PubMed Health⌕ Search

Biomedical subjects

Eran Leitersdorf

Publications and source records attributed to Eran Leitersdorf.

At least 19 recordsLinked to original sources
PubMed2006

Possible association between diabetes and bisphosphonate-related jaw osteonecrosis.

CONTEXT: Bisphosphonate-related osteonecrosis (BON) of the jaws is a newly identified condition for which the exact mechanism involved in its pathogenesis remains obscure. OBJECTIVE: The objective of the study was to evaluate whether diabetes mellitus (DM) may be a contributing factor in the development of BON. DESIGN: From 2004 to 2006, 31 patients were diagnosed with BON. The diagnosis of BON was based on the medical and dental history of each patient as well as the observation of clinical signs and symptoms of this pathological process. DM was based on two consecutive fasting blood glucose levels above 7 mmol/liter. SETTING: The study was completed in the Hebrew University-Hadassah Hospital referral center. RESULTS: Of the 31 patients with BON, 18 (58%) were found to have DM or impaired fasting glucose. The proportion of diabetic patients was much higher than expected relative to the incidence of DM in the general population (14%) and compared with the proportion of diabetic patients in a control group of oncological patients treated with bisphosphonates and without BON (12%) (P = 0.00003). CONCLUSIONS: This finding indicates that DM may be a risk factor for BON and that DM patients treated with bisphosphonates should be carefully monitored. We discuss here the bone metabolic pathways characteristic of DM patients and the way in which these pathways can augment the effects of bisphosphonates.

Aged↗
PubMed2006

Clozapine-induced systemic lupus erythematosus.

OBJECTIVE: To report a case of classic clozapine-induced systemic lupus erythematosus that also developed on rechallenge. CASE SUMMARY: A 32-year-old white woman diagnosed with schizophrenia presented in 1996 with clinical characteristics and laboratory markers consistent with drug-induced lupus (DIL). Clozapine, started 1 year prior, was withdrawn, with complete biological and clinical remission within 3 months. In 2004, 1 week after rechallenge with clozapine for uncontrolled schizophrenia, the patient developed clinical and biological signs and symptoms consistent with the diagnosis of DIL. Again, discontinuation of clozapine was followed by full remission within 2-3 months. DISCUSSION: DIL was first described more than 50 years ago, with multiple drugs implicated in the causation. Clozapine-induced lupus was reported recently, but does not meet the usual criteria for a diagnosis of DIL. We report a classic case of clozapine-induced lupus that, according to the Naranjo probability scale, demonstrates a highly probable relationship between DIL and clozapine. CONCLUSIONS: DIL demands a high index of suspicion for diagnosis. Although clozapine has an extensive safety profile, DIL must be considered as one of its serious adverse effects.

Adult↗
PubMed2006

Stent graft in treatment of penetrating thoracic aortic ulcer.

A 75-year-old woman presented with shortness of breath. Computed tomography pulmonary angiogram revealed two penetrating aortic ulcers in the descending aorta. Transesophageal echocardiogram examination confirmed the diagnosis. In the operating department, a stent graft to the thoracic aorta was inserted.

Aged↗
PubMed2006

Physicians underdiagnose and undertreat obesity in ishemic heart disease patients: data from the HOLEM Study Group.

BACKGROUND: Obesity is an independent risk factor for ischemic heart disease and affects the status of other risk factors for cardiovascular disease. OBJECTIVE: To study the attitude of physicians to obesity by examining discharge letters of overweight patients with ischemic heart disease. METHODS: We used the HOLEM database for this analysis. The HOLEM project was designed to study the NCEP (National Cholesterol Education Program) guideline implementation among patients with IHD at hospital discharge. We documented the recording of risk factors and treatment recommendations for IHD by reviewing the discharge letters of 2994 IHD patients admitted to four central hospitals in Israel between 1998 and 2000. A follow-up visit was held 6-8 weeks after discharge, at which time the diagnosis of IHD was verified, risk factor status was checked, height and weight were measured and drug treatment was reviewed. RESULTS: Mean body mass index was 28.3 kg/m2 and 32% were obese (BMI > or = 30 kg/m2). Only 39.6% of the obese patients and 65.8% of the morbidly obese patients (BMI > or = 40 kg/m2) had "obesity" noted in their discharge letters, and weight loss recommendation was written in only 15% of the obese patients' discharge letters. Acute episodes like acute myocardial infarction and unstable angina did not influence the notation of obesity, and only BMI and the number of additional risk factors were positively correlated with the notation of this risk factor. CONCLUSIONS: Despite the importance of obesity, weight status was not noted and weight loss was not recommended in most of the discharge letters of obese IHD patients.

Aged↗
PubMed2005

The association of common SNPs and haplotypes in the CETP and MDR1 genes with lipids response to fluvastatin in familial hypercholesterolemia.

OBJECTIVE: To examine whether genetic polymorphisms in the cholesteryl-ester transfer protein (CETP) and the P-glycoprotein drug transporter (MDR1), are associated with variable lipid response to fluvastatin. METHODS: Lipid levels were determined in a compliance-monitored clinical study at baseline and following 20 weeks of treatment with 40 mg dose of fluvastatin in 76 FH patients. CETP and MDR1 SNP genotyping was performed and linear regression was used to examine the associations between common SNPs and haplotypes and lipid response. RESULTS: Treatment with 40 mg of fluvastatin resulted in mean low density lipoprotein cholesterol (LDL-C) reduction of 21.5%; mean triglyceride (TG) reduction of 8.3%; and a mean high-density lipoprotein cholesterol (HDL-C) increase of 13.4%. Five tagging SNPs in both genes were used to reconstruct five and six haplotypes accounting for 71.4% and 90.2% of the observed haplotypes in the CETP and MDR1 genes, respectively. CETP-H13 and MDR1-h4 were associated with an increase in LDL-C response. CETP-H5 was significantly associated with decreased TG and HDL-C response, whereas MDR1-h10 was associated with decreased TG response. A multivariate regression model indicated an independent additive effect of CETP-H5 and MDR1-h10 on the level of TG response. CONCLUSIONS: CETP and MDR1 have independent effects on lipid changes following fluvastatin treatment. The results of this study may lead to an improved understanding of the genetic determinants of lipids response to treatment.

Adult↗
PubMed2005

The relation between NOD2/CARD15 mutations and the prevalence and phenotypic heterogeneity of Crohn's disease: lessons from the Israeli Arab Crohn's disease cohort.

The prevalence of Crohn's disease depends on geographic location and racial background. Arg702Trp, Gly908Arg, and Leu1007fsinsC mutations in the NOD2/CARD15 gene are associated with Crohn's disease in Caucasians. The mutation rate among Israeli Jewish patients is 27%-41%. The prevalence of Crohn's disease is much lower in the Israeli Arab compared to the Israeli Jewish population. We studied the NOD2/CARD15 mutation rate and disease phenotype (according to the Vienna classification) among the Israeli Arabs and compared them with those in an Israeli Jewish cohort. We recruited 66 Israeli Arab patients and 122 ethnically matched controls. Five patients (8.2%) and three controls (2.3%) carried one NOD2/CARD15 mutation. The phenotypic characteristics of the Arab and Jewish patients were very similar. We conclude that NOD2/CARD15 mutations do not contribute to Crohn's susceptibility in the Israeli Arab population and suggest that NOD2/CARD15 mutations have an important effect on Crohn's prevalence within a specific population but not on the phenotype.

Adult↗
PubMed2005

Cardiovascular risk assessment and treatment to target low density lipoprotein levels in hospitalized ischemic heart disease patients: results of the HOLEM study.

BACKGROUND: Hypercholesterolemia control status is lacking throughout the western world. OBJECTIVES: To examine whether the treatment recommendations given to ischemic heart disease patients at hospital discharge are compatible with the guidelines of the Israeli medical societies and the U.S. National Cholesterol Education Program for coronary artery disease prevention; and to study the effects of brief educational sessions on the adherence of physicians with the guidelines. METHODS: We included consecutive IHD patients admitted to four central hospitals in Israel between 1998 and 2000. The study was conducted in two phases. In phase 1, we reviewed discharge letters to document treatment recommendations given to each patient. In phase 2 we educated the practitioners by reviewing the Israeli medical societies and the NCEP guidelines and the quality of their recommendations in phase 1, after which we reevaluated the discharge letters. RESULTS: The study included 2,994 patients: 627 in phase 1 and 2,367 in phase 2. Of the patients who needed cholesterol-lowering according to their low density lipoprotein levels, 37.4% were not prescribed such drugs at discharge (under-treatment group). This proportion was reduced by education to 26.6% (P < 0.001) in phase 2. Of the treated patients, 65.6% did not reach the target LDLgoal in phase 1 (under-dosage group) as compared to 60.2% in phase 2 (P = 0.23). In phase 2 there was an increase in the percent of patients reaching LDL levels <130 mg/day (69.3% vs. 63.8% of patients prescribed medication, P = 0.01), but the percent of patients reaching' LDL levels <100 was not different in phase 2 after adjusting for age and gender (the odds ratio for reaching target LDL was 1.16, with 95% confidence interval of 0.95-1.43). CONCLUSIONS: Physician recommendations to IHD patients discharged from hospital were suboptimal. We documented a high proportion of under-treated and under-dosaged patients. Brief educational sessions have a beneficial effect on the usage of statins; however, additional effort in guideline implementations is needed.

Arteriosclerosis↗
PubMed2004

Atherosclerosis in the apolipoprotein-E-deficient mouse: a decade of progress.

Arguably the most critical advancement in the elucidation of factors affecting atherogenesis has been the development of mouse models of atherosclerosis. Among available models, the apolipoprotein E-deficient (apoE-/-) mouse is particularly popular because of its propensity to spontaneously develop atherosclerotic lesions on a standard chow diet. A Medline search reveals over 645 articles dedicated to studies using this reliable and convenient "super" animal model since its inception (Piedrahita JA et al, Proc Natl Acad Sci U S A 1992;89:4471-4475; Plump AS et al, Cell 1992;71:343-353) with a more or less steady increase from year to year. This review will examine our present understanding of the pathology and progression of plaques in this animal and highlight some of the nutritional, pharmacological, and genetic studies that have enhanced this understanding.

Animals↗
PubMed2004

Alcohol dehydrogenase polymorphisms influence alcohol-elimination rates in a male Jewish population.

BACKGROUND: Genetic variation in the alcohol dehydrogenase (ADH) enzyme is associated with an aversion to alcohol and a lower risk of alcoholism among Asians. There is growing evidence of a functional role of the ADH2*2 allele in alcohol-drinking patterns among Jews, who have traditionally exhibited low rates of alcoholism and alcohol-related problems. The mechanism by which this allelic effect is mediated is not yet clearly understood. This study examined the effect of ADH2*2 on alcohol-elimination rates (AER) under experimental conditions. METHODS: Young adult male Jews (N = 109) received an intravenous alcohol infusion; metabolism was measured by using standard breath alcohol concentration tests. A clamping technique was used to achieve and maintain a target breath alcohol concentration of 50 mg/100 ml for a defined time period. The AER at steady state was calculated. The alcohol disappearance rate was also calculated from the descending limb slope. Polymerase chain reaction was used for allelic determination of the ADH2 and ADH3 loci. RESULTS: The mean AER among ADH2*2 carriers was significantly higher (8.09 +/- 1.4 g/hr) than among ADH2*1 homozygotes (7.14 +/- 1.5 g/hr; p = 0.003). Significance was retained on adjustment for potential confounding covariates. The ADH2 allele explains 8.5% of the AER variance in this population. Little AER difference was observed across ADH3 genotype groups. The slope of the descending limb increased with increasing copies of the ADH2*2 allele. CONCLUSIONS: The rate of alcohol elimination is significantly associated with the ADH2 genotype of Jewish males. Evidence for variation in alcohol metabolism across ADH genotypic groups provides support for the role of physiologic protective factors in alcohol drinking and suggests that reduced drinking among Jews may be genetically as well as environmentally determined. We believe that application of the novel "Indiana clamp" enhances AER measurement accuracy, allowing for detection of hitherto undetectable differences.

Adult↗
PubMed2004

Apolipoprotein E genotyping: accurate, simple, high throughput method using ABI Prism SNaPshot Multiplex System.

Apolipoprotein E (apo E) is an essential constituent of several plasma lipoproteins, and plays an important role in lipoprotein metabolism. The apo E gene exhibits two common functional polymorphisms, producing 3 isoforms known to be associated with the risks of developing cardiovascular disease and susceptibility to Alzheimer's disease. Numerous different methods have been established for determining the three apo E isoforms, yet there are disadvantages and ambiguities associated with all of them. We used a method adapted for multiplex automated primer extension analysis by improving a commercially available protocol (SNaPshot) and simultaneously typing apo E single nucleotide polymorphisms (SNPs) encoding for isoforms at codon 112 and 158. This protocol relies on the extension with fluorescent dideoxyNTPs of a primer that ends one nucleotide 5' of a given SNP (minisequencing). Improvement of the method is achieved by incorporating into the minisequencing reaction two pooled primers corresponding to both apo E SNPs followed by analysis on an ABI PRISM 310 DNA sequencer. We found full concordance with genotypes determined using universal heteroduplex. This method is readily available for many laboratories and is a simple, unequivocal easy to use technique suitable for large amount of clinical samples that may provide a significant improvement over previously reported methods for apo E genotyping.

Alzheimer Disease↗
PubMed2004

Identification of a novel mutation in the gene for bone morphogenetic protein receptor II in an Israeli patient with familial primary pulmonary hypertension.

BACKGROUND: Primary pulmonary hypertension is a rare disorder, characterized by progressive pulmonary hypertension and right heart failure. It may be familial or sporadic. Mutations in bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor-beta receptor superfamily of receptors, underlie many cases of the disorder. OBJECTIVES: To perform molecular analysis of a patient with familial PPH and provide her and her family with suitable genetic counseling. METHODS: DNA was extracted from 10 ml whole blood, and the BMPR2 gene was screened for mutations. Individual exons were amplified by polymerase chain reaction and sequenced. Mutation confirmation and molecular characterization of additional family members was performed using restriction enzyme analysis followed by appropriate genetic counseling. RESULTS: We identified a novel T to C missense mutation expected to result in substitution of arginine for a conserved cysteine in the ligand-binding domain of BMPR2. Screening of family members demonstrated the presence of the mutation in the father and a younger asymptomatic sister of the index patient. CONCLUSIONS: Molecular diagnosis in PPH allows for identification of at-risk family members and raises the option of earlier diagnosis and possibly instituting earlier treatment in affected individuals. However, molecular screening of asymptomatic family members raises difficult ethical questions that can only be resolved by conducting large multicenter prospective studies in BMPR2 carriers.

Adult↗
PubMed2003

Risk for myopathy with statin therapy in high-risk patients.

Emerging data suggest that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) offer important benefits for the large population of individuals at high risk for coronary heart disease. This population encompasses a sizable portion of individuals who are also at high risk for drug-drug interactions due to their need for multiple medications. In general, statins are associated with a very small risk for myopathy (which may progress to fatal or nonfatal rhabdomyolysis); however, the potential for drug-drug interactions is known to increase this risk in specific high-risk groups. The incidence of myopathy associated with statin therapy is dose related and is increased when statins are used in combination with agents that share common metabolic pathways. Of particular concern is the potential for interactions with other lipid-lowering agents such as fibrates and niacin (nicotinic acid), which may be used in patients with mixed lipidemia, and with immunosuppressive agents, such as cyclosporine, which are commonly used in patients after transplantation. Clinicians should be alert to the potential for drug-drug interactions to minimize the risk of myopathy during long-term statin therapy in patients at high risk for coronary heart disease.

Calcium Channel Blockers↗
PubMed2002

Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor.

Sterol 27-hydroxylase (CYP27A1) is required for bile acid synthesis by both the classical and alternate pathways. Cyp27a1(-/-) mice exhibit a dramatic increase in the activity of cytochrome P450 3A (CYP3A), which catalyzes side-chain hydroxylations of bile acid intermediates, thereby facilitating their excretion in the bile and urine. We examine the role of the nuclear xenobiotic receptor PXR (pregnane X receptor) in this process. We demonstrate that expression of Cyp3a11 and other established PXR target genes is increased in the Cyp27a1(-/-) mice. WhenCyp27a1(-/-) mice are fed a diet containing either cholic acid or chenodeoxycholic acid, expression of CYP7A1, which catalyzes the rate-limiting step in bile acid biosynthesis, is strongly suppressed. In parallel, the induction of Cyp3a11 observed in these mice is reversed, suggesting that bile acid intermediates serve as PXR activators. In support of this hypothesis, three potentially toxic sterols (7alpha-hydroxy-4-cholesten-3-one, 5beta-cholestan-3alpha,7alpha,12alpha-triol, and 4-cholesten-3-one), including two that are known to accumulate in Cyp27a1(-/-) mice, are efficacious activators of mouse PXR. All three compounds are more potent activators of mouse PXR than of human PXR, which may explain in part why humans who lack functional CYP27A1 do not display a corresponding increase in CYP3A activity and are stricken with the disease cerebrotendinous xanthomatosis. Taken together, these results reveal the existence of a feedforward regulatory loop by which potentially toxic bile acid intermediates activate PXR and induce their own metabolism. In addition, this study demonstrates that animal models with alterations in gene expression can be used to identify endogenous ligands for orphan nuclear receptors.

Animals↗
PubMed2002

Platelet factor 4 enhances the binding of oxidized low-density lipoprotein to vascular wall cells.

Accumulation of low-density lipoprotein (LDL)-derived cholesterol by macrophages in vessel walls is a pathogenomic feature of atherosclerotic lesions. Platelets contribute to lipid uptake by macrophages through mechanisms that are only partially understood. We have previously shown that platelet factor 4 (PF4) inhibits the binding and degradation of LDL through its receptor, a process that could promote the formation of oxidized LDL (ox-LDL). We have now characterized the effect of PF4 on the binding of ox-LDL to vascular cells and macrophages and on the accumulation of cholesterol esters. PF4 bound to ox-LDL directly and also increased ox-LDL binding to vascular cells and macrophages. PF4 did not stimulate ox-LDL binding to cells that do not synthesize glycosaminoglycans or after enzymatic cleavage of cell surface heparan and chondroitin sulfates. The effect of PF4 on binding ox-LDL was dependent on specific lysine residues in its C terminus. Addition of PF4 also caused an approximately 10-fold increase in the amount of ox-LDL esterified by macrophages. Furthermore, PF4 and ox-LDL co-localize in atherosclerotic lesion, especially in macrophage-derived foam cells. These observations offer a potential mechanism by which platelet activation at sites of vascular injury may promote the accumulation of deleterious lipoproteins and offer a new focus for pharmacological intervention in the development of atherosclerosis.

Amino Acid Substitution↗
PubMed2002

Human sterol 27-hydroxylase (CYP27) overexpressor transgenic mouse model. Evidence against 27-hydroxycholesterol as a critical regulator of cholesterol homeostasis.

CYP27-overexpressed transgenic mice were generated with the use of a human full-length CYP27 coding region cloned into a ubiquitous expression vector. Positive transgenic mice were identified by tail DNA genotyping and high fecal 27-hydroxycholesterol content. The levels of 27-hydroxycholesterol were found to be 3-5 times higher in the circulation and the tissues of the overexpressed mice when compared with littermate controls. There were no gross morphological differences between the overexpressed mice and their controls. Total cholesterol and triglyceride levels were not affected by overexpression of CYP27. Serum lathosterol was also normal, suggesting a normal rate of cholesterol synthesis. Serum levels of 7alpha-hydroxycholesterol were unaffected, suggesting a normal rate of bile acid formation in the pathway involving cholesterol 7alpha-hydroxylase. Biliary bile acid composition was slightly affected by CYP27 overexpression in female but not in male mice. Fecal levels of neutral steroids were slightly but significantly increased in overexpressor female mice but not in male mice. Levels of 24-hydroxycholesterol in the circulation were significantly reduced in the overexpressed mice, probably as a consequence of a recently described catabolic pathway involving CYP27. Combined with the results of our previous work on mice with a disruption of the CYP27 gene, the present results suggest that the levels of 27-hydroxycholesterol are not of critical importance for cholesterol homeostasis in mice.

Animals↗
PubMed2002

Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia.

Sterol-regulatory element-binding protein (SREBP)-2 is a key regulator of cholesterol. When cells are deprived of cholesterol, proteolytic cleavage releases the NH(2)-terminal domain of SREBP-2 that binds and activates the promoters of SREBP-2-regulated genes including the genes encoding the low-density lipoprotein (LDL) receptor, 3-hydroxymethyl-3-glutaryl-(HMG-)CoA-synthase, and HMG-CoA-reductase. Thus, SREPB-2 gene activation leads to enhanced cholesterol uptake and biosynthesis. A novel protein polymorphism (SREBP-2-595A/G) discovered in the regulatory domain of human SREBP-2 was investigated regarding its impact on cholesterol homeostasis. In human embryonic kidney (HEK)-293-cells, the cleavage-rate of the SREBP-2-595A-isoform was slightly decreased compared to that of the SREBP-2-595G-isoform. Since cleavage of SREBP-2 activates the LDL receptor-mediated uptake of plasma cholesterol, we hypothesized the LDL receptor-mediated uptake to be decreased in homozygous SREBP-2-595A-carriers and thus, plasma total cholesterol (TC) to be higher than in SREBP-2-595G-carriers. Multiple linear regression analysis of population samples from Switzerland (N=1334) and Israel (N=923) demonstrated a significant positive, gene dose-dependent association of the SREBP-2-595A-isoform with higher plasma TC (P=0.001). This cholesterol-modulating effect was present in hypercholesterolaemic (DeltaTC=1.05 mmol/l, 14.4%; P=0.002; N=477), but absent in normocholesterolaemic subjects (DeltaTC=0.06 mmol/l, 1.4%; P=0.334; N=1780). In summary, a slightly but constantly decreased cleavage-rate of the SREBP-2-595A-isoform compared to that of the SREBP-2-595G-isoform may lead to a reduced transcriptional activation of the LDL receptor-gene weakening the SREBP-mediated compensation mechanisms, and may, therefore, be a critical factor in the development of polygenic hypercholesterolaemia.

Adolescent↗