Abstracts from Rambam Research Day, December 29, 2011

doi:10.5041/RMMJ.10071

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

From the Editor-in-Chief

Dear colleagues,

Maimonides, known as the Rambam, was one of the greatest Jewish arbiters; he was also a scientist, a researcher, and one of the greatest philosophers of the medieval ages. In fact, he was among the first to support evidence-based medicine.

This Supplement of the Rambam Maimonides Medical Journal presents the abstracts from Rambam Research Day. These abstracts represent the newest basic and clinical research coming out of Rambam Health Care Campus—research that is the oxygen for education and development of today’s generation of physicians. Hence, the research presented on Rambam Research Day is a foundation for future generations to understand patient needs and improve treatment modalities. Bringing research from the bench to the bedside and from the bedside to the community is at the heart of Maimonides’ scholarly and ethical legacy.

We hope you will appreciate the potential represented in these abstracts, which touch on nearly every aspect of clinical practice.

I would also like to thank Ms. Deborah Hemstreet, for the invaluable and professional editorial work that went into making this special issue of RMMJ possible.

The Rambam Maimonides Medical Journal would be pleased to publish other original basic and clinical research articles, and related abstracts, which will subsequently be applied to patient care. In addition, we are open to publishing such abstracts from meetings, seminars, or conferences. For more information on seeing your event’s abstracts published here, please contact our editorial board.

Sincerely Yours,

Shraga Blazer, M.D.
Editor-in-Chief
On behalf of the Editors

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

About Rambam Research Day

We are proud to introduce you to the Fifth Rambam Research Day, now established as a key annual event at Rambam Health Care Campus (Rambam), which accompanies the yearly meeting of the International Scientific Advisory Board of the Clinical Research Institute at Rambam (CRIR).

First and foremost we would like to thank Nobel Laureate Professor Aaron Ciechanover for serving as Chair of the Scientific Advisory Board for its inaugural first term of five years. Professor Ciechanover’s insights, contributions, and leadership have been a key ingredient in promoting the development of medical science and research at Rambam, with a particular emphasis on innovative programs for the clinician-scientist.

Over this period, Rambam launched two distinct competitive pathways for supporting clinician-scientists here: The “Ofakim” program provides start-up and bridge research funding for young staff physicians with strong research credentials and plans. The “Atidim” program is directed towards research training support for our residents, or as we call them in Israel “Mitmachim.” The Atidim program has received wide recognition, and served as an especially important example of Rambam’s dedication to medical trainees during the recent physician protest directed towards improving public health care in Israel’s major teaching hospitals.

We would also like to acknowledge the excellent collaboration and the fruitful research ties between Rambam and the Technion-Israel Institute of Technology, in particular the Ruth and Bruce Rappaport Faculty of Medicine.

At the same time, we would like to welcome Professor Chaim (Howard) Cedar as the incoming new Chair of our Scientific Advisory Board; he is stepping into an important leadership role in this capacity. We wish him, and all involved, success in promoting medical research within the clinical environment of our hospital, in particular by laying a groundwork by which our young physician scientists may become world leaders in their field.

We also thank our international Scientific Advisory Board members, Professors Eugene Braunwald, Irun Cohen, Hedvig Hricak, Scott Freidman, and Jacob Sznajder.

We are particularly proud of the 110 abstracts that will be presented at the meeting, and which are published in this special issue of the Rambam Maimonides Medical Journal (RMMJ). The abstracts cover all areas of medicine. They reflect the rich spectrum of clinical applied and basic research endeavors that characterize our medical center’s activities. Indeed, our primary mission of bringing health care to the community is achieved as we bring these research discoveries together with excellence in teaching. In reading through the abstracts, we were intrigued by the breadth and depth of the contributions, and by the commitment of Rambam’s staff to this research endeavor.

We would also like to recognize the Office for Promotion of Research, which is charged with coordination and oversight of all research activities at Rambam, including clinical research, applied research, competitive grants management, patent protection, institutional review board ethical approvals, and bringing forward innovative ideas to clinical practice. We are in the process of creating the Rambam Innovation Fund, which will be another vehicle for supporting applied research and taking it from the bench to clinical practice. We value collaboration with industry, which serves as an integral part of health care progress; over the years, several Rambam-originated research projects have led to amazing success in Israel, with practical application to health care.

We are particularly pleased to see this first Supplement to RMMJ, following six quarterly issues of RMMJ appearing online as an institutional open access publication. The Rambam Maimonides Medical Journal, edited by Professor Shraga Blazer, has featured excellent articles from world leaders and Nobel Laureates in the sciences and medicine. We jointly congratulate Professor Blazer for this achievement. Supporting Rambam Research Day via RMMJ is another way we show commitment to our patients, via the furthering of health care facilitated by progress in science, innovation, and technology.

Rafi Beyar, M.D., D.Sc.
Director, Rambam Health Care Campus (RHCC) and Associate Editor, RMMJ

Karl Skorecki, M.D.
Director, Medical & Research Development, RHCC and Associate Editor, RMMJ

Michael Aviram, D.Sc.
Director, Legacy Heritage Clinical Research Institute at Rambam and Deputy Editor, RMMJ

Ehud Klein, M.D.
Chair, Division of Psychaitry and Director, Research Division, RHCC

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Rambam Research Day Organizing Committee

Professor Ehud Klein, Chairman

Director Division of Psychiatry, Head Research Division

Professor Doron Aharonson

Director Intensive Coronary Care Unit

Professor Zaher Azzam

Director, Department of Internal Medicine B

Professor Shraga Blazer

Director, Department of Neonatology, and Editor-in-Chief, Rambam Maimonides Medical Journal

Dr. Gil Bolotin

Director, Department of Cardiac Surgery

Professor Benjamin Brenner

Director, Department of Hematology and Bone Marrow Transplantation

Dr. Yael Eilon

Nursing Research Coordinator

Professor Dan Hershko

Director, Breast Health Center

Professor Joseph Itskovitz

Director, Division of Gynecology and Obstetrics

Professor Shai Katz

Director, Department of Anesthesiology

Professor Ora Israel

Director, Department of Nuclear Medicine

Professor Naim Shehadeh

Director, Department of Pediatrics A, Meyer Childrens' Hospital

Dr. Hannah Sprecher

Director, Division of Laboratory Services

Professor David Yarnitsky

Director, Department of Neurology

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Program for the Fifth Rambam Research Day

Thursday, December 29, 2011

Rambam Health Care Campus, Haifa, Israel

07.30 Meet & Greet

Visit Posters Area

08.30 Opening Session: Greetings

Professor Rafael Beyar

General Director, Rambam Health Care Campus (RHCC)

Professor Eliezer Shalev

Dean, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology (IIT), Haifa, Israel

Professor Karl Skorecki

Director, Rappaport Research Institute, Technion-IIT, Director of Medical and Research Development RHCC

Professor Chaim Cedar

Department of Cellular Chemistry and Human Genetics, School of Medicine at the Hebrew University of Jerusalem, and Chairman, Scientific Advisory Committee of the Rambam Institute of Research, RHCC

Professor Michael Aviram

Director, The Clinical Research Institute at Rambam (CRIR), at RHCC

Professor Ehud Klein

Chairman, Research Division, RHCC

Keynote Lecture

09.00 Professor Yadin Dudai

Department of Neurobiology and Sara and Micahel Sela Chair in Neurobiology, Weizmann Institute of Science, Rehovot, Israel.

The Instability of Our Memories: Lessons from the Brain

Rambam Research Awards 2011

10.00 Ofakim Program: Basic & Clinical Research Awards to Young Staff Physicians

The Ofakim-Rambam Fund for Academic Excellence

Atidim Program: Residents Basic & Clinical Research Awards

The Etai Sharon Rambam-Atidim Fund for Academic Excellence

The Meyer Children's Prize for research in Pediatrics

Awardees will be announced at the Session

Presentation of the 2009 Atidim Grantees’ Research Work

10.20 Dr. Danny Eytan

Network Biology Research Laboratories, Lorry Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion-IIT, Department of Pediatrics A, RHCC

Activity Fluctuations and Representation in Neuronal Networks

10.30 Dr. Rabea Asleh

Department of Anatomy and Cell Biology, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-IIT, Department of Internal Medicine A, RHCC

Haptoglobin Genotype is a Key Regulator of Iron-mediated Lysosomal Destabilization in Diabetes Mellitus

10.45 Poster Presentations with Authors

Plenary Lectures

11.30 Professor Benjamin Brenner

Director, Department of Hematology and Bone Marrow Transplantation, RHCC and The Ruth and Bruce Rappaport Faculty of Medicine, Technion-IIT

Cancer and Thrombosis: Mechanisms and Implications

12.00 Dr. Ahmed Assalia

Deputy Director, Division of General Surgery, RHCC and The Ruth and Bruce Rappaport Faculty of Medicine, Technion-IIT

Surgical Treatment of Morbid Obesity

Oral Presentations by Rambam Research Day Awardees

13.15 Dr. Ilan Gruenwald

Neurourology Unit, RHCC and The Ruth and Bruce Rappaport Faculty of Medicine, Technion-IIT

Low-intensity Extracorporeal Shock Wave Therapy for Erectile Dysfunction in Phosphodiesterase-5 Inhibitor Responders: A Randomized, Double-blind, Placebo-controlled Study

13.30 Dr. Liran Shani

Department of Cardiac Surgery, RHCC and The Ruth and Bruce Rappaport Faculty of Medicine, Technion-IIT

A Novel Amiodarone-eluting Biological Glue for the Prevention of Postoperative Atrial Fibrillation: First Animal Trial

13.45 Dr. Anat Aharon

Thrombosis and Hemostasis Unit, Department of Hematology and Bone Marrow Transplantation, RHCC and The Ruth and Bruce Rappaport Faculty of Medicine, Technion-IIT

Microparticles Effects on Apoptosis, Angiogenesis and Migration in Healthy and Pathological Pregnancies

14.00 Dr. Odile Robicsek

Laboratory of Psychobiology, Department of Psychiatry, RHCC, The Ruth and Bruce Rappaport Faculty of Medicine, and INSERTECH, INSERM-Associated Laboratory Technion-IIT

Human Hair Follicle Derived Induced Pluripotent Stem Cells (iPSC) and Their Differentiation into Dopaminergic Neurons as a Model to Study

Neurodevelopmental Abnormalities in Schizophrenia

14.15 Closing Session

Concluding Remarks

Awards for Rambam Research Day Oral Presentations

Awards for Rambam Research Day Poster Presentations

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Activity Fluctuations and Representation in Neuronal Networks (ATIDIM)

Danny Eytan ^1,², Asaf Gal ¹, Avner Wallach ¹, Einat Kermany ¹, Netta Haroush ¹, Shimon Marom ¹

Abstract

Introduction:

At the cornerstone of neuroscience lies the attempt to correlate behavior and thought to brain states and activity patterns and transitions between such states. The underlying assumption to the studies we will present is that the most relevant level of description allowing such correlations is that of neuronal populations and interactions between such populations. The function of the nervous system, at the population or neuronal network level, can be studied in terms of three axes: Representation, Development, and Learning.

Materials and Methods:

The experimental system consists of large, random, cortical networks developing ex vivo coupled to multi-electrode-arrays. The networks are relatively free of predefined constraints and intervening variables, yet the electrophysiological, biochemical, and pharmacological properties of their neurons are mostly identical to neurons in vivo. The ex vivo developing model system enables extensive, multi-site sampling and manipulating of the relevant variables: electrical activity and the chemical milieu. The results presented here were collected by long-term recordings from these networks both at the level of the single, synaptically isolated neuron and at the level of the intact network under various environmental conditions and stimulation environments.

Results:

Basic biophysical aspects of response dynamics and their long-term fluctuations will be presented, at two different levels of organization: the single, isolated neuron and the intact assembly. We show that individual neurons and networks display a very complex, history dependent response patterns that pose constraints on possible representation schemes. Moreover, we will show the feasibility of such representation schemes and implications of their usage. Representation schemes at the network level can be viewed as different “codes,” with a gross division between rate and time-based codes. Finally, we will show some preliminary results regarding such fluctuations in the response dynamics at the level of intact organisms.

Conclusions:

The neuronal system, at any given level of organization is not only very “noisy” in its response dynamics but moreover—it is inherently non-stationary. This non-stationarity reflects internal processes, some of which are activity dependent. Our results describe the dynamics of the fluctuations in the responses to stimulation; at the network level, we show how these dynamics affect possible representation schemes with interplay between rate-based and time-based schemes. We show the advantages to either scheme depending on the stimulus properties.

Footnotes

Citation: RMMJ 2012;3 Suppl:6.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Haptoglobin Genotype is a Key Regulator of Iron-mediated Lysosomal Destabilization in Diabetes Mellitus

Rabea Asleh ^1,², Nina S Levy ², Rachel Miller-Lotan ², Andrew P Levy ²

Abstract

Introduction:

Iron plays a major role in oxidative stress generation and its accumulation in lysosomes seems critical in lysosomal destabilization and cell injury. A major source of intralysosomal iron is the degradation of hemoglobin (Hb) uptaken by cells as a complex with haptoglobin (Hp) following intravascular hemolysis. We have demonstrated in several prospective studies that diabetic individuals with the Hp 2-2 genotype are at a 3–5 fold relative risk of cardiovascular disease (CVD) as compared to diabetic individuals with Hp 1-1 genotype. Moreover, we found that Hp 2-2 is an inferior antioxidant as compared to Hp 1-1 in blocking hemoglobin and iron-mediated oxidation. We hypothesized that lysosomal loss of integrity is an Hp-genotype dependent, specifically in the setting of diabetes, and that vitamin E supplementation may reduce intracellular oxidation and lysosomal injury.

Methods:

To test our hypothesis we used both tissue culture cells, including CHO cells constantly transfected with the Hp-Hb scavenger receptor CD163 and macrophages expressing endogenous CD163, and an Hp-transgenic mouse model with and without diabetes. Lysosomal destabilization was assessed after lysosomal purification using a fluorimetric substrate for the lysosomal marker enzymes N-acetyl-β-glucosaminidase and in live cells using lysosensor yellow/blue DND-160 staining and confocal microscopy. Lysosomal oxidation was assessed by measuring the amount of lipid peroxides and redox active iron in purified lysosomes. Hb-mediated oxidation of purified low-density lipoprotein (LDL) and the effect of pH on LDL oxidation was assessed using TBARS assay.

Results:

We found a dramatic increase in lysosomal fragility in cells incubated with Hp 2-2-Hb complex and in lysosomes purified from Hp 2-2 diabetic mouse kidneys. Moreover, the amount of lipid peroxides and redox active iron associated with lysosomes purified from kidneys of Hp 2-2 diabetic mice, were significantly increased as compared to lysosomes purified from kidneys of Hp 1-1 diabetic mice. Vitamin E supplementation to Hp 2-2 diabetic mice resulted in a significant reduction in lysosomal fragility, lipid peroxidation, and redox active iron concentration. Iron-mediated oxidation proved to be more effective at acidic pH. We measured Hb-mediated oxidation of LDL at pH 4.5 (pH of lysosomes) and found that Hp 2-2 protein paradoxically increased oxidation of LDL while Hp 1-1 protein still conferred an antioxidant activity against glycated Hb.

Conclusions:

Hp 2-2 type is associated with a markedly increased iron-mediated lysosomal oxidation and destabilization. Vitamin E may block lysosomal injury thus explaining its beneficial effect on the development of diabetic vascular disease, selectively in the Hp 2-2 diabetic population.

Footnotes

Citation: RMMJ 2012;3 Suppl:6–7.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Cancer and Thrombosis: Mechanisms and Implications

Benjamin Brenner ¹

Abstract

Cancer and thrombosis are the two major disease states in the developed world. While the association of venous thromboembolism (VTE) with tumors was described over 150 years ago, clinical and basic research over the past 30 years have broadened our understanding of this association. The interactions of thrombosis and cancer are complex and involve issues related to pathogenic mechanisms, clinical presentation, prognosis, and treatment.

Pulmonary embolism is a major cause of death in cancer patients and cancer patients with VTE have an inferior survival compared to those without thrombosis. Recent epidemiological studies have reported on the prevalence of cancer-related VTE in solid tumors and hematological malignancies. Data obtained from VTE registries in North America and Europe have fostered our knowledge about the risk of developing deep vein thrombosis and pulmonary embolism in cancer patients with various tumor types in specific medical and surgical settings. Moreover, the information provided by registries such as RIETE, has enabled evaluation of the hemorrhagic risk in cancer patients with VTE, especially during anticoagulant therapy. Recent studies point towards a potential benefit that can be gained by applying risk stratification strategies, and may help in the management of cancer patients with VTE.

Procoagulant mechanisms on tumor cells primarily involve expression of hemostatic proteins on tumor cells, production of inflammatory cytokines, and adhesion of tumor cells to endothelium. Tissue factor (TF) plays a major role in tumor progression, metastasis, and angiogenesis through signaling via its intracellular domain. Recent data suggest that TF bearing microparticles (MPs) may play an essential role in these settings. The origin of these MPs varies and may include tumor cells, monocytes, platelets, and endothelial cells. Finally, cross-talk between TF and heparanase, which is known to increase angiogenesis and metastasis, has recently been reported. Exploring these mechanisms will potentially pave the way for novel therapeutic interventions in cancer patients as well as in those with thrombosis.

Cancer patients may present with systemic coagulation activation manifested as disseminated intravascular coagulation, which is frequently sub-acute or chronic in nature and may manifest with thrombosis. Thrombotic microangiopathy following chemotherapy or stem cell transplantation is a complex clinical presentation requiring elaborate laboratory evaluation, currently without satisfactory therapy and often associated with a dismal prognosis. Veno-occlusive disease of the liver is another example of a complex clinical manifestation following stem cell transplantation and chemotherapy.

The mechanisms of thrombohemorrhagic complications in acute promyelocytic leukemia can be partially ameliorated by vigorous platelet and blood products transfusion and early administration of all-trans-retinoic acid. The risk for thrombosis in childhood acute lymphoblastic leukemia is increased in patients harboring thrombophilia and during L-asparaginase therapy. Risk stratification and anticoagulant prophylaxis can reduce the thrombotic burden in these children.

A growing number of angiogenesis inhibitors have recently been approved for the treatment of a variety of solid and hematological tumors. Arterial and venous thrombosis is a major complication of many of these agents and ways for its prevention are currently under intense investigation. While potential contributors to thrombosis are related to the drug’s mechanism of action, the epidemiological data on the rate of thrombohemorrhagic complications are not yet affirmed for many of these agents. Current antithrombotic pharmacological interventions in cancer patients include prevention of VTE in various clinical settings and anatomical sites. The type of antithrombotic agent and duration of VTE treatment in cancer patients have been partially explored, using currently available antithrombotic agents, and advantage in secondary prevention of VTE has been demonstrated. Whether novel anticoagulants will have similar activity in cancer patients remains to be established.

Thus, thrombosis and cancer are two major pathologies that are intricately associated. Studies on the basic mechanisms of these interactions may lead to substantial clinical implications and improved patient care.

Footnotes

Citation: RMMJ 2012;3 Suppl:7–8.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Surgical Treatment of Morbid Obesity

Ahmed Assalia ¹

Abstract

Morbid obesity (MO) is considered the epidemic of the 21^st century. It is defined as body mass index (BMI) above 40 kg/m2, or a BMI > 35 with associated diseases. According to the National Institute of Health (NIH) consensus statement from 1992, conservative measures (diet and pharmacotherapy) for the treatment of MO will fail in the long term for more than 95% of cases. Currently, surgical management is the only effective proven modality in the treatment of MO.

Over the last decade, along with the introduction of minimally invasive techniques and new surgical procedures, we were able to improve surgical results, in terms of morbidity, mortality, and metabolic results. A great deal of data is available showing the favorable results of surgery for MO and type 2 diabetes mellitus (T2DM) associated with obesity (Diabesity). Mean weight loss after surgery is expected to reach a mean of 60–70% of the excess weight. Furthermore, following surgery, about 80–90% of patients with T2DM, more than 95% with obstructive sleep apnea and 70% with hypertension and hyperlipidemia, will recover from their disease. Significant improvement will be achieved in the rest. The durability of results is demonstrated in most of these patients for the mid- and long-term. The most common procedures include laparoscopic sleeve gastrectomy (LSG), laparoscopic gastric bypass (LGB), laparoscopic biliopancreatic diversion (BPD), and laparoscopic BPD with duodenal switch (BPD-DS). Several new surgical procedures are still under evaluation.

The results of bariatric surgery are being achieved by combining the restriction of intake, malabsorption, and hormonal changes.

Recently, intensive research is investigating the hormonal and metabolic consequences of surgery; bariatric surgery is now considered a well-established metabolic intervention. To ensure long-term success, a multi-disciplinary approach and close follow-up are pivotal.

Footnotes

Citation: RMMJ 2012;3 Suppl:8–9.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Low-Intensity Extracorporeal Shock Wave Therapy for Erectile Dysfunction in Phosphodiesterase-5 Inhibitor Responders: A Randomized, Double-Blind, Placebo-Controlled Study

Yoram Vardi ¹, Boaz Appel ¹, Omar Massarwi ¹, Ezra Gerber ¹, Elliot Sprecher ¹, Amichai Kilchevsky ¹, Ilan Gruenwald ¹

Abstract

Introduction:

Low-intensity extracorporeal shock-wave therapy (LI-ESWT) has been shown to promote neovascularization in various tissues throughout the human body.

Research Hypothesis:

Use of LI-ESWT can promote neovascularization in the penis thereby improving erectile function in men with erectile dysfunction (ED) of vasculogenic etiology.

Materials and Methods:

We enrolled 60 men with vasculogenic ED who had International Index of Erectile Function ED domain scores (IIEF-ED) without PDE5-I therapy between 1–19 (mean, 12.2). These men had previously responded to PDE5-Is (mean IIEF-ED domain: 22.7). The men were randomized to 12 sessions of LI-ESWT or sham treatment. LI-ESWT was applied to the penile shaft and crura at five different sites. Assessment of erectile function was performed prior to the first treatment and at 1 month after the final treatment session, using validated sexual function questionnaires and penile and systemic endothelial function testing. A change in the IIEF-ED Domain score of more than 5 points was used as the main outcome measure of treatment success.

Results:

The LI-ESWT treated group (treatment) evidenced a greater increase in Total IIEF and IIEF-ED from V1 to FU1 versus the sham group. Total IIEF: 12.2 ± 2.0 (change score mean ± SEM) vs. 3.2 ± 3.1, P = 0.0196. IIEF-ED: 6.7 ± 0.9 vs. 3.0 ± 1.4, P = 0.0322. Similar improvements were observed in the penile endothelial function, expressed by FMD maximum (FMD). For the treated group, FMD improved by a median 8.2 ml/min per deciliter (−17.0 to 124.8) vs. −0.1 (range −9.2 to 18.5) for the sham-treated group, P < 0.0001. Combining the objective and subjective parameters for each individual, we found that 22 patients in the active group (56%) showed significant improvement in both IIEF and FMD whereas only 1 patient in the placebo group (5%) showed an improvement in both, P < 0.0001. Importantly, the LI-ESWT treated group experienced a significantly greater increase in the IIEF Total Satisfaction category from visit 1 to follow-up 1, 1.9 ± 0.5, vs. the sham-treated group, 0.1 ± 0.4, P = 0.0054. None of the patients experienced adverse effects from the treatment.

Conclusions:

The new LI-ESWT treatment is effective, long lasting, and well tolerated by men with erectile dysfunction who had previously responded to pharmacotherapy.

Footnotes

Citation: RMMJ 2012;3 Suppl:9.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

A Novel Amiodarone-Eluting Biological Glue for the Prevention of Postoperative Atrial Fibrillation: First Animal Trial

Ziv Beckerman ¹, Adi Azran ¹, Ohad Kimhi ¹, Liran Shani ¹, Roni-Reuven Nir ¹, Gil Bolotin ¹

Abstract

Background:

Postoperative atrial fibrillation is the most common complication after cardiac surgery, leading to increased morbidity and mortality. Routine prophylactic use of amiodarone is not recommended due to associated systemic adverse effects. The aim of this study was to evaluate the efficacy of a novel local drug delivery system for the prevention of postoperative atrial fibrillation, while avoiding systemic distribution.

Methods:

Nine goats (five study goats, four controls) underwent left thoracotomy and right atrial epicardial electrodes attachment. An alginate based novel proprietary glue with amiodarone (1 mg/kg bw) was applied to the right atrial epicardium of the study group. In the control group, glue without amiodarone was applied. Atrial effective refractory period (AERP), and atrial response to burst pacing (rapid atrial response, RAR) were assessed at the following intervals: before and after application, and in the first, second, and third postoperative days (PODs). Myocardial, plasma, and extracardiac tissue amiodarone concentrations were analyzed by high-performance liquid chromatography (HPLC).

Results:

Mean HPLC drug levels were found to be within the therapeutic window in the right atrium of all tested animals from the first postoperative day (23510.86 ± 5230.69 ng/g). Amiodarone concentrations in plasma, skeletal muscle, and thyroid gland were below detection level. AERP did not change in both groups during the study. Baseline RAR inducibility was comparable between both groups (P = 0.27). Within the study group, a significant reduction in RAR inducibility was observed on POD3 (65% vs. 27%; P = 0.019). No such differences were found among the control group (44% vs. 41%; P = 0.86).

Conclusions:

The local delivery of amiodarone reduced atrial vulnerability to tachyarrhythmias, while extracardiac drug levels remained below detection. This novel technology should be further validated for the prevention of postoperative atrial fibrillation.

Footnotes

Citation: RMMJ 2012;3 Suppl: 9–10.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Microparticles Effects on Apoptosis, Angiogenesis and Migration in Healthy and Pathological Pregnancies

Einat Shomer ^1,², Sarah Katzenell ^1,², Yaniv Zipori ³, Rami N Sammour ⁴, Benjamin Brenner ^1,², Anat Aharon ^1,²

Abstract

Introduction:

Microparticles (MPs) are shed from activated or apoptotic cells and contribute to hypercoagulability in normal pregnancy and gestational vascular complications (GVC). However, the effects of MPs on vascular cells in pregnancy remain unknown.

Study Aims:

The objective of the study is to evaluate the impact of MPs on apoptosis, angiogenesis, and migration of human endothelial cells (EC), and placental human villous trophoblasts (HVT).

Material and Methods:

Microparticles were obtained in four study groups: non-pregnant women (NP), healthy pregnant females (HP), pregnant women with GVC, and pregnant females treated with low molecular weight heparin (LMWH). Microparticle characteristics and effects on EC and HVT were evaluated by TUNEL, ELISA, migration and tube formation assays.

Results:

Microparticles from the HP group caused apoptosis in HVT obtained from term placentas; MPs significantly increased in the GVC cohort (P < 0.0001). For the LMWH-treated group, MPs significantly reduced HVT apoptosis (P = 0.007) compared to MPs obtained in the GVC cohort. For all pregnancy groups, MPs improved viability of 24-week gestation HVT, while not affecting EC viability. HP-MPs significantly increased HVT migration (P < 0.0001) compared to untreated cells. Migration was reduced in cells exposed to GVC-MPs; this reduction was ameliorated by the MEK 1&2 inhibitor, suggesting involvement of the MAP kinase pathway. Migration of cells treated with MPs from the LMWH-treated group was similar to that observed in the HP -MP-treated cells. Levels of matrix metalloproteinase 9 (MMP-9) were significantly higher in the HP-MPs compared to the NP-MPs (P = 0.0008), but appeared to be lower in GVC-MPs compared to HP-MPs. The HP-MPs induced tube formation in EC in contrast to untreated cells. Remarkably, tube formation was abolished by MPs isolated from the GVC cohort, while MPs from the LMWH cohort improved tube formation.

Conclusions:

Microparticles obtained from pregnant women were found to have different effects on endothelial and trophoblast cells. While GVC MPs appear to increase apoptosis, reduce migration, and impair angiogenesis, compared to healthy pregnancy, MPs isolated from women treated with LMWH improve cell survival and function. These effects of MPs can determine the vascular cell fate and may influence pregnancy outcome.

Footnotes

Citation: RMMJ 2012;3 Suppl:10–11.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Human Hair Follicle Derived Induced Pluripotent Stem Cells (iPSC) and Their Differentiation into Dopaminergic Neurons as a Model to Study Neurodevelopmental Abnormalities in Schizophrenia

Odile Robicsek ¹, Rachel Karry ¹, Isabelle Petit ², Nava Salman ², Ehud Klein ¹, Daniel Aberdam ², Dorit Ben-Shahar ¹

Abstract

Introduction:

Reprogramming of somatic cells into induced pluripotent stem cells (iPSC) and differentiating them into different neuronal lineages is a new tool to model neurodevelopmental disorders, including schizophrenia. We hypothesized that keratinocytes isolated from hair follicles of schizophrenia patients could be an ideal source of somatic cells for reprogramming, due to their accessibility and common neuroectodermal origin with neurons.

Methods:

Four schizophrenia, and two healthy subjects, derived iPSC lines (Sch-iPSC and CTL-iPSC, respectively) were produced from hair follicle keratinocytes by infection with lentiviral particles expressing the polycistronic plasmid STEMCCA (Oct4, Sox2, Klf4, and c-myc). Characterized pluripotent iPSC were differentiated into Pax6⁺/Nestin⁺ neuronal precursors and then further differentiated into β3-tubulin⁺/TH⁺ dopaminergic cells and forebrain β3-tubulin⁺/TBR1⁺ glutamatergic cells using SMAD and TGFβ inhibition protocol or prolonged spontaneous EB differentiation, respectively.

Results:

While CTL-iPSC displayed a neuronal morphology and formed network-like structures, Sch-iPSC cells were much bigger, did not present morphological features of neurons, and seemed less developed. IF revealed that a large proportion of differentiated CTL-iPSC were β3-tubulin⁺/TH⁺. FACS confirmed that 70% of differentiated CTL-iPSC, yet only 3.6% of Sch-iPSC were β3-tubulin-positive. Differentiated CTL-iPSC released dopamine and its metabolite HVA significantly more than Sch-iPSC by HPLC. Levels of serotonin and its metabolite (5HIAA) were similar in both groups. Both CTL-iPSC and Sch-iPSC similarly differentiate into forebrain beta3-tubulin+/TBR1+ neuron-like cells. However, Sch-iPSC-derived neurons did not expressed TBR1, a marker of final stage of differentiation of forebrain neurons. Mitochondrial function including respiration, membrane potential (Δψ m), and mitochondrial network dynamics were abnormal at various developmental stages in schizophrenia derived cells, including keratinocytes, iPSC, neuronal precursors and differentiated neurons.

Conclusions:

The results of this study show neurodevelopmental impairments implicated in schizophrenia in a novel in vitro cellular model. Thus, the non-invasive painless means of HF keratinocytes-derived iPSC may provide new insights into neuron development and may serve as a tool for the design of alternative therapeutics to optimize drug therapy for the benefit of the patients.

Footnotes

Citation: RMMJ 2012;3 Suppl:11.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #03A: Relation between Changes in Red Cell Distribution Width and Clinical Outcomes in Acute Decompensated Heart Failure

Badira F Makhoul ^1,³, Amal Khourieh ³, Fadel Bahouth ¹, Doron Aronson ^2,^3,⁴, Zaher S Azzam ^1,^3,⁴

Abstract

Background:

Carbapenem-resistant enterobacteriacea (CRE) had recently emerged around the world. Beginning in 2006, almost all major hospitals in Israel observed a continuous increase in the number of clinical isolates of CRE and this occurrence has rapidly become a major ongoing national outbreak. Despite stringent adherence to the national practice guidelines, which include strict contact isolation and cohorting of identified carriers, we have not been able to control the outbreak.

Objectives:

We conducted a randomized prospective trial aimed at eradicating gastrointestinal tract CRE colonization, using oral antibiotic administration of gentamicin (GM), collistin (COL), or both.

Methods:

Consecutive hospitalized adult patients identified as CRE carriers by rectal surveillance cultures were included in the study. Rectal isolates were tested for GM and COL susceptibility using E test. Patients who did not consent, or whose isolates were resistant to both drugs, were followed with repeated rectal swabs to assess spontaneous eradication rate (control group). Patients with gentamicin sensitive (GM-S) collistin resistant (COL-R) rectal isolates were treated with oral gentamicin sulphate, 80 mg q.i.d. Patients with isolates that were COL-S but GM-R were treated with oral colistin sulphate, 100 mg q.i.d. Patients with isolates sensitive to both drugs were randomized to three groups of oral antibiotic treatment: GM, COL, or both. Oral treatment was given until eradication, or for a maximum of 60 days. Eradication was defined by the presence of three consecutive negative rectal swabs for CRE including PCR testing of the third specimen. Failure was defined when: 1) rectal swabs remained positive after 60 days of treatment or follow-up; 2) relapse occurred after apparent eradication; 3) rectal isolates turned resistant to the administered drug.

Results:

There were 152 patients in the study; 102 were followed for spontaneous eradication (controls) for a median of 150 days (range: 20–720), and 50 patients received one of three drug regimens: 26-GM; 16-COL; 8 patients received both drugs. Eradication rates in the three groups were 42%, 50%, and 37.5%, respectively; each of these were significantly higher than the 7% spontaneous eradication rate in the control group (P < 0.001, < 0.001 and 0.02, respectively), with no difference between the regimens. The eradication rate among the 50 patients on any treatment (44%), was also significantly higher than the 7% spontaneous eradication rate (P < 0.001). No significant side effects were observed, for any of the treatment regimens.

Conclusions:

Oral antibiotic treatment, with non-absorbable drugs to which CRE is susceptible, appears to be an effective and safe measure for eradication of CRE carrier state, and by that, may reduce patient-to-patient transmission and the incidence of clinical infection with this difficult to treat organism.

Footnotes

Citation: RMMJ 2012;3 Suppl:19.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #20B: Rapid Detection of Carbapenem-Resistant Acinetobacter Baumannii in a Clinical Setting

Yuval Geffen ¹, Raya Shalaginov ¹, Renato Finkelstein ², Hannah Sprecher ¹

Abstract

Background:

Acineotbacter baumannii (AB) plays a significant role in the colonization and infection of hospitalized patients. Starting in 2009, the prevalence of carbapenem-resistant (CR) AB isolates increased significantly in our institution, up to 76% in the beginning of 2011. Outbreaks of OXA-type carbapenemase-producing AB strains have been reported worldwide and bla_OXA-23 was reported as the most abundant acquired OXA gene. The aim of the present study was to establish a rapid and reliable PCR-based diagnostic assay for detection of CR-AB.

Material and Methods:

Seventy-four AB clinical isolates (mostly from lower respiratory tract samples) were tested using a PCR-based assay targeting the bla_OXA-23 gene followed by identification and antimicrobial susceptibility testing according to CLSI standards.

Results:

Out of 74 AB isolates, 64 were identified as CR-AB (Imipenem MIC > 16 μg/ml) and 10 as carbapenem sensitive (CS). None of the CS-AB isolates were bla_OXA-23 positive, while 60/64 (94%) CR-AB isolates were bla_OXA-23 positive, thus indicating that bla_OXA-23 could serve as a target for a rapid PCR-based detection of CR-AB. The PCR-based assay was then evaluated in a prospective setting using 77 rectal swabs that were taken as part of another routine surveillance program. These results were as follows: 55/77 rectal swabs were bla_OXA-23 positive, later confirmed by culture; in 2/77 swabs, bla_OXA-23 was not detected by PCR but later identified in CR-AB isolated from culture (96% sensitivity); and 20/77 swabs were bla_OXA-23-PCR negative, later confirmed by culture. Interestingly, 17 bla_OXA-23 positive swabs were obtained from patients with a confirmed CR-AB infection, suggesting that rectal swabs may serve as a reliable sample for CR-AB screening program.

Conclusions:

There were two main conclusions from this study:

In our institution, 94% of CR-AB isolates carry the bla_OXA-23 gene, indicating bla_OXA-23 gene as a suitable target for a PCR-based rapid assay for CR-AB detection.
An efficient screening program can be established based upon this rapid PCR-based assay performed directly on rectal swab samples, reducing turnaround time for CR detection to a minimum of only 4h.

Footnotes

Citation: RMMJ 2012;3 Suppl:19–20.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #21B: The Effect of Disinfection Material Accessibility on Hand Hygiene Compliance

Eran Brauner ¹, Hanny Bahouth ¹, Haim Gilshtein ¹, Haya Gratzenzon ¹, Orna Aluk ², Yoram Kluger ¹

Abstract

Introduction:

Health care associated infection (HCAI) is a worldwide epidemic. Cross infections result in high hospital morbidity and mortality. Hand hygiene compliance among health care personnel (HCP) is a key factor in combating HACI. The quality of interventional studies examining hand hygiene compliance is disappointing. The aim of this study was to examine the effect of personal feedback and alcohol dispenser accessibility on hand hygiene compliance.

Materials and Methods:

To monitor the hygiene efforts of staff, transmitters were worn as “smart” bracelets on the wrists of surgical ward personnel; transmitters were also placed under the alcohol dispensers at the entrance of each room. The transmitters communicated with sensor modules installed in each room’s ceiling. The system continuously monitored hand hygiene habits regarding pre-defined compliance and quality. At the second stage, dispensers were installed at the foot of each bed.

Results:

More than 300,000 hand hygiene-requiring events were recorded. Upon implementation of the surveillance system, a steep rise in personnel compliance to 24% was recorded. This decreased to a worrisome stable compliance of only 7.5% after a few weeks. For each collective/personal feedback, the compliance increased significantly, but again decreased within a short period. On-going surveillance and feedback helped maintain compliance above the minimal level. Compliance improved dramatically, to 29%, as alcohol dispensers became more accessible (P < 0.034).

Conclusions:

Continuous feedback and surveillance of personal compliance monitoring is an effective method of improving hand hygiene. Accessibility of alcohol dispensers significantly raises the compliance of hand hygiene among HCP. Therefore, such dispensers should be implemented in all surgical wards, simply by placing an alcohol dispenser on each bed.

Footnotes

Citation: RMMJ 2012;3 Suppl:20–21.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #22B: Candida Infection: Scanning Electron Microscope Observations in a Human Skin Model

Ayelet Raz-Pasteur ^1,², Yehuda Ullmann ^3,⁴, Israela Berdicevsky ¹

Abstract

Introduction:

Candida albicans is the principal fungal infectious agent in human infection. Superficial infections of skin and mucous membranes are the most common types of candidal infections of the skin. It has been well demonstrated that specific Candida species, notably C.albicans, selectively adhere to vaginal and buccal mucosal cells. This selective adherence is thought to contribute in part to predominance of C.albicans colonization and infection in human hosts.

Non-pathogenic species adhere poorly to corneocytes or mucosal cells and do not invade the stratum corneum in animal models. In the present study, we report observations on the way Candida infect the stratum corneum in a human skin model.

Aims:

The aim of this study is to characterize and compare initial adherence of C.albicans, C.tropicalis, and C.parapsilosis to the skin surface.

Methods:

Skin sections were inoculated with low and high concentrations of C.albicans, C.tropicalis, and C.parapsilosis, followed for one and five days, and then viewed by SEM

Results:

Candida albicans: C.albicans adhered to human epidermis in greater numbers than the other species at every time point studied (after 24 hours and after five days), and with both concentrations (10⁴ ml⁻¹ and 10⁶ ml⁻¹) after one day, and to a greater extent after five days, most of the C.albicans blastoconidia were coated with amorphous material linking adjacent blastoconidia and blastoconidia with the corneocyte surface. After five days, huge amounts of blastoconidia were shown, covering almost the entire skin model, the blastoconidia were embedded in a layer resembling biofilm. Candida tropicalis: Low amounts of blastoconidia were observed with C.tropicalis in comparison to C.albicans. After five days at the higher concentrations, the blastoconidia were coated with the material linking adjacent blastoconidia and they were covered with a biofilm. Candida parapsilosis: After one day at low and high concentrations, only a few blastoconidia were observed. After five days of incubation, more blastoconidia adhered in both concentrations. Control skin: After one day and after five days we observed normal epidermis.

Conclusions:

Electron microscopy observations revealed that all three yeasts tested adhered to the skin, but C.albicans covered the entire skin model to a higher extent than C.tropicalis or C.parapsilosis. Mucin-like material coated the blastoconidia mainly in C.albicans. All Candida species have shown characteristics resembling biofilm formation.

Footnotes

Citation: RMMJ 2012;3 Suppl:21.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #27B: Blood Stream Infections in Severe Burns Patients-Early and Late Bacteremia: A Nine Year Study

Ayelet Raz-Pasteur ¹, Khetam Hussein ¹, Renato Finkelstein ^1,³, Yehuda Ullmann ^2,³, Dana Egozi ²

Abstract

Introduction:

Bacterial infection is a major problem in the management of burn victims today. It is now estimated that about 75% of the mortality following burn injuries is related to infections. Bloodstream infections (BSIs) and the development of sepsis are among the most common infection complications occurring in severe burn patients. Therefore, it is important to carry out periodic reviews of the epidemiology of BSIs in these patients.

Aims:

This study was designed to evaluate the microbiological data of BSIs and antibiotic susceptibility over a period of almost a decade, and specifically the changes during the hospitalization period with the distribution of early versus late bacteremia, in severe burn patients at the Rambam Health Care Campus.

Methods:

Retrospective computerized data was retrieved for all severe burn patients hospitalized in our institution from January 2001 to December 2009. We further divided that period into three-year sub-groups, and the hospitalization period into four week-long segments.

For the first week, BSI was defined as early sepsis; for the second week on, BSI was defined as late sepsis.

Results:

Out of the 159 severe burns patients included in the study, at least 74 had one BSI episode. The main blood infectious pathogens identified, with equal distribution, were S.aureus, Acinetobacter baumannii, Klebsiella pneumonia, and P.aeruginosa. Of note, the first episodes of bacteremia were diagnosed most frequently during the first week of hospitalization. When we differentiated between early and late bacteremia, we found that in early bacteremia the presence of resistant bacteria and Candida was minor, with no MRSA and Imipenem-resistant P.aeruginosa (PSE-IMP). In late bacteremia, we noticed an increased prevalence of resistant bacteria (MRSA, CRKP, and PSE-IMP). In addition, the only bacterium that was observed to increase significantly during the nine-year period was Carbapenem Resistant Klebsiella Pneumoniae (CRKP).

Conclusions:

In severe burn patients, most of the first BSI episodes appeared very early during hospitalization, even at the beginning of the first week.

The incidence and variety of resistant bacteria and fungal isolates increased in accordance with the length of hospitalization (early vs. late bacteremia).

The only bacterium that increased significantly during the nine-year study period was CRKP.

Footnotes

Citation: RMMJ 2012;3 Suppl:21–22.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #59B: Hospital-Acquired Klebsiella pneumonia Bacteremia: Risk Factors for Carbapenem-Resistance and Predictors for Mortality

Khetam Hussein ¹, Ayelet Raz-Pasteur ², Ami Neuberger ¹, Yael-Shachor Meyouhas ^1,³, Ilana Oren ^1,³, Renato Finkelstein ^1,³, Imad Kassis ^1,³

Abstract

Introduction:

Carbapenem-resistant Enterobacteriaceae, especially Klebsiella spp., has recently become a major health problem worldwide. Since 2006, the incidence of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections has increased dramatically in Israel. Bloodstream infections (BSIs) caused by these strains were associated with high rates of treatment failure and mortality.

Aims:

The aim of this study was to identify risk factors for carbapenem-resistance and predictors of mortality among adult patients with hospital-acquired bacteremia due to Klebsiella pneumonia.

Methods:

The study was performed by means of a retrospective cohort study.

Results:

Between January 1, 2006 and December 31, 2008, there were 510 patients with K. pneumonia bacteremia in our hospital. Of these, 317 patients, including 103 patients with carbapenem-resistant K. pneumonia (CRKP), fulfilled our inclusion criteria and were evaluated. When 214 patients with carbapenem-susceptible K. pneumonia (CSKP), were compared with the CRKP patients, several characteristics were significantly more common among CRKP patients, including hematological malignancy, renal failure, chronic liver disease, previous bone marrow transplantation, mechanical ventilation, central vein catheterization, urinary catheterization, hemodialysis, stay in the ICU or in the hematology department, and prior antibiotic use. On multivariable analysis, prior use of macrolides (OR, 3.3;95% CI, 1.295–8.45; P = 0.012) and any antibiotic exposure for ≥ 14 days (OR, 17.3;95% CI, 4.568–65.5;P < 0.001) remained independent factors associated with CRKP. The mortality rate among patients with CRKP was significantly higher than that of patients with CSKP (45 of 103 CRKP patients, 43.7% vs. 62 of 214 CSKP patients, 29% respectively, P < 0.001). On multivariable analyses, bed ridden status (OR 2; 95% CI, 1–3.8, P = 0.044), chronic liver disease (OR 4.8; 95% CI, 1.8–12.8; P = 0.002), Charlson Comorbidity Index > 5 (OR 6.7; 95% CI, 2.4–18.9; P < 0.001), mechanical ventilation (OR 4; 95% CI, 2.2–7.2; P < 0.001), and hemodialysis (OR, 2.7;95% CI, 1.2–6.2; P = 0.019) remained independently associated with mortality among patients with K. pneumonia bacteremia.

Conclusions:

This study confirms that previous antibiotic exposure is a risk factor for severe infections due to CRKP. Mortality among patients with K. pneumonia bacteremia is associated with severity of illness and many other well-known serious co-morbidities, but not with carbapenem-resistance.

Footnotes

Citation: RMMJ 2012;3 Suppl:22–23.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #60B: Campylobacter Bacteremia: A 10-Year Single-Center Experience

Khetam Hussein ¹, Yael Shachor-Meyouhas ^1,³, Ayelet Raz-Pasteur ², Ilana Oren ^1,³, Imad Kassis ^1,³

Abstract

Introduction:

Campylobacter bacteremia (CB) is a rare disease, occurring mainly in patients with immune deficiency or other serious underlying conditions, including liver disease, hypogammaglobulinemia, HIV infection, as well as in extreme ages.

Aims:

This study was designed to evaluate the clinical characteristics and risk factors for CB in a tertiary referral center, serving over a million citizens in northern Israel, with over 40,000 blood cultures taken annually.

Methods:

The study utilized retrospective computerized data from January 2000 to October 2010.

Results:

There were 36 patients with CB, including seven patients less than 18 years of age, three neonates, and seven patients over 65 (mean age 42 years, range 1 month–91 years). Common underlying conditions were hematological malignancy (16), solid tumor (2), organ transplantation (2), chronic liver disease (3), and diabetes mellitus (2). Three patients had underlying disease. Of note were 23 (64%) patients on immunosuppressive therapy at the time of bacteremia. The most common symptom among these patients was fever followed by abdominal pain, diarrhea and vomiting. Campylobacter bacteremia was asymptomatic in three cases. Three patients had a concomitant positive stool culture.

Campylobacter jejunii was the most common isolated species (15 isolates, 41.6%), followed by C.coli (4 isolates, 11%), and C. fetus (2 isolates, 5.5%). Species were not identified in 15 cases (41.6%). Most isolates were susceptible to macrolide drugs (29/31 tested, 94%), Aminoglycosides (23/24 tested, 96%), and clindamycin (18/20 tested, 90%). However, 14/30 tested (53%) were resistant t fluroquinolones. Antibiotic treatment was given to 31 patients but the treatment was adequate (according to in vitro susceptibility) in only 18 patients (58%). The different regimens included quinolones, macrolides, penicillins, aminoglycosides, and a combination of aminoglycosides and beta-lactam drugs. Relapse occurred in three patients. The thirty-day mortality rate was 8.3% (3 patients); in only one case was mortality due to CB.

Conclusions:

In this study, most episodes of CB occurred among severely immunocompromised patients and were caused by C. jejunii. The mortality rate was low despite the discrepancy between antibiotic regimens and in vitro susceptibility results.

Footnotes

Citation: RMMJ 2012;3 Suppl:23.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #94B: Incidence and Risk Factor for Endocarditis among Patients with Hospital-Acquired and Health Care-Associated Staphylococcus Aureus Bacteremia

Renato Finkelstein ^1,⁶, Yoram Agmon ^2,⁶, Ilana Oren ^1,⁶, Eyal Braun ^1,⁶, Imad Kassis ^1,⁶, Hanna Sprecher ³, Ayeley Raz ^1,⁶, Igor Mogilewski ⁴, Farid Nakhul ^5,⁶, Tania Mashiach ¹, Shimon Reisner ^2,⁶

Abstract

Introduction:

Staphylococcus aureus (SA) is an increasing cause of bacteremia, both in the community and in the hospital setting. Cardiac valves are probably the most important site of metastatic infection. The reported incidence of infective endocarditis (IE) among patients with SA bacteremia (SAB) varied from 5% to 30%. Staphylococcus aureus infective endocarditis (SAIE) is a characteristic community-acquired infection; however, most cases today occur in a health care setting. The purpose of the present investigation was to determine the incidence and risk factors for development of IE in a large cohort of patients with health care-associated (HCA) and hospital-acquired (HA) SAB.

Methods:

Consecutive patients with health care-associated and hospital-acquired SAB) were prospectively recruited over a 30-month period. Patients were followed up for at least 12 weeks after the initial positive blood culture result. The primary end point was diagnosis of IE.

Results:

Infective endocarditis occurred in 11 (3.6%) of 303 patients. Patient characteristics at diagnosis and associated with IE included the number of positive blood cultures obtained during hospitalization (P = 0.003), the duration of bacteremia (P < 0.001), bacteremia persisting for > 3 days (odds ratio (OR), 14.5; 95% confidence interval (CI), 4.0-52.8; P < 0.001), performance of echocardiography (OR, 1.88; 95% CI, 1.69–2.1; P = 0.001), presence of a well-known predisposing risk for IE (OR, 57.2; 95% CI, 13.6–240.5; P < 0.001), a non-fatal McCabe scoring (OR, 2.10; 95% CI, 1.4–3.1; P = 0.02), and fever duration related to the infection (P = 0.02). On multivariable analysis, the presence of a predisposing risk for IE, persistent bacteremia, and non-fatal McCabe scoring remained significantly associated with IE.

Conclusions:

The incidence of IE among patients with HCA and HA SAB is lower than that found in different settings. We identified three clinical characteristics as risk factors for IE among patients with SAB acquired in a health care setting. Although TEE remains the best way to confirm or to diagnose IE in all patients with SAB, this goal is not achievable for all, and its results are not always definitive. Therefore, the present investigation enhances the clinician’s ability to identify which patients with healthcare-related and nosocomial SAB are more prone to develop IE.

Footnotes

Citation: RMMJ 2012;3 Suppl:23–24.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #98B: Reducing Surgical Site Infection Rates in Orthopedic Implant Surgery: Results of a Six-Year Infection Control Program

Renato Finkelstein ¹, Orna Eluk ¹, Talia Mashiach ¹, Dani Levin ², Bezalel Peskin ², Gabriel Nirenberg ², Suhil Karkabi ², Michael Soudry ²

Abstract

Background:

This work reports the results of an infection control program for on surgical site infections (SSIs) complicating total hip and total knee replacement.

Methods:

This prospective cohort study involved patients undergoing total hip and total knee replacement. Interventions included prospective surveillance, chlorhexidine 4% showers, depilation before surgery, administration of preoperative antibiotic prophylaxis in the operating room, and comprehensive postdischarge follow-up. Infections were evaluated using the Center for Disease Control and Prevention definitions. Logistic regression models were fitted to assess infection rates over time, adjusting for factors known to affect SSI rates (National Nosocomial Infections Surveillance System risk index category, type of operation, sex, age, emergency operation, administration of preoperative antibiotic prophylaxis, and length of stay in hospital before surgery).

Results:

From April 1, 2002 to May 31, 2008, 1720 consecutive procedures were evaluated. Rates of organ/space infections remained low, but unchanged over the study period (mean 1.09%). The overall infection rate, the rates of superficial (SUP) SSIs, and deep incisional SSIs during the first two years were 7.90%, 5.78%, and 0.96%, respectively. By the end of the study, these rates decreased to 1.96%, 1.06%, and 0.0, respectively (P < 0.001, < 0.001, and 0.03, respectively). The rate of SSIs due to S. aureus decreased from 1.54% to 0.30% (P = 0.02). The adjusted odds ratios for these infections at the end of the study, as compared to March 31, 2004, were as follows: total number of infections, 0.23 (95% confidence interval (CI-95), 012-0.44), SUP 0.17 (CI-95, 0.07–0.39), and all SSIs due to S. aureus 0.14 (CI-95, 0.03–0.64).

Conclusions:

We observed significant reductions in infection rates in most types of infections, particularly in the overall rate of SSIs and infections due to S. aureus. These differences remained significant when adjusted for potential confounding variables.

Footnotes

Citation: RMMJ 2012;3 Suppl:24–25.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #99B: Compliance with Antibiotic Prophylaxis and Outcomes during a 10-Year Infection Control Program in Cardiac Surgery

Renato Finkelstein ¹, Galit Rabino ¹, Tania Mashiach ¹, Yaron Bar-El ^2,3, Zvi Adler ², Victor Kertzman ², Oved Cohen ^2,3, Simha Milo ²

Abstract

This study aimed at evaluating the correlation between compliance with appropriate antibiotic prophylaxis (AP) and the risk of surgical site infection (SSI) in cardiac surgery (CS).

Methods:

Prospective cohort study. The use of a recommended preoperative AP regimen (cefazolin or vancomycin administered within 2h prior to the first incision) was accessed and SSIs were evaluated by a comprehensive post-discharge follow-up program. Definitions from the Center for Disease Control and Prevention were used. Logistic regression models were fitted to assess infection rates over time, adjusting for factors known to affect SSI rates (National Nosocomial Infections Surveillance System risk index category, type of operation, sex, age, emergency operation, administration of preoperative AP, and length of stay in hospital before surgery).

Results:

From January 1, 1997 through December 31, 2006, 3,220 consecutive procedures were evaluated. As compared with a baseline period (first two years), by the end of the program there were significant reductions in rates of superficial (SUP) SSIs (4.7% vs. 2.6%, P < 0.001), mediastinitis (MED) (2.2% vs. 0.2, P < 0.001), and of all SSIs together (10.3% vs. 5.4%, P < 0.001). The adjusted odds ratios for these infections at the end of 2006, compared with December 31, 1998, were as follows: SUP 0.5 (95% confidence interval (CI-95), 0.26–0.96, MED 0.09 (CI-95, 0.01–0.72), and all SSIs 0.47 (CI-95, 0.3–0.75), respectively. Compliance with the recommended AP increased from 92.1% to 99.8% by the end of the program (P < 0.001). Of the 2,610 patients who received the recommended AP, 127 (4.9%) subsequently had SUP SSI. Of the 105 patients who received AP in a period of time different of that recommended, 14 (13.3%) had such infections (P = 0.001, RR 0.36 (CI-95 0.21–0.61)

Conclusions:

Maximizing appropriate AP reduces SSI rates in cardiac surgery.

Footnotes

Citation: RMMJ 2012;3 Suppl:25.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #04C: Influence of Vitamin D Status on Bone Density in Young HIV Infected Israeli Women

Edurado Shaha ^1,², Elena Segal ³, Zila Shen-Orr ⁴, Gamal Hassoun ¹, Eynat Kedem ¹, Shimon Pollack ^1,², Sophia Ish-Shalom ^2,³

Abstract

Background:

Decreased bone mineral density (BMD) was reported in HIV infected patients. Mechanisms leading to this decrease are poorly understood.

Aim:

To assess degree of sun exposure, clothing habits, vitamin D status, and BMD in young HIV infected Israeli women of Ethiopian (ET) and Caucasian (CA) origin.

Patients and Methods:

Seventy-five HIV infected women aged 34.5 ± 8.5 years with regular menses that were followed up at the Institute of Allergy, Clinical Immunology & AIDS were studied. HIV status and treatment regimen were collected from patients’ charts. Patients filled a questionnaire about sun exposure, daily calcium intake and dress habits. Laboratory evaluation included routine biochemistry, hydroxyvitamin D (25(OH)D) by ¹²⁵I- radioimmunoassay, Intact parathyroid hormone (PTH) by STAT. Bone turnover was assessed by plasma total procollagen type1 amino-terminal peptide (P1NP) and collagen beta cross-laps (CTX). BMD measurements of lumbar spine (LS), femoral neck (FN) and total hip (TH) were performed using dual energy X-ray absorptiometry (Lunar DPX scanner). BMD results were expressed in comparison to aged matched controls (Z-scores).

Results:

There were 43 Ethiopian patients (pts) (57.3%) and 32 (42.6%) Caucasian (CA) pts. Otherwise, there were no significant differences in demographics, actual and past HIV status, antiretroviral treatment, and bone turnover markers between the groups.

The 25(OH)D serum levels < 10 ng/ml (severe vitamin D deficiency) were observed in 28 (65%) of ET vs. 2 (6.25%) of CA(p = 0.001). Plasma PTH was 72.14 ± 57.37 ng/l (normal 12–65), in ET vs. 31.23 ± 14.21 in CA (P < 0.001). Seventeen (40.4%) of the ET had sun exposure < 1 hour/day, vs. 6 (19.4%) of CA patients (P = 0.07); daily calcium intake was 514 mg (ET) vs. 164 mg (CA), P = 0.001. Avoidance of sun exposure was observed in 21 (67.7%) ET, vs. 16 (39%) CA, P = 0.019.

Z-scores in ET and CA were: at LS −1.8 ± 1.1 vs. −0.79 ± 0.88, respectively, P = 0.001; at FN −1.12 ± 1.1 vs. −0.59 ± 0.87, p 0.02, at TH −0.94 ± 1.1 vs. −0.25 ± .1.1, P = 0.007. BMD Z scores < −1 at LS were observed in 26 (89.7%) vs. 20 (48.8%), P < 0.01, at FN −20(69%) vs. 17 (41.5%), P < 0.03, at TH 17 (58.6%) vs. 9 (22%), P < 0.001 of severely vitamin D deficient pts vs. pts with 25(OH)D > 10 ng/ml, respectively.

Conclusions:

Osteopenia was found to be frequent in young ET and CA HIV infected women. Vitamin D deficiency, low calcium intake, limited sun exposure, and clothing habits might affect BMD in this group of patients. A significantly lower BMD in dark skinned patients (ET) might be at least partially explained by their poorer vitamin D status.

Footnotes

Citation: RMMJ 2012;3 Suppl:25–26.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #05C: Post Fracture Osteoporosis Treatment Program: Is it Efficient?

Elena Segal ^1,⁴, Marina Nodelman ¹, Doron Norman ^2,⁴, Michael Soudry ^2,⁴, Daniela Militianu ³, Sophia Ish-Shalom ^1,⁴

Abstract

Introduction:

Low trauma events are common in the elderly. Patients with fragility fractures have a fivefold risk for further osteoporotic fractures. Orthopedic care usually does not include initiation of fracture prevention treatment.

Patients/Methods:

A Fractures Prevention Program (FPP) was initiated at Rambam Health Care Campus in March 2009. All patients (pts) with fragility fractures were referred from the Department of Orthopedic Surgery to the Bone and Mineral Metabolism Unit for fracture prevention treatment (consult during hospitalization and outpatient clinic after discharge).

Results:

A total of 900 pts were followed, ages 50–107 (75.18 ± 11.7), 247 (27.4%) men, and 653 (72.6%) women. There were 593 (66%) hip fractures, 60 (7%) vertebral fractures, 247 (27%) other fractures (humerus, wrist, tibia, and fibula); 155 (17%) pts had previous fragility fractures. All hip radiographs were retrospectively assessed by a bone radiologist; five pts (0.8%) met the atypical fractures criteria. These five were treated with alendronate for 2–9 years; none were diagnosed with an atypical fracture during hospitalization. Prior to hospitalization 156 pts (17.3%) received a fracture prevention treatment: 152 (23.2%) women (134 (88.2%) oral bisphosphonates; 10 (6.5%) raloxifen; 5 (3.3%) teriparatide); 4 (1.6%) men, alendronate. A 25OHD serum level prior to hospitalization was available for 239 (26.5%) pts. Mean 25OHD was 26.5 ± 14.7 (4–118) ng/ml; in 85 (35.6%) pts 25OHD ≤20 ng/ml, 25 (10.5%) 25OHD ≤10 ng/ml. 154 (17.1%) pts (23 (9.3%) men, 131 (20.1%) women) adhered to the FPP. Femoral neck and midshaft fractures were found in 98 (63.6%) pts; other fractures were found in 56 (36.4%) pts.

There were 746 (82.9%) pts not included in the FPP. Of these, 693 refused to join, and 52 (10.6%) women and 1 (0.3%) man were treated in the community. Of the 693 pts that refused the FPP, 18 (2.4%) died. Of the patients being treated, 207 (23%) pts in FPP and 53 in the community, therapies were as follows: alendronate, 80 pts (38.6%); risedronate, 46 pts (22.2%); raloxifen, 5 pts (2.4%); zoledronate, 32 pts (15.4%); teriparatide, 28 pts (13.5%); and calcium and vitamin D prior to starting bisphosphonate, 16 pts (7.7%). Of the five patients with atypical fracture, four were switched to teriparatide, and one patient refused.

Conclusion:

The majority of elderly patients remain untreated after fragility fractures. Hospital based FPP increased the rate of post fracture treatment by only 6%. Diagnosis of atypical fractures deserves special clinical and radiologic attention during hospitalization.

Footnotes

Citation: RMMJ 2012;3 Suppl:26–27.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #06C: Assessment of PTH Response, Using New DIASORIN 1-84 PTH Third Generation Assay, to Oral 50000 Units Vitamin D3 Load

Raya Gendelman ¹, Marina Nodelman ², Elena Segal ^2,³, Marina Kustanovich ², Sophia Ish-Shalom ^2,³

Abstract

Background:

To date, measurement of intact 1-84 PTH serum levels in clinical research and practice was subject to assay-induced variability, due to use of antibodies that detect PTH fragments. The new DiaSorin 1–84 PTH, is a third generation assay that measures only 1–84 PTH and is hypothesized to provide better precision in the assessment of this hormone.

Methods:

In order to test this hypothesis serum PTH was assessed in 57 healthy volunteers who were administered oral vitamin D3 load of 50,000 IU and in 31 pts who received placebo. Serum samples for 25OHD and PTH were collected before vitamin D administration and at day 1, 7, 14, and 28 thereafter. PTH was measured with Roche’s second-generation assay and with new DiaSorin 1–84 PTH. Results were assessed using a two-way repeated measures multivariate model with Bonferroni correction.

Results:

Serum 25OHD significantly increased in the vitamin D group from day 0 to 14 and 28. A weak significant negative correlation was demonstrated between 25OHD and PTH serum levels: r −0.166 P = 0.001 for Roche and r − 0.267 P = 0.0001 for PTH DiaSorin that displayed a superior correlation to the increase in serum 25OHD, P = 0.01.

Conclusion:

Correlation between Vitamin D and the DiaSorin new 1–84 PTH is better than the correlation with the intact PTH (Roche). This may indicate that measuring the 1–84 PTH could be of more accurate clinical value, might bring uniformity, and serve as a better tool for clinical and research evaluation.

Footnotes

Citation: RMMJ 2012;3 Suppl:27.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #14C: AHNAK––A Novel Regulator of GLUT4: Role in Obesity and Insulin Resistance

Dafna Rozentzweig Ben-Yosef ¹, Chava Harel ^1,², Ahmad Assalia ², Ahmad Mahajna ², Irit Hochberg ¹, Maya Ramdas ², Michal Armoni ^1,², Theodore P Ciaraldi ³, Robert R Henry ³, Eddy Karnieli ^1,³

Abstract

Introduction:

High levels of free fatty acids play an important role in the pathogenesis of insulin resistance in obesity and Type 2 Diabetes. However, the mechanisms involved are yet unclear. Arachidonic acid (AA)—a well described model for hyperlipidemia, repressed GLUT4 gene expression via a specific GLUT4 promoter region (−222/−197 bp), but the mediator remained elusive.

Methods:

Using the GLUT4 promotor region as bait for mediators in AA-treated cardiomyocytes, followed by mass spectrometry analysis, we detected the AHNAK/desmoyokin giant protein in association with the GLUT4-promoter (GLUT4-P). This association was confirmed by ChIP assay.

Hypothesis:

We examined the hypothesis that AHNAK—a novel giant protein—plays a major role in regulating glucose homeostasis in vitro and in vivo in human adipose cells. Unveiling this part of AHNAK function may serve as a potential molecular target for enhancing insulin sensitivity in obesity and diabetes.

Results:

In subcutaneous adipose tissue obtained from obese patients undergoing bariatric surgery, AHNAK mRNA levels correlated with the degree of weight loss (R² = 0.943; P = 0.005). In human abdominal adipocytes, AHNAK and Glut4 protein levels were inversely correlated (R = −0.810, P < 0.05). Gene silencing of AHNAK by siRNA in primary rat adipocytes enhanced Glut4 protein levels by two-fold, and protected GLUT4 expression from AA-induced repression. The potential role of AHNAK on GLUT4 translocation was studied in muscle-derived L6 GLUT4myc cells. Compared to mock transfection, AHNAK silencing increased basal and insulin-stimulated cell surface levels of GLUT4 to ∼150% and ∼230%, respectively.

Conclusions:

We have shown that AHNAK is a novel regulator of GLUT4, reduces its gene expression, and impairs its translocation machinery, thus contributing to the pathogenesis of insulin resistance. Hence, AHNAK may serve as a potential molecular therapeutic target in obesity and DM2.

Footnotes

Citation: RMMJ 2012;3 Suppl:27–28.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #96C: Empirical Testing of the ‘Infancy-Childhood Transition’ Theory of Adaptive Life History

Yonatan Crispel ¹, Oren Katz ¹, Ze’ev Hochberg ^1,²

Abstract

Introduction:

The infancy-childhood transition (ICT) theory claims an adaptive role for the age at ICT in maturation, body composition and growth, such that delayed ICT (DICT) results in short stature. To test this theory empirically, ICT was assumed to be controlled by weaning from lactation.

Material and Methods:

First generation (F1) Sprague-Dawley pups, which usually wean on d21, were weaned by transfer to non-lactating foster-mothers on d16, d21, or d26. On d60, females and males were mated within the weaning groups and second-generation (F2) pups were followed for growth, maturation, puberty, and body composition by MRI.

Results:

Early weaned pups (d16) reached d60 lengths of 41.9 ± 0.5 cm (F1) and 38.8 ± 1.6 cm (F2), vs. that of late weaned (d26) F1 and F2 pups with d60 lengths of 35.7 ± 1.5 (P < 0.001) and 35.4 ± 1.2 cm (P < 0.001), respectively. Likewise, the d16 F1 females grew faster (P < 0.001); however, early weaning led to reduced BMI. The d90 BMI was greater on d26 than d16 in males (P < 0.05) and females (P < 0.001); they showed glucose intolerance and insulin resistance, yet their body composition by NMR on d10 showed smaller body fat mass and greater lean body mass. Second generation pups shifted their infantile maturation: male pups of d16 parents had fur earlier at d8.7 ± 0.7 (d8.0 ± 0.5 in females) vs. d10.4 ± 1.6 in F2 d26 (P < 0.05), (10.7 ± 0.7 in females, P < 0.05). Pinnae detachment was also earlier on d10.7 ± 0.8 (10.6 ± 0.7 in F) in d16 F2 males as compared to 13.1 ± 0.6 in d26 F2 males (P < 0.05; P < 0.05 in females). Eye opening occurred on d15.7 ± 0.5 in d16 F2 males (15.5 ± 0.5 in females), as compared to 16.4 ± 0.5 (P < 0.05) in d26 F2 males (16.3 ± 0.5 in females, P < 0.05). Puberty also shifted: Vaginal opening and first estrous occurred in d16 F2 females on mean d35.0 and d40.1, respectively, as compared to d26 F2 on d36.9 (P < 0.05) and d42.4 (P < 0.05). Testicular growth of d16 F2 males started on d33, reaching a maximum volume of 4.1 ml on d58, as compared to d34 onset, maximum volume 3.3ml (P < 0.001) on d72 (P < 0.001) in d26 F2 males.

Conclusions:

Long lactation and DICT in rats results in shorter bulkier animals with delayed development and puberty; these changes are transmitted to the next generations.

Footnotes

Citation: RMMJ 2012;3 Suppl:28–29.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #108C: Trans-Generation Shift of Life History by Modulation of the Infancy Stage

Oren Katz ², Yonatan Crispel ², Ze’ev Hochberg ^1,²

Abstract

Introduction:

The pre-adult life history of rats is divided into infancy, as defined by lactation, and juvenility to reach sexual maturity by age 45 days. In a previous study, we showed that late weaning results in short/obese/glucose intolerance phenotype.

Aims:

Here we investigated the developmental and behavioral consequence of short vs. long infancy, as determined by weaning age.

Methods:

Sprague-Dawley pups (generation F1), which are usually weaned at d21, were weaned by transfer to non-lactating foster-mothers at age d16, 21, or 26, and separated from the foster-mothers on d30. On d60, females and males were mated within the weaning groups and second-generation (F2) pups were followed for their developmental milestones and behaviors.

Results:

Second generation pups shifted their infantile developmental milestones such that male pups of early weaning parents (d16) grew fur earlier (males, d8.7 ± 0.7; females, d8.0 ± 0.5), as compared to d10.4 ± 1.6 in pups of late weaning parents (d26) (P < 0.05), 10.7 ± 0.7 in females, P < 0.05. Pinnae detachment was also earlier in d16 F2 pups at d10.7 ± 0.8 (10.6 ± 0.7 in females) as compared to d13.1 ± 0.6 in d26 F2 (P < 0.05) pups, d13.4 ± 0.5 in females (P < 0.05). Eye opening occurred at d15.7 ± 0.5 in d16 F2 pups (15.5 ± 0.5 in females), as compared to 16.4 ± 0.5 (P < 0.05) in d26 F2 pups (females, 16.3 ± 0.5, P < 0.05). Vaginal opening of generation F2 pups also shifted, such that d16 F2 females opened at d35.0 ± 0.6, as compared to d26 for F2 pups, at d35.9 ± 0.7 (P < 0.05). Testicular volume of the d16 group was 1.0 ± 0.1 ml on d31, as compared to 0.8 ± 0.2 ml for d26 F2 pups (P > 0.05), and 2.8 ± 0.3 ml on d51 for the d16 F2 group, as compared to 2.3 ± 0.3 ml for d26 F2 pups (P < 0.05). The d26 offspring were less mobile, anxious before sexual maturation, and less novelty seeking.

Conclusions:

The age at weaning determines the stages of growth, and this is transmitted over generations. Shorter infancy results in a trans-generational shift to earlier infantile and juvenile development, and hyperactive anxious behavior.

Footnotes

Citation: RMMJ 2012;3 Suppl:29.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #25D: Contribution of Decreased Migration of Monocytes to Impaired Inflammation in Gaucher Disease

Noam Bettman ², Tamar Katz ^1,², Hanna Rosenbaum ^1,², Irit Avivi ^1,²

Abstract

Introduction:

Abstract

Background:

Recommendations to follow with liver biopsy patients receiving methotrexate for psoriasis are based on the risk to develop liver damage as outlined by the American College of Rheumatology. Recent data suggest that methotrexate may be less hepatotoxic than previously assumed.

Methods:

We have retrospectively collected data in patients with psoriasis who had liver biopsies performed between 1995 and 2010.

Results:

Of 30 patients (mean age 9.14 ± 51.80), 25 were classified as high risk according to the American College of Rheumatology. High body mass index (mean 2.15 ± 28.28), and hyperlipidemia (44%) were amongst the most common co-morbidities, but exposure to medications with liver side effects was also very common (42%). No exposure to significant alcohol consumption was noted in this High body mass index group.

The median cumulative methotrexate dose was 2,522 mg (range 1500–6000) over a median period of 44 months (range 15–96). Twenty-five liver biopsies were analyzed and 68% were classified as Roenigk Grade 1, 20% as Grade 2, and 12% as Grade 3a. Six patients had follow up biopsies after exposure to a very high cumulative dose of methotrexate, median 5040 mg (range 3010–8000) over a median period of 68 months (range 35–110). Of those, three showed no change, one revealed improvement, and the remaining two biopsies, that previously were classified Roenigk Grade 1, changed to Roenigk Grade 2.

Conclusions:

Methotrexate related liver injury in high-risk psoriatic patients exposed to high cumulative doses of methotrexate is less frequent than previously thought. The recommendation for liver biopsy in this population needs revision, especially in patients who are not exposed to significant alcohol consumption.

Footnotes

Citation: RMMJ 2012;3 Suppl:34.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #101E: Microcapsules Made of Hydrogel Polymer Cell Constructs for Intravascular Liver Tissue Engineering

Omri Nayshool ³, Julie Carmel ¹, Tarek Saadi ¹, Arie Arish ², Zachar Bramnik ², Iris Mironi-Harpaz ⁴, Dror Seliktar ⁴, Yaacov Baruch ^1,³

Abstract

Introduction:

The liver is the natural microenvironment for hepatocytes transplantation, but unfortunately, engraftment efficiency is low. New polymer technology allows making biosynthetic hydrogels constructs with fibrinogen, cross-linked with polyethylene glycol (PEG) and diacrylates side chains. The cell construct polymerized upon exposure to UV light. Pluronic^® FF127 (Invitrogen, Ltd., Paisley, UK) synthetic copolymer, exhibits a similar reversible reaction when exposed to 37°C. The hydrogel micro scaffolds after intravascular injection may reduce shear stress and immediate immunological pressure, and thus may improve engraftment. We first tested the two types of scaffolds in vitro.

Aims:

The aims of this study were to assess in vitro Huh7 viability and function after polymerization within PEGylated fibrinogen hydrogel constructs and Pluronic^® F127. We also assessed intraportal transplantation efficiency of PEG-Fib microcapsules constructs with adult hepatocytes.

Methods:

Methods used were as follows:

Assessment of Huh7 cells viability by propidium iodide (PI)/fluorescein diacetate (FDA), and MTT assays.
Evaluation of cell function using albumin concentration and CYP1A activity.
Evaluation of microcapsules with HUH7 or adult hepatocytes engraftment efficiency in rats model in vivo using semiquantitative PCR (human 16q23.1) or real time qPCR (rat SRY gene) and histology compares to isolated cells.

Results:

Material and Methods:

MPs were isolated from MDA231 cells following exposure to starvation or chemotherapy agents (Doxorubicin, Paclitaxel). MPs were characterized and their effects on EC were assessed by FACS, FXa chromogenic assay, migration and tube formation assay.

Results:

Stimulation of MDA231 resulted in increased cell apoptosis and release of MPs; MDA-MPs were found to express low levels of TF (10%) compared to their parent cells (80%, P = 0.0003). Conversely, the TFPI level expressed by MDA-MPs appeared to be high (35%) compared to their parent cells, and went down following high-dose chemotherapy (9%, P = 0.02). Furthermore, MDA-MPs assessed after high-dose chemotherapy, showed a five- to eight-fold increase in procoagulant activity compared to MPs evaluated following low-dose chemotherapy (P = 0.016). Microparticles explored after low-dose chemotherapy expressed lower levels of VEGF-R1 (23%) than those observed post high-dose chemotherapy (54%, P = 0.03). The MDA-MPs evaluated following starvation adhered to EC, penetrated into the cells and affected cell hemostatic balance and tube formation, while MPs assessed after low-dose chemotherapy inhibited tube formation.

Conclusions:

Breast cancer MPs exposed to low-dose chemotherapy present low thrombogenicity, low level of VEGF-R1 and inhibit angiogenesis, while MPs exposed to high-dose chemotherapy show high thrombogenicity and high VEGF-R1 levels. These findings may clarify, in part, the role of tumor MPs in hypercoagulability and angiogenesis associated with chemotherapy in cancer.

Footnotes

Citation: RMMJ 2012;3 Suppl:38.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #44G: Carboplatin Dosing in Non-Small Cell Lung Carcinoma Patients using Calvert Formula and Cockroft-Gault Equation for GFR Estimation: A Reliable Method?

Gil Bar-Sela ¹, Orit Kaidar-Person ¹, Fadi Mari ¹, Suheir Assady ², Nissim Haim ¹

Abstract

Introduction:

Carboplatin dosing is based on renal function rather than on body surface area. The most commonly used method to calculate carboplatin dose is the Calvert formula. Estimated glomerular filtration rate (eGFR) is calculated according to the Cockroft-Gault (CG) equation, which relies on serum creatinine level (Scr), age, and weight. However, Scr can change due to numerous (cancer and non-cancer) causes, and does not necessarily reflect true GFR. Paradoxically, a decrease in Scr unrelated to a change in renal function will be translated to a higher carboplatin dose. This study was undertaken to evaluate retrospectively the reliability of using the CG for eGFR used for carboplatin dosing according to the Calvert formula.

Patients and Methods:

The records of patients with advanced non-small-cell lung carcinoma (NSCLC) treated with first-line carboplatin-containing chemotherapy were retrospectively analyzed, excluding patients with renal insufficiency. The theoretical carboplatin doses derived from the Calvert formula, using the CG equation, were calculated for each chemotherapy cycle using the actual Scr. The fluctuations in the theoretical carboplatin doses were analyzed. The discrepancies between the actual carboplatin doses prescribed by the physician and the theoretical doses were also assessed.

Results:

Materials and Methods:

Final pathology and CT data for FNAC were retrospectively reviewed and compared for all patients who underwent Parotidectomy between 2000 and 2010. Literature review was based on trials comparing FNAC with final histological evaluation of parotid tumors identified through an extensive Medline search of the English literature. Outcome measures analyzed included percentage of non-diagnostic samples, sensitivity, specificity, positive predictive value, negative predictive value, and the accuracy of FNAC.

Results:

Sensitivity of FNAC in the present study (90%) was higher compared to previous series. Specificity of FNAC in the present study (98%) was equally high as that calculated. Diagnostic accuracy of FNAC was equally high (88%) in our study compared to previous series.

Conclusions:

Fine-needle aspiration cytology should be interpreted as a complementary diagnostic tool and combined with clinical features, physical examination, and imaging to increases the diagnostic yield. Fine-needle aspiration cytology can contribute to the diagnosis of parotid gland malignancy and should be performed in all patients, especially those over 60. Ultrasound guidance is recommended in lesions smaller than 25 mm.

Footnotes

Citation: RMMJ 2012;3 Suppl:41.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #49G: Maxillary Resection: A Retrospective Study

Imad Abu-El Naaj ^1,², Yoav Leiser ^1,², Amir Wolff ¹, Micha Peled ^1,²

Abstract

Introduction:

The term maxillectomy is used currently to describe a variety of surgical approaches performed to treat broad spectrum of diseases involving the maxillary bones, mainly neoplastic tumors. This work reports our experience in the variety of maxillary diseases such as odontogenic and non-odontogenic tumors, mucormycosis, and others as malignant tumors requiring surgical intervention, and analyses of our data with regards to neck dissection performed in malignant tumors, squamous cell carcinoma (SCC) of the maxilla.

Materials and Methods:

A retrospective analysis of 66 maxillectomies were reviewed and recorded between the years 2000 and 2009. Each patient’s data sheet was reviewed; epidemiology analysis was performed and recorded for age, gender, histopathological diagnosis, and size of tumor. For SCC, neck dissection, chemoradiotherapy and survival rate was also analyzed.

Results:

The average age was 54 years (range 5–84 years). The majority of patients receiving maxillectomy suffered from malignant tumors (41, 59%) compared with non-malignant pathologies (25, 41%). Squamous cell carcinoma accounted for 40% of all cases. Male to female ratio was almost equal (1.6:1). However, when looking at oral maxillary SCC patients, the male group was dominant at 2:1. The overall mortality rate was 23%; however, two groups showed a higher mortality rate: the SCC group showed a 41% mortality rate, and a much higher mortality rate was found in the mucormycosis of the upper jaw group, which accounted for five deaths out of six patients with maxillary mucormycosis. Twenty-five patients had SCC of the upper jaw and para-nasal sinuses. Seventeen of them had neck dissections. Out of the SCC group, six patients (24%) were identified with loco-regional lymph node metastases.

Conclusions:

In the present study, we presented our experience in maxillectomies regardless of the reason. Since the primary disease is not always due to oncological reasons, a global and accurate classification is needed to describe the surgical procedure that will be carried out. A high percentage of the SCC patients (24%) had cervical metastases. This strongly supports the need for routine elective neck dissection for treatment of maxillary SCC, even if clinical examination is negative.

Footnotes

Citation: RMMJ 2012;3 Suppl:41–42.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #50G: Incidence of Oral Cancer Occult Metastasis and the Survival of T1-T2, N0 Oral Cancer Patients

Imad Abu El-Naaj ^1,³, Yoav Leiser ^1,³, Myrela Shveis ¹, Edmond Sabo ^2,³, Micha Peled ^1,³

Abstract

Introduction:

In head and neck cancer, the most important prognostic factor is the presence or absence of neck metastasis. Although a debate is still present in the current literature regarding the “wait and see” policy in T1/T2 oral cancers, a large number of clinicians support the necessity of neck dissection especially in cases of oral tongue carcinoma due to poor prognosis and high risk of recurrence.

This present study summarizes and reports the incidence of occult metastasis in oral cancer treatment in the department of oral and maxillofacial surgery at the Rambam Medical Center in the last 10 years.

Materials and Methods:

A total of 142 neck dissection performed in our department in the last 10 years (1998–2009), a series of 68 patients (44 males and 22 females) treated for T1,T2, N0 oral cancer were included in this retrospective study. All patients underwent surgical resection of the oral cancer and selective neck dissection of the ipsilateral side.

Results:

Occult lymph node metastasis were detected in 11 patients (16% overall, 9 tongue, 1 buccal mucosa, 1 gingiva of mandible). Occult metastasis frequency from tongue carcinoma was 34% (9 of 26 cases). The 5-year-survival in the present study was 78.9%. In patients treated following the surgical management with either chemotherapy, radiotherapy or brachytherapy, or a combination of the three, the overall survival decreased significantly to 22.5% (P = 0.006, Log Rank).

Conclusions:

The incidence of occult metastasis in oral cancer patients, in the present study, was 16% overall. In tongue carcinomas, a much higher incidence (34%) of occult metastasis was detected. Furthermore, the need for chemo-radio therapy following the initial surgical management, mainly due to occult metastasis, was found to be a significant negative predictor of patient’s outcome. The results of the present study emphasize the need for prophylactic neck dissection in oral cancer patients diagnosed with T1, T2, N0 disease, especially when the primary lesion is localized in the tongue.

Footnotes

Citation: RMMJ 2012;3 Suppl:42.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #51G: Mouse Model for the Study of Hepranase Role in Oral Cancer Formation

Yoav Leiser ^1,², Imad Abu El-Naaj ^1,², Edmond Sabo ^2,³, Israel Vlodavsky ², Micha Peled ^1,²

Abstract

Introduction:

Numerous studies have shown that metastases formation depends on the ability of tumor cells to invade basement membranes and tissue barriers in a process involving enzymes capable of degrading extracellular matrix (ECM) components. One of these enzymes is heparanase, an endoglycosidase that degrades heparan sulfate.

Research Hypothesis:

In a previous study, we have shown that the nuclear localization of heparanase is found in all oral verrucous carcinomas, very well differentiated tumors that do not metastasize, as opposed to only 28% of nuclear localization detected in oral squamous cell carcinomas. Heparanase expression level also significantly correlated with the degree of tumor differentiation. Moreover, while cytoplasmic localization of heparanase was associated with high-grade carcinomas, nuclear localization of the enzyme was found primarily in low grade, well-differentiated tumors, the aim of the present study was to use an in vivo model to study heparanase role in cancer formation and progression.

Materials and Methods:

Results:

Baseline CPM was found to be correlated with duloxetine efficacy (r = 0.628, P < 0.001, efficient CPM is marked negative), such that less-efficient CPM predicted efficacious use of duloxetine. Regression analysis (R² = 0.673; P = 0.012) showed that drug efficacy was predicted only by CPM (P = 0.001) and not by pre-treatment pain levels, neuropathy severity, depression level, or patient assessment of improvement by placebo. Furthermore, beyond its predictive value, the treatment-induced improvement in CPM was correlated with drug efficacy (r = −0.411, P = 0.033). However, this improvement occurred only in patients with less-efficient CPM (16.8 ± 16.0 to −1.1 ± 15.5, P < 0.050). No predictive role was found for TS.

Conclusions:

The coupling of CPM and duloxetine efficacy highlights the importance of pain pathophysiology in the clinical decision-making process. This evaluative approach promotes personalized pain therapy.

Footnotes

Citation: RMMJ 2012;3 Suppl:48–49.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #38Hp: Bedouin Wives on the Home Front: Living with Men Serving in the ISRAEL Defense Forces

Yael Caspi ¹, Ortal Slobodin ², Nina Kammerer ³, Guy Enosh ⁴, Shai Shorer ⁴, Ehud Klein ^1,⁵

Abstract

Abstract

Introduction:

The understanding of neuropathic pain has been greatly advanced by experimental models of nerve injury. Most widely used models of neuropathic pain involve injuries that produce an admixture of intact and degenerating axons in close juxtaposition. It is hypothesized that this mixing of injured and intact axons is essential to the development of neuropathic pain. How these various components contribute to neuropathic pain is not completely understood. The purpose of this study was to examine whether markers of nerve injury are up-regulated in nerve that is exposed to degenerating nerve explants, to the exclusion of direct nerve injury.

Methods:

Laboratory rats were randomized to one of five surgical procedures: sham surgery (skin incision only) nerve-tie control (nerve-exposure and elevation onto nerve tie), long sciatic nerve fenestration, degenerating nerve explant over long sciatic nerve fenestration (DNE), and nerve transection. Dorsal root ganglia from L5 were harvested at one week post-operative survival and stained for markers of nerve injury, especially activating transcription factor 3 (ATF-3). Sciatic nerve sections were stained for routine histology and macrophages.

Results:

Histological sections confirmed the close juxtaposition of intact and degenerating nerve fibers in the DNE model animals. Both DNE and long sciatic nerve fenestration resulted in an increased number of macrophages in the sciatic nerve at one week post-op. Sham surgery was not associated with increased nerve injury markers in the dorsal root ganglion, by contrast, sciatic nerve transection resulted in a dramatic up-regulation of injury markers. Nerve tie-control animals demonstrated a very small but measurable increase in ATF-3 staining. Long sciatic nerve fenestration and DNE manipulations resulted in small but measurable increases in nerve injury markers that were not statistically distinguishable.

Conclusions:

Exposure of intact nerve to degenerating nerve factors by means of nerve explant is does not induce an up-regulation of nerve injury markers in transplant-tolerant Lewis rats. The extent to which indirect injury in response to neuro-degeneration as an independent mechanism of neuropathic pain merits additional study.

Footnotes

Supported in part by the Legacy Heritage research fund, the Blaustein Research Fund and an NIH grant NS048146 (BBM).

Citation: RMMJ 2012;3 Suppl:54.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #106H: Computational Modeling of the Two-Axon C-Fiber

Beth B Murinson ¹, Alyza Skaist ², Philippe Taieb ³

Abstract

Introduction:

Despite the critical role of C-fibers in the initiation and transmission of nociceptive signals, little is known about the nature and extent of electrochemical interactions between axons and Schwann cells, and axons and axons, within the C-fiber (Remak) bundle. Axons and Schwann cells within the C-fiber exhibit electrochemical properties that are distinctly different from those of myelinated axons. Yet, much of what is known about axonal signal transmission is based on properties particular to myelinated axons, e.g. saltatory conduction, highly focal ionic fluxes, appraisal of energetic requirements, and pathological alterations such as demyelination. The purpose of this study is to exam the electrochemical properties of non-myelinated axons in more detail.

Materials and Methods:

In collaboration with the National Resource for Cell Analysis and Modeling at the University of Connecticut, we have established a computationally intensive model of the two-axon/single-Schwann cell C-fiber bundle. This model incorporates elements of sodium and potassium channels that have distinct features in axons and Schwann cells, as well as functioning Na-K-ATPases in axon and Schwann cell membranes. In order to establish realistic dimensions for the C-fiber unit, the current model is based on a scanned cross-sectional electron micrograph of a two-axon/single Schwann cell Remak bundle taken from rat nerve.

Results:

The model is computationally represented as existing within an interstitial bath of 4 by 2 microns, and contains two axons, each approximately 800 nanometers in diameter. A major computational challenge is the representation of the peri-axonal space, which has significantly smaller dimensions, i.e. 11 nanometers. Preliminary results from this model indicate the dimensions of the peri-axonal space have a profound impact on the concentration shifts of extra-axonal potassium ions as well as sodium ions during action potential propagation. The dramatic shifts in potassium ion concentrations in the peri-axonal space are observed within the model to have a significant effect on the membrane potential of the nearby Schwann cell membrane, leading to depolarization.

Conclusions:

We conclude that models of unmyelinated axon-Schwann cell systems are useful for understanding the unique electrochemistry of C-fibers and that further study is needed.

Footnotes

Footnotes

Citation: RMMJ 2012;3 Suppl:57–58.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #37J0: Serum Galactomannan Screening for the Diagnosis of Invasive Pulmonary Aspergillosis in Children after Haematopoietic Stem Cell Transplantation and High Risk Leukemia

Irina Zaidman ¹, Roni Gefen ¹, Yael Shachor-Meyouhas ^2,⁴, Israela Avidor ³, Imad Kassis ^2,⁴

Abstract

Introduction:

Invasive Fungal Infections (IFI) constitutes a substantial source of morbidity and mortality among immunocompromised patients. Morbidity and mortality among patients following HSCT is high. Rapid diagnosis and early treatment of IFI are crucial, yet, limited by other complications of HSCT and the need for invasive procedures mainly to identify invasive pulmonary Aspergillosis (IPA). Our study was designed to investigate the impact of serial Serum Galactomannan Assay (GMA) on the diagnosis of IPA.

Methods:

Children with high-risk leukemia or following HSCT were included. Serum samples for GMA (Platela, Aspergillus EIA, Biorad, France) were taken twice weekly from patients at high risk for IFI over 10 months (February–November 2010). Results over 0.5 were considered positive. Patients suspected of having IPA were stratified as possible, probable, and definite according to recent consensus (Clinical Infectious Diseases 2008; 46:1813–21).

Results:

There were 27 patients in the study: median age was 11 (range 1–21 years) and 306 samples were processed. Of 22 HSCT children, 15 were after allogeneic, and 7 patients after autologous bone marrow transplantation. Five patients had high-risk leukemia and 20 patients had a prolonged period of screening from 1 to 7 months. In 7 children, only 1–3 samples were obtained.

This IRB-approved study aimed to assess and compare the quality of colonoscopies performed in one teaching hospital to those performed at one community service.

Methods:

Documentation of the presence or absence of standardized quality indicators (QIs) were tabulated from 700 colonoscopy reports from the academic center, vs. 824 from the community endoscopy service, all for patients over age 40. The American Society for Gastrointestinal Endoscopy (ASGE) quality indicators (QIs) were used as benchmarks.

Results:

There was no statistically significant difference between the colonoscopy results from the hospital vs. community endoscopy services regarding patients’ demographics (age, gender ratio), depth of exam (92.4% vs. 94.1% complete), polyp detection rate (29.1% vs. 26.8%) and biopsies in patients with diarrhea (75% vs. 67%). Indications for colonoscopy differed: gastrointestinal bleeding was more common at Rambam hospital, screening was more commonly listed as the indication for colonoscopy in the community. Premedication varied: more fentanyl and dormicum and less propofol were used in the community. Good bowel preparation was more frequently reported in the community (68.8% vs. 47.2% in hospital, P < 0.0001). Follow-up recommendations were more often documented in the community (74% vs. 53% in hospital, P < 0.0001). The range for many QIs varied greatly amongst physicians.

Conclusions:

Remediation of weaknesses in the quality of colonoscopies seems plausible through upgrading electronic medical records and increasing awareness of QIs. Colonoscopies performed in both hospital and community services were of good quality compared to the relevant literature, with significant variations in some QIs. Vigilance seems worthwhile to assure quality of colonoscopies.

Footnotes

Citation: RMMJ 2012;3 Suppl:63.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #88L: Polymorphisms in the Rac1 and Other Apoptotic Genes: Do They Alter Clinical Response to Azathioprine in Patients with Inflammatory Bowel Disease?

Eduard Koifman ¹, Amir Karban ^1,^2,⁵, Edna Efrati ^3,⁴, Hila Elkin ³, Norberto Krivoy ^3,⁴, Yehuda Chowers ^2,⁵

Abstract

Introduction:

Thiopurines are valuable drugs in the treatment of inflammatory bowel disease. The precise molecular mechanism of action of these drugs remains unclear despite more than 50 years of use. Recently, azathioprine and its metabolites were found to control T cell apoptosis by modulation of Rac1 activation.

Aim:

Assess whether polymorphisms in Rac1 gene and other apoptosis genes predict the response to azathioprine and whether they interact with clinical predictors.

Methods:

Cohort of 187 patients treated with azathioprine for Crohn’s disease (CD) (n = 156) or ulcerative colitis (UC) (n = 31) was genotyped for 7 single nucleotide polymorphisms (SNPs) in Rac1 gene, as well as for Fas ligand 843 T > C, Caspase-9 93 C > T, AOX1 3404 A > G. Real-time PCR was conducted using TaqMan SNP genotyping assays. Clinical data was obtained retrospectively by reviewing medical records.

Results:

The overall rate of remission induction with azathioprine was 74% for Crohn’s disease and 71% for UC. After median follow-up of 7 years, 75% of CD and 81% of UC patients remained in remission. Among Rac1 SNPs, in our cohort heterogeneity was found only in Rac1 690T > C: response rates were similar for both genotypes (P = 0.52) but all the patients with TC genotypes (n = 10) retained remission compared to 76% (n = 123) with TT genotype (P = 0.12). Patients with Fas ligand 843 TT genotype responded in 85%, while with CT/CC only in 70% (P = 0.05). Analysis of clinical data revealed that patients with inflammatory (85%, P = 0.02) and ileal Crohn’s (85%, P = 0.05) disease responded better to the treatment. Women remained in remission in higher rates than men (84% vs. 68%, P = 0.05).

Conclusions:

We observed association between Fas ligand 843 TT genotype and a better response to thiopurines. Further studies in different populations are needed.

Footnotes

Citation: RMMJ 2012;3 Suppl:63–64.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #112L: Early Histological Findings Quantified by Histomorphometry Allow Prediction of Clinical Phenotype in Crohn’s Colitis

Amir Klein ¹, Rami Eliakim ¹, Amir Karban ¹, Yoav Mazor ¹, Ofer Ben-Izhak ², Yehuda Chowers ^1,³, Edmond Sabo ^2,³

Abstract

Background:

The clinical course of Crohn’s disease (CD) is variable and relevant for treatment selection. Early aggressive treatment may change disease course, but should be balanced with safety considerations. Diagnostic tools for prediction of disease course are lacking. Histomorphometric analysis allows for quantitative measurements of size, shapes, and orientation of cells and structures in tissues. The aim of the study is to evaluate the histomorphometric features of early colonic biopsies from patients with Crohn’s disease and their relationship to evolving clinical phenotypes.

Methods:

Colonic biopsies from fifty CD colitis patients classified according to the Montreal classification with at least 5 years post biopsy follow up were analyzed using histomorphometry. The quantitative results were used to predict post biopsy clinical phenotypes and outcomes. Data analysis was performed using statistical and Neural Network (NNET) models.

Results:

Differences were observed between clinical phenotypes in the number of inflammatory cells (P = 0.003), lymphocyte aggregates (P = 0.005) and optical density of mature and young collagen (P = 0.008, P = 0.01 respectively). A crypt area of more than 1.8 mm² was associated with phenotype B3 (P = 0.03, OR-3.9). A count of 23 eosinophils or less per field was associated with B2 phenotype (P = 0.03, OR-5.5). Smokers differed from non-smokers in the average crypt area, number of inflammatory cells and fractal dimensions (P = 0.03, P = 0.03, P = 0.01 respectively). Multivariate analysis successfully differentiated between B1 and B2 phenotypes with a sensitivity of 90% and a specificity of 95%; between B2 and B3 phenotypes, with a sensitivity of 89% and a specificity of 70%; and between B1 and B3 phenotypes, with a sensitivity of 47% and a specificity of 95%. We also successfully predicted surgery with a sensitivity of 86% and a specificity of 80%. Finally, a neural network model correctly predicted clinical phenotypes with an accuracy of 94%.

Conclusions:

To our knowledge, this is the first study that applied histomorphometry on early biopsies in order to predict the clinical phenotypes in Crohn’s colitis. Measurements allowed differentiation and prediction of clinical phenotypes and outcomes such as surgery. This novel approach in combination with other biologic variables and clinical predictors may significantly increase the ability to classify and predict the clinical course of CD colitis patients, thus improving their management. Prospective validation on larger cohorts is still needed.

Footnotes

Citation: RMMJ 2012;3 Suppl:64–65.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #30M: The Economic Benefit of Oral Formulation of Nimodipine Over Intravenous Formulation

Salim Hadad ¹, Laila Nassar ¹, Leon Levi ²

Abstract

Abstract

Introduction:

Abstract

Introduction:

Mass lesions involving the Temporo-Mandibular Join (TMJ) are not commonly encountered. Their prompt diagnosis and treatment are essential for appropriate patient care. Those lesions may grow from either the joint space, or the temporal or the mandibular component of the joint. The purpose of this review is to cover the imaging findings of a variety of mass lesions of the TMJ, with emphasis on the radiological differential diagnosis.

Materials and Methods

Cases of mass lesions involving the TMJ were collected from our clinical database and teaching files.

Results

The results were as follows.

Developmental: Condylar hyperplasia is mostly idiopathic and unilateral with slowly progressive enlargement of one side of the mandible. On imaging, asymmetrical condylar enlargement is depicted.

Infection: Septic arthritis is most commonly a result of direct extension from adjacent infectious focus, or might be a part of a systemic blood born process. Usually, diagnosis is easily made based on clinical presentation; however, in chronic conditions with destructive changes, an infectious lesion might be misdiagnosed as a neoplasm. Osteomyelitis may rarely preferentially affect the bones adjacent to the joint.

We studied telomere length, subtelomeric DNA methylation, and telomeric-repeat-containing RNA (TERRA) expression in several hiPS cell clones derived from normal neonatal foreskin fibroblasts.

Results:

Methods:

Eight RA pts with inadequate response to DMARDs (mean age/disease duration 62.7 yrs, disease duration 7.7 yrs) with active RA (inclusion criteria DAS28 > 4.5) were recruited. Six patients consumed POMx (5 ml/bid) during 12 weeks. Smoking, diabetes mellitus, daily prednisone dose > 10 mg, recent (< 1 month) parenteral steroids, and previous or concomitant biological therapy were exclusion criteria. Treatment efficacy was assessed using DAS28 (ESR) and HAQ-DI at weeks 0 and 12.

Results:

POMx reduced DAS28 by 17% (P < 0.02). This could be mostly related to a significant reduction (62%) in number of tender joints (P < 0.05). POMx consumption was also associated with a significant reduction in serum oxidative stress, measured as lipid peroxides (P < 0.02), and by a significant increase in serum HDL-associated PON1 activity (P < 0.02). Addition of POMx to serum from RA patients reduced AAPH-induced lipid peroxidation by up to 25% compared to age-matched healthy controls (18%).

Conclusions:

Consumption of POMx reduces disease activity in RA patients. This effect could be related to its antioxidative capacity and raised activity of PON1. Thus, dietary supplementation of POMs may be a useful additive strategy to attenuate clinical symptoms in active RA and reduce cardio-vascular risk. Further studies regarding POMs influence on RA activity on large patient’s cohort is warranted.

Footnotes

Citation: RMMJ 2012;3 Suppl:77.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #83T: Ultrasound Assessment of Enthesis Thickening in Psoriatic Arthritis Patients Treated with Adalimumab Compared to Methotrexate

Irena Litinsky ^1,², Alexandra Balbir-Girman ^3,⁴, Jonathan Wollman ^1,², Uri Arad ^1,², Daphna Paran ^1,², Dan Caspi ^1,², Ori Elkayam ^1,²

Abstract

Background:

Main signs of Psoriatic arthropathy (PsA) are arthritis, tendinitis, enthesitis, and spinal involvement. Musculoskeletal ultrasound (MSUS) has become the gold standard for examination of tendons; it has already been proven in monitoring synovitis in rheumatoid arthritis (RA) patients (pts).

Objectives:

This study assesses the effect of adalimumab (ADA) compared to methotrexate (MTX) on the thickness of tendons and enthesis in PsA pts.

Methods:

Thirty-two pts with active PsA were included. Group 1: 21 PsA pts starting ADA treatment; 14 women, 7 men, mean age 51.9 ± 9.5 years. Group 2: 11 PsA pts beginning MTX; 5 women, 6 men, mean age 45.1 ± 14.3 years. Disease activity was assessed by the number of tender (TJ) and swollen joints (SJ), inflamed enthesitis (IE), pain assessment (PA), patient (PDA) and physician (PGDAI) disease activity evaluation by visual analogue scale (VAS). The MSUS assessment and thickness measurement of the extensor (ET) and flexor tendons (FT) of the second and third fingers of both hands, plantar fascia (PF) and Achilles tendon (AT) bilaterally were performed before initiating the therapy, 6 and 12 weeks (wks) after.

Results:

In Group 1, all disease activity parameters improved at visit three, and reached statistical significance for the number of TJ (10.38 vs. 6.06, P = 0.0071), SJ (8.19 vs. 4.94, P = 0.04), PF (71.52 vs. 43.44, P = 0.006), and PGDAI (70.45 vs. 40.95, P = 0.0014). Decreased thickness was observed for AT bilaterally, and was significant on the left (Lt) side (0.38 vs. 0.33, P = 0.02), and for Lt PF (0.13 vs. 0.10, P = 0.01). A statistically significant positive correlation was found between the decrease of thickness of the ETs and the number of TJ and IE, PGAD, PGA.

In Group 2, parameters of IE (P = 0.04), PGA (P = 0.017), and PGDA (P = 0.05) decreased significantly, while the number of TJ and SJ did not change. No changes were observed in the thickness of both AT and PF, FT and ET tendons of hands after 12 wks. Six wks after initiating ADA, thickness of Lt AT, the second Rt FT and the number of TJ, SJ, PF, and PGA were significantly decreased in comparison to the MTX group (P = 0.007; P = 0.05 P = 0.032; P = 0.001; P = 0.034 and P = 0.003, respectively).

Conclusion:

In pts with PsA, treatment with ADA, compared to MTX, significantly improved signs of disease activity as well as MSUS parameters of enthesis such as AT and PF. The MSUS monitoring of enthesis is a useful tool for monitoring PsA enthesopathy.

Footnotes

Citation: RMMJ 2012;3 Suppl:78.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #93T: Medication Reconciliation in the Geriatric In-patients

Sohair Bishara-Swaid ¹, Laila Nassar ¹, Salim Hadad ¹

Abstract

Introduction:

Medication errors and medication related problems are one of the leading causes of morbidity and mortality among the geriatric patients, both in the outpatient and the inpatient environment. A large percentage of medication errors occur at hospitalization and transition from different departments. These medication errors can be avoided by managing a comprehensive and consecutive process of “Medication Reconciliation.” It is a formal process of obtaining and documenting a complete and accurate list of the patient’s current medications upon admission and comparing this list to the physician’s admission, transfer, and\or discharge orders, to identify and resolve discrepancies and errors in medication list.

Methods:

The process of medication reconciliation will be conducted for elderly patients (age > 65) at the internal medicine wards. Inclusion criteria: age > 65 years, on more than five medications. (1) Designing a personalized Med Rec worksheet (2) advanced communication between the health care providers. (3) When the patient is admitted to the internal medicine ward, the pharmacist collects an accurate and complete medication history using a predesigned Med Rec worksheet (the verification step), the same process is repeated when the patient is transited to a different department. If any discrepancies are identified, the physician is notified (the clarification step), the error is corrected by the treating physician (the reconciliation step). When discharged, the patient meets with the pharmacist for education and consultation, and outpatient follow up is conducted when possible.

Expected Results:

The expected number of patients is 30 in duration of 2 months. As observed in previous similar studies, we expect decreased medication related problems, and increased patient awareness and adherence.

Expected Conclusion:

Unintentional medication discrepancies are common at interfaces between the health care transitions, due to insufficient communication and inaccurate medication reconciliation, which can lead to serious drug related problems. A comprehensive and consecutive Med Rec process must be carried out for bridging the gaps in continuity of care, therefore providing safety and efficacy of health for patients during transitions in care. The pharmacist’s involvement is essentially important at various points in the Med Rec process, by identifying, solving, and preventing drug-related problems. The shared responsibility of health care providers (physicians, nurses and pharmacist), is the key to a successful Med Rec process.

Footnotes

Citation: RMMJ 2012;3 Suppl:78–79.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #87U: A Modified Thoracotomy Technique Reduces the Intensity of Acute Postoperative Pain

Ran Kremer ¹, Yonathan Crispel ², Shiri Fadel ², David Yarnitsky ², Michal Granot ³, Lael Anson Best ¹

Abstract

Introduction:

The standard posterolateral thoracotomy is associated with substantial morbidity, and is rated as one of the procedures inducing the most intense pain. Since enhanced pain experienced during the acute postoperative phase is a major predisposing factor for the development of chronic pain, attenuating acute postoperative pain (APOP) following thoracotomy has become an especially relevant need in the clinical arena. Accordingly, this study aimed at revealing whether a modified thoracotomy technique, which less invasively and more gradually accessed the chest cavity, would be associated with the attenuation of pain intensity during the acute postoperative phase.

Materials and Methods:

Eighty-four patients (Group 1) have undergone the standard posterolateral thoracotomy, while forty-five patients (Group 2) have been operated according to a modified technique, mainly guided by a lower degree of invasiveness and a gradual ribs expansion. APOP was measured both at rest (APOP_rest) and during physical activity (APOP_provoked) of hand elevation and cough within 5 days after surgery. The effect of pain catastrophization in response to experimental pain applied before surgery on APOP intensity was also explored.

Results:

A linear regression analysis revealed that lower APOP_provoked scores were significantly associated with the modified thoracotomy technique (P < 0.001), with no effect of individual pain catastrophization levels, age or gender. APOP_rest was comparable in both groups.

Conclusions:

These observations (i) point to the importance of the modified surgical technique, allowing the attenuation of APOP while achieving the primary surgical goals, and (ii) emphasize the complexity of APOP as a composition of distinct processes of the pain system.

Footnotes

Citation: RMMJ 2012;3 Suppl:79–80.

Rambam Maimonides Med J. 2012 Jan 31;3(1):Supplement 1. doi: 10.5041/RMMJ.10071

Poster #91U: Renal Dysfunction Associated with Increased Intra-Abdominal Pressure in Experimental Heart Failure: Nephroprotective Effects of Phosphodiesterase-5 Inhibition

Bishara Bishara ¹, Niroz Abu saleh ², Hoda Awad ², Nabil Ghrayeb ³, Ilia Goltsman ², Suheir Assady ⁴, Iyad Khamaysi ⁵, Zaid Abassi ^2,⁶

Abstract

Introduction:

Methods:

Following signed informed consent (parental), blood samples were drawn, for DNA extraction, from all available patients (n = 10) and parents (n = 6), pertaining to three nuclear families, from one kindred. Clinical, neurological, and developmental assessments were undertaken in selected patients. Two distinct phenotypes, A and B were delineated, marked by mental retardation, either moderate or severe, respectively, and salient dysmorphic features associated with early scenescence (phenotype B). Whole genome SNP array analysis using the “HumanCytoSNP-12v2.1 DNA Analysis BeadChip Kit (Illumina)” was undertaken on two affected individuals demonstrating distinct phenotypes.

Results:

Whole genome SNP array analysis identified an unbalanced cryptic translocation involving a terminal 5 Mb deletion (100273988–106353482) of 14q32.2–14Q32.3 and a terminal 5 Mb duplication (125708–5329074) of 10p15.3–10P15.1 in patients with phenotype A. An alternate unbalanced recombinant, namely terminal 5 Mb deletion (125708–5329074) of 10p15.3–10p15 and terminal 5 Mb duplication (100273988–106353482) of 14q32.2–14q32.3, was shown in patients with phenotype B.

Conclusions:

Investigations of apparently balanced chromosomal rearrangements in patients with abnormal phenotype by molecular cytogenetics tools, especially by array CGH, have become the gold standard for deciphering cryptic chromosomal abnormalities.

Footnotes

Citation: RMMJ 2012;3 Suppl:84.

PERMALINK

Abstracts from Rambam Research Day, December 29, 2011

From the Editor-in-Chief

About Rambam Research Day

Rambam Research Day Organizing Committee

Program for the Fifth Rambam Research Day

Activity Fluctuations and Representation in Neuronal Networks (ATIDIM)

Danny Eytan

Asaf Gal

Avner Wallach

Einat Kermany

Netta Haroush

Shimon Marom

Abstract

Introduction:

Materials and Methods:

Results:

Conclusions:

Footnotes

Haptoglobin Genotype is a Key Regulator of Iron-mediated Lysosomal Destabilization in Diabetes Mellitus

Rabea Asleh

Nina S Levy

Rachel Miller-Lotan

Andrew P Levy

Abstract

Introduction:

Methods:

Results:

Conclusions:

Footnotes

Cancer and Thrombosis: Mechanisms and Implications

Benjamin Brenner

Abstract

Footnotes

Surgical Treatment of Morbid Obesity

Ahmed Assalia

Abstract

Footnotes

Low-Intensity Extracorporeal Shock Wave Therapy for Erectile Dysfunction in Phosphodiesterase-5 Inhibitor Responders: A Randomized, Double-Blind, Placebo-Controlled Study

Yoram Vardi

Boaz Appel

Omar Massarwi

Ezra Gerber

Elliot Sprecher

Amichai Kilchevsky

Ilan Gruenwald

Abstract

Introduction:

Research Hypothesis:

Materials and Methods:

Results:

Conclusions:

Footnotes

A Novel Amiodarone-Eluting Biological Glue for the Prevention of Postoperative Atrial Fibrillation: First Animal Trial

Ziv Beckerman

Adi Azran

Ohad Kimhi

Liran Shani

Roni-Reuven Nir

Gil Bolotin

Abstract

Background:

Methods:

Results:

Conclusions:

Footnotes

Microparticles Effects on Apoptosis, Angiogenesis and Migration in Healthy and Pathological Pregnancies

Einat Shomer

Sarah Katzenell

Yaniv Zipori

Rami N Sammour

Benjamin Brenner

Anat Aharon

Abstract

Introduction:

Study Aims:

Material and Methods:

Results:

Conclusions:

Footnotes