-7 Arteritis is treated with a combination of corticosteroids and cytotoxic agents. Anticoagulants and antiplatelet agents are used for deep venous thrombosis, though there has never been a properly controlled study to justify this treatment in BD.8 The thrombin-antithrombin complex (TAT) is a marker of intravascular thrombin formation. Prothrombin fragments 1+2 (PF1.2) are peptide fragments generated when prothrombin is activated to thrombin. TAT and PF1.2 are both biological markers of thrombin generation and thus correlate with thrombotic risk.9 10 Several studies have shown increased levels of PF1.2 and TAT in patients with BD.11 12 These alterations probably reflect the activation of the coagulation cascade in these patients and are not the cause of the thrombosis. Vasculitis, the main pathological process in BD, can partially explain the thrombotic phenomena.13 Why such thrombosis is not so common in other vasculitides, and why it occurs in only about 25% of patients with BD, is still unclear. As knowledge about the cause of venous and arterial thrombosis is growing, it is now clear, that thrombosis may result from a combination of hereditary and acquired abnormalities. It is speculated that a combination of abnormalities of procoagulants, anticoagulants, and fibrinolytic factors, together with the vasculitis and the endothelial injury, accounts for the clinical thrombosis in this subgroup of patients with BD. The present review is a critical summary of the published data …

Fosinopril reduces ADP-induced platelet aggregation in hypertensive patients

Platelets are intimately involved in atherosclerosis, and hypertension is a known risk factor for coronary artery disease. The angiotensin-converting enzyme (ACE) inhibitors were demonstrated to reduce hypertension and attenuate atherosclerosis. Because increased platelet aggregation was shown in hypertensive patients, the effect of a new ACE inhibitor, fosinopril, on platelet aggregation was studied. Fosinopril therapy (10 mg/day for 4 weeks) in 18 male hypertensive patients showed > or = 31% reduction in ADP-induced platelet aggregation. In vitro studies showed that fosinopril had similar inhibitory effect on ADP-induced platelet aggregation. No inhibitory effect could be detected with collagen as the aggregating agent. Finally, inhibition of platelet aggregation by fosinopril was less effective in platelets derived from hypertensive patients as compared with platelets derived from normal subjects. We conclude that fosinopril possesses a significant inhibitory activity on ADP-induced platelet aggregation both in vitro and in vivo.

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.

Diet and lupus

The effect of dietary modifications has been extensively studied in lupus animal models. Calorie, protein, and especially fat restriction, caused a significant reduction in immune-complex deposition in the kidney, reduced proteinuria and prolongation of the mices life span. The addition of polyunsaturated fatty acids (PUFAs), such as fish oil or linseed oil, was also related to decreased mice morbidity and mortality in animal models of lupus and of antiphospholipid syndrome. PUFAs such as eicosapetaenoic acid (EPA) and docosahexaenoic acid (DHA) competitively inhibit arachidonic acid with a resultant decrease in inflammmatory eicosanoids and cytokines. Human studies support the effect of a PUFAs-enriched diet, both scrologically and clinically. Large scale clinical studies are needed to confirm the primary results.

Response of Thai hospitals to the tsunami disaster.

The disaster caused by the Tsunami of 26 December 2004 was one of the worst that medical systems have faced. The aim of this study was to learn about the medical response of the Thai hospitals to this disaster and to establish guidelines that will help hospitals prepare for future disasters. The Israeli Defense Forces (IDF) Home Front Command (HFC) Medical Department sent a research delegation to Thai hospitals to study: (1) pre-event hospital preparedness; (2) patient evacuation and triage; (3) personnel and equipment reinforcement; (4) modes used for alarm and recruitment of hospital personnel; (5) internal reorganization of hospitals; and (6) admission, discharge, and secondary transfer (forward management) of patients. Thai hospitals were prepared for and drilled for a general mass casualty incident (MCI) involving up to 50 casualties. However, a control system to measure the success of these drills was not identified, and Thai hospitals were not prepared to deal with the unique aspects of a tsunami or to receive thousands of victims. Modes of operation differed between provinces. In Phang Nga and Krabi, many patients were treated in the field. In Phuket, most patients were evacuated early to secondary (district) and tertiary (provincial) hospitals. Hospitals recalled staff rapidly and organized the emergency department for patient triage, treatment, and transfer if needed. Although preparedness was deficient, hospital systems performed well. Disaster management should focus on field-based first aid and triage, and rapid evacuation to secondary hospitals. Additionally, disaster management should reinforce and rely on the existing and well-trusted medical system.

Seizures as a presenting symptom of phaeochromocytoma in a young soldier

New onset of seizures in young adults is frequently related to alcohol withdrawal, toxic exposure, central nervous system trauma and neoplasm. We describe a young soldier presenting to the emergency department with seizures and transient coma. On admission, he had hypertension, marked leukocytosis, hyper-glycaemia, acidosis, elevated creatinine and elevated creatine phosphokinase of muscle origin. A thorough work-up revealed elevated urinary catecholamines, and a left adrenal mass was found on MRI and MIBG scan. The patient underwent laparoscopic adrenalectomy and completely recovered. This is the first description of seizures as a presenting symptom of phaeochromo-cytoma.

Case study of the terrorist bombing in Tel Aviv market – putting all the eggs in one basket might save lives

Objectives: On 1 November 2004 a suicide bomber detonated himself in Tel Aviv, in a crowded open market space, resulting in 3 dead victims and 34 casualties. This event in a central urban area was handled quickly by experienced emergency medical service (EMS) teams. We analysed evacuation destinations of urgent casualties in order to learn whether severe casualties should all be evacuated to the closest trauma centre. Alternatively, they might be distributed to all nearby hospitals, both trauma and non‐trauma centres. A third possibility is directing urgent casualties only to trauma centres, dividing them between the close trauma centre and a ‘second cycle’ distant level A trauma centre. Methods: Data were collected from formal debriefings carried out after the event in the Ministry of Health, in the Israeli Defense Forces Medical Corps (IDF MCs) and in the Home Front Command (HFC). Other debriefings, in which we took part, were those of the EMS and participating hospitals. We analysed these data to learn...

Halofuginone inhibits multiple myeloma growth in vitro and in vivo and enhances cytotoxicity of conventional and novel agents

Multiple Myeloma (MM), a malignancy of plasma cells, remains incurable despite the use of conventional and novel therapies. Halofuginone (HF), a synthetic derivative of quinazolinone alkaloid, has recently been shown to have anti‐cancer activity in various preclinical settings. This study demonstrated the anti‐tumour activity of HF against a panel of human MM cell lines and primary patient‐derived MM cells, regardless of their sensitivity to conventional therapy or novel agents. HF showed anti‐MM activity in vivo using a myeloma xenograft mouse model. HF suppressed proliferation of myeloma cells alone and when co‐cultured with bone marrow stromal cells. Similarly, HF induced apoptosis in MM cells even in the presence of insulin‐like growth factor 1 or interleukin 6. Importantly, HF, even at high doses, did not induce cytotoxicity against CD40 activated peripheral blood mononuclear cells from normal donors. HF treatment induced accumulation of cells in the G0/G1 cell cycle and induction of apoptotic cell death associated with depletion of mitochondrial membrane potential; cleavage of poly (ADP‐ribose) polymerase and caspases‐3, 8 and 9 as well as down‐regulation of anti‐apoptotic proteins including Mcl‐1 and X‐IAP. Multiplex analysis of phosphorylation of diverse components of signalling cascades revealed that HF induced changes in P38MAPK activation; increased phosphorylation of c‐jun, c‐jun NH(2)‐terminal kinase (JNK), p53 and Hsp‐27. Importantly, HF triggered synergistic cytotoxicity in combination with lenalidomide, melphalan, dexamethasone, and doxorubicin. Taken together, these preclinical studies provide the preclinical framework for future clinical studies of HF in MM.

BMI at Age 17 Years and Diabetes Mortality in Midlife: A Nationwide Cohort of 2.3 Million Adolescents

OBJECTIVE The sequelae of increasing childhood obesity are of major concern. We assessed the association of BMI in late adolescence with diabetes mortality in midlife. RESEARCH DESIGN AND METHODS The BMI values of 2,294,139 Israeli adolescents (age 17.4 ± 0.3 years), measured between 1967 and 2010, were grouped by U.S. Centers for Disease Control and Prevention age/sex percentiles and by ordinary BMI values. The outcome, obtained by linkage with official national records, was death attributed to diabetes mellitus (DM) as the underlying cause. Cox proportional hazards models were applied. RESULTS During 42,297,007 person-years of follow-up (median, 18.4 years; range <1–44 years) there were 481 deaths from DM (mean age at death, 50.6 ± 6.6 years). There was a graded increase in DM mortality evident from the 25th to the 49th BMI percentile group onward and from a BMI of 20.0–22.4 kg/m2 onward. Overweight (85th to 94th percentiles) and obesity (the 95th percentile or higher), compared with the 5th to 24th percentiles, were associated with hazard ratios (HRs) of 8.0 (95% CI 5.7–11.3) and 17.2 (11.9–24.8) for DM mortality, respectively, after adjusting for sex, age, birth year, height, and sociodemographic variables. The HR for the 50th through 74th percentiles was 1.6 (95% CI 1.1–2.3). Findings persisted in a series of sensitivity analyses. The estimated population-attributable fraction for DM mortality, 31.2% (95% CI 26.6–36.1%) for the 1967–1977 prevalence of overweight and obesity at age 17, rose to a projected 52.1% (95% CI 46.4–57.4%) for the 2012–2014 prevalence. CONCLUSIONS Adolescent BMI, including values within the currently accepted “normal” range, strongly predicts DM mortality up to the seventh decade. The increasing prevalence of childhood and adolescent overweight and obesity points to a substantially increased future adult DM burden.