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.

Enhanced cardiovascular risk and altered oxidative status in elders with moderate excessive body fat.

Aging and obesity are linked to oxidative stress. Oxidative stress may mediate age-related cardiovascular diseases. Although the body mass index (kg/m2) defines obesity (≥30) and overweight (25-29.9), it may fail to detect crucial differences in body fat content in elders. Consequently, we measured body fatness in 42 healthy elders and evaluated their cardiovascular risk factors and the extent of their physical activity. We assessed plasma, erythrocytes, and saliva oxidative stress biomarkers in this population. A higher fat mass was associated with a less active lifestyle, more metabolic syndrome components, an enhanced Framingham 10-year risk score, and augmented insulin resistance. Individuals with excessive body fat had significantly less oral peroxidase enzymes activity than those with normal body fat. Erythrocyte susceptibility to oxidative hemolysis, previously reported to be elevated with physical activity, was marginally lower in the higher fat group. Other biomarkers of oxidative stress in saliva, plasma, and erythrocytes were similar in both groups. A 6% elevation in body fat with a less active lifestyle and an increased cardiovascular risk is associated with a decline in salivary anti-oxidative activity. Such reduced activity may contribute to deteriorating oral health in obese elders. Thus, this study provides novel information on the contribution of excessive body fat to oxidative status and cardiovascular risk in old age.

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.

Green tea: a promising natural product in oral health.

Green tea is a leading beverage in the Far East for thousands of years; it is regarded for a long time as a health product. Green tea is important source of polyphenol antioxidants. Polyphenols including epigallocatechin 3 gallate (EGCG) constitute the most interesting components in green tea leaves. Green tea has the potential to protect against various malignant, cardiovascular and metabolic diseases. There is a growing body of evidence pointing a beneficial role of green tea and its polyphenols in oral health. Green tea protects against bacterial induced dental caries. Tea polyphenols possess antiviral properties, believed to help in protection from influenza virus. Additionally, green tea polyphenols can abolish halitosis through modification of odorant sulphur components. Oral cavity oxidative stress and inflammation, consequent to cigarette smoking and cigarettes' deleterious compounds nicotine and acrolein, may be reduced in the presence of green tea polyphenols. Generally, green tea defends healthy cells from malignant transformation and locally has the ability to induce apoptosis in oral cancer cells. All together, there is an increasing interest in the health benefits of green tea in the field of oral health. Nonetheless, there is still a need for more clinical and biological studies to support guidelines for green tea intake as part of prevention and treatment of specific oral pathologies.

[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 therapy results in a reduction in HDL function in individuals with diabetes and the haptoglobin 2-1 genotype.

OBJECTIVE: Vitamin E provides cardiovascular protection to individuals with diabetes and the haptoglobin 2-2 genotype but appears to increase cardiovascular risk in individuals with diabetes and the haptoglobin 2-1 genotype. We have previously demonstrated that the haptoglobin protein is associated with HDL and that HDL function and its oxidative modification are haptoglobin genotype dependent. We set out to test the hypothesis that the pharmacogenetic interaction between the haptoglobin genotype on cardiovascular risk might be secondary to a parallel interaction between the haptoglobin genotype and vitamin E on HDL function. RESEARCH DESIGN AND METHODS: Fifty-nine individuals with diabetes and the haptoglobin 2-1 or 2-2 genotypes were studied in a double-blind placebo controlled crossover design. Participants were treated with either vitamin E (400IU) or placebo for 3 months and crossed over for an equivalent duration. Serum was collected at baseline and after the completion of each treatment. HDL functionality as well as HDL associated markers of oxidation and inflammation were measured after each interval in HDL purified from the cohort. RESULTS: Compared to placebo, vitamin E significantly increased HDL function in haptoglobin 2-2 but significantly decreased HDL function in haptoglobin 2-1. This pharmacogenetic interaction was paralleled by similar non-significant trends in HDL associated lipid peroxides, glutathione peroxidase, and inflammatory cargo. CONCLUSION: There exists a pharmacogenetic interaction between the haptoglobin genotype and vitamin E on HDL function (clinicaltrials.gov NCT01113671).

Antioxidants in the prevention of atherosclerosis: the importance of proper patient selection.

We wish to comment on the recent publication by Katiski and Manes. We absolutely agree with the reviewers that there has been no consistent protective effect of any single antioxidant or combination against cardiovascular morbidity and mortality. However, one reason why antioxidant trials may have failed to show clinical benefit in these studies may be related to inappropriate patient selection. Thus, we would like to present a recent prospective double blind placebo controlled study (ICARE), which assessed potential cardiovascular benefit from vitamin E in a subgroup of patients with both Diabetes Mellitus (DM) and the Haptoglobin (Hp) 2-2 genotype-agroup with very high oxidative stress. We believe that groups with evidence of a significant pro-oxidative and pro-inflammatory milieu such as the diabetic patients with the Hp 2-2 genotype, may benefit from antioxidants. Thus, better identification of such sub-groups, which will respond favorably to treatment with antioxidants is worthy of investigation.

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.

Factor analysis of risk variables associated with low-grade inflammation.

BACKGROUND: Chronic subclinical inflammation, manifesting as elevated levels of inflammatory markers such as C-reactive protein (CRP), predicts future atherothrombotic events. The pathophysiology of low-grade inflammation is complex, and multiple intercorrelated conditions have been associated with elevated CRP. METHODS: Principal factor analysis was used to investigate clustering of variables associated with elevated CRP using data from 1435 subjects without known coronary disease. Components of the metabolic syndrome, uric acid, liver enzymes, pulmonary function tests, smoking status, cardiorespiratory fitness (measured by maximal treadmill test), and high-sensitivity C-reactive protein were determined in each subject. RESULTS: Factor analysis identified three factors, which explained 51.0% of the total variance in the dataset (24.4% factor 1, 17.3% factor 2, and 9.3% factor 3). Based on factor loadings of >or=0.5, these factors were interpreted as (1) "metabolic factor" including BMI, fasting glucose, HDL cholesterol, triglycerides, systolic blood pressure, and uric acid; (2) a cardiorespiratory factor that included fitness level, forced expiratory volume in 1s and sex; and (3) "smoking" factor that included cigarette smoking and age. Each of these factors was significantly associated with the presence of high-risk CRP (>or=3mg/L) in the study population. The ability of a multivariate model that included these three factors to predict high-risk CRP was comparable to a model containing the original 10 variables (area under the receiver-operator characteristics curve 0.7 vs. 0.72, respectively). CONCLUSION: Metabolic perturbations, cardiorespiratory fitness, and smoking are separate and largely independent factors in the pathophysiology of chronic, low-grade inflammation.