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Biomedical subjects

E Levy

Publications and source records attributed to E Levy.

At least 19 recordsLinked to original sources
PubMed2007

Asymmetrical regulation of scavenger receptor class B type I by apical and basolateral stimuli using Caco-2 cells.

Cholesterol uptake and the mechanisms that regulate cholesterol translocation from the intestinal lumen into enterocytes remain for the most part unclear. Since scavenger receptor class B type I (SR-BI) has been suggested to play a role in cholesterol absorption, we investigated cellular SR-BI modulation by various potential effectors administered in both apical and basolateral sides of Caco-2 cells. With differentiation, Caco-2 cells increased SR-BI protein expression. Western blot analysis showed the ability of cholesterol and oxysterols in both cell compartments to reduce SR-BI protein expression. Among the n-3, n-6, and n-9 fatty acid families, only eicosapentaenoic acid was able to lower SR-BI protein expression on both sides, whereas apical alpha-linolenic acid decreased SR-BI abundance and basolateral arachidonic acid (AA) raised it. Epidermal growth factor and growth hormone, either in the apical or basolateral medium, diminished SR-BI cellular content, while insulin displayed the same effect only on the basolateral side. In the presence of proinflammatory agents (LPS, TNF-alpha, IFN-gamma), Caco-2 cells exhibited differential behavior. SR-BI was downregulated by lipopolysaccharide on both sides. Finally, WY-14643 fibrate diminished SR-BI protein expression when it was added to the apical medium. Biotinylation studies in response to selected stimuli revealed that regulatory modifications in SR-BI protein expression occurred for the most part at the apical cell surface irrespective of the effector location. Our data indicate that various effectors supplied to the apical and basolateral compartments may impact on SR-BI at the apical membrane, thus suggesting potential regulation of intestinal cholesterol absorption and distribution in various intracellular pools.

CD36 Antigens↗
PubMed2006

Luttinger-liquid behavior in weakly disordered quantum wires.

We have measured the temperature dependence of the conductance in long V-groove quantum wires fabricated in GaAs/AlGaAs heterostructures. Our data are consistent with recent theories developed within the framework of the Luttinger-liquid model, in the limit of weakly disordered wires. We show that, for the relatively low level of disorder in our quantum wires, the value of the interaction parameter g congruent with 0.66, which is the expected value for GaAs. However, samples with a higher level of disorder show conductance with stronger temperature dependence, which does not allow their treatment in the framework of perturbation theory. Fitting such data with perturbation-theory models leads inevitably to wrong (lower) values of g.

Journal Article↗
PubMed2006

Overproduction of intestinal lipoprotein containing apolipoprotein B-48 in Psammomys obesus: impact of dietary n-3 fatty acids.

AIMS/HYPOTHESIS: Emerging evidence underscores the important role of the small intestine in the pathogenesis of dyslipidaemia in insulin resistance and type 2 diabetes. We therefore tested the hypothesis that n-3 fatty acids improve the various events governing intra-enterocyte lipid transport in Psammomys obesus gerbils, a model of nutritionally induced metabolic syndrome. MATERIALS AND METHODS: Experiments were carried out on Psammomys obesus gerbils that were assigned to an isocaloric control diet and a diet rich in fish oil for 6 weeks. RESULTS: Increased dietary intake of fish oil lowered body weight and improved hyperglycaemia and hyperinsulinaemia. It simultaneously decreased de novo intestinal lipogenesis and lipid esterification of the major lipid classes, e.g. triglycerides, phospholipids and cholesteryl esters, particularly in insulin-resistant and diabetic animals. Accordingly, lessened activity of monoacylglycerol and diacylglycerol acyltransferase was recorded. As assessed in cultured jejunal explants incubated with either [(14)C]-oleic acid or [(35)S]-methionine, fish oil feeding resulted in diminished triglyceride-rich lipoprotein assembly and apolipoprotein (apo) B-48 biogenesis, respectively. The mechanisms did not involve apo B-48 transcription or alter the gene expression and activity of the critical microsomal triglyceride transfer protein. Rather, the suppressed production of apo B-48 by n-3 fatty acids was associated with intracellular proteasome-mediated posttranslational downregulation in insulin-resistant and diabetic animals. CONCLUSIONS/INTERPRETATION: Our data highlight the beneficial impact of n-3 fatty acids on adverse effects of the metabolic syndrome and emphasise their influence on intestinal lipid transport, an effect which may limit postprandial lipaemia and the risk of atherosclerosis.

Acyltransferases↗
PubMed2006

Cavernous carotid origin aneurysm rupture with intracerebral intraparenchymal hemorrhage after treatment of a traumatic Barrow type A cavernous carotid artery fistula.

This case report demonstrates delayed rupture of a cavernous carotid fistula and aneurysm into the temporal lobe 12 years after treating a direct cavernous carotid artery fistula using detachable silicon balloons. The ultimate treatment was performed using arterial endovascular sacrifice. Successful treatment of cavernous carotid fistulas may ultimately lead to formation of cavernous aneurysms. Although these lesions rarely cause intraparenchymal hemorrhage, the risk for such an event must be taken into consideration when patients are treated for the initial lesion.

Adult↗
PubMed2005

Iron-ascorbic acid-induced oxidant stress and its quenching by paraoxonase 1 in HDL and the liver: comparison between humans and rats.

Paraoxonase 1 (PON1) is a serum enzyme closely associated with high-density lipoprotein (HDL), which may protect against atherosclerosis by hydrolyzing lipid peroxides and several organophosphorus compounds. The purpose of the present study was to test the hypothesis that lipid peroxidation modifies the activity and protein mass of PON1 in humans and rats. Our findings revealed that the bulk of the activity monitored by the hydrolysis of paraoxon and phenyl acetate was confined to liver intracellular endoplasmic reticulum-derived microsomes and was mostly recovered in circulating HDL3. Confirmation was obtained by the determination of PON1 expression by Western blot. It is noteworthy that PON1 levels were consistently decreased in human sera, HDL, and liver microsomes compared with rat counterparts. Concomitant with iron-ascorbate-mediated lipid peroxidation, there was a decline in PON1 activity and protein in both HDL3 and microsomes, which was attenuated by butylated hydroxytoluene antioxidant treatment. The current data indicate that PON1 localization in microsomes and HDL3 could represent a selective cellular and lipoprotein response to oxidative stress. This was tested by the iron-ascorbate oxygen-radical generating system. It is also proposed that the increased PON1 level may have a function related to the well-known atherosclerosis resistance of rats.

Animals↗
PubMed2005

A clinical rating scale for Batten disease: reliable and relevant for clinical trials.

BACKGROUND: Batten disease (juvenile neuronal ceroid lipofuscinosis [JNCL]) is an autosomal recessive neurodegenerative disorder characterized by blindness, seizures, and relentless decline in cognitive, motor, and behavioral function. Onset is in the early school years, with progression to death typically by late adolescence. Development of a clinical instrument to quantify severity of illness is a prerequisite to eventual assessment of experimental therapeutic interventions. OBJECTIVE: To develop a clinical rating instrument to assess motor, behavioral, and functional capability in JNCL. METHODS: A clinical rating instrument, the Unified Batten Disease Rating Scale (UBDRS), was developed by the authors to assess motor, behavioral, and functional capability in JNCL. Children with verified JNCL were evaluated independently by three neurologists. Intraclass correlation coefficients (ICCs) were used to estimate the interrater reliability for total scores in each domain. Interrater reliability for scale items was assessed with weighted kappa statistics. RESULTS: Thirty-one children with confirmed JNCL (10 boys, 21 girls) were evaluated. The mean age at symptom onset was 6.1 +/- 1.6 years, and the mean duration of illness was 9.0 +/- 4.4 years. The ICCs for the domains were as follows: motor = 0.83, behavioral = 0.68, and functional capability = 0.85. CONCLUSIONS: The Unified Batten Disease Rating Scale (UBDRS) is a reliable instrument that effectively tests for neurologic function in blind and demented patients. In its current form, the UBDRS is useful for monitoring the diverse clinical findings seen in Batten disease.

Adolescent↗
PubMed2005

Mechanisms of lipid malabsorption in Cystic Fibrosis: the impact of essential fatty acids deficiency.

Transport mechanisms, whereby alimentary lipids are digested and packaged into small emulsion particles that enter intestinal cells to be translocated to the plasma in the form of chylomicrons, are impaired in cystic fibrosis. The purpose of this paper is to focus on defects that are related to intraluminal and intracellular events in this life-limiting genetic disorder. Specific evidence is presented to highlight the relationship between fat malabsorption and essential fatty acid deficiency commonly found in patients with cystic fibrosis that are often related to the genotype. Given the interdependency of pulmonary disease, pancreatic insufficiency and nutritional status, greater attention should be paid to the optimal correction of fat malabsorption and essential fatty acid deficiency in order to improve the quality of life and extend the life span of patients with cystic fibrosis.

Journal Article↗
PubMed2004

Insulin resistance syndrome in a representative sample of children and adolescents from Quebec, Canada.

OBJECTIVES: To estimate the prevalence of insulin resistance syndrome (IRS) in a representative sample of youth. To test for the independent contribution of insulin resistance (IR) and adiposity to clustering of metabolic risk factors. To identify the underlying components of IRS. To examine the relationship between adiposity and fasting plasma levels of free fatty acids (FFA). METHODS: In 1999, we conducted a school-based survey of a representative sample of youth aged 9, 13 and 16 y in Quebec, Canada. Age-specific questionnaire data, standardized clinical measurements and a fasting blood sample were available for 2244 subjects. Fasting insulin and HOMA were used as surrogate measures of IR. RESULTS: In all age-sex groups, adiposity indices, blood pressure (BP), plasma glucose and triglycerides (TG) increased significantly with increasing insulin quartiles while HDL cholesterol (HDL-C) decreased. The overall prevalence of IRS defined as hyperinsulinaemia combined with two or more risk factors including overweight, high systolic BP, impaired fasting glucose, high TG and low HDL-C, was 11.5% (95% CI: 10.2-12.9). There were no significant differences in the prevalence of IRS across ages or between sexes. The independent contribution of adiposity to clustering of risk factors was stronger than that of fasting insulin (or HOMA-IR). Factor analysis revealed three factors (BMI/insulin/lipids, BMI/insulin/glucose and diastolic/systolic BP) consistent across ages suggesting that more than one pathophysiologic process underlies IRS. Although elevation of FFA might be in the causal pathway linking obesity to IR, we did not detect any consistent association between measures of fatness and fasting plasma FFA. CONCLUSION: IRS is highly prevalent in youth, even among children as young as age 9 y. Factor analysis identifies three physiologic domains within IRS with a unifying role for markers of IR and adiposity.

Adolescent↗
PubMed2004

The Delta>15 Kb deletion French Canadian founder mutation in familial hypercholesterolemia: rapid polymerase chain reaction-based diagnostic assay and prevalence in Quebec.

Approximately one in 500 individuals in Western population has autosomal dominant familial hypercholesterolemia due to mutations in the low-density lipoprotein receptor (LDLR) gene. Screening for these mutations is hampered by their large number, except in founder populations. We identified the breakpoint of the >15 kb deletion involving the LDLR gene promoter and exon 1, responsible for more than 60% of French Canadian hypercholesterolemia cases, as well as the breakpoint of the 5 kb deletion of exons 2 and 3 that accounts for an additional 5% of cases. Both deletions appear to be because of homologous recombination by unequal crossing-over between the left arms of Alu repeats. Using RepeatMasker, we determined that 55% of the LDLR gene is composed of Alu elements; thus, it is not surprising that most LDLR rearrangements involve at least one Alu. Furthermore, we developed a rapid polymerase chain reaction-based assay for the French Canadian-1 (>15 kb) and French Canadian-5 (5 kb) hypercholesterolemia alleles. Screening a representative population sample of 943 French Canadian youths whose LDL cholesterol levels were above the 50th percentile allowed us to estimate the prevalence of the >15 kb allele as 0.11% (95% confidence interval, 0.03-0.38).

Base Sequence↗
PubMed2003

Both insulin resistance and diabetes in Psammomys obesus upregulate the hepatic machinery involved in intracellular VLDL assembly.

OBJECTIVE: In the current study, we examined the mechanisms that regulate hepatic apolipoprotein B (apoB)-containing lipoprotein secretion in Psammomys obesus, a good animal model for the investigation of insulin resistance and diabetes. METHODS AND RESULTS: When fed chow ad libitum, 22% maintained normoglycemia and normoinsulinemia (group A), 33% exhibited normoglycemia and appreciable hyperinsulinemia (group B), and 45% developed overt diabetes (group C). Body weight gain, plasma free fatty acid elevation, hypertriglyceridemia, and hypercholesterolemia characterized groups B and C. Triton WR-1339 injection, at fasting, resulted in higher plasma VLDL-triglyceride and VLDL-apoB accumulation in groups B and C, suggesting increased VLDL production by the liver. Pulse-chase labeling experiments in cultured hepatocytes with [35S]methionine revealed reduced intracellular degradation and enhanced secretion of newly synthesized apoB in groups B and C. Concomitant with the raised triglyceride and cholesterol contents in the livers of groups B and C, there was an increase in lipogenesis and in the activity of microsomal triglyceride transfer protein, monoacylglycerol acyltransferase, and diacylglycerol transferase. Pretreatment of hepatocytes with proteasomal inhibitors eliminated the differences in apoB secretion among groups A, B, and C. CONCLUSIONS: Our data indicate that both insulin resistance and diabetes triggered the intracellular machinery involved in VLDL assembly and secretion.

Acetylcysteine↗
PubMed2003

The cost-effectiveness of fondaparinux compared with enoxaparin as prophylaxis against thromboembolism following major orthopedic surgery.

BACKGROUND: The selective antithrombotic fondaparinux is more effective than the low-molecular-weight heparin enoxaparin for prevention of venous thromboembolism (deep-vein thrombosis [DVT] or pulmonary embolism) in patients undergoing major orthopedic surgery, but its cost-effectiveness is undetermined. OBJECTIVES: To evaluate the cost-effectiveness of fondaparinux relative to enoxaparin as prophylaxis against venous thromboembolism (VTE) for patients undergoing total hip replacement, total knee replacement or hip fracture surgery in the UK. PATIENTS/METHODS: A decision analysis model was created simulating the impact of fondaparinux and enoxaparin on patient outcomes and costs over various time points up to 5 years following surgery. The main outcome measures were treatment costs per patient and the incidence of clinical VTE and VTE-related deaths. A weighted (combined) cohort reflects the proportion of patients undergoing these procedures in 2000/2001. RESULTS: In the combined cohort, compared with enoxaparin, fondaparinux is expected to produce 20 fewer clinical VTE events and 3.2 fewer VTE-related deaths per 1000 procedures at 5 years. Cost savings at 5 years are pound 27 per patient with fondaparinux (discounted at 6% per year). In each of the three surgical groups, fondaparinux leads to lower expected costs per patient and to a smaller number of VTE events and VTE-related deaths. RESULTS are sensitive to the price difference between fondaparinux and enoxaparin and variation in the rate of late DVT. The analysis is robust to variations in all other key parameters. CONCLUSIONS: Compared with enoxaparin, fondaparinux is more effective and reduces costs to the healthcare system. At current prices, fondaparinux is the recommended strategy in the UK for prophylaxis following major orthopedic surgery.

Anticoagulants↗
PubMed2003

Butyrate induced Caco-2 cell apoptosis is mediated via the mitochondrial pathway.

BACKGROUND: During the process of tumorigenesis most colon cancer cells acquire resistance to apoptosis. The short chain fatty acid butyrate is well established as an antitumour agent which selectively induces apoptosis in colon cancer cells but not in normal intestinal epithelial cells. AIMS: To analyse the signalling pathway of butyrate induced apoptosis. METHODS: Using Caco-2 cells we focused on the bcl family of proteins, mitochondrial pathway, and caspase signalling cascade involved in butyrate induced apoptosis. Techniques employed included western blots, immunofluorescence, as well as experiments with peptide inhibitors of specific caspases. RESULTS: Butyrate induced a clear shift of the mitochondrial bcl rheostat towards a proapoptotic constellation, as demonstrated by upregulation of proapoptotic bak accompanied by reduced antiapoptotic bcl-x(L) levels. This was associated with translocation of cytochrome-c from the mitochondria to the cytosol, resulting in activation of the caspase cascade via caspase-9. Key executioner enzymes were caspases-3 and -1. No effect of butyrate on regulatory proteins of the inhibitor of apoptosis family was observed. CONCLUSIONS: Butyrate induced Caco-2 cell apoptosis via the mitochondrial pathway. Upregulation of bak and translocation of cytochrome-c were upstream of the caspase cascade. Subsequently, this cascade was activated via the formation of an apoptosome.

Apoptosis↗
PubMed2003

Vascular responses to alpha-adrenergic stimulation and depolarization are enhanced in insulin-resistant and diabetic Psammomys obesus.

Since vascular complications often accompany diabetes, we examined the influence of the endothelial lining on vascular reactivity in Psammomys obesus, a desert gerbil that acquires insulin resistance and diabetes when exposed to a laboratory diet. Vasoconstriction to phenylephrine and depolarizing KCl, as well as carbachol endothelium-dependent relaxation, were assessed in rings of thoracic aortae obtained from three groups: (i) group A, normoglycemic-normoinsulinemic; (ii) group B, normoglycemic-hyperinsulinemic, and (iii) group C, hyperglycemic-hyperinsulinemic animals. As expected, marked hypertriglyceridemia and hypercholesterolemia characterized groups B and C, which developed enhanced contractile responsiveness to phenylephrine and KCl compared with controls (group A). Furthermore, both experimental groups displayed a significant decrease in endothelium-dependent relaxation to carbachol. Altered lipid profiles are considered to play some role in the observed modification of aortic reactivity. Overall, our data indicate that vascular contractile responsiveness is enhanced early in the development of insulin resistance and diabetes in the female P. obesus.

Adrenergic alpha-Agonists↗
PubMed2002

The cost of osteoporosis in men: the French situation.

The objective of this study was to estimate the annual direct medical costs of osteoporosis and osteoporotic fractures incurred by French men > or =50 years of age. Costs were assessed from a societal perspective for 1999 and expressed in Euros. An expert panel was consulted to identify fractures attributable to osteoporosis according to International Classification of Diseases (ICD)-10 codes. Available age- and gender-specific osteoporosis attribution probabilities (OAP) were used to derive the proportion of health-care utilization for fractures resulting from osteoporosis. Hospital and ambulatory care costs due to fractures were obtained from French databases. A total of 23,260 acute hospitalizations were found to be caused by osteoporosis, 52% of which are for hip fractures. Mean cost per stay varied widely according to the site of fracture, from 1300 (wrist fracture) to 5900 (hip fracture). Consequently, the total cost of acute hospitalization amounts to 97.6 million, with hip fractures accounting for 73.2% of the expenditures. Rehabilitation and convalescence costs were estimated to be 90.8 million, generating a total hospital cost of 188.4 million. The total outpatient costs were estimated to be 9.1 million. Thus, the total medical costs of male osteoporosis amount to 197.5 million. A sensitivity analysis was performed to test the robustness of this figure. We estimate the number of fractures by applying international incidence rates from the literature to the French male population aged > or =50 years, whereas the OAP and unit costs were kept constant. This approach yielded an estimate of 21,857 fractures, which is only 6% below the base case. When compared with values from other countries, our study results appear very conservative.

Aged↗
PubMed2002

Combination of vinorelbine, epirubicin, and cyclophosphamide as neoadjuvant chemotherapy for locally advanced breast cancer: phase II study.

Achievement of a pathologic complete response after primary chemotherapy in breast cancer can predict long-term outcome. We have investigated a combination of epirubicin, cyclophosphamide, and vinorelbine as neoadjuvant chemotherapy in locally advanced breast cancer (LABC). From January 1997 to May 1999, 30 chemonaive patients were treated (T2 or T3 histologically proven invasive breast carcinoma). Treatment was vinorelbine 25 mg/m2 day 1 and day 3, epirubicin 30 mg/m2/d, days 1 to 3, cyclophosphamide 350 mg/m2/d, days 1 to 3, every 14 days for 4 courses. Twenty-nine patients were evaluable. Median age: 48 years (range: 28-66 years); 26 had ductal invasive carcinoma and 4 lobular invasive carcinoma; median tumor size: 7 cm; median number of induction cycles: four. Clinical objective response was seen in 24 patients (relative risk: 86%), 14 complete responses, 10 partial responses, four stable disease (no significant changes). Twenty-nine patients had surgical treatment. Pathologic response rate was complete response in 32% (no residual tumor), in situ carcinoma: 11%, invasive or unchanged tumor remaining: 57%. Ninety-eight cycles were administered; major toxicities were hematologic: grade IV Hb in 5% and grade IV neutropenia in 60% of cycles. Ten patients required hospitalization for febrile neutropenia. Other toxicities were mild to moderate. The vinorelbine/epirubicin/cyclophosphamide regimen resulted in a high pathologic complete response rate in LABC with a good tolerance profile, and warrants further evaluation.

Adult↗
PubMed2002

Lipopolysaccharide modulation of normal enterocyte turnover by toll-like receptors is mediated by endogenously produced tumour necrosis factor alpha.

BACKGROUND: Circulating levels of endotoxin (or lipopolysaccharide (LPS)) and anti-endotoxin antibodies are increased in patients with inflammatory bowel disease, supporting the hypothesis of a role for endogenous bacterial products in the pathogenesis of these disorders. AIM: The aim of this study was to analyse the direct effects of LPS on intestinal epithelial cell turnover. METHODS AND RESULTS: LPS significantly inhibited growth of the human non-transformed immature crypt cell line (HIEC), whereas IEC-6 cell proliferation was stimulated by LPS. As LPS is a physiological inducer of tumour necrosis factor alpha (TNFalpha) in various cell systems and this cytokine exerted similar anti-proliferative (HIEC) or growth stimulatory (IEC-6 cells) effects, the study thus tested the hypothesis that endogenously produced TNFalpha in response to LPS mediates this growth modulatory effect in an autoparacrine/paracrine way. Therefore, during LPS stimulation, the biological activity of TNFalpha was blocked using neutralising anti-TNFalpha antibodies, as well as inhibitory, antagonistic antibodies directed against the p55 TNF receptor, signalling the antimitotic TNFalpha effect in HIEC. Both experimental approaches completely abolished the growth modulatory effects of LPS in HIEC/IEC-6 cells. Production and secretion of TNFalpha by HIEC/IEC-6 cells in response to LPS was confirmed on mRNA and protein level by reverse transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay. LPS signalling was independent of CD14 in HIEC, as these cells lack this receptor. However, HIEC expressed TLR4 and MD2 resulting in a fully functional signalling complex as demonstrated by RT-PCR, western blot, and immunofluorescence analyses. CONCLUSION: These results support the hypothesis that LPS induced changes of intestinal epithelial cell turnover may directly contribute to the pathogenesis of inflammatory epithelial cell lesions by endogenous TNFalpha production by enterocytes.

Antibodies, Monoclonal↗