Yishai Levy

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 ≥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).

Obesity is the major determinant of elevated C-reactive protein in subjects with the metabolic syndrome

OBJECTIVE: To investigate the relationship between C-reactive protein (CRP) and various characteristics of the metabolic syndrome.DESIGN: Population-based cross-sectional study.SUBJECTS: A total of 1929 subjects undergoing a medical examination in a preventive medicine clinic (age, 50±10 y; 63% males).RESULTS: The proportion of subjects with CRP levels above the cut point generally used to indicate an obvious source of infection or inflammation (>10 mg/l) was 3, 7, and 15% in subjects who were normal weight, overweight, and obese, respectively. Subjects with obesity had markedly higher CRP level compared to patients without obesity regardless of whether they had the metabolic syndrome. However, there was no significant difference in CRP levels between nonobese subjects without the metabolic syndrome and subjects in whom the diagnosis of the metabolic syndrome was based on criteria other than obesity (adjusted geometric mean CRP 1.75 vs 2.08 mg/l, P=0.79). Similarly, CRP levels did not differ among obese subjects with and without the metabolic syndrome (adjusted geometric mean CRP 3.22 vs 3.49 mg/l, P=0.99). There was a linear increase in CRP levels with an increase in the number of metabolic disorders (P trend <0.0001), which was substantially diminished after controlling for body mass index (BMI) (P trend=0.1). Stepwise multivariate linear regression analysis identified BMI, triglyceride levels, HDL cholesterol levels (inversely), and fasting glucose as independently related to CRP levels. However, BMI accounted for 15% of the variability in CRP levels, whereas triglycerides, HDL cholesterol and fasting glucose levels accounted for only ∼1% of the variability in CRP levels.CONCLUSION: Obesity is the major factor associated with elevated CRP in individuals with the metabolic syndrome. CRP levels in the range suggesting a source of infection or inflammation (>10 mg/l) are more common among obese subjects than in nonobese subjects.

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.

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.

Effect of a Mediterranean Meal on Postprandial Carotenoids, Paraoxonase Activity and C-Reactive Protein Levels

Background and Aim: Atherosclerosis involves oxidative and inflammatory mediators regulated by fat and antioxidants. Therefore, we studied the postprandial evolution of plasma lipids, carotenoids, C-reactive protein (CRP), and human serum paraoxanase activity (PON1) following two different fatty meals. Subjects and Methods: Eight healthy males consumed a 45% fat 1,000 Kcal Mediterranean-like (Med) meal (monounsaturated 61% of fat) compared to a Western-like (Wes) (saturated 57% of fat) meal. Blood was collected at baseline (time 0) 2, 4 and 7 h postprandial. Plasma lipids, glucose, insulin, total carotenoids, CRP, and PON1 were analyzed. Results: There was a marginal increase in cholesterol and glucose after both meals. Triglycerides increased modestly (to less than 200 mg/dl) and insulin increased (more in the Wes-like meal) but still within normal range, indicating a low glycemic index for both meals. Only the Med-like meal resulted in a significant increase in both PON1 activity (16%, p < 0.02) and carotenoids (74%, p < 0.02) with a 2-hour postprandial decrease in CRP (6%, p < 0.02). Conclusion: A postprandial monounsaturated fatty acid rich meal increases both plasma carotenoids and PON1 with a decrease in CRP levels, thus providing a novel potential explanation to the protective properties of a Mediterranean diet against atherogenesis.

Dietary Supplementation of a Natural Isomer Mixture of Beta-Carotene Inhibits Oxidation of LDL Derived from Patients with Diabetes mellitus

Background: Accelerated atherosclerosis is common in patients with diabetes mellitus which may be linked to increased lipid peroxidation. Therefore, we compared the oxidation of LDL derived from patients with diabetes to normoglycemic controls and followed-up the effect of dietary β-carotene supplementation on LDL oxidation. Methods: Twenty patients with long-standing non-insulin-dependent diabetes mellitus were studied in comparison with age- and sex-matched control subjects. Dunaliella bardawil-derived β-carotene was supplemented to the patients for 3 weeks, 60 mg daily dose. LDL oxidation was analyzed by measuring malondialdehyde (MDA), lipid peroxides (PD), and conjugated dienes (CD) generation in response to CuSO4-induced oxidation. LDL lipid composition and the LDL associated vitamins A, E and carotenoids were also measured. Results: LDL susceptibility to oxidation by CuSO4 was increased in the patients by 40% with a 35% shorter lag time required for the initiation of LDL oxidation, i.e. 56 ± 6 min in patients vs. 85 ± 9 min in controls (p <0.01). Patients showed increased cholesterol/phospholipid and polyunsaturated/saturated ratios, as well as reduced content of LDL associated vitamins. Upon β-carotene supplementation, there was a significant elevation in plasma and in LDL all-trans β-carotene [from 0.296 ± 0.020 to 0.968 ± 0.133 μg/mg LDL protein (p < 0.01)] paralleled by a significant reduction in LDL susceptibility to oxidation, as exhibited by increased lag time up to 115 ± 10 min (p < 0.01) and reduction in MDA and PD generation (by 25 and 40%), respectively (p < 0.01). Conclusions: Increased susceptibility to oxidation of LDL derived from patients with diabetes mellitus is associated with abnormal LDL lipid composition and antioxidant content. Natural β-carotene dietary supplementation normalizes the enhanced LDL oxidation and consequently may be of importance in delaying accelerated development of atherosclerosis in these patients.

Increased Low-Density Lipoprotein Levels After Splenectomy: A Role for the Spleen in Cholesterol Metabolism in Myeloproliferative Disorders

Patients with myeloproliferative disorders demonstrate decreased plasma cholesterol and apolipoprotein B concentrations, and this has been related to the presence of a large spleen. Patients that underwent splenectomy in the past demonstrated normal plasma cholesterol levels. Plasma high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I were also reduced in these patients, but were normal after splenectomy. To study the immediate effect of splenectomy on the plasma lipid pattern, three patients with myeloproliferative disease and a large spleen who were undergoing splenectomy were compared with two control groups, one undergoing orthopedic operations and the second, cholecystectomy. In the control groups, plasma lipids tended to decrease for the first 2 days after surgery and then returned to preoperative levels. After splenectomy, however, plasma cholesterol, low-density lipoprotein (LDL), and apolipoprotein B significantly increased, reaching maximum levels after 4 days. Plasma HDL as well as apolipoprotein A-I decreased 1 day after splenectomy, but then increased over and above their preoperative concentrations. These results suggest an important role for the spleen in cholesterol metabolism in these patients. The spleen appears to be an important site for LDL catabolism in these patients.

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).

Dual Therapy With Statins and Antioxidants Is Superior to Statins Alone in Decreasing the Risk of Cardiovascular Disease in a Subgroup of Middle-Aged Individuals With Both Diabetes Mellitus and the Haptoglobin 2-2 Genotype

Diabetes Mellitus (DM) is associated with a state of increased oxidative stress.1 Paradoxically, however, antioxidants have not been found to provide CVD benefit to DM individuals in several prospective clinical trials.2–11 However, the inability to demonstrate benefit may have been attributable to inadequate patient selection as antioxidants may only benefit those with particularly high levels of oxidative stress.12 A polymorphism in the Haptoglobin (Hp) gene, an antioxidant protein, appears to permit identification of individuals with high oxidative stress and who may benefit from antioxidant therapy.13 There exists 2 classes of alleles at the Hp genetic locus, 1 and 2, and the antioxidant capacity of the Hp 2 protein is inferior to the Hp 1 protein.14–18 Robust clinical data has shown that individuals homozygous for the Hp 2 allele (Hp 2-2 genotype), 40% of DM individuals, have an up to 500% increased risk of CVD.19–22 A vast amount of basic science, animal, and epidemiological data has provided the logic for targeting vitamin E administration specifically to DM individuals with the Hp 2-2 genotype.13 Most importantly we have recently reported in the ICARE study (Israel CArdiovascular events Reduction with vitamin E [ClinicalTrials.gov# NCT00220831]) a prospective randomized placebo controlled trial of vitamin E therapy in DM individuals with the Hp 2-2 genotype, that vitamin E therapy results in a 50% reduction in CVD events.22 …

Adult onset Still's disease as a cause of ARDS and acute respiratory failure

We report a case of a young woman with pyrexia and progressive lung disease who developed acute respiratory distress syndrome (ARDS) and required prolonged mechanical ventilator support. The patient had a markedly elevated serum ferritin concentration of 7880 mug/L, a specific finding for the adult onset Stills disease (AOSD). Treatment of the patient with supportive and immunosuppressive therapy, resulted in patient survival and cure. The early consideration of the diagnosis of AOSD in patients with fever of unknown origin and a compatible clinical course may modify its severe complications.