A Friend and a Foe: 50 Years of the Apolipoprotein E Research Trail.

BACKGROUND: An arginine-rich apolipoprotein was discovered 50 years ago and became known as apolipoprotein E (ApoE) 10 years later. ApoE is associated with triglyceride-rich lipoproteins and mediates the clearance of these lipoproteins from the plasma. The ApoE-deficient hypercholesterolemic mice are an excellent platform for experimental atherosclerosis because they are similar to human pathology with regard to an atherogenic diet. ApoE is mainly produced in the liver and central nervous system cells. Three alleles determine six ApoE phenotypes with different metabolic effects and plasma cholesterol levels. Type III dysbetalipoproteinemia is associated with wide-spread atherogenesis with a defective ApoE2 resulting in delayed clearance of triglyceride-rich lipoproteins. ApoE4 substantially increases the risk including age of onset, progression, and prognosis of Alzheimer's disease. Therefore, much effort has been directed to the elucidation of the pathogenic role of ApoE related to amyloid ß (Aß) acquisition in the brain. The ApoE trail passing from an enigmatic protein to a major player in cardiovascular and neurodegenerative disorders is reviewed.

[REDUCTION OF ANTIBIOTIC CONSUMPTION IN RAMBAM HEALTH CARE CAMPUS - THE ROLE OF AN ANTIBIOTIC STEWARDSHIP PROGRAM].

INTRODUCTION: Antibiotic stewardship programs (ASP) are designed to optimize antibiotic use in hospitals. Antibiotic consumption is one of the measures assessing the effects of ASPs. AIMS: To evaluate the effect of an ASP on antibiotic consumption in our hospital and compare it to hospitals in Israel and worldwide. METHODS: Between October 2012 and March 2013 an ASP was implemented in Rambam Hospital. The program included educational activities, publication of local guidelines for empirical antibiotic treatment, structured infectious diseases consultations, pre-authorization antibiotic restrictions and stop orders. We compared antibacterial antibiotic consumption in defined daily doses (DDD)/100 hospital days (HD) between the periods before (1/2010-3/2013) and after (4/2013-9/2014) implementing the ASP. The study was conducted in the medical departments, hematology, the intensive care unit (ICU) and all pediatric wards. RESULTS: Total antibiotic consumption before implementing the ASP was 96±11.2 DDD/100 HD in medical departments, 186.4±42.8 in the ICU and 185.5±59 in hematology; all values were higher than the worldwide-reported averages for these departments. Following the ASP, total antibiotic consumption decreased by 12% (p=0.008) in the medical departments and by 26% (p=0.002) in hematology, mostly due to reductions in non-restricted antibiotics. No significant changes were observed overall in the ICU and in pediatric wards. There was a significant reduction in consumption of vancomycin and carbapenems in all settings, the latter was reduced to nearly half. Amikacin use quadrupled in the medical departments. CONCLUSIONS: Implementation of an ASP lead to a reduction in non-restricted and restricted antibiotic consumption, especially carbapenems.

Green tea and vitamin E enhance exercise-induced benefits in body composition, glucose homeostasis, and antioxidant status in elderly men and women.

OBJECTIVE: To investigate the effects of green tea plus vitamin E in addition to exercise on body composition and metabolic and antioxidant parameters in healthy elderly individuals. DESIGN: Interventional randomized controlled prospective trial. METHODS: For 12 weeks, 22 elderly men and women (age: 71.1 ± 1.2 years; body mass index: 28.3 ± 0.5 kg/m(2) [mean ± SE]) undertook 30 minutes of moderately intense walking 6 d/wk. They were randomly assigned to ingest either green tea plus vitamin E (GTVE; 3 cups and 400 IU, respectively; n = 11) or placebo (n = 11). Data on anthropometrics, fasting insulin and glucose levels, physical fitness, dietary intake, safety parameters, and biomarkers of oxidation status were recorded and analyzed at the start and end of the study. RESULTS: Though dietary intake was unchanged, improved exercise capacity was followed by a significant reduction in body weight and fasting insulin levels in all participants. Additional consumption of GTVE resulted in a twofold increase in serum vitamin E (from 20.4 to 40.6 µmol/L, p < 0.001) and a decrease of men's and women's waist circumferences (from 100.8 and 95.7 to 96.9 and 85.0 cm, p < 0.05 and p < 0.01, respectively) and fasting glucose levels (from 5.30 to 4.98 mmol/L, p < 0.01). Plasma protein carbonyls dropped (from 0.93 to 0.77 nmol/mg protein, p < 0.05), whereas erythrocyte catalase activities increased (from 26.7 to 29.7 U/g hemoglobin, p < 0.05) in the GTVE group only. Oral peroxidase activities were increased in both groups. CONCLUSIONS: A daily dose of GTVE in healthy elderly men and women may improve exercise-induced benefits in body composition and glucose tolerance and may also lower oxidative burden.

Green tea and its major polyphenol EGCG increase the activity of oral peroxidases.

Oral peroxidases (OPO) consist mainly of salivary peroxidase and myeloperoxidase and are involved in oral defense mechanisms. Salivary peroxidase is synthesized and secreted by salivary glands, whereas myeloperoxidase is found in polymorphonuclear leukocytes, which migrate into the oral cavity at gingival crevices. Green tea is the world's second most popular drink after water. Polyphenols are the most biologically active group of tea components. The purpose of our study was to elucidate the interaction between green tea & EGCG (Epigallocatechin 3-gallate), its main polyphenol and OPO. In previous studies we have shown that elderly trained people who drink green tea for 3 months, have a higher level of OPO activity compared to non-drinkers. Thus, we decided to extend our project in order to understand the above observations by studying the interaction of green tea and OPO both in vitro and in vivo. Addition of green tea and black tea infusions (50 µl/ml) and EGCG (50 µM) to saliva, resulted in a sharp rise of OPO activity +280% (p = 0.009), 54% (p = 0.04) and 42% (p = 0.009), respectively. The elevation of OPO activity due to addition of green tea and EGCG was in a dose dependent manner: r = 0.91 (p = 0.001) and r = 0.637 (p = 0.019), respectively. Also, following green tea infusion mouth rinsing, a rise of OPO activity was observed: +268% (p = 0.159). These results may be of great clinical importance, as tea consumer's oral epithelium may have better protection against the deleterious effects of hydroxyl radicals, produced by not removed hydrogen peroxides in the presence of metal ions. Higher OPO activity upon green tea drinking may provide an extra protection against oxidative stress in the oral cavity.

[Mediastinal cancer presenting as dermatomyositis--a case report].

We present a case of a 47-year-old man with mediastinal cancer manifesting as a rash, myaLgia and muscle weakness, in addition to the typical laboratory test results and histological changes compatible with dermatomyositis. The skin and muscLe findings followed the relapse of cancer which responded well to a combination of chemo and radiation therapy. Disease prevaLence in Rambam MedicaL Center during the past decade is also described. Dermatmyositis is a myositis with cutaneous manifestations. In a significant percent of the cases it can occur as a paraneoplastic syndrome. It was described as coetisting with various cancers, mostly adenocarcinomas. The majority of the cases occur in males above the age of 45 years. Malignancy can occur simultaneously with dermatomyositis or up to 3 years thereafter. Ovarian cancer is an exception, for it can be diagnosed up to six years after dermatomyositis. Therefore, it is advised to perform cancer screening in adult patients with dermatomyositis. Screening shouLd incLude extensive laboratory and imaging work-up. However, the mechanisms underlying paraneoplastic dermatomyositis are not fully understood. A possible antigenic similarity between cancer cell popuLations and regenerating myoblasts is suggested; this can result in an autoimmune autoantibody-mediated response in genetically predisposed patients. Numerous laboratory and clinical characteristics are associated with a high risk of malignancy. An update on paraneoplastic dermatomyositis is provided.

Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial.

OBJECTIVE: Clinical trials of vitamin E have failed to demonstrate a decrease in cardiovascular events. However, these studies did not address possible benefit to subgroups with increased oxidative stress. Haptoglobin (Hp), a major antioxidant protein, is a determinant of cardiovascular events in patients with Type 2 diabetes mellitus (DM). The Hp gene is polymorphic with 2 common alleles, 1 and 2. The Hp 2 allelic protein product provides inferior antioxidant protection compared with the Hp 1 allelic product. We sought to test the hypothesis that vitamin E could reduce cardiovascular events in DM individuals with the Hp 2-2 genotype, a subgroup that comprises 2% to 3% of the general population. METHODS AND RESULTS: 1434 DM individuals > or = 55 years of age with the Hp 2-2 genotype were randomized to vitamin E (400 U/d) or placebo. The primary composite outcome was myocardial infarction, stroke, and cardiovascular death. At the first evaluation of events, 18 months after initiating the study, the primary outcome was significantly reduced in individuals receiving vitamin E (2.2%) compared with placebo (4.7%; P=0.01) and led to early termination of the study. CONCLUSIONS: Vitamin E supplementation appears to reduce cardiovascular events in individuals with DM and the Hp 2-2 genotype (ClinicalTrials.gov NCT00220831).

The effect of tomato-derived lycopene on low carotenoids and enhanced systemic inflammation and oxidation in severe obesity.

BACKGROUND: Fat tissue mediates the production of inflammatory cytokines and oxidative products, which are key steps in the development of type 2 diabetes and atherosclerosis. Antioxidant-rich diets protect against chronic diseases. Antioxidants may interfere with pro-inflammatory signals. OBJECTIVES: To investigate the effect of the potent tomato-derived antioxidant carotenoid, lycopene, on plasma antioxidants (carotenoids and vitamin E), inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-alpha) and oxidation products (conjugated dienes). METHODS: Eight obese patients (body mass index 37.5 +/- 2.5 kg/m2) were compared with a control group of eight lean, age and gender-matched subjects (BMI 21.6 +/- 0.6 kg/m2), before and after 4 weeks of lycopene supplementation (tomato-derived Lyc-O-Mato) (30 mg daily). RESULTS: Plasma carotenoids were significantly reduced in the obese compared to control subjects (0.54 +/- 0.06 vs. 0.87 +/- 0.08 microg/ml, P < 0.01). CRP levels were significantly higher (6.5 vs. 1.1 mg/L, P = 0.04) in obese vs. controls, as were IL-6 and conjugated dienes (3.6 and 7.9-fold, respectively). CRP, IL-6 and conjugated dienes correlated with BMI, while IL-6 and conjugated dienes correlated inversely with carotenoids (P < 0.05). Following lycopene treatment, a significant elevation of plasma carotenoids (1.79 vs. 0.54 microg/ml) and specifically lycopene (1.15 vs 0.23 microg/ml) (P < 0.001) occurred in the treatment vs. the placebo group, respectively. Markers of inflammation and oxidation products were not altered by lycopene. CONCLUSIONS: Obese patients showed abnormally higher markers of inflammation and oxidation products and lower plasma carotenoids. The lack of reduction of pro-inflammatory markers could be attributed to the short period of the study and the small number of participants. More studies are needed on the protective qualities of natural antioxidant-rich diets against obesity-related co-morbidities.

Lessepsian migration and tetrodotoxin poisoning due to Lagocephalus sceleratus in the eastern Mediterranean.

BACKGROUND: The Suez Canal permits migration of fish from the Indo-Pacific Ocean to the Mediterranean Sea. This phenomenon (Lessepsian migration) has enabled poisonous fish species to colonize the Mediterranean Sea. OBJECTIVE: To report clinical tetrodotoxin poisoning after consumption of the Lessepsian immigrant fish Lagocephalus sceleratus caught on the Israeli coast of the eastern Mediterranean. CASE SERIES: Thirteen patients aged 26-70years were admitted after consuming L. sceleratus. Signs of toxicity appeared within 1h. The main manifestations included vomiting, diarrhea, headache, paraesthesias, slurred speech, muscle weakness, dyspnea, hypertension, tachycardia, respiratory arrest, seizures and coma. Treatment was supportive, including mechanical ventilation (two patients). Patients recovered within 4days. All fish were identified as L. sceleratus, a species known to contain tetrodotoxin. DISCUSSION: The diagnosis of tetrodotoxin poisoning was suggested by typical clinical manifestations together with temporal proximity to consumption of tetrodotoxin-containing fish. To the best of our knowledge, this is the first case series of tetrodotoxin poisoning reported from the eastern Mediterranean and due to L. sceleratus. Man made disruption of the ecological balance has resulted in the spread of tetrodotoxin-containing fish from the Indo-Pacific region to the Mediterranean Sea. Increased awareness is required to identify tetrodotoxin poisoning in an atypical fauna.

Limited efficacy of gastrointestinal decontamination in severe slow-release carbamazepine overdose.

OBJECTIVE: To report the limited efficacy of both multiple doses of activated charcoal (MDAC) and whole bowel irrigation (WBI) in a patient with severe overdose of slow-release carbamazepine. CASE SUMMARY: A 25-year-old man was admitted in a comatose state with seizures after a suicide attempt with slow-release carbamazepine. Serum carbamazepine concentration on admission (16 h postingestion) was 52.08 microg/mL. The patient was mechanically ventilated and treated with MDAC and a 4 hour charcoal hemoperfusion. Carbamazepine concentration at the end of hemoperfusion was 27.16 microg/mL. Despite continuous treatment with MDAC, a rebound in carbamazepine concentration to 36 microg/mL was observed 32 hours after hemoperfusion (58 h postingestion). WBI was performed over a 10 hour period. The carbamazepine concentration continued to increase to 38.55 microg/mL and seizures recurred. After WBI was performed, MDAC was reinstituted; 33 hours later (102 h postingestion), the carbamazepine concentration began to decline. The hospitalization course was complicated by pneumonia, which necessitated continuation of mechanical ventilation and administration of antibiotics. The patient recovered completely and was discharged without sequelae 15 days after admission. DISCUSSION: Serum carbamazepine concentration and toxicity were effectively reduced by hemoperfusion. The role of MDAC coadministered during hemoperfusion cannot be ruled out. However, a rebound in carbamazepine concentration with recurrent seizures was observed despite MDAC and WBI. The most likely explanation for this rebound (65 h postingestion, 39 h posthemoperfusion) is prolonged absorption, possibly from a pharmacobezoar. Redistribution cannot be excluded, but this is not supported by the concentration-time course and previous reports. CONCLUSIONS: Both MDAC and WBI may be ineffective in reducing absorption and enhancing elimination in overdose of slow-release carbamazepine. Repeated hemoperfusion or other elimination enhancement techniques should be considered when the clinical and toxicokinetic course suggests the presence of a refractory pharmacobezoar.

Exhaustive exercise modifies oxidative stress in smoking subjects.

BACKGROUND: Exhaustive exercise is associated with increased metabolic rate and accelerated generation of reactive oxygen species. Cigarette smoke also contains oxidants that may participate in the development of atherosclerosis. However, data on the association between exercise and smoking are sparse. METHODS: A homogenous group of 30 young men (15 smokers and 15 nonsmokers; mean age, 23.7 +/- 2.6 years), healthy, trained subjects, were assessed before and after a standard maximal exercise test. RESULTS: Exercise led to increased protein oxidation (carbonyl assay) in both smokers (+17.7%, P < 0.001) and nonsmokers (+19.1%, P < 0.05), elevation in plasma conjugated dienes (+ 157%, P < 0.04), and plasma lipid peroxides (+14%, P < 0.059) in smokers versus nonsmokers after exercise. Plasma antioxidants levels were significantly lower in the smoking group, with reduction in total carotenoids (-36.5%, P < 0.001), vitamin A (-80%, P < 0.001), and vitamin E (-64%, P < 0.002), compared with nonsmokers. A significant rise in leakage of muscle enzymes (CPK, LDH) and urine proteins (microalbumin and myoglobin) occurred in all subjects after exercise. CRP levels were higher in smokers compared with nonsmokers before and after exercise. CONCLUSIONS: Our results suggest that unnoticed interaction exists between smoking and intense exercise, which indicates that smokers are more susceptible to oxidative insults probably due to lower antioxidant capacity.

Effect of obesity on the relationship between plasma C-reactive protein and coronary artery stenosis in patients with stable angina.

INTRODUCTION: The association between plasma C-reactive protein (CRP) and the extent of coronary artery disease (CAD) in patients with stable angina remains controversial. Obesity is strongly associated with elevated CRP levels, potentially confounding the relationship between CRP and CAD severity. METHODS AND RESULTS: We studied 830 subjects without CAD and 218 patients with CAD undergoing elective coronary angiography. Geometric means of CRP were computed in a two-way analysis of covariance model in which study participants were stratified into nine groups according to CAD status (no CAD, single-vessel disease or multivessel disease) and tertiles of BMI. There was a significant interaction between CAD and categories of BMI with regard to CRP level (P=0.002). In the lower tertile of BMI, patients with CAD had markedly higher CRP concentration compared to control subjects (1.16, 1.80 and 2.82 mg/L in subjects without CAD, patients with single-vessel disease and patients with multivessel disease, respectively; P=0.003). However, the relationship between CRP and CAD became weaker for patients in the second BMI tertile (P=0.15), whereas no significant relationship was observed for patients in the third BMI tertile (P=0.75). In patients undergoing coronary angioplasty (n=195), BMI was independently related to the magnitude of the angioplasty-induced CRP elevations (P=0.002). CONCLUSION: The level of obesity is essential to the interpretation of the relationship between CRP and severity of CAD. The production of inflammatory mediators with increasing levels of obesity becomes the dominant determinant of plasma CRP levels and masks the vascular contribution due to CAD.

Association between elevated liver enzymes and C-reactive protein: possible hepatic contribution to systemic inflammation in the metabolic syndrome.

OBJECTIVE: The objective of this study was to test whether the frequent association between liver enzyme elevations and various components of the metabolic syndrome is associated with higher C-reactive protein (CRP) levels. METHODS AND RESULTS: Alanine aminotransferase (ALT), alkaline phosphatase (Alk-P), and high-sensitivity CRP were measured in 1740 subjects. Adjusted geometric mean CRP was calculated for subjects with normal and elevated ALT and for subjects with normal and elevated Alk-P, adjusting for age, sex, smoking, physical activity, body mass index, fasting glucose, triglycerides, the presence of hypertension and low HDL cholesterol, and use of aspirin or hormone replacement therapy. Adjusted CRP levels were higher in subjects with elevated ALT (2.21 versus 1.94 mg/L, P=0.028) or elevated Alk-P (2.58 versus 1.66 mg/L, P<0.0001). Logistic regression showed that compared with subjects with normal liver function tests, the adjusted odds for high-risk CRP (>3 mg/L) were significantly higher in subjects with elevated ALT (OR, 1.5; 95% CI, 1.2 to 1.9, P=0.002) or elevated Alk-P (OR, 2.1; 95% CI, 1.7 to 2.6, P<0.0001). CONCLUSIONS: Elevations of liver enzymes are associated with higher CRP concentrations. Hepatic inflammation secondary to liver steatosis is a potential contributor to the low-grade inflammation associated with the metabolic syndrome.

The association between cardiorespiratory fitness and C-reactive protein in subjects with the metabolic syndrome.

OBJECTIVES: We sought to study relationship between cardiorespiratory fitness and C-reactive protein (CRP) in subjects with the metabolic syndrome. BACKGROUND: Recent studies have shown an association between the metabolic syndrome and chronic subclinical inflammation, as determined by elevated CRP. Cardiorespiratory fitness is associated with a lower risk of diabetes and improved insulin resistance. METHODS: Physical fitness was assessed in 1,640 subjects using the Bruce treadmill protocol and expressed as maximal metabolic equivalents. The level of CRP was measured using a high-sensitivity assay. RESULTS: Geometric mean CRP was calculated across quartiles of fitness after adjustment for age, gender, smoking, use of medications, and coronary disease. A strong inverse trend toward decreasing CRP levels with increasing fitness quartiles was present in subjects without metabolic abnormalities, subjects with one or two metabolic abnormalities, and subjects with the metabolic syndrome (all p

Ramipril-induced agranulocytosis confirmed by a lymphocyte cytotoxicity test.

A 50-year-old man who had chronic renal failure presented with neutropenic fever four days after ramipril was initiated. Agranulocytosis due to other causes was ruled out after a bone marrow aspiration and biopsy examination were performed. A relationship between the drug and the adverse effect was suggested. It was established by a novel lymphocyte cytotoxicity test.

C-Reactive protein is inversely related to physical fitness in middle-aged subjects.

INTRODUCTION: Physical fitness has a protective effect with regard to the risk of developing coronary disease or diabetes. C-reactive protein (CRP) levels are directly related to increased risk of coronary disease and diabetes. However, data on the association between physical fitness and CRP are sparse. METHODS: Physical fitness was assessed in a population-based cross-sectional study (n = 892; age 50 +/- 9 years) using the Bruce treadmill protocol. CRP was measured using a high-sensitivity assay. RESULTS: Geometric mean CRP levels were calculated across quartiles of physical fitness after adjustment for age, gender, body mass index, smoking habit, presence of diabetes and hypertension, HDL cholesterol and triglyceride levels, and use of hormone replacement therapy, statins, and aspirin. CRP levels decreased with increasing quartiles of fitness (P for trend <0.0001). When used as a continuous variable in a stepwise linear regression model, the geometric mean of CRP decreased by 0.061 mg/L (95% confidence interval (CI) 0.034-0.089 mg/L) for each 1 unit increase in metabolic equivalents (METs). Multivariate logistic regression models showed that compared to subjects in the lowest fitness quintile, subjects in the highest fitness quintile had significantly lower adjusted odds of having a high-risk (>3 mg/L) CRP level (OR 0.53; 95% CI 0.39-0.71, P = 0.007). CONCLUSION: CRP concentration decreases continuously with increasing levels of physical fitness. The health-related salutary effects of physical fitness may be mediated, in part, through an antiinflammatory mechanism.

Admission C-reactive protein levels and 30-day mortality in patients with acute myocardial infarction.

BACKGROUND: Elevated C-reactive protein levels are associated with an increased risk of subsequent cardiovascular events in patients with unstable angina. However, limited information is available concerning the value of C-reactive protein levels in patients with acute myocardial infarction. METHODS: We prospectively studied 448 consecutive patients (mean [+/- SD] age, 60 +/- 12 years) with acute myocardial infarction. Serum C-reactive protein levels were measured within 12 to 24 hours of symptom onset, and divided into tertiles. Infarct size was determined by echocardiographic examination that was performed on day 2 or 3. Patients were followed for 30 days for mortality and subsequent cardiac events. RESULTS: At 30 days, 4 deaths (3%) occurred in patients in the lowest C-reactive protein tertile, 15 (10%) in patients in the middle tertile (P = 0.02 vs. the lowest tertile), and 33 (22%) in patients in the highest tertile (P <0.001 vs. the lowest tertile). In a multivariate analysis, C-reactive protein in the upper tertile was associated with 30-day mortality (relative risk = 3.0; 95% confidence interval [CI]: 1.3 to 7.2; P = 0.01) and the development of heart failure (odds ratio = 2.6; 95% CI: 1.5 to 4.6; P = 0.0006). C-reactive protein levels were not associated with the development of postinfarction angina, recurrent myocardial infarction, or the need for revascularization. CONCLUSION: Plasma C-reactive protein level obtained within 12 to 24 hours of symptom onset is an independent marker of 30-day mortality and the development of heart failure in patients with acute myocardial infarction. These findings suggest that C-reactive protein levels may be related to inflammatory processes associated with infarct expansion and postinfarction ventricular remodeling.