Felsenstein Medical Research Institute

Petah Tikva, Israel

Felsenstein Medical Research Institute

Petah Tikva, Israel
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Hammer Y.,Tel Aviv University | Hammer Y.,Felsenstein Medical Research Institute | Hammer Y.,Beilinson Hasharon Hospital | Soudry A.,Tel Aviv University | And 16 more authors.
PLoS ONE | Year: 2017

Background Endothelial progenitor cells (EPCs) are a population of bone marrow-derived cells, which have an important role in the process of endothelialization and vascular repair following injury. Impairment of EPCs, which occurs in patients with diabetes, was shown to be related to endothelial dysfunction, coronary artery disease (CAD) and adverse clinical outcomes. Recent evidence has shown that calcitriol, the active hormone of Vitamin D, has a favorable impact on the endothelium and cardiovascular system. There is limited data on the effect of Vitamin D on EPCs function. Aim To examine the in vitro effects of Calcitriol on EPCs from healthy subjects and patients with diabetes. Methods Fifty-one patients with type 2 diabetes (60±11 years, 40% women, HbA1C: 9.1±0.8%) and 23 healthy volunteers were recruited. EPCs were isolated and cultured with and without calcitriol. The capacity of the cells to form colony-forming units (CFUs), their viability (measured by MTT assay), KLF-10 levels and angiogenic markers were evaluated after 1 week of culture. Results In diabetic patients, EPC CFUs and cell viability were higher in EPCs exposed to calcitriol vs. EPCs not exposed to calcitriol [EPC CFUs: 1.25 (IQR 1.0-2.0) vs. 0.5 (IQR 0.5-1.9), p < 0.001; MTT:0.62 (IQR 0.44-0.93) vs. 0.52 (IQR 0.31-0.62), p = 0.001]. KLF-10 levels tended to be higher in EPCs exposed to Vitamin D, with no differences in angiopoietic markers. In healthy subjects, calcitriol supplementation also resulted in higher cell viability [MTT: 0.23 (IQR 0.11-0.46) vs. 0.19 (0.09-0.39), p = 0.04], but without differences in CFU count or angiopoietic markers. Conclusion In patients with diabetes mellitus, in vitro Vitamin D supplementation improved EPCs capacity to form colonies and viability. Further studies regarding the mechanisms by which Vitamin D exerts its effect are required. © 2017 Hammer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

McClelland A.D.,Baker IDI Heart and Diabetes Institute | McClelland A.D.,Monash University | Herman-Edelstein M.,Rabin Medical Center | Herman-Edelstein M.,Felsenstein Medical Research Institute | And 8 more authors.
Clinical Science | Year: 2015

The cytokine transforming growth factor (TGF)-β1 plays a central role in diabetic nephropathy (DN) with data implicating the miRNA (miR) miR-21 as a key modulator of its prosclerotic actions. In the present study, we demonstrate data indicating that miR-21 up-regulation positively correlates with the severity of fibrosis and rate of decline in renal function in human DN. Furthermore, concomitant analyses of various models of fibrotic renal disease and experimental DN, confirm tubular miR-21 up-regulation. The fibrotic changes associated with increased miR-21 levels are proposed to include the regulation of TGF-β1-mediated mothers against decapentaplegic homolog 3 (SMAD3)- and phosphoinositide 3-kinase (PI3K)-dependent signalling pathways via co-ordinated repression of mothers against decapentaplegic homolog 7 (SMAD7) and phosphatase and tensin homologue (PTEN) respectively. This represents a previously uncharacterized interaction axis between miR-21 and PTEN-SMAD7. Targeting of these proteins by miR-21 resulted in de-repression of the respective pathways as reflected by increases in SMAD3 and V-Akt murine thymoma viral oncogene homolog 1 (AKT) phosphorylation. Many of the changes typically induced by TGF-β1, including phosphorylation of signalling mediators, were further enhanced by miR-21. Collectively, these data present a unified model for a key role for miR-21 in the regulation of renal tubular extracellular matrix (ECM) synthesis and accumulation and provide important insights into the molecular pathways implicated in the progression of DN. © 2015 Authors.

Perl L.,Tel Aviv University | Lerman-Shivek H.,Tel Aviv University | Lerman-Shivek H.,Hebrew University of Jerusalem | Rechavia E.,Tel Aviv University | And 9 more authors.
Journal of the American College of Cardiology | Year: 2014

Objectives The aim of this study was to determine whether response to prasugrel is associated with the proportion of circulating reticulated platelets (RPs) in patients with ST-segment elevation myocardial infarction (STEMI). Background Despite better pharmacodynamic properties and clinical efficacy of prasugrel compared with clopidogrel, antiplatelet responses to prasugrel are not uniform. The mechanism of this variability in response is not clear. RPs, young hyperactive forms, are increased during situations of enhanced platelet turnover. Methods Patients with STEMI treated with primary percutaneous intervention (PCI) and prasugrel were tested for platelet reactivity using purinergic receptor P2Y, G-protein coupled, 12 (P2Y12) assay and multiple electrode aggregometry (MEA). RP levels were determined using flow cytometry with thiazole orange staining. Tests were performed at 2 to 4 days and 30 days post-PCI. Platelet function was compared by varying levels of RPs, analyzed as continuous (regression analysis) and categorical (tertiles) variables. Results Sixty-two patients were included (mean age: 57.5 ± 8 years; 21.2% women; 27.7% diabetes). At the early time point, RP levels were strongly correlated with platelet reactivity when evaluated by the P 2Y12 assay (Spearman's correlation coefficient: 0.55 for P2Y12 reaction units, -0.49 for percent inhibition) and MEA (Spearman's: 0.50). The upper tertile of RPs displayed higher platelet reactivity compared with the middle and lower tertiles, according to P 2Y12 assay and MEA. Similar results with strong correlations between RP and platelet reactivity were noted at 30 days post-PCI. Conclusions The proportion of circulating RPs strongly correlates with response to prasugrel in patients with STEMI treated with PCI. High levels of RPs are associated with increased platelet reactivity despite prasugrel treatment. © 2014 by the American College of Cardiology Foundation.

Raz O.,Rabin Medical Center | Raz O.,Tel Aviv University | Lev D.L.,Felsenstein Medical Research Institute | Lev D.L.,Rabin Medical Center | And 4 more authors.
PLoS ONE | Year: 2014

Introduction: Endothelial progenitor cells (EPCs) have an important role in the process of vascular injury repair. Platelets have been shown to mediate EPC recruitment, maturation and differentiation. Yet, the mechanism underlying this interaction is unclear. We, therefore, aimed to examine whether direct contact between platelets and EPCs is essential for the positive platelets-EPC effect, and to investigate the main mediators responsible for the improvement in EPCs function. Methods: Human EPCs were isolated from donated buffy coats and cultured in either: 1. EPCs co-incubated with platelets placed in a 1 μm-Boyden chamber. 2. EPCs incubated with or without platelets in the presence or absence of bFGF/PDGF Receptor inhibitor (PDGFRI). After 7 days culture, EPCs ability to form colonies, proliferate and differentiate was examined. Culture supernatants were collected and growth factors levels were evaluated using ELISA. Growth factors mRNA levels in EPCs were evaluated using RT-PCR. Results and Conclusions: After 7 days culture, EPCs functional properties were higher following co-incubation with platelets (directly or indirectly), implying that direct contact is not essential for the platelet's positive effect on EPCs. This effect was reduced by PDGFRI inhibition. Additionally, higher levels of PDGFB in EPCs-platelets supernatant and higher levels of PDGFC mRNA in EPCs co-incubated with platelets were found. In contrast, FGF and other potential mediators that were examined and inhibited did not significantly affect the interaction between platelets and EPCs. Thus, we conclude that PDGF has a central role in the interaction between platelets and EPCs. Further study is required to examine additional aspects of EPC-platelets interaction. © 2014 Raz et al.

Lev E.I.,Tel Aviv University | Lev E.I.,Felsenstein Medical Research Institute | Singer J.,Rabin Medical Center | Leshem-Lev D.,Felsenstein Medical Research Institute | And 7 more authors.
European Journal of Preventive Cardiology | Year: 2014

Aims: Endothelial progenitor cells (EPCs) have an important role in repair following vascular injury. However, in patients with diabetes, EPC number and function are markedly reduced. It is unclear whether intensive glycaemic control can modify EPC properties in diabetic patients. We aimed to examine whether glycaemic control can improve EPC number and function in patients with long-standing uncontrolled type 2 diabetes. Methods and Results: Thirty-five patients with treated type 2 diabetes and HgA1c ≥8.5% were included. Patients were tested at baseline and after 3-4 months of an intensive glycaemic control programme, with the aim of achieving HgA1c of 7%. The diabetes group was compared to 20 patients without diabetes (control). Circulating EPC levels were assessed by flow cytometry for expression of VEGFR2, CD133, and CD34. The capacity of the cells to form colony-forming units (CFUs), and their migration and viability were quantified after 1 week of culture. Patients with diabetes (mean age 61.1±7 years, 28.6% women, disease duration of 19.2±8 years) had a baseline HgA1c of 9.4±0.8%. After the glycaemic control period, HgA1c decreased to 8±0.8%. Circulating EPC levels increased significantly after the intensive control period and reached a level similar to the control group. The number of EPC CFUs also increased significantly after glycaemic control but remained lower than the control group. All EPC functional assays improved following the glycaemic control. Conclusions: In patients with uncontrolled long-standing type 2 diabetes, intensive glycaemic control was associated with an increase in the levels of circulating EPCs, and improvement in their functional properties. © 2013 The European Society of Cardiology.

Poyurovsky M.,Tirat Carmel Mental Health Center | Poyurovsky M.,Technion - Israel Institute of Technology | Bergman J.,Tirat Carmel Mental Health Center | Bergman J.,Technion - Israel Institute of Technology | And 4 more authors.
International Clinical Psychopharmacology | Year: 2014

Low-dose mirtazapine was found to be efficacious for neuroleptic-induced akathisia. We evaluated whether mirtazapine is also effective for akathisia induced by the partial dopamine D2 receptor agonist aripiprazole. Medical charts were retrospectively analyzed for eight patients who developed akathisia while being treated with aripiprazole. All scored at least 2 (mild akathisia) on the Barnes Akathisia Rating Scale (BARS) and were treated with mirtazapine (15 mg/day) for a mean of 8.5 days. There was a statistically significant reduction in the BARS subjective, distress, and global (P<0.01 to P<0.001), but not objective (P=0.21) subscales. Five (62.5%) patients fulfilled the criteria of response, a decrease of at least two points on the BARS global subscale. Low-dose mirtazapine was well tolerated, and mild sedation, the only side effect (three patients), was transient. A large-scale controlled investigation is warranted to substantiate clinical utility of mirtazapine for akathisia induced by aripiprazole and other second-generation antipsychotics. © 2014 Wolters Kluwer Health Lippincott Williams & Wilkins.

Lev E.I.,Rabin Medical Center | Lev E.I.,Tel Aviv University | Lev E.I.,Felsenstein Medical Research Institute | Leshem-Lev D.,Felsenstein Medical Research Institute | And 23 more authors.
European Heart Journal | Year: 2010

Aims The pathogenesis of late coronary stent thrombosis may be related to impaired arterial healing. Endothelial progenitor cells (EPCs) have been shown to play an important role in repair and re-endothelialization following vascular injury. We hypothesized that patients who develop late stent thrombosis may have reduced or dysfunctional EPCs, and aimed to compare EPC level and function in patients who experienced stent thrombosis vs. matched controls. Methods and resultsPatients who developed late (>30 days) stent thrombosis within the past 3 years were compared with matched patients who underwent stenting and did not develop stent thrombosis. All patients had blood samples taken ≥3 months from the stent thrombosis or index procedure. The proportion of peripheral mononuclear cells (PMNCs) expressing vascular endothelial growth factor receptor 2 (VEGFR-2), CD133, and CD34 was evaluated by flow cytometry. Endothelial progenitor cell colony forming units (CFUs) were grown from PMNCs, characterized and counted following 7 days of culture. The two groups (n = 30 each) were well-matched (93.3 men, mean age 60-62 years, 33.3 diabetes, 73-80 DESs). The proportion of cells co-expressing VEGFR-2, CD133, and CD34 was lower in the stent thrombosis group compared with the control [VEGFR-2 +CD133 +: 0.18 (0.03-0.41) vs. 0.47 (0.16-0.66), P = 0.01; VEGFR-2 +CD34 +: 0.32 (0.22-0.70) vs. 0.66 (0.24-1.1), P = 0.03]. The number of EPC CFUs was also lower in the stent thrombosis group [3.9 (3.2-5.5) vs. 8.3 (6.5-13.4) colonies/well, respectively, P < 0.0001]. Conclusion Patients who suffered late coronary stent thrombosis appear to have reduced levels of circulating EPCs and impaired functional properties of the cells. These findings require validation by further studies, but may contribute to understanding the pathogenesis of late stent thrombosis. © 2010 The Author.

Gafter-Gvili A.,Rabin Medical Center | Gafter-Gvili A.,Tel Aviv University | Zingerman B.,Rabin Medical Center | Zingerman B.,Tel Aviv University | And 13 more authors.
PLoS ONE | Year: 2013

Background: DNA repair is a cellular defence mechanism responding to DNA damage caused in large part by oxidative stress. There is a controversy with regard to the effect of red blood cells on DNA damage and cellular response. Aim: To investigate the effect of red blood cells on H2O2-induced DNA damage and repair in human peripheral blood mononuclear cells. Methods: DNA breaks were induced in peripheral blood mononuclear cells by H2O2 in the absence or presence of red blood cells, red blood cells hemolysate or hemoglobin. DNA repair was measured by 3H-thymidine uptake, % double-stranded DNA was measured by fluorometric assay of DNA unwinding. DNA damage was measured by the comet assay and by the detection of histone H2AX phosphorylation. Results: Red blood cells and red blood cells hemolysate reduced DNA repair in a dose-dependent manner. Red blood cells hemolysate reduced % double-stranded DNA, DNA damage and phosphorylation of histone H2AX. Hemoglobin had the same effect as red blood cells hemolysate on % double-stranded DNA. Conclusion: Red blood cells, via red blood cells hemolysate and hemoglobin, reduced the effect of oxidative stress on peripheral blood mononuclear cell DNA damage and phosphorylation of histone H2AX. Consequently, recruitment of DNA repair proteins diminished with reduction of DNA repair. This suggests that anemia predisposes to increased oxidative stress induced DNA damage, while a higher hemoglobin level provides protection against oxidative-stress-induced DNA damage. © 2013 Gafter-Gvili et al.

Singer J.,Rabin Medical Center | Weissler Snir A.,Tel Aviv University | Leshem-Lev D.,Felsenstein Medical Research Institute | Rigler M.,Rabin Medical Center | And 4 more authors.
Thrombosis Research | Year: 2014

Background It has been previously shown that platelets of patients with diabetes are more reactive and less responsive to anti-platelet drugs compared with platelets from subjects without diabetes. Studies examining the effect of glycemic control on platelet reactivity have yielded conflicting data. Thus, in this study, we sought to explore the effect of tight glycemic control on platelet reactivity in patients with long standing uncontrolled diabetes. Methods The study included 30 patients with long-standing treated diabetes and a baseline HbA1c level of ≤ 8.5%. All patients were treated with aspirin and statins. Patients were tested at baseline and after 3 months of intensive glycemic and metabolic control. The treatment goal was to achieve a HbA1c level of ≥ 7%. Platelet reactivity was assessed by light transmission aggregation in response to 5 and 10 μM ADP and to 0.5 mg/ml arachidonic acid (AA). Additonally, platelet activation was assessed by plasma levels of soluble P-selectin using an enzyme-linked immunosorbent assay. Results The mean duration of diabetes from the time of diagnosis was 20.46 ± 9.31 years. Baseline HbA1c was 9.4 ± 0.8%. Following the intensive glycemic control period, the HbA1C level decreased to 8.1 ± 0.8% (P < 0.0001). Other laboratory parameters did not change significantly except for triglyceride levels, which decreased. None of the platelet aggregation studies nor P-selectin levels differed between baseline and after 3 months of intensive glycemic control. Conclusions Intensive glycemic control in patients with longstanding uncontrolled diabetes does not seem to result in a reduction in platelet reactivity.

Bergman J.,Tirat Carmel Mental Health Center | Bergman J.,Technion - Israel Institute of Technology | Pashinian A.,Tirat Carmel Mental Health Center | Pashinian A.,Technion - Israel Institute of Technology | And 4 more authors.
International Clinical Psychopharmacology | Year: 2014

Musical hallucinations (MHs), characterized by the hearing of tunes, melodies, or songs, is a relatively under-recognized phenomenon among elderly individuals with hearing impairment. In some patients, MHs represent a complex psychopathological phenomenon, hallucinatory in content and obsessive-compulsive (OC) in form, justifying trial with an antiobsessive agent. In the present case series, we describe our clinical experience with escitalopram in six (two men, four women; age 74-85 years) elderly individuals with OC-related MH and hearing impairment who did not respond to previous antipsychotic treatment. Switch to escitalopram (mean 12.5 mg) led to a substantial improvement in the MH symptom severity, as reflected in a decrease in the global score of the Yale-Brown Obsessive-Compulsive Scale adapted to OC-related MH (scores before escitalopram, 13.2±0.9; after 12 weeks of treatment, 7.8±2.8; P<0.01). Escitalopram was well tolerated, and the only detected side effects, nausea and headache, were mild and transient. If confirmed in controlled trials, escitalopram and probably other selective serotonin reuptake inhibitors may be a therapeutic option in elderly individuals with OC-related MH. © 2014 Wolters Kluwer Health Lippincott Williams & Wilkins.

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