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ספר מחקר שערי צדק

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    ספר מחקר שערי צדק ספר מחקר שערי צדק Presentation Transcript

    • Research Report 2013 Research Report 2013 ResearchReport2013 SHAARE ZEDEK MEDICAL CENTER JERUSALEM SHAARE ZEDEK MEDICAL CENTER JERUSALEM SHAAREZEDEKMEDICALCENTERJERUSALEM A ngi ogra phy CARDIOLOGY Complementary Medicine Digestive Diseases Em ergency G a u c h e r geria trics Care ivf ETHICS Medical Genetics Nursing Gynecology& Obstetrics Pathology Pediatric Genetics Pediatric Hem atology-O ncology PediatricPulmonology Pediatric Rehumatology PEDIATRIC UROLOGY pl astic surgery Psychiatry Pulmonary Reproductive Endocrinology Research & Development Rheumatology Ultrasound Neurology N E P H R O L O G Y NEP HR OL OG Y Cardiothoracic Surgery Intensive Care neuropediatric Pediatric Gastroenterology Otolaryngology Endocrinology 2013
    • Shaare Zedek Medical Center Jerusalem Research Report 2013
    • Published by the Department of Resource Development and Public Affairs Shaare Zedek Medical Center, Jerusalem P.O.B 3235 Jerusalem 91031 Tel: 02-6666622, Fax: 02-6522950 www.szmc.org.il Project Head: Professor Dan Turner Assistant Project Head: Dr. Keren-Or Amar Coordinator: Leora Shoham-Peters English Editor: Esther Singer Design and Production: viim.co.il
    • Research and Development at the Shaare Zedek Medical Center 8 Internal Medicine  13 Division of Internal Medicine 14 Department of Hematology 21 Digestive Diseases Institute 41 Gaucher Clinic  45 Medical Genetics Institute 54 Stem Cell Research Laboratory 64 Institute of Oncology 67 Integrated Oncology Department 72 Nephrology Unit 77 Neurology and Toxicology Service and Unit 81 Pulmonary Unit 91 Neurology Department 95 Department of Geriatrics 98 Rheumatology Unit 102 Endocrine Unit 106 Angiography Unit – Interventional Radiology Unit 110 Department of Cardiology 115 Pediatrics123 Division of Pediatrics 124 Pediatric Gastroenterology Unit 125 Pediatric Infectious Diseases Unit 135 Pediatric Rheumatology Unit 141 Neuropediatric Unit 148 Department of Neonatology 156 3 Shaare Zedek Medical Center, Jerusalem
    • Division of Pediatric Nephrology 161 Pediatric Pulmonology Unit 167 Pediatric Hematology-Oncology 172 Pediatric Endocrinology Unit 176 Obstetrics, Gynecology & IVF 179 In Vitro Fertilization (IVF) Unit 180 Pediatric Genetics Unit 183 Reproductive Endocrinology and Genetics Unit 187 Zohar Preimplantation Genetic Unit (PGD) 193 Department of Obstetrics and Gynecology 198 Department of Obstetrics and Maternal Fetal Medicine 202 Surgery and Anesthesia 209 Department of General Surgery 210 Department of Cardiothoracic Surgery 216 Department of Plastic Surgery 222 Department of Anesthesiology - Perioperative Medicine and Pain Treatment 225 Department of Otolaryngology - Head and Neck Surgery 230 Department of Pediatric Urology 235 Department of Orthopedic Surgery 240 Imaging, Emergency, ICU and Pathology 245 Intensive Care Unit (ICU) 246 Imaging Department 251 Ultrasound Unit 255 Institute of Pathology 259 Emergency Department 261 Research Report 2013 4
    • Nursing and Complementary Care 265 Medical Ethics Department 266 Consultation - Liaison Psychiatry Unit 269 Center for Integrated Complementary Medicine 272 Nursing Division 276 Index279 5 Shaare Zedek Medical Center, Jerusalem
    • Research Report 2013 6
    • A medical institution on the cutting edge of science and technological development, Shaare Zedek Medi- cal Center takes considerable pride in our expanding high-level research.  This latest edition of the Shaare Zedek Research Report testi- fies to the growing range of studies carried out by our staff. Our physicians, who embrace research as part of their prac- tice of modern medicine, are not only excellent role models for the next generations of physicians but clearly demon- strate that research is a central component of what it means to be a quality caregiver in the 21st century.  Clinical medicine must go hand in hand with advances in sci- ence if we are to ensure that our patients receive truly com- prehensive attention. We are confident that the recent agreement between Shaare Zedek and the Yissum Research Development Company of the Hebrew University of Jerusalem will lead to significant discoveries with concrete applications in transfer technology. We are convinced that the accomplishments made possible by this agreement will allow us to take giant steps forward in clinical practice for the betterment of the medical community both in Israel and around the world. I would like to express my thanks and appreciation to Prof. Dan Turner, Managerial Coordinator of Research in the hos- pital, Dr. Keren-Or Amar, Director of Shaare Zedek’s Re- search and Development Authority and Ms. Leora Shoham- Peters for all their efforts in the compilation and publication of this report. Prof. Jonathan Halevy, MD Director General 7 Shaare Zedek Medical Center, Jerusalem
    • Research and Development at the Shaare Zedek Medical Center Dr. Keren-Or Amar Head, The Research Authority Prof. Dan Turner Director General Assistant for R&D Over the past several years there has been a significant in- crease in both the volume and cutting edge research con- ducted at Shaare Zedek Medical Center. This stems primarily from the hospital staff’s growing involvement in research and the increasing recognition of the hospital by other national and international academic institutions. In addition, several recent major administrative reforms in the managerial sec- tor have further facilitated research endeavors in the hospi- tal. These major steps include the appointment of a research affiliate to Director General Prof. Jonathan Halevy in 2009 (Prof. Dan Turner) as an integral partner in the senior hos- pital management, reflecting the high priority ascribed by the hospital management to promoting research activity. This paved the way for an agreement with Yissum, the tech- nology transfer company of the Hebrew University, in June 2011. This strategic collaboration has vastly extended re- search opportunities and joint projects with laboratories at the Hebrew University and enables Shaare Zedek's research- erstobenefitfromYissum’sprofessionalintellectualproperty management services. The immediate result has been the rise in research projects with a potential for commercialization. In the last 18 months, Shaare Zedek has signed two license agreements, and four patents are pending. In addition, more than ten projects are in different stages of the commercializa- tion process, compared to none in the years preceding these reforms. Finally, the Shaare Zedek Research & Development Authority, which was established in September 2011 and is headed by Dr. Keren-Or Amar, has prioritized the coordina- tion of research activities in the hospital. The R&D Authority facilitates and assists the hospital staff in obtaining external Research Report 2013 8
    • and internal research support, handles legal and research contacts with third parties, sets up research collaborations with external labs and researchers, and coordinates the hospital’s con- tinuous contacts with Yissum and funding agencies. In late 2011, a lawyer (Matan Menachem) was asked to oversee the legal side of the hospital’s research activity. Much effort has been in- vested in ensuring timely execution of contracts with industry and other research authorities. An internal regulatory reform, passed in 2012, now enables parties to conduct legal negotia- tions while ethics submissions are in process, thereby considerably reducing the start time of research projects. However, the rapid development of the hospital’s research activities is first and foremost the outcome of a growing number research projects initiated by researchers. One clear indication of the success of this venture is the accelerating number of peer-reviewed articles published by the physicians and researchers of Shaare Zedek (Figure 1). Figure 1: Increase in the number of peer-reviewed publications at Shaare Zedek Medical Center ThelatestpublicationoftheIsraelNationalInstituteforHealthPolicy(NIHP)Researchranked Shaare Zedek among the top eight hospitals in terms of number of publications (Glazer et al, 2012) and we assume it would rank even higher if the hospital publications were compared in terms of number of physicians employed or number of hospital beds . The number of approv- als of clinical research projects authorized by the institutional ethics committee (headed by Dr. Van Dijk) has almost doubled in five years (Figure 2). 9 Research & Development
    • Figure 2: Number of clinical research projects approved by the institutional ethics committee The contribution of research conducted by physicians to humankind is crucially important, but it is also our belief that physicians who are involved in research also deliver better clinical care. Almost every department at Shaare Zedek is involved in clinical research, and high im- pact basic science projects are conducted in eight research labs. Clinical trials initiated either by hospital physicians or by the biomedical industry are carried out regularly at the hospital in which the units, departments, staff and patients serve as the infrastructure for these studies. A modest animal facility enables in-vivo experiments for small studies. The close collaboration with Yissum and the affiliation of Shaare Zedek with the Hebrew University has created ad- ditional opportunities for using the labs and infrastructure of the University. The stimulating atmosphere of research activity and the high motivation of the hospital researchers have led to ahighpercentageofinvestigator-initiatedclinicalstudiesandbasicscienceprojects(Figure3). Research Report 2013 10
    • Figure 3: Distribution of research projects at Shaare Zedek Medical Center Clearly, the increase in research interest and the motivation of the hospital staff, coupled with the administrative reforms initiated by the hospital management, have had a profound impact on the research environment at Shaare Zedek. We will continue to promote and nurture these exciting research activities at Shaare Zedek, thus contributing and transforming the future practice of medicine for the benefit of all. References Glazer K, Israeli A, and Katz U. Financial arrangements between universities to hospitals in Israel, the current situation, failures and recommendations. The Israel National Institute for Health Policy Research publications, February 2012. 11 Research & Development
    • Research Report 2013 12
    • Internal Medicine GlasbergDepartmentofInternalMedicineA CharlesW.andMollieMarkDepartmentofInternalMedicineB DynaandFalaWeinstockHematologyOncologyDayCareCenter DynaandFalaWeinstockDigestiveDiseasesInstitute FuldFamilyDepartmentofMedicalGenetics ChechickCancerCellResearchLaboratory DavidBartonOncologyServices MirskyCancerResearchInstitute ParvizOhebshalomCancerPain&PalliativeMedicineClinic EmanuelHollanderDepartmentofGeriatrics Jack&MildredMishkinGeriatricRehabilitationCenter Els&CharlesBendheimDepartmentofCardiology HarryH.BerenCardiologyPavilion JackMahfarCardiologyServiceDivision NathanandVivianFinkCardiologyRehabilitationServices
    • T he Division of Internal Medicine consists of five in- patientdepartments,eightsubspecialtyunitsandsev- eral closely associated departments admitting annu- ally about 10,000 patients. The departments – cardiology, gastroenterology, Gaucher clinic, genetics, geriatrics, hema- tology, infectious disease, intensive care, nephrology, neurol- ogy, oncology, pulmonology, rheumatology – deal with the entire field of internal medicine, including cardiovascular ail- ments, infectious diseases, endocrine and metabolic prob- lems (including diabetes), kidney dysfunction, hematological diseases and others. Internal Medicine Department A is headed by Prof. Gideon Nesher, an internist and rheumatologist, and includes two attending physicians, 4 residents and 2 interns. Internal Medicine B is directed by Dr. Shoshana Zevin, an internist and clinical pharmacist. Internal Medicine C was recently ex- panded from 22 to 34 beds. The Department of Geriatrics, di- rected by Prof. Moshe Sonnenblick and his deputy Dr. Reuven Friedmann, consists of three in-patient units, each run by senior geriatricians (Dr. Deborah Shapira, Dr. Ilya Galperin and Dr. Lena Feldman) and a rehabilitation unit headed by a specialist in rehabilitation medicine (Dr. Ezra Shapiro). The onco-hematology department is directed by Dr. Thomas Tichler, a veteran oncologist. The department consists of two subunits, hematology and oncology, served intensively by the hematology and oncology specialists. The Division of Internal Medicine is also a training facility Division of Internal Medicine Research Report 2013 14
    • and some 35 residents are in different stages of their specialization. The residency program prides itself on accepting immigrants from various countries as well as Israelis graduating from foreign medical schools. In addition to teaching residents, the Division is frequented by large numbers of medical students from the Hebrew University-Hadassah Medical School. Each year, groups of fourth year students (i.e., in their first year of clinical training) attend 13-week rotations in internal medicine. Sixth year students attend one-month rotations as sub-interns, in addition to subspecialty clerkships. Finally, we run a 9-week program for Israeli students studying in Hungary and elsewhere. Areas of Research Activity The Division of Internal Medicine is the largest academic center in Shaare Zedek Medical Center, with about one hundred attending physicians in the various departments and units. Of these, more than half are engaged in clinical and/or basic research, and more than thirty have official academic positions, ranging from lecturer, through senior lecturer and associate professor, to professor. The Division of Internal Medicine actively promotes research, both lo- cally initiated as well as in cooperation with other medical centers in the country and abroad. Multiple studies are simultaneously conducted under the auspices and sponsorship of large pharmaceutical companies, as part of phase III randomized clinical trials involving many hos- pitals and countries. In order to stimulate research, the Division of Internal Medicine pro- vides extensive mentorship to young researchers, including a three-month annual protected period for research, free access to a senior statistician, as well as up to twenty annual grants of $5000 each for its attending physicians submitting research proposals after these receive peer-reviewed approval. The specific fields of research include infection control and hospital epidemiology, antimicrobial use, medical administration and education. Internal Medicine A has investigated trends in vasculitis including giant cell arteritis in Jerusalem over a period of 20 years. Internal Medicine B has in particular conducted research on the clinical pharmacol- ogy of nicotine and the characteristics of nicotine addiction in the Israeli population, including a study of nicotine withdrawal during the Sabbath. Representative Research The largest study conducted over the last several years, and supported by a large grant from the Israel Ministry of Health, involving a multi-center study initiated at Shaare Zedek and conducted simultaneously in the Hadassah hospitals, pioneered intervention to reduce rates of hospital acquired infections. We developed two detailed checklists, based on published in- fection control guidelines, for daily use by infection control practitioners in departments and operating rooms, and assessed their impact on nosocomial infection rates. The checklists in- cluded 20 subheadings (±150 items). Projects nurses conducted rounds in study (but not con- 15 Internal Medicine
    • trol)departments;duringeachround,thenursesselected15-20itemsforobservation,marked the checklists according to appropriateness of observed behavior and provided on-the-spot correctiveeducation.Ratesofadherencewiththechecklist,antibioticuse,numberofobtained and positive cultures, and positive staff hand and patient environment cultures were reported monthly as areport card torelevant personnelandadministrators.Withactive surveillancewe determined the rate of nosocomial infections in the first and last month of this 1-year project. The baseline nosocomial infection rate was similar in the study and control departments: 37/345 (11%) and 26/270 (10%) respectively. In the last month, the rate in the study depart- ment decreased to 16/383 (4%)(p<0.01) compared to no change in the control group (21/248 (8%)(NS). The overall rate of adherence to guidelines increased from 80% to 91% (p<0.01). These data show that the use of checklists during infection control rounds, combined with monthly reports, was associated with a significant decrease in nosocomial infections. 0 2 4 6 8 10 12 % Study departments Control Departments Rate of hospital acquired infections, in the first and last month of the study 1st month last month P<0.01 P=NS Research Report 2013 16
    • PUBLICATIONS 1. Rudensky B, Broide E, Berko N, Wiener-Well Y, Yinnon AM, Raveh D. Direct fluconazole susceptibility testing of positive Candida blood cultures by flow cytometry. Mycoses 2009; 51: 200-204. 2. Ben-Chetrit E, Wiener-Well Y, Yinnon AM. Mycobacterium abscessus infection in insulin injection sites in a diabetic patient. Harefuah 2009;148(11):756-8,794. 3. Breuer GS, Nesher R, Nesher G. Effect of biopsy length on the rate of positive temporal artery biopsies. Clin Exp Rheumatol 2009; 27 (suppl. 52): S10-13. 4. Nesher G, Oren S. Lijovetzky G, Nesher R. Vasculitis of the temporal arteries in the young. Semin Arthritis Rheum 2009; 39: 96-107. 5. Breuer GS, Nesher G, Nesher R. Rate of discordant findings in bilateral temporal artery biopsies to diagnose giant cell arteritis. J Rheumatol 2009, 36:794-796. 6. Wiener-Well Y, Raveh D, Schlesinger Y, Yinnon AM, Rudensky B. Cefuroxime for empiric treatment of community-acquired pneumonia: is the a generation gap? Chemotherapy 2009; 55: 97-104. 7. Friedmann R, Raveh D, Zartzer E, Rudensky B, Broide E, Attias D, Yinnon AM. Prospective evaluation of carriage and infections due to Extended-Spectrum β-Lactamase producing Enterobacteriaceae among newly admitted patients. Infect Control Hosp Epid 2009; 30: 534-542. 8. Melamud B, Shilo S, Munter G. Life-threatening hypoglycemia due to false measurement of glucose in a peritoneal dialysis patient. Isr Med Assoc J 2010; 12(2): 125-6. 9. Shapiro DS, Sonnenblick M, Galperin I, Melkonyan L, Munter G. Severe hyponatraemia in elderly hospitalized patients: prevalence, aetiology and outcome. Intern Med I 2010; 40(8):574-80. 10. Ben-Chetrit E, Merin O. Images in clinical medicine. Spontaneous tension pneumothorax. N Engl J Med 2010; 25:362(12). 11. Ben-Chetrit E, Ben-Chetrit A, Berkun Y, Ben-Chetrit E. Pregnan- cy outcomes in women with familial Mediterranean fever receiving 17 Internal Medicine
    • colchicine: is amniocentesis justified? Arthritis Care Res (Hoboken) 2010;62(2):143-8. 12. Lawrence YR, Pokroy R, Berlowitz D, Aharoni D, Hain D, Breuer GS. Splenic infarction: an update on William Osler’s observations Isr Med Assoc J. 2010; 12:362-365. 13. Rudensky B, Yinnon AM, Shutin O, Broide E, Wiener-Well Y, Bitran D, Raveh DP. The cellular immunological reponses of patients undergoing coronary artery bypass grafting compared with those of patients undergoing valve replacement. Eur J Cardio-Thor Surg 2010; 37: 1056-1062. 14. Esayag Y, Nikitin I, Bar-Ziv J, Cytter R, Hadas-Halpern I, Zalut T, Yinnon AM. Diagnostic value of chest radiographs in bedridden patients suspected of having pneumonia. Am J Med 2010; 123: 88.e1-88.e6. 15. Wiener-Well Y, Schlesinger Y, Raveh D, Fink D, Yinnon AM. Q fever endocarditis: not al- ways expected. Clin Microbiol Infect 2010; 16: 359-362. 16. Dejaco C et al.(International Work Group for PMR and GCA): Definition of remission and relapse in polymyalgia rheumatica: data from a literature search compared with a Delphi- based expert consensus. Ann Rheum Dis 2011; 70:447-453. 17. Segel, R, Anikster Y, Zevin S, Steinberg A, Gahl WA, Fisher D, Staretz-Chacham Segel R, O, Zimran A, Altarescu G. A safety trial of high dose glyceryl triacetate for Canavan disease. Mol Genet Metab 2011;103(3):203-6. 18. Altarescu G, Rachmilewitz D, Zevin S. Relationship between CYP2A6 genetic poly- morphism, as a marker of nicotine metabolism, and ulcerative colitis. Isr Med Assoc J 2011;13(2):87-90. 19. Furer V Hersch M, Silvetzki N, Breuer GS, Zevin S. Nicotiana glauca (tree tobacco) intoxi- cation--two cases in one family. J Med Toxicol 2011;7(1):47-51. 20. Ben- Chetrit E, Ben-Chetrit E. Colchicine dose reduction in patients with nor- mal liver and kidney function: comment on the article by Terkeltaub et al. Arthritis Rheum 2011;63(11):3647-8. 21. Wiener-Well Y, Galuti M, Rudensky B, Attias D, Yinnon AM. The importance of bacterial load on medical and nursing gowns in transmission of virulent organisms in hospitals. Am J Infect Control 2011; 39: 555-9. Research Report 2013 18
    • 22. Furer V, Hersch M, Silvetzki N, Breuer GS, Zevin S. Mocptoama glauca (tree tobacco) intoxication – two cases in one family. J Med Toxicol 2011; 7:555-9. 23. Yinnon AM, Wiener-Well Y, Jerassy Z, Dor M, Freund R, Mazouz B, Lupyan T, Shapira S, Attias D, Assous MV, Block C, Raveh D, Freier-Dror Y, Moses AE, Benenson S. Increas- ing implementation of infection control guidelines to reduce nosocomial infections rates: Pioneering the Report Card. J Hosp Infect, 2012; 81: 169-176. 24. Ben-Chetrit E, Munter G. Purple urine. JAMA 2012;307(2):193-4. 25. Winchester Behr T, Sonnenblick M, Nesher G, Munter G. Hyponatraemia in older people as a sign of adrenal insufficiency: a case-control study. Intern Med J 2012;42(3):306-10. 26. Breuer GS, Nesher G: What does imaging tell us about polymyalgia rheumatica? Rheu- matology 2012; 51:5-6. 27. Behr TW, Sonnenblick M, Nesher G, Munter G. Hyponatremia in older people as a sign of adrenal insufficiency: a case-control study. Intern Med J 2012; 42:306-310. 28. Samuels N, Zisk-Rony RY, Zevin S, Yinnon AM, Oberbaum M. Use of herbal medicine among patients hospitalized in a department of internal medicine. Accepted for publication. 29. Wiener-Well Y, Goffman I, Assous MV, Yinnon AM. The clinical significance of isolation of two different organisms from urine specimens of patients with an indwelling catheter. Submitted for publication. 30. Kassirer Y, Rudensky B, Zalut T, Yinnon AM. Improving adherence to blood culture sam- pling guidelines through educational intervention. Submitted for publication. 31. Sylvetsky N, Zehavi O, Raveh D, Henshke-Bar-Meir R, Yinnon AM, Zevin S. Impact of a monitoring unit in the medical department on patient outcome. Submitted for publication. 32. Amitai S, Assous MV, Lachish T, Kopuit P, Bdolah-Abram T, Yinnon AM, Wiener-Well Y. Impact on mortality of and risk factors for bacteriuria and urinary tract infection due to carbapenem-resistant Klebsiella pneumoniae. Submitted for publication. 33. Novoselsky Persky MA, Yinnon AM, Freier-Dror Y, Henshke R.. Communication between residents and attending physicians on call after hours. Submitted for publication. 19 Internal Medicine
    • 34. Zimmerman FS, Assous MV, Bdolah-Abram T, Lachish T, Yinnon AM, Wiener-Well Y. Dur- ing of carriage of carbapenem-resistant Enterobacteriaceae following hospital discharge. Submitted for publication. Research Report 2013 20
    • T he Department of Hematology, directed by Professor Jacob Rowe, is staffed by six senior physicians, two in- terns and two residents alongside a dedicated team of nurses.  The Department is a member of the National Cancer Institute in the United States, which was made possible through an affiliation with Northwestern University, a mem- ber of the Eastern Cooperative Oncology Group.  The primary diseases treated in the Department are leuke- mia, lymphoma and myeloma. The Department coordinates bone marrow transplants. At any given time, there are about twentyleukemiacasesbeingtreated,withthatnumberonthe constant rise – including an increasing number of referrals from other area hospitals. The Department of Hematology is well known for its extraordinary efforts and personal com- mitment to provide the highest level of care— which often involves procuring medications or specialized facilities that are not covered by third party insurers. Areas of Research Activity Studies are focused on translational clinical research. The De- partment is an affiliate of the Feinberg School of Medicine, Northwestern University in Chicago and as such enters pa- tientsintostudiesconductedbytheNationalCancerInstitute in the US through participation in the Eastern Cooperative Oncology Group. Currently a study on acute myeloid leuke- mia (AML) is being conducted to find a less toxic, but no less efficacious, regimen for the treatment of older patients with Department of Hematology 21 Hematology
    • this devastating disease. In a major phase III study the use of Clofarabine as a single agent is being evaluated. Patients who achieve a complete remission are evaluated , for the first time in a prospective genetically randomized manner, for the performance of a reduced-intensity al- logeneic transplantation. A prospective phase III study is also evaluating a less toxic induction regimen (5-azacytidine) for older patients who are unable to tolerate the rigors of standard induction therapy. Another major translational study involves a very early look at the bone marrow of patients receiving induction therapy for AML (on day 5) evaluating both the mor- phological and immunological characteristics to determine whether an earlier examination of thebonemarrowcanprovidemoreaccurateprognosticinformationand,thus,amoretailored therapy. The Hematology Department also participates in several phase II and III studies in multiple myeloma, diffuse-large cell lymphoma and chronic lymphocytic leukemia. New agents are be- ingstudiedinaphaseIIIstudyinmyelomaandweareparticipatinginaverylargeinternation- al phase III study evaluating the role of Rituximab, administered in varying routes. In chronic lymphocytic leukemia CLL), the Hematology department has become an important referral center in Israel for clinical, epidemiologic genetic and immunological research. Several major studies evaluating newer monoclonal antibodies and less toxic regimens for older patients are ongoing. Representative Research Determiningwhenapatientwithacuteleukemiaisrefractorytoprimarytherapyremainscon- troversial. Patients who do not respond fully to AML (induction therapy) are generally consid- eredasrefractoryandtheirpost-remissiontherapyisaltered.Inotherwords,suchpatientsare considered to be probably incurable with chemotherapy alone and are usually referred for an allogeneic transplant if a donor is available. Many publications have considered that patients who have residual leukemia in the middle of their induction therapy - typically on day 14 - also have a poor prognosis and all such patients are referred for an allogeneic transplantation, even if they have a complete response following the completion of induction therapy. Referring all such patients for an allogeneic transplantation clearly impacts on the morbidity and mortality of such patients. In a series of studies in the Eastern Oncology Group over the past two decades, all patients were evaluated on day 14 and if they had residual leukemia on day 14, a second cycle of induc- tion therapy was offered. Specifically, if a patient achieved a complete response to the first cycle or after a second cycle of therapy (in other words someone who needs 1 or 2 cycles to achieve complete remission), their subsequent post-remission therapy was not altered. Hence the decision as to the future course of action once patients went into complete remission was Research Report 2013 22
    • not altered by the fact that the bone marrow had residual leukemia early on day 14, provided the patient went into remission after the second cycle. The analysis showed that patients who achieved a complete remission after 1 or 2 cycles had an identical prognosis, in contrast to the prevailing view. Therefore, not all patients who have a positive bone marrow necessarily have a poor prognosis and provided they achieve remission with a second cycle, they have an identical prognosis as those who are in remission after only one cycle. Publications 1. Rowe JM. Optimal management of adults with ALL. Br. J Haematol 2009; 144:468-483. 2. Rowe JM. Closer to the truth in AML. Blood 2009; 113: 4129-4130. 3. Elhasid R, Leshem YA, Ben Arush MW, Rowe JM, Shehadeh N. Insulin-related metabo- lism following hematopoietic stem cell transplantation in childhood. Pediatr Diabetes 2009; 10:149-154. 23 Hematology
    • 4. Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wi- ernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia-chromosome positive acute lymphoblastic leukaemia confirms superiority of allogeneic transplant over chemotherapy in the pre-imatinib era: Results from the international ALL trial MRC UKALLXII/ECOG2993. Blood 2009; 113:4489-4496. 5. Gregory J, Kim H, Alonzo T, Gerbing R, Woods W, Weinstein H, Shepherd L, Schiffer C, Appelbaum F, Willman C, Wiernik P, Rowe J, Tallman M, Feusner J. Treatment of children with acute promyelocytic leukemia: Results of the first North American Intergroup trial INT0129. Pediatr Blood Cancer 2009; 53:1005-1010. 6. Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Socié G; ATG-Fresenius Trial Group (Finke J, Rowe JM,. Socié G.) Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol 2009; 10:855-864. 7. Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. 2009; 361:1249-1259. 8. Greenberg PL, Sun Z, Miller KB, Bennett JM, Tallman MS, Dewald G, Paietta E, van der Jagt R, Houston J, Thomas ML, Cella D, Rowe JM. Treatment of myelodysplastic syn- dromes patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase III trial by the Eastern Cooperative Oncology Group (E1996). 2009; 114:2393-400. 9. Avivi I, Avraham S, Koren-Miachelovitz M, Zuckerman T, Aviv A, Ofran Y, Benyamini N, Nagler A, Rowe JM, Nagler RM. Oral integrity and salivary profile in myeloma patients un- dergoing high-dose therapy followed by autologous SCT bone marrow transplant. Bone Marrow Transplantation 2009; 43:801-806. 10. Mansour MR, Sulis ML, Duke V, Foroni L, Jenkinson S, Koo K, Allen CG, Gale RE, Buck G, Richards S, Paietta E, Rowe JM, Tallman MS, Gold- stone AH, Ferrando AA, Linch DC. Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on Research Report 2013 24
    • the MRC UKALLXII/ECOG E2993 protocol. J Clin Oncol 2009; 27:4352-4356. 11. Tosello V, Mansour MR, Barnes K, Paganin M, Sulis ML, Jenkinson S, Allen CG, Gale RE, Linch DC, Palomero T, Real P, Murty V, Yao X, Richards SM, Goldstone A, Rowe J, Basso G, Wiernik PH, Paietta E, Pieters R, Horstmann M, Meijerink JP, Ferrando A. WT1 muta- tions in T-ALL. Blood 2009; 114:1038-1045. 12. Stroopinsky D, Avivi I, Rowe JM, Avigan D, Katz T. Allogeneic induced human FOXP3+IFN- g+ T cells exhibit selective suppressive capacity. Eur. J Immunol 2009; 39:2703-15. 13. Zuckerman T, Rowe JM. Hematopoietic stem cell transplantation for adults with acute lymphoblastic leukemia. Curr Opin Hematol 2009; 16:453-459. 14. Rowe JM. Optimal induction and post–remission therapy for AML in first complete remis- sion. Hematology American Society of Hematology Education Program 2009; 396-405. 15. Goldstone AH, Rowe JM. Transplantation in adult ALL. Hematology American Society of Hematology Education Program 2009; 593-600. 16. Rowe JM. Is there a role for intensifying induction therapy in acute myeloid leukemia (AML)? Best Pract Res Clin Haematol 2009; 22: 475-478. 17. Rowe JM. Advances and controversies in the biology and therapy of acute leukemia and myelodysplasia. Best Pract Res Clin Haematol 2009; 22: 509-515. 18. Fernandez HF, Rowe JM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. Letter. NEJM 2009; 361:2578. 19. Marks DI, Paietta EM, Moorman AV, Richards SM, Buck G, Dewald G, Ferrando A, Field- ing AK, Goldstone AH, Ketterling RP, Litzow MR, Luger SM, McMillan AK, Mansour M, Rowe JM, Tallman MS, Lazarus HM. T-cell acute lymphoblastic leukemia in adults: clini- cal features, immunophenotype, cytogenetics and outcome from the large randomised prospective trial (UKALL XII/ECOG 2993). Blood 2009; 114:5136-5145. 20. Hochhaus A, O’Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, Goldman JM, Müller MC, Radich JP, Rudoltz M, Mone M, Gathmann I, Larson RA; IRIS Investigators. (Hughes TP, Rowe J, Sentini V). Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009; 23:1054-1061. 25 Hematology
    • 21. Hershko C, Ronson A. Iron deficiency, helicobacter infection and gastritis. Acta Haematol 2009; 122:97-102. 22. Cortes JE, Baccarani M, Guilhot F, Druker BJ, Branford S, Kim DW, Pane F, Pasquini R, Goldberg SL, Kalaycio M, Moiraghi B, Rowe JM, Tothova E, De Souza C, Rudoltz M, Yu R, Krahnke T, Kantarjian HM, Radich JP, Hughes TP. Phase III, Randomized, Open-Label Study of Daily Imatinimb Mesylate 400 mg Versus 800 mg in Patients With Newly Diag- nosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase Using Molecu- lar End Points: Tyrosine Kinase Inhibitor Optimization and Selectivity Study. J Clin Oncol 2010; 28:424-430. 23. Litzow MR, Othus M, Cripe LD, Gore SD, Lazarus HM, Lee SJ, Bennett JM, Paietta EM, Dewald GW, Rowe JM, Tallman MS; for the Eastern Cooperative Oncology Group Leu- kemia Committee. Failure of three novel regimens to improve outcome for patients with relapsed or refractory acute myeloid leukaemia: a report from the Eastern Cooperative Oncology Group. Br J Haematol 2010; 148:217-225. 24. Fernandez HF, Rowe JM. Induction therapy in acute myeloid leukemia: intensifying and targeting the approach. Curr Opin Hematol 2010; 17:79-84. 25. Elhasid R, Rowe JM. Hematopoietic stem cell transplantation in neutrophil disorders: severe congenital neutropenia, leukocyte adhesion deficiency in chronic granulomatous disease. Clin Rev Allergy Immunol 2010; 38:61-67. 26. Elhasid R, Kilic SS, Ben-Arush M, Etzioni A, Rowe JM. Prompt recovery of recipient he- matopoiesis after two consecutive haploidentical peripheral blood SCTs in a child with leukocyte adhesion defect III syndrome. Bone Marrow Transplant 2010; 45:413-414. 27. Van Vlierberghe P, Palomero T, Khiabanian H, Van der Meulen J, Castillo M, Van Roy N, De Moerloose B, Philippé J, González-García S, Toribio ML, Taghon T, Zuurbier L, Cauwelier B, Harrison CJ, Schwab C, Pisecker M, Strehl S, Langerak AW, Gecz J, Sonneveld E, Pieters R, Paietta E, Rowe JM, Wiernik PH, Benoit Y, Soulier J, Poppe B, Yao X, Cordon- Cardo C, Meijerink J, Rabadan R, Speleman F, Ferrando A. PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat Genet 2010;42:338-342. 28. Rowe JM. Getting to the root of (it) ALL. Blood 2010; 115:3649-3650. 29. Dann EJ, Bar-Shalom R , Tamir A, Epelbaum R, Avivi I, Ben-Shachar M, Gaitini D, Rowe JM. Dynamic Scoring Model to Elucidate the Significance of Post-induction Interim Research Report 2013 26
    • F18FDG-PET/CT Scanning in Patients with Hodgkin Lymphoma.Haematologica 2010; 95:1198-206. 30. Lavi R, Rowe JM, Avivi I. Lumbar Puncture: It Is Time to Change the Needle. Eur Neurol 2010; 64:108-113. 31. Pe’er J, Rowe JM, Frenkel S, Dann EJ. Testicular lymphoma, intraocular (vitreoretinal) lymphoma, and brain lymphoma: involvement of three immunoprivileged sites in one pa- tient. Am J Hematol 2010; 85:631-633. 32. Porter DL, Alyea EP, Antin JH, Delima M, Estey E, Falkenburg JH, Hardy N, Kroeger N, Leis J, Levine J, Maloney DG, Peggs K, Rowe JM, Wayne AS, Giralt S, Bishop MR, van Besien K. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Com- mittee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2010;16(11):1467-503. Epub 2010 33. NCI First International Workshop on the Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2010; 16(11):1467-503. 34. Rowe JM. Prognostic Factors in Adult Acute Lymphoblastic Leukaemia. Br J Haematol 2010; 150(4):389-405. 35. Tallman M, Douer D, Gore S, Powell BL, Ravandi F, Rowe JM, Ranganathan A, Sanz MA. Treatment of Patients with Acute Promyelocytic Leukemia: A Consensus Statement on Risk-Adapted Approaches to Therapy. Clinical Lymphoma, Myeloma & Leukemia 2010;10(3) S122-S126. 36. De Keersmaecker K, Real PJ, Gatta GD, Palomero T, Sulis ML, Tosello V, Van Vlierberghe P, Barnes K, Castillo M, Sole X, Hadler M, Lenz J, Aplan PD, Kelliher M, Kee BL, Pandolfi PP, Kappes D, Gounari F, Petrie H, Van der Meulen J, Speleman F, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Soulier J, Avran D, Cavé H, Dastugue N, Raimondi S, Meijerink JP, Cordon-Cardo C, Califano A, Ferrando AA. The TLX1 oncogene drives aneuploidy in T cell transformation. Nat Med 2010; 16(11):1321-1327. 37. Wiernik PH, Dutcher JP, Yao X, Venkatraj U, Falkson CI, Rowe JM, Cassileth PA. Phase II Study of Interleukin-4 in Indolent B-cell Non-Hodgkin Lymphoma and B-cell Chronic 27 Hematology
    • Lymphocytic Leukemia: A Study of the Eastern Cooperative Oncology Group (E5Y92). J Immunother 2010; 33(9):1006-1009. 38. Cripe LD, Uno H, Paietta EM, Litzow MR, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Luger S, Tallman MS. Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled, trial of the Eastern Cooperative Oncology Group (ECOG 3999). Blood 2010; 116(20):4077-4085. 39. Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and over-all survival for adults with acute promyelocytic leu- kemia: North American Leukemia Intergroup Study C9710. Blood 2010; 116(19):3751-7. 40. Elhasid R, Krivoy N, Rowe JM, Sprecher E, Adler L, Elkin H, Efrati E. Influence of gluta- thione S-transferase A1, P1, M1, T1 polymorphisms on oral busulfan pharmacokinetics in children with congenital hemoglobinopathies undergoing hematopoietic stem cell trans- plantation. Pediatr Blood Cancer 2010; 55(6):1172-9. 41. Rowe JM. The evolving paradigm of prognostic factors in AML: Introduction to the Acute Leukemia Forum 2010. Best Pract Res Clin Haematol 2010;23(4):453-6. 42. Tallman M, Douer D, Gore S, Powell BL, Ravandi F, Rowe J, Ranganathan A, Sanz MA. Treatment of patients with acute promyelocytic leukemia: a consensus statement on risk- adapted approaches to therapy. 2010;10:S122-6. 43. Rowe JM, Kim HT, Cassileth PA, Lazarus HM, Litzow MR, Wiernik PH, Tallman MS. Adult patients with acute myeloid leukemia who achieve complete remission after one or two cycles of induction have a similar prognosis: A report on 1,980 patients registered to six studies conducted by the Eastern Cooperative Oncology Group. Cancer 2010; 116(21):5012-21. 44. Elhasid R, Krivoy N, Rowe JM, Sprecher E, Efrati E. Glutathione S-transferase T1-null seems to be associated with graft failure in hematopoietic SCT. Bone Marrow Transplant 2010; 45(12):1728-31. 45. Gupta V, Tallman MS, He W, Logan BR, Copelan E, Gale RP, Khoury HJ, Klumpp T, Koreth J, Lazarus HM, Marks DI, Martino R, Rizzieri DA, Rowe JM, Sabloff M, Waller E, Dipersio JF, Bunjes DW, Weisdorf DJ. Comparable survival after HLA-well-matched unrelated or Research Report 2013 28
    • matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis. Blood 2010; 16;116(11):1839-48. 46. Rowe JM, Tallman MS. How I treat acute myeloid leukemia. Blood 2010; 116(17):3147- 56. 47. Mesa RA, Yao X, Cripe LD, Li CY, Litzow M, Paietta E, Rowe JM, Tefferi A, Tallman MS. Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase-2 trial E4903. Blood 2010; 116(22):4436-8. 48. Tallman MS, Kim HT, Montesinos P, Appelbaum FR, de la Serna J, Bennett JM, Deben G, Bloomfield CD, Gonzalez J, Feusner JH, Gonzalez M, Gallagher R, Gonzalez-San Miguel JD, Larson RA, Milone G, Paietta E, Rayon C, Rowe JM, Rivas C, Schiffer CA, Vellenga E, Shepherd L, Slack JL, Wiernik PH, Willman CL, Sanz MA. Does microgranular variant morphology of acute promyelocytic leukemia independently predict for a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group. Blood 2010; 116(25):5650-9. 49. Koren-Michowitz M, le Coutre P, Duyster J, Scheid C, Panayiotidis P, Prejzner W, Rowe JM, Schwarz M, Goldschmidt N, Nagler A. Activity and tolerability of nilotinib: a retrospec- tive multicenter analysis of chronic myeloid leukemia patients who are imatinib resistant or intolerant. Cancer 2011; 117(1):230. 50. Zuckerman T, Benyamini N, Sprecher H, Fineman R, Finkelstein R, Rowe JM, Oren I. SCT in patients with carbapenem resistant Klebsiella pneumoniae: a single center experience with oral gentamicin for the eradication of carrier state. 2011; 46(9):1226-30. 51. Rowe JM. Interpreting data on transplant selection and outcome in adult acute lympho- blastic leukemia (ALL). Biol Blood Marrow Transplant 2011; 17: 576-583. 52. Ofran Y, Rowe JM. Induction and postremission strategies in acute myeloid leukemia: what is new? Curr Opin Hematol 2011;18(2):83-8. 53. Rowe JM. Maintenance therapy in AML with emphasis on the immunotherapeutic options. Ann Hematol 2011; 90:525-530. 54. Fernandez HF, Sun Z, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald G, Ket- terling RP, Rowe JM, Lazarus HM, Tallman MS. Autologous transplantation gives en- couraging results for young adults with favorable-risk acute myeloid leukemia but is 29 Hematology
    • not improved with gemtuzumab ozogamicin. Blood 2011; 117(20):5306-13. 55. Buyse M, Squifflet P, Lucchesi KJ, Brune ML, Castaigne S, Rowe JM. Assessment of the consistency and robustness of results from a multicenter trial of remission maintenance therapy for acute myeloid leukemia. Trials 2011; 12:86. 56. Buyse M, Michiels S, Suqifflet P, Lucchesi K, Hellstrand K, Brune ML, Castaigne S, Rowe JM. Leukemia-free survival as a surrogate endpoint for overall survival in the evalu- ation of maintenance therapy for patients with acute myeloid leukemia in complete remis- sion. Haematologica 2011; 96(8); 1106-12. 57. Rowe JM, Ganzel C. Management of acute lymphoblastic lymphoma in adults. Hematol- ogy Education, Education program for annual congress of the European Hematology As- sociation 2011; 5(1): 9-19. 58. Park JH, Qiao B, Panageas KS, Schymura MJ, Jurcic JG, Rosenblat TL, Altman JK, Douer D, Rowe JM, Tallman MS. Early death rate in acute promyelocytic leukemia re- mains high despite all-trans retinoic acid. Blood 2011; 118(5): 1248-54. 59. Ganzel C, Rowe JM, Ruchlemer R. Primary effusion lymphoma in a HIV-negative patient associated with hypogammaglobulinemia. Am J Hematol 2011; 86(9):777-81. 60. Avivi I, Fineman R, Haddad N, Katz T, Oren I, Rowe JM, Zuckerman T. Fatal Kaposi sar- coma after allogeneic stem cell transplant. Leuk Lymphoma 2011; 52(12):2402-4. 61. Ganzel C, Rowe JM. Prognostic factors in adult acute leukemia. Hematol Oncol Clin North Am 2011; 25(6):1163-87. 62. Khalil A, Ben Barak A, Zaidman i, Elhasid R, Rowe JM, Ben-Arush M. Polyserositis as a Manifestation of Graft-Versus-Host Disease. Pediactric Hematology and Oncology 2011; 28:691-693. 63. Rowe JM. Evaluation Of Prognostic Factors In AML. Best Practice & Research Clinical Haematology 2011; 24: 485-488. 64. Van Vlierberghe P, Ambesi-Impiombato A, Perez-Garcia A, Haydu JE, Rigo I, Hadler M, Tosello V, Della Gatta G, Paietta E, Racevskis J, Wiernik PH, Luger SM, Rowe JM, Rue M, Ferrando AA. ETV6 mutations in early immature human T cell leukemias. J Exp Med 2011; 208(13):2571-9. Research Report 2013 30
    • 65. Smith MR, Neuberg D, Flinn IW, Grever MR, Lazarus HM, Rowe JM, Dewald G, Bennett JM, Paietta EM, Byrd JC, Hussein MA, Appelbaum FR, Larson RA, Litzow MR, Tallman MS. Incidence of therapy-related myeloid neoplasia after initial therapy for chronic lympho- cytic leukemia with fludarabine-cyclophosphamide versus fludarabine: long-term follow- up of US Intergroup Study E2997. Blood 2011; 29;118(13):3525-7. 66. Bairey O, Ruchlemer R, Rahimi-Levene N, Herishanu Y, Braester A, Berrebi A, Polliack A, Klepfish A,Shvidel L. Israeli CLL Study Group (ICLLSG). Presenting features and out- come of chronic lymphocytic leukemia patients diagnosed at age 80 years or more. An ICLLSG study. Ann Hematology 2011; 90:1123-9, 2011. 67. Avivi I, Hardak E, Shaham B, Igla M, Rowe JM, Dann EJ. Low incidence of long-term re- spiratory impairment in Hodgkin lymphoma survivors. Ann Hematol. 91(2); 215-21, 2012. 68. Armand P, Kim HT, Zhang MJ, Perez WS, Dal Cin PS, Klumpp TR, Waller EK, Litzow MR, Liesveld JL, Lazarus HM, Artz AS, Gupta V, Savani BN, McCarthy PL, Cahn JY, Schouten HC, Finke J, Ball ED, Aljurf MD, Cutler CS, Rowe JM, Antin JH, Isola LM, Di Bartolomeo P, Camitta BM, Miller AM, Cairo MS, Stockerl-Goldstein K, Sierra J, Savoie ML, Halter J, Stiff PJ, Nabhan C, Jakubowski AA, Bunjes DW, Petersdorf EW, Devine SM, Maziarz RT, Bornhauser M, Lewis VA, Marks DI, Bredeson CN, Soiffer RJ, Weisdorf DJ. Classifying Cy- togenetics in Patients with Acute Myelogenous Leukemia in Complete Remission Under- going Allogeneic Transplantation: A Center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant 2012; 18(2);280-8. 69. Dann EJ, Blumenfeld Z, Bar-Shalom R, Avivi I, Ben-Shachar M, Goor O, Libster D, Gaitini D, Rowe JM, Epelbaum R. A 10-year experience with treatment of high and standard risk Hodgkin disease: Six cycles of tailored BEACOPP, with interim scintigraphy, are effective and female fertility is preserved. Am J Hematol 2012; 87(1):32-6. 70. Hardak E, Oren I, Dann EJ, Yigla M, Faibish T, Rowe JM, Avivi I. The Increased Risk for Pneumocystis Pneumonia in Patients Receiving Rituximab-CHOP-14 Can Be Prevented by the Administration of Trimethoprim/Sulfamethoxazole: A Single-Center Experience. Acta Haematol 2012; 127(2):110-4. 71. Ofran Y, Rowe JM. Treatment for relapsed acute myeloid leukemia: what is new? Curr Opin Hematol 2012; 19(2):89-94. 72. Ntziachristos P, Tsirigos A, Vlierberghe PV, Nedjic J, Trimarchi T, Flaherty MS, Ferres- Marco D, da Ros V, Tang Z, Siegle J, Asp P, Hadler M, Rigo I, Keersmaecker KD, Patel 31 Hematology
    • J, Huynh T, Utro F, Poglio S, Samon JB, Paietta E, Racevskis J, Rowe JM, Rabadan R, Levine RL, Brown S, Pflumio F, Dominguez M, Ferrando A, Aifantis I. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med 2012; 6;18(2):298-303. 73. Stroopinsky D, Katz T, Rowe JM, Melamed D, Avivi I. Rituximab-induced direct inhibition of T-cell activation. Cancer Immunol Immunother 2012; 61(8):1233-41. 74. Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer 2012. In press. 75. 352. Ganzel C, Becker J, Mintz PD, Lazarus HM, Rowe JM. Hyperleukocytosis, leukosta- sis and leukapheresis: practice management. Blood Rev 2012; 26(3):117-22. 76. Sive JI, Buck G, Fielding A, Lazarus HM, Litzow MR, Luger S, Marks DI, McMillan A, Moor- man AV, Richards SM, Rowe JM, Tallman MS, Goldstone AH. Outcomes in older adults with acute lymphoblastic leukemia (ALL): results from the international MRC UKALL XII/ ECOG2993 trial. Br J Haematol 2012; 157(4):463-71. 77. Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, Van Vlierberghe P, Dolgalev I, Thomas S, Aminova O, Huberman K, Cheng J, Viale A, Socci ND, Heguy A, Cherry A, Vance G, Higgins RR, Ketterling RP, Gallagher RE, Litzow M, van den Brink MR, Lazarus HM, Rowe JM, Luger S, Ferrando A, Paietta E, Tallman MS, Melnick A, Abdel- Wahab O, Levine RL. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 22; 366(12):1079-89. 78. Della Gatta G, Palomero T, Perez-Garcia A, Ambesi-Impiombato A, Bansal M, Carpenter ZW, De Keersmaecker K, Sole X, Xu L, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Mei- jerink JP, Califano A, Ferrando AA. Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL. Nat Med 2012; 26;18(3):436- 40. 79. Samon JB, Castillo-Martin M, Hadler M, Ambesi-Impiombato A, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Jakubczak JL, Randolph S, Cordon-Cardo C, Ferrando AA. Pre- clinical analysis of the gamma-secretase inhibitor PF-03084014 in combination with gluco- corticoids in T - cell acute lymphoblastic leukemia. Mol Cancer Ther 2012; 11(7):1565-75. Research Report 2013 32
    • 80. Haydu JE, De Keersmaecker K, Duff MK, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Ferrando A. An activating intragenic deletion in NOTCH1 in human T-ALL. Blood 2012; 119(22):5211-4. 81. Shlush LI, Chapal-Ilani N, Adar R, Pery N, Maruvka Y, Spiro A, Shouval R, Rowe JM, Tzukerman M, Bercovich D, Izraeli S, Marcucci G, Bloomfield CD, Zuckerman T, Skorecki K, Shapiro E. Cell lineage analysis of acute leukemia relapse uncovers the role of replica- tion-rate heterogeneity and miscrosatellite instability. Blood 2012; 120(3):603-12. 82. Zuckerman T, Rowe JM. Concise guide to hematology. Eds. Schmaier AH, Lazarus HM. Blackwell 2012; 235-250. 83. Ruchlemer R. Two genes, tipifarnib, and AML. Blood 2012; 119:2-3. 84. Shvidel L, Braester A, Bairey O, Rahimi-Levene N, Herishanu Y, Tadmor T, Klepfish A, Ruchlemer R, Shtalrid M, Berrebi A, Polliack A; on behalf of the Israeli CLL Study Group. (2012) Cell surface expression of CD25 antigen (surface IL-2 receptor alpha-chain) is not a prognostic marker in chronic lymphocytic leukemia: results of a retrospective study of 281 patients. Ann Hematol 2012. In press. 85. Zuckerman T, Ganzel C, Tallman MS, Rowe JM. How I treat hematologic emergencies in adults with acute leukemia. Blood 2012. In press. 86. Ganzel C, Rowe JM. Total ambulatory hemato-oncological care - a myth or reality? Leuk Lymphoma 2012. In press. 87. Ganzel C, Rowe JM. Total ambulatory hemato-oncological care - a myth or reality? Leuk Lymphoma 2012. In press. 88. Duarte RF, Canals C, Onida F, Olavarria E, Arcese W., Ferrant A., Narni F., Lambertenghi G., Bacigalupo A., Bunjes D., Rowe J.M., Schmitz N., Sureda A. HLA-Identical Allogeneic Stem Cell Transplantation (alloSCT) for Patients With Primary Cutaneous T-Cell Lymphoma (CTCL): A Retrospective Analysis of the Lymphoma Working Party of the European Blood and Marrow Transplantation Group (EBMT-LWP). 2009 Bone Marrow Transplant Tandem Meetings. Tampa, Florida, February, 2009. Biology of Blood and Marrow Transplantation 15 (Suppl. 2): 53a. 89. 267. Avigan D., Rosenblatt J., Vasir B., Wu Z., Bissonnette A., Somaiya P., MacNamara C., Uhl L., Avivi I., Katz T., Zarwan C., Joyce R., Levine J.D., Lowe K., Dombagoda D., 33 Hematology
    • Tzachanis D., Boussiotis V., Giallombardo N., Mortellite J., Conway K., Fitzgerald D., Rich- ardson P., Anderson K., Munshi N., Rowe JM, Tsumer M., Bishart L., Kufe D. Fusion Cell Vaccination In Conjunction With Stem Cell Transplantation Is Well Tolerated, Induces Anti- Tumor Immunity and Is Associated With Responses In Patients With Multiple Myeloma. 2009 Bone Marrow Transplant Tandem Meetings. Tampa, Florida, February, 2009. Biol- ogy of Blood and Marrow Transplantation 2009; 15 (Suppl. 2): 174a,. 90. 268. Duarte R.F., Canals C. , Onida F., Olavarría E., Arcese W., Ferrant A., Narni F., Lambertenghi Deliliers G. , Bacigalupo A., Bunjes D. , Rowe J.M., Schmitz N., Sureda A. HLA-identical allogeneic stem cell transplantation for patients with primary cutaneous T-cell lymphoma: a retrospective analysis of the Lymphoma Working Party of the European Blood and Marrow Transplantation Group. Thirty fifth annual meeting of the European Group for Blood and Marrow Transplantation (EBMT). Göteborg, Sweden, March 2009. Bone Marrow Transplantation 2009; 43(Suppl. 1), 259a. 91. 269. Elhasid R, Efrati E, Khalil A., Stein J., Zaidman I., Ben Arush M., Rowe J.M., Krivoy N. Allogeneic transplantation using adjusted blood busulfan levels results in a very low incidence of veno-occlusive disease, irrespective of the presence of the glutathione S- transferase M1 null genotype. Thirty fifth annual meeting of the European Group for Blood and Marrow Transplantation (EBMT). Göteborg, Sweden, March 2009. Bone Marrow Transplantation 2009; 43 (Suppl. 1): 802a. 92. Zuckerman T., Benyamini N. , Haddad N., Fineman R. , Avivi I., Sabo E., Rowe J.M., Oren I. Emergence of uncommon infection in bone marrow transplantation: the modern Trojan horse? Thirty fifth annual meeting of the European Group for Blood and Marrow Transplantation (EBMT). Göteborg, Sweden, March 2009. Bone Marrow Transplantation 2009; 43(Suppl. 1): 884a. 93. Fernandez HF, Sun Z, Litzow MR, Luger SM, Paietta EM, Dewald G, Ketterling R, Rowe JM, Lazarus, HM, Tallman MS. A randomized trial of anthracycline dose intensifica- tion during induction of younger patients with acute myeloid leukemia: Results of Eastern Cooperative Oncology Group study E1900. Forty fifth Annual Meeting of the American Society of Oncology. Orlando, FL, May 2009. J Clin Oncol 2009; 27 (15s): 7003a. 94. Dann EJ, Badian A, Stravets T, Kertsman E, Phenklbaum S, Zuckerman T, Haddad N, Elhasid R, Bonstein L, Rowe J.M. Extracorporeal photochemotherapy for acute and chronic GVHD, a report of 102 patients treated in a single institution. Fourteenth Congress of the European Hematology Association, Berlin, Germany, June 2009. Haematologica 2009; 94: 0550a. Research Report 2013 34
    • 95. Brune L, Rowe JM, Buyse ME, Squifflet P, Castaigne S, Allard SE, Hellstrand K. Six-year outcomes update from a randomized phase 3 trial in AML: durable effect of remission maintenance immunotherapy with histamine dihydrochloride and low-dose IL-2. Four- teenth Congress of the European Hematology Association, Berlin, Germany, June 2009. Haematologica 2009; 94: 0845a. 96. Rosenblatt J, Avivi I, Vasir B, Katz T, Uhl L, Wu Z, Somaiya P, Mills H, Joyce R, Levine JD, Tzachanis D, Boussiotis V, Glotzbecker B, Francoeur K, Dombagoda D, Tsumer M, Bisharat L, Giallombardo N, Conway K, Fitzgerald D, Barhad R, Richardson P, Anderson KC, Munshi NC, Rowe JM, Kufe D, Avigan D. Dendritic Cell Tumor Fusion Vaccination in Conjunction with Autologous Transplantation for Multiple Myeloma. Fifty first annual meet- ing of the American Society of Hematology, New Orleans, LA, December 2009. Blood 2009; 114: 783a. 97. Elhasid R, Zaidman I, Khalil A, Zuckerman T, Haddad N, Katz T, Ben Arush M, Rowe JM. Allogeneic Stem Cell Transplantation in Congenital Hemoglobinopathies –  A Curative Ap- proach When Performed as a Primary Therapeutic Modality: A Single Center Experience. Fifty first annual meeting of the American Society of Hematology, New Orleans, LA, De- cember 2009. Blood 2009;114: 1144a. 98. Dann E, Bar-Shalom R, Tamir A, Ben-Shachar M, Avivi I, Zuckerman T, Haddad N, Rosen- baum H, Fineman R, Goor O, Libster D, Blumenfeld Z, Rowe JM, Epelbaum R. For Stan- dard and High-Risk Patients with Hodgkin Lymphoma Six Cycles of Tailored BEACOPP, Based On Interim Scintigraphy, Are Effective and Female Fertility Is Preserved. Fifty first annual meeting of the American Society of Hematology, New Orleans, LA, December 2009. Blood 2009;114: 1552a. 99. O’Brien S, Schiller G, Damon LE, Lister J, Ravandi F, Douer D, Masood A, Ben-Yehuda D, Rowe JM, Gökbuget N, Aulitzky W, Stock W, Coutre S, Heffner L, Larson ML, Seiter K, Hagey AE, Deitcher SR, Kantarjian HM. Pivotal Phase 2 Study of Weekly Vincristine Sulfate Liposomes Injection (VSLI, Marqibo®) in Adults with Philadelphia Chromosome- Negative Acute Lymphoblastic Leukemia (ALL) in Second Relapse or Progressing Follow- ing Two Anti‑leukemia Treatment Lines. Fifty first annual meeting of the American Society of Hematology, New Orleans, LA, December 2009. Blood 2009;114: 3088a. 100. Koren-Michowitz M, le Coutre PD, Duyster J, Scheid C, Panayiotidis P, Prejzner W, Rowe JM, Schwarz M, Goldschmidt N, Nagler A. Prior Response to Imatinib Predicts Response to Second Line Treatment with Nilotinib in CML Patients Resistant or Intol- erant to Imatinib. Fifty-first annual meeting of the American Society of Hematology, 35 Hematology
    • New Orleans, LA, December 2009. Blood 2009; 114: 3297a. 101. Fernandez HF, Sun Z, Litzow MR, Luger SM, Paietta EM, Dewald GW, Ketterling RP, Ben- nett JM, Rowe JM, Lazarus HM, Tallman MS. Autologous Hematopoietic Cell Transplan- tation as Consolidation for Younger Patients with Acute Myeloid Leukemia in First Com- plete Remission: Follow-up of E1900. Fifty-first annual meeting of the American Society of Hematology, New Orleans, LA, December 2009. Blood 2009;114: 3405a. 102. Witzens-Harig M, van Hazel G, Chamone DFA, Ruffert K, Rowe JM, Lazzarino M, Foà R, Poddubnaya R, Ho AD, Ivanova V, Vranowsky A, Hipp J, Oertel S. Safety and Efficacy in Patients Receiving Maintenance Rituximab for Follicular Lymphoma: Early Results From Phase IIIb MAXIMA Trial. Fifty-first annual meeting of the American Society of Hematology, New Orleans, LA, December 2009. Blood 2009;114: 3756a. 103. Rosenblatt J, Avivi I, Vasir B, Katz T, Uhl L, Wu Z, Somaiya P, Mills H, Joyce RM, Levine JD, Tzachanis D., Boussiotis V, Glotzbecker B, Francoeur K, Dombagoda D, Tsumer M, Bisharat L, Giallombardo N, Conway K, Fitzgerald D, Barhad R, Richardson P, Anderson KC, Munshi N, Rowe JM, Kufe D, Avigan D. Dendritic cell fusion vaccination in conjunc- tion with autologous transplantation for multiple myeloma. 2010 BMT Tandem Meetings, Orlando, Florida, February 2010. Biol Blood Marrow Transplant 2010;16:65a. 104. Fielding AK, Buck G, Lazarus HM, Litzow MR, Luger S, Marks DI, McMillan A, Moorman AV, Paietta E, Richards SM, Tallman MS, Rowe JM, Goldstone AH. Imatinib Significantly Enhances Long-Term Outcomes. In Philadelphia Positive Acute Lymphoblastic Leukae- mia; Final Results of the UKALLXII/ECOG2993 Trial. Fifty-second annual meeting of the American Society of Hematology, Orlando, FL, December 2010. Blood 2010;116: 169a. 105. Shlush LI, Chapal N, Adar R, Izraeli S, Rowe JM, Skorecki K, Shapiro E, Zuckerman T. Single-Cell Phylogenetic analysis provides Novel Insight Into Resistance Mechanisms In AML. Fifty-second annual meeting of the American Society of Hematology, Orlando, FL, December 2010. Blood 2010; 116:178a. 106. De Keersmaecker K, Real PJ, Della Gatta G, Palomero T, Sulis ML, Tosello V, Van Vlierber- ghe P, Barnes K, Castillo M, Sole X, Hadler M, Lenz J, Aplan P, Kelliher M, Kee BL, Pandolfi PP, Kappes D, Gounari F, Petrie H, Van der Meulen J, Speleman F, Paietta E, Racevskis J, Tallman M, Rowe JM, Soulier J, Avran D, Cavé H, Dastugue N, Raimondi SC, Meijerink J, Cordon-Cardo C, Califano A, Ferrando A. BCL11B Mutations In T-Cell Acute Lympho- blastic Leukemia. Fifty second annual meeting of the American Society of Hematology, Orlando, FL, December 2010. Blood 2010; 116: 471a. Research Report 2013 36
    • 107. Sive JI, Buck G, Fielding A, Lazarus HM, Litzow MR, Luger S, Marks DI, McMillan A, Rich- ards SM, Rowe JM, Tallman MS, Goldstone AH. Inability to Tolerate Standard Therapy Is a Major Reason for Poor Outcome In Older Adults with Acute Lymphoblastic Leukemia (ALL): Results From the International MRC/ECOG Trial. Fifty-second annual meeting of the American Society of Hematology, Orlando, FL, December 2010. Blood 2010;116: 493a, . 108. Litzow MR, Buck G, Dewald G, Fielding A, Ketterling R, Lazarus HM, Luger S, Marks DI, McMillan A, Moorman AV, Paietta E, Richards SM, Rowe JM, Tallman MS, Goldstone AH. Outcome of 1,229 Adult Philadelphia Chromosome Negative B Acute Lymphoblastic Leu- kemia (B-ALL) Patients (pts) From the International UKALLXII/E2993 Trial: No Difference In Results Between B Cell Immunophenotypic Subgroups. Fifty-second annual meeting of the American Society of Hematology, Orlando, FL, December 2010. Blood 2010; 116: 524a. 109. Strickland SA, Sun Z, Ketterling RP, Cherry AM, Cripe LD, Dewald G, Higgins RR, Lazarus HM, Litzow MR, Luger SM, Paietta E, Rowe JM, Uno H, Vance GH, Tallman MS. Mono- somal Karyotype (MK) In Older Patients with Acute Myeloid Leukemia (AML) on Eastern Cooperative Oncology Group (ECOG) Therapeutic Trials: Poor Prognostic Impact of MK, but Not of Monosomy 7. Fifty-second annual meeting of the American Society of Hema- tology, Orlando, FL, December 2010. Blood 2010;116:579a. 110. Armand F, Perez W, Zhang M-J, Kim H, Klumpp TR, Dal Cin P, Waller EK, Litzow MR, Lies- veld JL, Lazarus HM, Artz A, Gupta V, Savani BN,. McCarthy PL, Cahn J-Y, Schouten H, Finke J, Ball ED, Aljurf M, Cutler C, Rowe JM, Antin JH, Isola LM, Di Bartolomeo P, Camitta B, Miller AM, Cairo MS, Stockerl-Goldstein KE, Sierra J, Savoie ML, Halter J, Stiff PJ, Nabhan C, Jakubowski AA, Bunjes D, Petersdorf EW, Devine SM, Maziarz R, Bornhauser M, Lewis VA, Marks DI, Bredeson CH, Soiffer R, Weisdorf DJ. Cytogenetics Abnormalities Predict the Outcome of Allogeneic Transplantation In AML: A CIBMTR Study. Fifty-second annual meeting of the American Society of Hematology, Orlando, FL, December 2010. Blood 2010;116 :680a. 111. Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A Multi-Center Prospective Randomized Study Comparing Ibritumomab Tiux- etan (Zevalin) and High-Dose BEAM Chemotherapy (Z-BEAM) Vs. BEAM Alone as the Conditioning Regimen Prior to Autologous Stem-Cell Transplantation In Patients with Ag- gressive Lymphoma; Possible Advantage for Z-BEAM In Low-Risk Patients. Fifty-second annual meeting of the American Society of Hematology, Orlando, FL, December 2010. Blood 2010; 116: 686a. 37 Hematology
    • 112. Patel JP, Abdel-Wahab O, Gonen M, Figueroa ME, Fernandez HF, Sun Z, Racevskis J, Van Lierberghe P, Dolgalev I, Cheng J, Viale A, Socci N, Heguy A, Ketterling R, Gallagher RE, Litzow MR, Rowe JM, Ferrando A, Paietta E, Tallman MS, Melnick RM, Levine R. High-Throughput Mutational Profiling In AML: Mutational Analysis of the ECOG E1900 Trial. Fifty-second annual meeting of the American Society of Hematology, Orlando, FL, December 2010. Blood 2010;116: 851a. 113. Geng H, Neuberg D, Paietta E, Deng X, Li Y, Xin Y, Racevskis J, Ketterling R, Richards SM, Tallman MS, Rowe JM, Litzow MR, Elemento O, Melnick AM. Integrative Genome-Wide DNA Methylation and Gene Expression Analysis Reveals Biological and Clinical Insights In Adult Acute Lymphoblastic Leukemia. Fifty-second annual meeting of the American Soci- ety of Hematology, Orlando, FL, December 2010. Blood 2010; 116: 852a. 114. Park JH, Panageas KS, Schymura MJ, Qiao B, Jurcic JG, Rosenblat TL, Altman JK, Douer D, Rowe JM, Tallman MS. A Population-Based Study In Acute Promyelocytic Leukemia (APL) Suggests a Higher Early Death Rate and Lower Overall Survival Than Commonly Reported In Clinical Trials: Data From the Surveillance, Epidemiology, and End Results (SEER) Program and the New York State Cancer Registry In the United States Between 1992–2007. Fifty-second annual meeting of the American Society of Hematology, Or- lando, FL, December 2010. Blood 2010;116: 872a. 115. Smith MR, Neuberg D, Flinn IW, Grever MR, Bennett JM, Dewald G, Paietta EM, Litzow MR, Rowe JM, Lucas D, Kitada S, Jelinek DF, Gribben JG, Byrd JC, Reed JC, Hus- sein MA, Appelbaum FR, Larson RA, Moore DF, Jr, Tallman MS. Increased Incidence of Therapy Related Myeloid Neoplasia (t-MN) After Initial Therapy for CLL with Fludarabine- Cyclophosphamide (FC) Vs Fludarabine (F): Long-Term Follow-up of US Intergroup Study E2997. Fifty-second annual meeting of the American Society of Hematology, Orlando, FL, December 2010. Blood 2010;116: 924a. 116. Nagler A, Shimoni A, Avivi I, Rowe JM, Beider K, Hardan I, Abraham M, Wald H, Galun E, Shaw HL, Eizenberg O, Peled A. BKT140 Is a Novel CXCR4 Antagonist with Stem Cell Mobilization and Antimyeloma Effects: An Open-Label First Human Trial In Patients with Multiple Myeloma Undergoing Stem Cell Mobilization for Autologous Transplantation. Fifty-second annual meeting of the American Society of Hematology, Orlando, FL, Decem- ber 2010. Blood 2010;116: 2260a. 117. Dann EJ, Bairey O, Bar-Shalom R, Izak M, Korenberg A, Akria L, Attias D, Filanovsky K, Abdach L, Goldschmidt N, Epelbaum R, Rowe JM, Ben Yehuda D, Shpilberg O, Paltiel OB. Tailored Therapy In Hodgkin Lymphoma, Based on Predefined Risk Factors and Early Research Report 2013 38
    • Interim PET/CT, Can Lead to Modification and Safe Reduction In Therapy: Results of 134 Patients on the Israel National Hodgkin Study. Fifty-second annual meeting of the Ameri- can Society of Hematology, Orlando, FL, December 2010. Blood 2010;116: 2809a. 118. Luger S, Yao X, Paietta E, Ketterling R, Rybka W, Litzow MR, Rowe JM, Larson R, Tall- man MS. Tipifarnib Is Well Tolerated as Maintenance Therapy In Acute Myeloid Leukemia (AML). Significant, but Non-Fatal, Hematologic Toxicity Not Ameliorated by Dose Reduc- tion. Preliminary Results of the Phase III Intergroup Trial E2902. Fifty-second annual meet- ing of the American Society of Hematology, Orlando, FL, December 2010. Blood 2010; 116: 3315a. 119. Katz T, Stroopinsky D, Rowe JM, Avivi I. Rituximab Directly Decreases T Cell Activation, Both In Vivo and In Vitro. Fifty-second annual meeting of the American Society of Hematol- ogy, Orlando, FL, December 2010. Blood 2010; 116: 3935a. 120. Foá R, Di Rocco A, van Hazel G, Chamone DFA, Ruffert K, Rowe JM, Arcaini L, Poddub- naya I, Ho AD, Ivanova V, Vranovsky A, Witzens-Harig M. Maintenance Rituximab Every 2 Months for 2 Years Is Effective and Well Tolerated In Patients with Follicular Lymphoma with Both Standard or Rapid Infusion: Updated Results From the Phase IIIb MAXIMA Study. Fifty-second annual meeting of the American Society of Hematology, Orlando, FL, December 2010. Blood 2010; 116: 3945a. 121. Bairey O, Ruchlemer R, Rahimi-Levene N, Herishanu Y, Braester A, Klepfish A, and Sh- videl L. Presenting Features and Outcome of Elderly Chronic Lymphocytic Leukemia Pa- tients Diagnosed at the Age of 80 Years or Above. An ICLLSG Study. Blood Supplement 2010;116: 4620. 122. Ganzel C, Ben-Yehuda D., Mali A., Goldschmidt N. High incidence of skin rash in patients with Hairy Cell Leukemia. Presented at the thirty-third International Society of Hematology meeting, Jerusalem, 2010. 123. Ganzel C, Galina Pogrebijsky G., Krichevsky S., Neuman T., Ben-Yehuda D. The separate diagnosis of Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL) in a single patient may not signify a common clonal origin. American Society of Hematology, Fifty- second annual meeting, 2010, Blood, 2010; 116: 4824. 124. Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A multi-center prospective randomized study comparing yttium-19 ibritumomab tiuxetan (zevalin) and high-dosed BEAN chemotherapy (Z-BEAN) versus BEAN prior to 39 Hematology
    • autologous stem cell transplantion in patients with aggressive lymphoma. Thirty-Seventh annual meeting of the European Group for Blood and Marrow Transplantation EGBMT (EBMT). Paris, France. Bone Marrow Transplantation 2011; 46: 266a. 125. Ruchlemer R,  Elstein D,  Broide E,  Reinus C, Maayaan H, and  Zimran A. Gaucher Dis- ease and LGL Proliferations: Provocative Commonality? Poster at the American Society of Hematology meeting Blood Supplement, 2011. 126. Vine J, Bar Cohen S, Ruchlemer R, Goldschmidt N, Levin M, Libster D,  Gural A,  Gatt ME, Lavie D, Ben-Yehuda D, and Rund D. Polymorphisms in Exons 2 and 7 of the Human Organic Cation Transporter (hOCT1) (Solute Carrier Family 22, SLC22A1): Correlation with Imatinib Levels and Clinical Course in Chronic Myeloid Leukemia Patients. Poster at the American Society of Hematology meeting. Blood Supplement, 2011. 127. Tadmor T, Shvidel L, Aviv A, Ruchlemer R, Bairey O, Yuklea M, Herishanu Y, Braester A, Rahimi-Levene N Vernea F, Ben-Ezra J, Bejar J, Polliack A. Significance of Bone Marrow Reticulin Fibrosis in Chronic Lymphocytic Leukemia: a Study of Therapy “Naïve” Patients with Prognostic Implications. Abstract at the European Hematology Association, 2012. Research Report 2013 40
    • T he Digestive Diseases Institute headed by Professor Eran Goldin was established in 2011 to provide a framework for the diagnosis and treatment of the wide variety of gastrointestinal related diseases. The new concept behind this Institute is to group experts from differ- ent disciplines in one comprehensive center and link the fields of gastro, oncology, surgery and imaging, etc. The goal is to achieve greater coordination among experts while ensur- ing a focus on advanced clinical treatment, as well as training interns and students and carrying out basic and advanced research of the digestive system. The Institute is made up of several units including the En- doscopy Unit under the direction of Dr. Dov Wengrover, the Inflammatory Bowel Diseases Center (headed by Professor Goldin), the Neurogastroenterology Service and the Pelvic Floor Unit (directed by Dr. Joseph Lysy) the Pancreatic Biliary Center (headed by Dr. Alain Dancour), and the Liver Unit (di- rected by Dr. Yoav Lurie). Additional staff include Dr. Julian Paz, Dr. Ariella Shitrit and Dr. Ina Gapanovich who act as se- nior specialists in the Institute. In the Institute more than 15,000 digestive system proce- dures are performed every year including video capsular en- doscopies, manomatries, and PH monitoring. The Institute actsasareferencecenterforcomplexcasesfromalloverIsrael and abroad. A new center for prevention of malignancies of the digestive tract was established in 2012. Digestive Diseases Institute 41 Digestive Diseases
    • Areas of Research Activity Research is a major area of activity in the Institute, and involves numerous local, national and international projects of a clinical and basic scientific nature. The research staff includes a PhD researcher and a lab technician. The Unit for Clinical Studies has three research coordina- tors.The major research area of the Institute involves inflammatory bowel diseases (IBD), liver diseases and the investigational projects in endoscopy and new technologies. One research project involves a study of the recruitment of eotoxin and eosinophiles in IBD in a rat model of partial portal vein ligation. publications 1. Mizrahi M, Adar T, Ilan Y. Idiopathic right-sided endocarditis: an uncommon manifestation of pulmonary cavitations. Harefuah 2009; 148(4):233-4, 277. 2. Lalazar G, Adar T, Ilan Y.  Point of care continuous C(13)-methacetin breath test improves decision making in acute liver disease : results of a pilot clinical trial. World J Gastroenterol 2009; 28;15(8):966-72. 3. Mizrahi M, Adar T, Orenbuch-Harroch E, Elitzur Y. Non-ST elevation myocardial infarction after high dose intravenous immunoglobulin infusion. Case Report Med. 2009 Feb. 22e 4. Adar T, Mizrahi M, Pappo O, Scheiman-Elazary A,  Shibolet O. Adalimumab-induced au- toimmune hepatitis. J Clin Gastroenterol 2010 44(1):e20-2. 5. Marcus EL, Arnon R, Sheykenman A, Kaine GC, Lysy J. Esophageal obstruction due to enteral feed bezoar: A case report and literature review. World Journal of Gastrointestinal Endoscopy 2010; 16(2): 352-356. 6. Mizrahi M, Lalazar G, Adar T, Raz I, Ilan Y. Assessment of insulin resistance by 13C glu- cose breath test: a new tool for early diagnosis and follow up for high risk patients. Nutr J 2010; (27): 9-25. 7. Mizrahi M, Adar T, Shouval D, Bloom AI, Shibolet O. Endotipsitis – persistent infection of transjugular intrahepatic portosystemic shunt: pathogenesis, clinical features and man- agement Liver Int 2010; 30(2):175-83. Research Report 2013 42
    • 8. Mizrahi M, Roemi L, Shouval D, Adar T, Korem M, Moses A, Bloom A, Shibolet O. Bac- trermia and “Endotipsitis” following transjugular intrahepatic portosystemic shunting. World J Hepatol 2011; 27; 3(5):130-6. 9. Oberbaum M, Lysy J, Gropp C. From Nebuchadnezzar to the Randomized Controlled trial-Milestones in the development of clinical research. Harefuah; 2011. 10. Levin A, Cohen J. M, Mindrul V, Lysy J. Delayed fecal incontinence following surgery for anal fissure. Int J Colorectal Dis 2011; 26(12):1595-9. 11. Mizrahi M, Almogy G, Adar T, Lysy J. Dumping syndrome following Nissen funduplication in an adult patient diagnosed by continuous online 13C/12C monitoring of 13C-octanoic acid breath test “a case report”. BMC Gastroenterol. 2011; (19):11-98. 12. Adar T, Ben Ya’acov A, Lalazar G, Lichtenstein Y, Nahman D, Mizrahi M, Wong V, Muller B, Rawlin G, Ilan Y.Oral administration of immunoglobulin G-enhanced colostrum allevi- ates insulin resistance and liver injury and is associated with alterations in natural killer T cells. Clin Exp Immunol 2012; 167(2):252-60. 13. Adar T, Tayer-Shifman O, Mizrahi M, Tavdi S, Barak O, Shalit M. Dapsone induced eosino- philic pneumonia. Eur Ann Allergy Clin Immunol 2012; 44(3):144-6. 14. Shteyer E, Wengrower D, Benuri-Silbiger I, Gozal D, Wilschanski M, Goldin E. retro- grade cholangiopancreatography in neonatal cholestasis. J Pediatr Gastroenterol Nutr 2012;55(2):142-5. 15. Mizrahi MC, Reicher-Atir R, Levy S, Haramati S, Wengrower D, Israeli E, Goldin E. Effects of guided imagery with relaxation training on anxiety and quality of life among patients with inflammatory bowel disease. Psychol Health 2012; 27(12):1463-79. 16. Wengrower D, Zanninelli G, Latella G, Necozione S, Metanes I, Israeli E, Lysy J, Pines M, Papo O, Goldin E. Losartan reduces trinitrobenzene sulphonic acid-induced colorectal fibrosis in rats. Can J Gastroenterol 2012; 26(1):33-9. 17. Dotan I, Alper A, Rachmilewitz D, Israeli E, Odes S, Chermesh I, Naftali Timna, Frazer G, Bar-Gil Shitrit A, Peles V, Reif S. Maternal Inflammatory bowel disease has short and long term effect on the health of their offspring. A multicenter study in Israel. Accepted for publication JCC August 2012. 43 Digestive Diseases
    • Published Abstracts 1. Lysy J,  Shafra-Tikva S, Goldin E, Greenberg D.”The neighbour around the corner” A model for an early detection of prostate cancer in the Gastroenterology unit. Gastroenter- ology 2009. 2. Ariella S, Adar T, Goldin E, Lysy J. Trapping of balloon in  rectocele during rectal manom- etry is predictive of defecography results. Gastroenterology 2012. Research Report 2013 44
    • T he Gaucher Clinic was founded in 1989 as the first na- tional referral out-patient clinic for patients with Gau- cher disease by Prof. Ari Zimran, along with Prof. Ayala Abrahamov who had overseen pediatric patients with metabolic diseases as part of her out-patient population. In 1993 they were joined by Dr. Deborah Elstein. For the past 19 years this has been the “Gaucher team” and is occasionally supplemented by young physicians and medical students on rotation or doing research projects. Gaucher disease is the most common inherited disorder af- fecting Ashkenazi Jews, and is especially prevalent in Israel. Nevertheless, it is still a rather rare disease, and many pa- tients are often treated by physicians who are not familiar with the manifestations. More importantly, general practitio- ners are not always aware of new treatment modalities and adjuvant therapies. Patients with Gaucher disease come to the clinic for complete baseline evaluations, follow-up examinations, consultations regarding specific conditions such as army service, pregnancy etc., and for treatment. Patients are offered a holistic ap- proach guided by senior specialists in all fields of medicine, including surgeons, orthopedists, and gynecologists. Recently we have been able to offer bone mineral density evaluations using a state-of-the-art DEXA (dual energy x-ray absorptiometry) machine. Gaucher Clinic 45 Gaucher
    • Areas of Research Activity The Unit conducts research on low-dose, low-frequency enzyme therapy, type 3c Gaucher disease, a unique variant of Gaucher disease among Arabs with progressive calcification of the heart valves, early-onset parkinsonism in patients with Gaucher disease, the ethical con- siderations involved in providing enzyme therapy to babies with the neuronopathic forms of Gaucher disease, outcome of pregnancies in women with Gaucher disease, echocardiography of pulmonary hypertension among patients with Gaucher disease, follow-up of patients who have undergone orthopedic interventions especially hip replacements, the incidence of can- cers in Gaucher disease, use of anesthesia in pregnant and thrombocytopenic patients with Gaucher disease, and the impact of expensive therapies on national health budgets. Representative Research Because of the increased incidence of Parkinson's disease in patients and carriers of Gaucher disease, we are collaborating on a questionnaire-based study to evaluate the clinical status of affectedpatientsandobligatecarriers.Wearealsoinvolvedinseveralbonedensitometrystud- ies in patients with Gaucher disease, patients with Prader-Willi syndrome, post-partum and post-lactation, in the over 85 years of age, and after fractures. Our clinic was the first medical group outside the US to introduce enzymatic replacement therapy (ERT) with alglucerase (Ceredase ®, Genzyme Inc., MA) in December, 1990 and Prof. Zimran was also active in lobbying for its registration by the Ministry of Health in Israel. We participated in the trial with the recombinant form, imiglucerase (Cerezyme®, Genzyme Inc., MA) using the low-dose, low-frequency regimen which is still the starting regimen for adults in Israel. From 1998-2002 our clinic was involved in three pivotal trials testing the safety and efficacy of the concept of substrate reduction therapy (SRT) with miglustat (Zavesca, Acte- lion Therapeutics, Allschwil, Switzerland) as an oral therapeutic regimen which can cross the blood-brain barrier. In 2004 we initiated a seminal Phase I/II clinical trial as a single-center with a wild-type sequence enzymatic preparation, gene-activated glucocerebrosidase (velaglu- cerase alfa) by Shire Human Genetic Therapies (Cambridge, MA, USA). We also participated in all three subsequent Phase III clinical trials with velaglucerase alfa and the extensions of all four trials. The naïve patients of the seminal trial completed 7 years of exposure and the patients in the other trials, including those who were switched from Cerezyme, who entered an extension phase, benefitted from at least 4 years on velaglucerase alfa. This drug (Vpriv) received both FDA and EMA approval in 2010 and is available commercially in Israel. Inaddition,weparticipatedintheseminalPhaseIIItrialsinadultandpediatricpatients,naive as well as patients switching over from Cerezyme, with an intravenous ERT, taliglucerase alfa, Research Report 2013 46
    • manufactured by the Israeli biotherapeutics company, Protalix Pharmaceutics (Carmiel, Israel) which uses a high-yield plant cell system that is readily up-scalable in disposable bioreactors and free from exposure to mammalian tissues. This drug received FDA and EMA approval in 2012 and is available commercially in Israel. For the past four years we have also participated in a multi-national, multi-center Phase II trial with eliglustat tartrate (Genzyme-Sanofi Corporation, Cambridge, MA, USA) an oral SRT which unlike miglustat cannot cross the blood-brain barrier. In November 2008, our clinic committed to a pilot study using ambroxol, a well-known oral over-the-counter treatment for acute or chronic respiratory disorders associated with viscid or excessive mucus. Although intravenous ERT is still the standard of care for Gaucher disease, there is considerable interest in small-molecule-based oral pharmacological chaperones. This investigator-initiated pilot study was successfully completed and we are actively looking to initiate a clinical trial in the very near future. The clinic has taken an active interest in the ultra-rare clinical entity of Late-onset Tay-Sachs disease (LOTS), which is also a lysosomal storage disease, and is predominantly found among Ashkenazi Jews. We currently are in touch with several of the approximately 100 patients identified throughout the world. 47 Gaucher
    • Publications 1. Pront R, Margalioth EJ, Green R, Eldar-Geva T, Maimoni Z, Zimran A, Elstein D. Prevalence of low serum cobalamin in infertile couples. Andrologia 2009;41(1):46-50. 2. Zimran A, Ilan Y, Elstein D. Enzyme replacement therapy for mild patients with Gaucher disease. Am J Hematol 2009; 84(4):202-4. 3. Grisaru-Granovsky S, Rabinowitz R, Ioscovich A, Elstein D, Schimmel M. Congenital dia- phragmatic hernia: review of the literature in reflection of unresolved dilemmas. Acta Pae- diatr 2009;98(12):1874-81. 4. Grabowski GA, Kacena K, Cole JA, Hollak CE, Zhang L, Yee J, Mistry PK, Zimran A, Char- row J, vom Dahl S. Dose-response relationships for enzyme replacement therapy with imi- glucerase/alglucerase in patients with Gaucher disease type 1.Genet Med 2009;11(2):92- 100. 5. Zimran A, Morris E, Mengel E, Kaplan P, Belmatoug N, Hughes DA, Malinova V, Heitner R, Sobreira E, Mrsić M, Granovsky-Grisaru S, Amato D, vom Dahl S. The female Gaucher patient: the impact of enzyme replacement therapy around key reproductive events (men- struation, pregnancy and menopause). Blood Cells Mol Dis 2009;43(3):264-88. 6. Lebel E, Elstein D, Zimran A, Itzchaki M. Cementless total hip arthroplasties in Gaucher disease: long-term follow-up. Am J Orthop 2009;38(3):130-2. 7. Lebel E, Phillips M, Elstein D, Zimran A, Itzchaki M. Poor results of drilling in early stages of juxta-articular osteonecrosis in 12 joints affected by Gaucher disease. Acta Orthop 2009;80(2):201-4. 8. Ilan Y, Elstein D, Zimran A. Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent. Immunol Cell Biol 2009;87(7):514- 24. 9. Elstein D, Zimran A. Review of the safety and efficacy of imiglucerase treatment of Gau- cher disease. Biologics 2009;3:407-17. 10. Greenwood A, Altarescu G, Zimran A, Elstein D. Vitamin D Receptor (VDR) Polymorphisms in the Cardiac Variant of Gaucher Disease. Pediatr Cardiol 2010 ;31(1):30-2. Research Report 2013 48
    • 11. Altarescu G, Seror-Bukris O, Zimran A, Elstein D. Proteinase-activated receptor (PAR1) polymorphic variant correlates with thrombocytopenia in Gaucher disease. Blood Cells Mol Dis 2010;44(2):79-81. 12. Hollak CE, vom Dahl S, Aerts JM, Belmatoug N, Bembi B, Cohen Y, Collin-Histed T, Deegan P, van Dussen L, Giraldo P, Mengel E, Michelakakis H, Manuel J, Hrebicek M, Parini R, Reinke J, di Rocco M, Pocovi M, Sa Miranda MC, Tylki-Szymanska A, Zimran A, Cox TM. Force majeure: therapeutic measures in response to restricted supply of imiglu- cerase (Cerezyme) for patients with Gaucher disease. Blood Cells Mol Dis 2010;44(1):41- 7. 13. Weinreb NJ, Cappellini MD, Cox TM, Giannini EH, Grabowski GA, Hwu WL, Mankin H, Martins AM, Sawyer C, vom Dahl S, Yeh MS, Zimran A. A validated disease severity scor- ing system for adults with type 1 Gaucher disease. Genet Med 2010;12(1):44-51 14. Hollak CE, Aerts JM, Belmatoug N, Bembi B, Bodamer O, Cappellini D, Collin-Histed T, Cox TM, Deegan P, Giraldo P, Hughes D, Lukina E, Manuel J, Michelakakis H, Di Rocco M, Vellodi A, Zimran A. Guidelines for the restart of imiglucerase in patients with Gaucher disease: recommendations from the European Working Group on Gaucher disease. Blood Cells Mol Dis 2010;44(2):86-7. 15. Elstein D, Gellman A, Altarescu G, Abrahamov A, Hadas-Halpern I, Phillips M, Margalit M, Lebel E, Itzchaki M, Zimran A. Disease severity in sibling pairs with type 1 Gaucher disease. J Inherit Metab Dis 2010;33(1):79-83. 16. Hadas-Halpern I, Deeb M, Abrahamov A, Zimran A, Elstein D. Gaucher disease: spectrum of sonographic findings in the liver. J Ultrasound Med 2010;29(5):727-33. 17. Greenwood A, Elstein D, Zimran A, Altarescu G. Effect of vitamin D receptor (VDR) genotypes on the risk for osteoporosis in type 1 Gaucher disease. Clin Rheumatol 2010;29(9):1037-41. 18. Zimran A, Altarescu G, Phillips M, Attias D, Jmoudiak M, Deeb M, Wang N, Bhirangi K, Cohn GM, Elstein D. Phase I/II and extension study of velaglucerase alfa (Gene-Activat- edTM human glucocerebrosidase) replacement therapy in adults with type 1 Gaucher disease: 48-month experience. Blood 2010; 115(23):4651-6. 19. Hadas-Halpern I, Deeb M, Abrahamov A, Zimran A, Elstein D. Gaucher disease: spectrum of sonographic findings in the liver. J Ultrasound Med 2010;29(5):727-33. 49 Gaucher
    • 20. Zimran A, Altarescu G, Elstein D. Nonprecipitous changes upon withdrawal from imiglu- cerase for Gaucher disease because of a shortage in supply. Blood Cells Mol Dis 2010; ;46(1):111-4. 21. Shemesh T, Whybra C, Delgado-Sanchez S, Beck M, Elstein D, Altarescu G. Paraoxonase (PON1) Gene Polymorphisms in Fabry Disease: Correlation with Renal Disease. Nephron Clin Pract 2010;116(4):c289-c293. 22. Eitan Y, Abrahamov A, Phillips M, Elstein D, Zimran A. Sixteen years of prenatal consulta- tions for the N370S/N370S Gaucher disease genotype: what have we learned? Prenat Diagn 2010;30(10):924-7. 23. Marks A, Greenstein J, Berger MT, Shapiro J, Elstein D, Ioscovich A. Peripartum anes- thesia in grand-grand multiparous women (≥10 births). Health Care Women Int 2010; 31(10):938-45. 24. Lieblich M, Altarescu G, Zimran A, Elstein D. Vitamin D Receptor (VDR) polymorphic vari- ants in patients with cancer and Gaucher disease. Blood Cells Mol Dis 2011;46(1):92-4. 25. Altarescu G, Renbaum P, Eldar-Geva T, Varshower I, Brooks B, Beeri R, Margalioth EJ, Levy-Lahad E, Elstein D, Zimran A. Preimplantation genetic diagnosis (PGD) for a treat- able disorder: Gaucher disease type 1 as a model. Blood Cells Mol Dis 2011;46(1):15-8. 26. Fadeev A, Ioscovitch A, Rivlis A, Grisaru-Granovsky S, Samueloff A, Schimmel MS, El- stein D. Prospective study of maternal and neonatal outcome in great-grand multiparous women (≥10 births) and in aged-matched women with lesser parity. Arch Gynecol Obstet 2011;284(4):799-805. 27. Elstein D, Cohn GM, Wang N, Djordjevic M, Brutaru C, Zimran A. Early achievement and maintenance of the therapeutic goals using velaglucerase alfa in type 1 Gaucher disease. Blood Cells Mol Dis 2011;46(1):119-23. 28. Lebel E, Ioscovich A, Itzchaki M, Zimran A, Elstein D. Hip arthroplasty in patients with Gaucher disease. Blood Cells Mol Dis 2011;46(1):60-5. 29. Hughes DA, Al-Sayed M, Belmatoug N, Bodamer O, Böttcher T, Cappellini M, Co- hen IJ, Eagleton T, Elstein D, Giraldo P, Jones S, Kaplinsky C, Lund A, Machac- zka M, Mengel E, Pastores GM, Rosenbaum H, Sjo M, Tiling N, Tsaftaridis P, Zim- ran A, Weinreb N. Early access experience with VPRIV(®): Recommendations Research Report 2013 50
    • for ‘core data’ collection. Blood Cells Mol Dis 2011 ;47(2):140-2. 30. Rosenbloom B, Balwani M, Bronstein JM, Kolodny E, Sathe S, Gwosdow AR, Taylor JS, Cole JA, Zimran A, Weinreb NJ. The incidence of Parkinsonism in patients with type 1 Gau- cher disease: data from the ICGG Gaucher Registry.Blood Cells Mol Dis 2011;46(1):95- 102. 31. Granovsky-Grisaru S, Belmatoug N, vom Dahl S, Mengel E, Morris E, Zimran A. The management of pregnancy in Gaucher disease. Eur J Obstet Gynecol Reprod Biol 2011;156(1):3-8. 32. Zimran A. Velaglucerase alfa: a new option for Gaucher disease treatment. Drugs Today (Barc) 2011;47(7):515-29. 33. Zimran A. How I treat Gaucher disease. Blood. 2011 Aug 11;118(6):1463-71. 34. Segel R, Anikster Y, Zevin S, Steinberg A, Gahl WA, Fisher D, Staretz-Chacham O, Zimran A, Altarescu G. A safety trial of high dose glyceryl triacetate for Canavan disease. Mol Genet Metab 2011;103(3):203-6. 35. Osher E, Fattal-Valevski A, Sagie L, Urshanski N, Amir-Levi Y, Katzburg S, Peleg L, Ler- man-Sagie T, Zimran A, Elstein D, Navon R, Stern N, Valevski A. Pyrimethamine increases β-hexosaminidase A activity in patients with Late Onset Tay Sachs. Mol Genet Metab. Mol Genet Metab 2011;102(3):356-63. 36. Elstein D. Recent Advances in Treatment Approaches to Gaucher Disease. Curr Pharm Biotechnol 2011;12(6):854-60. 37. Svobodová E, Mrázová L, Lukšan O, Elstein D, Zimran A, Stolnaya L, Minks J, Eberová J, Dvořáková L, Jirsa M, Hřebíček M. Glucocerebrosidase gene has an alternative upstream promoter, which has features and expression characteristic of housekeeping genes. Blood Cells Mol Dis 2011;46(3):239-45. 38. Simchen MJ, Oz R, Shenkman B, Zimran A, Elstein D, Kenet G. Impaired platelet func- tion and peripartum bleeding in women with Gaucher disease. Thromb Haemost 2011;105(3):509-514. 39. Spectre G, Roth B, Ronen G, Rosengarten D, Elstein D, Zimran A, Varon D, Rev- el-Vilk S. Platelet adhesion defect in type I Gaucher Disease is associated with 51 Gaucher
    • a risk of mucosal bleeding. Br J Haematol. 2011 May;153(3):372-8. 40. Altarescu G, Elstein D. Fabry disease in an oligosymptomatic male. Isr Med Assoc J 2011;13(3):191-2. 41. Elstein D, Foldes AJ, Zahrieh D, Cohn GM, Djordjevic M, Brutaru C, Zimran A. Significant and continuous improvement in bone mineral density among type 1 Gaucher disease patients treated with velaglucerase alfa: 69-month experience, including dose reduction. Blood Cells Mol Dis 2011;47(1):56-61. 42. Ribner A, Altarescu G, Zimran A, Elstein D. Osteopontin polymorphic susceptibility factor for Parkinson’s disease among patients with Gaucher disease. Mov Disord 2011;26(7):1341- 3. 43. Altarescu G, Renbaum P, Eldar-Geva T, Brooks B, Varshaver I, Avitzour M, Margalioth EJ, Levy-Lahad E, Elstein D, Epsztejn-Litman S, Eiges R. Preventing mucopolysaccharidosis type II (Hunter syndrome): PGD and establishing a Hunter (46, XX) stem cell line. Prenat Diagn 2011. [Epub ahead of print] 44. Zimran A, Brill-Almon E, Chertkoff R, Petakov M, Blanco-Favela F, Terreros Muñoz E, Solorio-Meza SE, Amato D, Duran G, Giona F, Heitner R, Rosenbaum H, Giraldo P, Mehta A, Park G, Phillips M, Elstein D, Altarescu G, Szleifer M, Hashmueli S, Aviezer D. Pivotal trial with plant-cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Blood 2011;118(22):5767-73. 45. Michaelson-Cohen R, Elstein D, Ioscovich A, Armon S, Schimmel MS, Butnaru A, Samu- eloff A, Grisaru-Granovsky S. Severe heart disease complicating pregnancy does not pre- clude a favourable pregnancy outcome: 15 years’ experience in a single centre. J Obstet Gynaecol 2011;31(7):597-602. 46. Ioscovich A, Fadeev A, Rivilis A, Elstein D. Requests and usage of epidural analgesia in grand-grand multiparous and similar-aged women with lesser parity: prospective obser- vational study. J Perinat Med 2011;39(6):697-700. 47. Elstein D, Tiomkin M, Hadas-Halpern I, Zimran A. Organ volume by computed tomo- graphy correlates with longitudinal axis on ultrasound in patients with Gaucher disease. Ultrasound Q 2011;27(4):25-8. 48. Elstein D, Altarescu G, Maayan H, Phillips M, Abrahamov A, Hadas-Halpern I, Tiomkin M, Research Report 2013 52
    • Zimran A. Booster-effect with velaglucerase alfa in patients with Gaucher disease switched from long-term imiglucerase therapy: Early Access Program results from Jerusalem. Blood Cells Mol Dis 2012;48(1):45-50. 49. Givol N, Goldstein G, Peleg O, Shenkman B, Zimran A, Elstein D, Kenet G. Thrombocy- topenia and bleeding in dental procedures of patients with Gaucher disease. Haemophilia 2012;18(1):117-21. 50. Saranjam H, Sidransky E, Levine W, Zimran A, Elstein D. Mandibular and dental manifes- tations of Gaucher disease. Oral Dis 2012;18(5):421-9. 51. Samuels N, Elstein D, Lebel E, Zimran A, Oberbaum M. Acupuncture for symptoms of Gaucher disease. Complement Ther Med 2012;20(3):131-4. 52. Elstein D, Schachamorov E, Beeri R, Altarescu G. X-inactivation in Fabry disease. Gene 2012 [Epub ahead of print] 53. Chetrit EB, Alcalay RN, Steiner-Birmanns B, Altarescu G, Phillips M, Elstein D, Zimran A. Phenotype in patients with Gaucher disease and Parkinson disease. Blood Cells Mol Dis. 2012. 54. Altarescu G, Beeri R, Eiges R, Epsztejn-Litman S, Eldar-Geva T, Elstein D, Zimran A, Margalioth EJ, Levy-Lahad E, Renbaum P. Prevention of lysosomal storage diseases and derivation of mutant stem cell lines by preimplantation genetic diagnosis. Mol Biol Int. 2012;2012:797342. 55. Zimran A, Pastores GM, Tylki-Szymanska A, Hughes DA, Elstein D, Mardach R, Eng C, Smith L, Heisel-Kurth M, Charrow J, Harmatz P, Fernhoff P, Rhead W, Longo N, Giraldo P, Ruiz JA, Zahrieh D, Crombez E, Grabowski GA. Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase. Am J Hematol. 2012. 53 Gaucher
    • T he Medical Genetics Institute was established in 1996. It is directed by Prof. Ephrat Levy-Lahad, and includes three board certified specialists in Medical Genetics: Prof. Gheona Altarescu, whose is also a specialist in Internal Medicine and is Head of the Zohar Preimplantation Diagno- sis Unit (PGD), Dr. Reeval Segel, who is also a specialist in Pediatrics and directs the Cytogenetics and microarray ser- vice, and Dr. Rachel Michaelson-Cohen, who is also a special- istinObstetricsandGynecology.Geneticsimpactsallareasof medicine and the diverse medical backgrounds of the senior physicians in the Institute ensures expertise in a broad range of fields. The Institute provides services through various clinics, which in addition to the physicians are staffed by M.Sc. and Ph.D. genetic counselors. The major clinics include: Cancer Genet- ics, which was one of the first of its kind in Israel, Pediatric Genetics, for evaluation of children with intellectual disabili- ties or congenital malformations and Prenatal Genetics, for the evaluation of pregnancies at risk for genetic disease or fe- talmalformations.TheInstitutealsocoordinatesanumberof multidisciplinary clinics: 1) The Neurofibromatosis clinic for both children and adults with this common, complex disease, operates in collaboration with the Pediatric Neurology Unit, Adult Neurology Dept., Pediatric Ophthalmology Unit , Pedi- atric Orthopedics Unit, Plastic Surgery, all at Shaare Zedek, and Pediatric Neurosurgery at Dana Hospital in Tel Aviv; 2) The Neurogenetics Clinic, in collaboration with the Pediatric Neurology Unit, diagnoses and treats children with combined Medical Genetics Institute Research Report 2013 54
    • neurological and genetic issues, e.g. Prader Willi disease; 3) The Noga clinic, which offers fol- low-up and surveillance for female BRCA1/BRCA2 carriers who are at high risk of breast and ovarian cancer, operates in collaboration with the Gynecology service and the Breast Surgery Unit; 4) The Fetal Malformation clinic operates in collaboration with the Prenatal Ultrasound service, the Neonatal Intensive Care Unit and all subspecialties of the Pediatrics Department. The multidisciplinary clinics are national referral centers, and serve patients from all over the country. The diagnostic Medical Genetics Laboratory is directed by Paul Renbaum, Ph.D. and includes a Molecular Genetics laboratory headed by Rachel Beeri, Ph.D., a Cytogenetics and microarray laboratory headed by Dr. Reeval Segel, and a Molecular Pathology Laboratory headed by Dr. Eli Golomb, a specialist in Pathology. The laboratories provide genetic testing in all these areas. In addition to the clinical laboratories, there are research laboratories within the molecular laboratory, and a stem-cell research lab, headed by Rachel Eiges, Ph.D.. Research is performed by graduate students and post-doctoral fellows through our affiliation with the Medical Re- search Institute at the Hebrew University Faculty of Medicine. Areas of Research Activity Research is a major focus of the Medical Genetics Institute, and reflects the research interests of its senior personnel. • Cancer Genetics. The Shaare Zedek teams have been studying risks of cancer associated with inherited mutations, in particular mutations in the BRCA1 and BRCA2 genes. Women who inherit mutations in these genes have a much higher risk of breast and ovarian cancer, and these mutations are particularly common in Ashkenazi Jewish women. We are study- ing genetic and environmental factors that influence this risk. For example, we have found that variations in other genes are important, and that risk is increasing in women today comparedtocarriersinpreviousgenerations.Wehaverecentlycompletedastudyproviding evidence for population screening of these mutations in Jewish women. We are also col- laborating with Palestinian colleagues to determine inherited mutations that affect breast cancer risk in Arab women. • Inherited diseases in children. A major focus is identifying the mutations responsible for genetic diseases in children. In Jerusalem, marriage between relatives or within a small ethnic group is still common, and combined with large family size, this results in a higher frequency of genetic diseases in children. Some diseases are common, e.g. Tay Sachs, which is now prevented by prior testing, but many of these often devastating diseases are specific 55 Medical Genetics
    • to a particular family. Advances in genetic technology make it possible to identify the muta- tion causing the disease. This can help the family prevent further affected children (e.g. by PGD) and also provides important insights into the functions of various genes. We have already identified 7 new disease genes in the past 3 years. • The genetic basis of Cerebral Palsy. Cerebral Palsy (CP) is a common cause of motor and intellectual disability in children, but its cause is often unknown. We are investigating the possibility that small changes in the structure of the chromosomes, small additions (dupli- cations) and missing sections (deletions) underlie CP. These small changes, which are called CNVs (Copy Number Variations) are not detectable by regular microscopy, and are only seen using specialized methods, called arrays. Representative Research In 2001 we were called to see a terminally ill child in the Pediatrics Department. She was nine years old and suffered from a debilitating, progressive neurological disease. She was born with a very small head (severe microcephaly) and although she learned to walk, over time she devel- oped muscular weakness which eventually precluded her from eating, and ultimately impaired her breathing, leading to her death a short time later. Her devoted parents were Ashkenazi Jews, and were first cousins. They told us that their second child, a girl, had previously died of the same condition at the age of 12 months. They thought that one of their nephews has died years before of a similar condition. The couple also had 10 healthy children. It was clear to them and to us that the disease was genetic, and that they were both carriers. We determined thattheirdaughters’conditionwas“pontocerebellarhypoplasiawithspinalmuscularatrophy” (PCH-SMA).Thisconditionwasdescribedinthemedicalliteraturebutitscausewasunknown. Although, unfortunately their affected daughters had died, they were very interested in find- ing out the cause of the disease, for the future generations of the family. We used a strategy called “positional cloning” where a gene is identified by virtue of its location: we searched for a chromosomal region that was different in the affected person compared to the healthy rela- tives. We were able to find a region on chromosome 5, for which the affected girl had inherited the same segments from both her mother and her father, in a pattern that was different from thatfoundinallherhealthysiblings,Therewereover70genesinthatregion,andwepainstak- ingly started to sequence all of them. In 2009, we found a mutation, i.e. a “spelling mistake” in one of these genes, called VRK1. This gene was not known to be involved in neurological func- tion. When we tested other Ashkenazis, we found that this is an “Ashekanzi mutation”, like Tay Sachs, but much rarer. 1/250 Ashkenaz carry this mutation, so if two random Ashkenazis get married, there is only a 1/62,500 chance they will be at risk for having a child with this disease. Our discovery had several important outcomes: for the family, we are now able to test all relatives and tell them if they are at risk for having an affected child. Future spouses mar- Research Report 2013 56
    • rying into the family can be tested to prevent recurrence. When we published the findings in the American Journal of Human Genetics, Ashkenazi children with a similar condition, whose diagnosis was not known, were found to have the same mutation – there are a number of such families in the USA and in Israel. This project is an example of genetics research starting at the bedside – with a child affected with a disease of unknown origin, culminating in identifying the reason for the illness, and providing hope to other families, as well as new insights into various disease processes. The figure shows the genetic region harboring the SMA-PCH gene, VRK1. Circles indicate fe- males and squares indicate males (affected are in black). Siblings are connected to the same horizontal line, spouses are connected by a horizontal line between them. Only the affected girl inherited the segment marked in yellow from both her parents. The numbers indicate 02-6666034 The genetic region harboring the SMA-PCH gene, VRK1. Circles indicate females an indicate males (affected are in black). Sibling are connected to the same horizontal lin are connected by a horizontal line between them. Only the affected girl inherited the s marked in yellow from both her parents. The numbers indicate the length of DNA seg 57 Medical Genetics
    • the length of DNA segments (markers) tested. In the area bounded in red, the affected girl inherited the same marker length from both parents. This is to be expected since they are first cousins and had both inherited the mutation from a common grandparent. (from Renbaum et al. Am J Hum Genet 2009). Publications 1. Renbaum P, Kellerman E, Jaron R, Geiger D, Segel R, Lee M, King MC, Levy-Lahad E.; Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene. Am J Hum Genet 2009; 85(2):281-9. 2. Eitan R, Michaelson-Cohen R, Levavi H, Beller U.The counseling and management of young healthy BRCA mutation carriers. Int J Gynecol Cancer. 2009 Oct;19(7):1156-9. 3. Michaelson-Cohen R, Beller U. Managing menopausal symptoms after gynecological cancer. Curr Opin Oncol; 2009 ;21(5):407-11. 4. Manchanda R, Menon U, Michaelson-Cohen R, Beller U, Jacobs I. “HNPCC or Lynch Syndrome: the Gynaecological perspective”. Current opinion in Obstetrics and Gynecol- ogy 2009;21(1):31-8. 5. Segel R, Levy-Lahad E, Pasutto F, Picard E, Rauch A, Alterescu G, Schimmel MS: Pul- monary hypoplasia-Diaphragmatic hernia-Anophthalmia-Cardiac defect (PDAC) syn- drome due to STRA6 Mutations - What are the minimal criteria? Am J Med Genet 2009; 149A(11):2457-63. 6. Zeharia A, Shaag A, Pappo O, Mager-Heckel AM, Saada A, Beinat M, Karicheva O, Man- del H, Ofek N, Segel R, Marom D, Rötig A, Tarassov I, Elpeleg O.: Acute infantile liver failure due to mutations in the TRMU gene. Am J Hum Genet 2009;85(3):401-7. 7. Altarescu G, Eldar-Geva T, Brooks B, Zylber-Haran E, Varshaver I, Margalioth EJ, Levy-La- had E, Renbaum P. Preimplantation genetic diagnosis (PGD) for nonsyndromic deafness by polar body and blastomere biopsy. J Assist Reprod Genet 2009; 26(7):391-397. 8. Altarescu G, Eldar-Geva T, Varshower I, Brooks B, Haran EZ, Margalioth EJ, Levy-Lahad E, Renbaum P. Real-time reverse linkage using polar body analysis for preimplantation ge- Research Report 2013 58
    • netic diagnosis in female carriers of de novo mutations. Hum Reprod 2009; 24(12):3225- 3229. 9. Liy Altarescug, Renbaump, Eldar-Gevat, Levy-Lahade, Margalioth E, Zhong, Hahns, Hol- zgrevew. Non-invasive prenatal diagnosis using cell-free fetal DNA in maternal plasma from PGD pregnancies. Reprod Biomed Online 2009; 19(5):714-720. 10. Ounallah-Saad H, Beeri R, Goshen I, Yirmiya R, Renbaum, P, Levy-Lahad E. Transcrip- tional regulation of the murine Presenilin-2 gene reveals similarities and differences to its human orthologue. Gene 2009;446(2):81-9. 11. Levy-Lahad E. Invited commentary. Population based BRCA1/BRCA2 screening in Ash- kenazi Jews: A call for evidence Genet Med 2009;11(9):620-1. 12. Dunys J, Sevalle J, Giaime E, Pardossi-Piquard R, Vitek MP, Renbaum P, Levy-Lahad E, Zhang YW, Xu H, Checler F, da Costa CA. p53-dependent control of transactivation of the Pen2 promoter by presenilins. J Cell Sci 2009;122(Pt 21):4003-8. 13. Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, Müller L, Ze- schnigk C, Botti C, Rabinowitz R, Uyanik G, Crocq MA, Kraus U, Degen I, Faes F.: New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet2010. 14. Tsafrir A, Altarescu G, Margalioth E, Brooks B, Renbaum P, Levy-Lahad E, Rabinowitz R, Varshaver I, Eldar-Geva T. PGD for fragile X syndrome: ovarian function is the main deter- minant of success. Human Reprod 2010; 25(10);2629-36. 15. Reish O, Huber C, Altarescu G Chapman-Shimshoni D Levy-Lahad E C, Renbaum P Mashevich M, Munnich A, Cormier-Daire V. Mosaic compound heterozygosity of SHOX re- sulting in Leri-Weill dyschondrosteosis with marked short stature: implications for disease mechanisms and recurrence risks. Am J Med Genet A 2010 152A(9):2230-5. 16. Wolf I, Laitman Y, Rubinek T, Abramovitz L, Novikov I, Beeri R, Kuro-O M, Koeffler HP, Catane R, Freedman LS, Levy-Lahad E, Karlan BY, Friedman E, Kaufman B. Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ash- kenazi origin.Oncogene 2010;29(1):26-33. 17. Reish O, Shefer-Kaufmann N, Shimshoni DC, Renbaum P, Orr-Urtreger A, Steiner H, Rapoport M, Levy-Lahad E, Altarescu G. Frequencies of C282Y and H63D alleles in the 59 Medical Genetics
    • HFE gene among various Jewish ethnic groups in Israel: a change of concept required. Genet Med 2010;12(2):122-5. 18. Levy-Lahad E. Fanconi anemia and breast cancer susceptibility meet again. Nat Genet 2010;42(5):368-9. Invited commentary. 19. Özçelik T, Kanaan M Avraham KB, Yannoukakos D, Mégarbané A, Tadmouri GO Middle- ton L, Romeo G, Mary- King MC, Levy-Lahad E. Collaborative genomics for human health and cooperation in the Mediterranean region. Nat. Genet 2010;42(8):641-5. 20. Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, Opitz JM, Levy- Lahad E, KlevitRE, King MC. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome Am J Hum Genet 2010;87(2):282-8. 21. Epsztejn-Litman S, Eiges R. Genetic manipulation of human embryonic stem cells. Meth- ods Mol Biol 2010;584:387-411. 22. Ben-Neriah Z, Michaelson-Cohen R, Inbar-Feinberg M, Nadjari M, Zeligson S, Shaag A, Zenvirt S, Elpeleg O, Levy-Lahad E. A deleterious founder mutation in the BMPER gene causes diaphanospondylodysostosis (DSD). Am J Med Genet A 2011;155A(11):2801-6. 23. Michaelson-Cohen R, Elstein D, Ioscovich A, Armon S, Schimmel MS, Butnaru A, Samu- eloff A, Grisaru-Granovsky S. Severe heart disease complicating pregnancy does not pre- clude a favourable pregnancy outcome: 15 years’ experience in a single centre.J Obstet Gynaecol 2011;31(7):597-602. 24. Michaelson-Cohen R, Keshet I, Straussman R, Hecht M, Cedar H, Beller U. Genome-wide de novo methylation in epithelial ovarian cancer. Int J Gynecol Cancer 2011 ;21(2):269-79 25. Belostotsky R, Ben-Shalom E, Rinat C, Becker-Cohen R, Feinstein S, Zeligson S, Segel R, Elpeleg O, Nassar N, and Frishberg Y: Mutations in the mitochondrial seryl-tRNA synthe- tase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, (HUPRA syndrome) Am J Hum Genet 2011;88(2):193-200. 26. Segel R, Anikster Y, Zevin S, Steinberg A, Gahl WA, Fisher D, Staretz-Chacham O, Zimran A and Altarescu G: A Safety Trial of High Dose Glyceryl Triacetate for Canavan Disease. Mol Genet Metab 2011 ;103(3):203-6. Research Report 2013 60
    • 27. Altarescu G, Renbaum P, Eldar-Geva T, Varshower Brooks B, Beeri B, Margalioth EJ, Levy-Lahad E, Elstein D, Zimran A. Preimplantation genetic diagnosis (PGD) for a treat- able disorder: Gaucher disease type 1 as a model. Blood Cells Mol Dis 2011; 46(1):15-18 28. Altarescu G, Reish O, Renbaum P, Levy-Lahad E, Ron El R. Preimplantation genetic di- agnosis (PGD) for SHOX-related in conjunction with trisomy 21—detection by molecular analysis. J Assist Reprod Genet 2011;28(3):233-238. 29. Altarescu G, Renbaum P, Eldar-Geva T, Brooks B, Varshaver I, Margalioth EJ, Levy-Lahad E, Elstein D, Epsztejn-Litman S, Eiges R. Preventing mucopolysaccharidosis type II (Hunt- er syndrome): preimplantation genetic diagnosis (PGD) and establishing a Hunter (46,XX) stem cell line. Prenat Diagn 2011;31(9):853-860. 30. Altarescu G, Barenholtz O, Renbaum P, Beeri R, Levy-Lahad E, Margalioth EJ, Brooks B, Varshaver I, Eldar-Geva T. Preimplantation genetic diagnosis: prevention of the birth of children affected with endocrine diseases. J Pediatr Endocr Met 2011; 24(7-8):543-548. 31. Lieberman S, Zuckerman S, Levy-Lahad E, Altarescu G. Conflicts regarding genetic coun- seling for fragile X syndrome screening: a survey of clinical geneticists and genetic coun- selors in Israel. Am J Med Genet A 2011;155A(9):2154-60. 32. Sanz-García M, Vázquez-Cedeira M, Kellerman E, Renbaum P, Levy-Lahad E, Lazo PA. Substrate profiling of human vaccinia-related kinases identifies coilin, a Cajal body nuclear protein, as a phosphorylation target with neurological implications. J Proteomics.2011. [Epub ahead of print] PubMed PMID:21920476. 33. Brownstein Z, Friedman LM, Shahin H, Oron-Karni V, Kol N, Rayyan AA, ParzefallT, Lev D, Shalev S, Frydman M, Davidov B, Shohat M, Rahile M, Lieberman S,Levy-Lahad E, Lee MK, Shomron N, King MC, Walsh T, Kanaan M, Avraham KB. Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in middle eastern families. Genome Biol 2011;12(9):R89. 34. Zangen D, Kaufman Y, Zeligson S, Perlberg S, Fridman H, Kanaan M,Abdulhadi-Atwan M, Abu Libdeh A, Gussow A, Kisslov I, Carmel L, Renbaum P,Levy-Lahad E. XX Ovar- ian Dysgenesis Is Caused by a PSMC3IP/HOP2 Mutation that Abolishes Coactivation of Estrogen-Driven Transcription. Am J Hum Genet 2011;89(4):572-9. 35. Pierce SB, Spurrell CH, Mandell JB, Lee MK, Zeligson S, Bereman MS, Stray SM, Fok- stuend S, MacCoss MJ, Levy-Lahad E, King MC, Motulsky AG. Garrod’s fourth inborn 61 Medical Genetics
    • error of metabolism solved by the identification of mutations causing pentosuria. Proc Natl Acad Sci USA 2011;108(45):18313-7. 36. Milman Krentsis I, Sela I, Eiges R, Blanchard V, Berger M, Becker Cohen M, Mitrani- Rosenbaum S. GNE is involved in the early development of skeletal and cardiac muscle. PLoS One 2011;6(6):e21389. Epub 2011 Jun 24. 37. Ben-Yosef D, Frumlin T, Malcov M, Eldar Cohen T, Altarescu G, Renbaum P, Geva-Eldar T, Epsztejn-Litman S, Eiges R. Female sex bias in human embryonic stem cell lines. Stem Cells Dev 2012; 21(3):363-372. 38. Toperoff G, Aran D, Kark JD, Rosenberg M, Dubnikov T, Nissan B, Wainstein J, Fried- lander Y, Levy Lahad E, Glaser B, Hellman A. Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood. Hum Mol Genet 2012;21(2):371-83. 39. Ben-Yosef D, Amit A, Malcov M, Frumkin T, Ben-Yehudah A, Eldar I, Mey-Raz N, Azem F, Altarescu G, Renbaum P, Beeri R, Varshaver I, Eldar-Geva T, Epsztejn-Litman S, Levy- Lahad E, Eiges R. Female sex bias in human embryonic stem cell lines. Stem Cells Dev. 2012;21(3):363-72. 40. Saada A, Edvardson S, Shaag A, Chung WK, Segel R, Miller M, Jalas C and Elpeleg O: Combined OXPHOS complex I and IV defect, due to mutated complex I assembly factor C20ORF7. J Inherit Metab Dis 2012;35(1):125-31. 41. Altarescu G, Geva TE, Grisaru-Granovsky S, Bonstein L, Miskin H, Varshver Margalioth EJ, Levy-Lahad E, Renbaum P. Preimplantation genetic diagnosis for fetal neonatal allo- immune thrombocytopenia due to antihuman platelet antigen maternal antibodies. Obstet Gynecol 2012;119(2 Pt 1):338-343. 42. Shkedi-Rafid S, Gabai-Kapara E, Grinshpun-Cohen J, Levy-Lahad E. BRCA genetic test- ing of individuals from families with low prevalence of cancer: experiences of carriers and implications for population screening. Genet Med 2012. 43. Breuer O, Abdulhadi-Atwan M, Zeligson S, Fridman H, Renbaum P, Levy-Lahad E,Zangen DH. A novel severe N-terminal splice site KISS1R gene mutation causes hypogonado- tropichypogonadism but enables a normal development of neonatalexternal genitalia. Eur J Endocrinol. 2012;167(2):209-16. Epub 2012 May 22.PubMed PMID: 22619348. Research Report 2013 62
    • 44. Altarescu G, Beeri R, Eldar-Geva T, Varshaver I, Margalioth EJ, Levy-Lahad E, Renbaum P. Preimplantation Genetic Diagnosis (PGD) for germline mosaicism. RBM Online 2012. In press. 63 Medical Genetics
    • T he Stem Cell research laboratory was founded in 2008 and is part of the Medical Genetics Institute. It is di- rectedbyDr.RachelEiges.Thelabismainlyengagedin basic research studies. Part of its mission is to establish a li- brary of diseased human embryonic stem cell (HESC) lines as a universally available resource. Its affiliation with the Medi- cal Genetics Institute distinguishes it from many other em- bryonic stem cell-driving centers worldwide, as it benefits from a continuous supply of disease-carrying embryos spe- cifically for HESC line derivation. This is because the Institute maintains one of the world’s largest resources of genetically diseased embryos associated with its internationally known program in Pre-Implantation Genetic Diagnosis (PGD). PGD refers to a highly sophisticated diagnostic procedure for couples at high risk of transmitting a genetic defect. It in- volves the molecular testing of 3-5 day old in-vitro fertilized embryos for the genetic defect that is carried by the parent(s), and commonly results in the creation of affected embryos in culture. The stem cell lab generates a collection of mutant HESC lines that it makes available to the research community and serves as a platform for future studies of the etiology, bi- ology and management of various human diseases. Mutant HESCs represent an invaluable research tool since they can continuously expand and can potentially develop into all cell types in the body, providing an important and unlimited cell source of diseased cells in culture. Moreover, they recapitu- late early stages of embryonic development as they differen- tiate in-vitro, offering an alternative model system to study Stem Cell Research Laboratory Research Report 2013 64
    • human embryogenesis at stages which are otherwise inaccessible for research. HESCs can be utilized for investigating underlying mechanisms of diverse human pathologies, and can be particularly useful for exploring crucial developmental processes whose defect is embryoni- cally lethal. Diseased HESCs can be exceptionally useful for drug development, screening and evaluation since they offer a sufficient supply of impaired cells in culture. Areas of Research Activity Apart from establishing a universal cell depository of HESCs, the Stem Cell lab investigates basic biological questions related to specific genetic disorders using mutant human embryonic stem cell lines as a model system. Specifically, it focuses on diseases causing tri-nucleotide re- peat expansions. Pathogenic mutations involving TNRs underpin over 20 different hereditary neurodegenerative and neuromuscular diseases. In each case, inappropriate amplification of a DNA repeat unit (3bp long) beyond a critical length results in an unstable genetic region, with the number of repeats variable across generations and within tissues of affected individuals. The lab is interested in elucidating the molecular mechanisms that are associated with various molecular aspects of pathologically large expansions in the genome, and in particular, fragile X syndrome, the most common heritable cause of mental impairment, and Myotonic Dystrophy type 1 (DM1), a prevalent cause of myopathy in adults. In both of these heritable conditions theinheritedexpansionleadstolocalepigeneticmodificationsandregionalalterationsingene activity. To this end, the lab established 9 cell lines from fragile X embryos and 14 cell lines from DM1 embryos, the largest set of HESCs with tri-nucleotide expansions worldwide to date. These novel cell lines are being used to explore the effect of the mutation on epigenetic gene silencing, delay in DNA replication timing and repeat somatic instability, all of which are features that are highly pronounced in fragile X and DM. Representative Research Myotonic dystrophy type 1 is the most common autosomal dominant myopathy in adults, af- fecting1in8,000individualsinthegeneralpopulation.Itiscausedbyexpansionofanunstable tri-nucleotide CTG repeat (50 to 4,000 copies) located in the end of the dystrophia myotonica- protein kinase gene (DMPK). DM1 is characterized by myotonia, muscle wasting, cataracts, endocrine changes, and frequently by heart conduction defects (80% of patients), arrhythmias and cardiac myopathy. The aim of this study was to explore the molecular mechanism/s by which the CTG expansions lead to inactivation of genes at the DM1 locus. Specifically, it aimed to identify changes in the organization and condensation of the DNA near the repeats and ex- plore whether these changes lead to regional changes in gene transcription in diseased cardiac muscle cells obtained in culture. We focused on cardiomyocytes since DM1 patients often ex- hibit heart complications, mostly conduction defects but also arrhythmias and myopathy, and 65 Stem Cell Research
    • because the genes that are located near the repeats are highly expressed in the heart. For this purpose we used a unique set of DM1-affected HESC lines we established in the lab that can be easily and reproducibly induced to differentiate into functional cardiomyocytes in culture. Our DM1-affected HESCs line offers a unique opportunity to study these abnormalities at the molecular and cellular levels in cardiac muscle cells - diseased cells that are otherwise difficult to obtain for research. Publications 1. Altarescu G, Renbaum P, Eldar-Geva T, Brooks B, Varshaver I, Margalioth EJ, Elstein D, Levy-Lahad E, Avitzour M, Epstein-Litman S, Eiges R. Preventing mucopolysaccharidosis Type II (Hunter syndrome): Preimplantation genetic diagnosis followed by establishing of a stem cell line for Hunter Syndrome. Prenatal Diagnosis 2011[Epub ahead of print, PMID: 21706504]. 2. Ben-Yosef D, Amit A, Malcov M, Frumkin T, Eldar , Raz N, Azem F, Altarescu G, Renbaum P, Beeri R, Varshaver I, Eldar-Geva T, Epsztejn-Litman S, Levy-Lahad E, Eiges R. Female Sex Bias in Human Embryonic Stem Cell Lines. Stem Cells and Development 2011 [Epub ahead of print, PMID: 21585244]. 3. Milman I, Sela I, Eiges R, Blanchard V, Bergen M, Becker-Cohen M and Mitrani-Rosen- baum S. GNE is involved in the early development of skeletal and cardiac muscle. PLOS One 2011 [Epub ahead of print, PMID: 21731727]. 4. Dagan S, Avitzour MS, Stein M, Altarescu G, Renbaum P, Eldar-Geva T, Aharon P, Ben- Yosef D, Mitrani-Rosenbaum S, Levy-Lahad E, Epsztejn-Litman S, Eiges R. Aberrant methylation spreading is dictated by CTG expansion size in Myotonic Dystrophy affected human embryonic stem cells. 2011; Submitted. Research Report 2013 66
    • G uided by Prof. Gabizon’s expertise in the emerging field of Nanomedicine, the Experimental Oncology Unit is at the forefront of new developments in so- phisticated nanoparticulate formulations for the delivery of a variety of anti-cancer agents. Prof. Alberto Gabizon’s research spearheaded the develop- ment of liposome carriers to reduce the toxicity of currently used chemotherapeutic agents and to improve drug delivery to the tumor site. His research work was critical in the devel- opment of Doxil (also known as Caelyx), a long-circulating li- posomal formulation of a widely used anticancer agent, doxo- rubicin, which was the first nanomedicine to receive FDA approval and is currently marketed worldwide for the treat- ment of a variety of cancers including ovarian cancer and breast cancer. Further preclinical and clinical research with Doxil at the Oncology Institute over the last decade has con- tributed important new data on pharmacokinetic, safety, and therapeutic aspects of Doxil. Areas of Research Activity One particular recent achievement has been the development of a novel liposome formulation of a derivative of mitomycin, now known as Promitil, which is entering clinical trials this year. Promitil is much less toxic and has greater therapeutic efficacy than the parent drug mitomycin, and appears to be effective as well against some types of multidrug-resistant cancers, which are very difficult to treat. Institute of Oncology 67 Oncology
    • Another important area of active laboratory research is the targeted delivery of liposome con- tents to tumor cells through the folate receptors which are highly expressed in many cancer types.Thisapproachisparticularlyeffectivewhendeliveringdrugsknownasbisphosphonates which are not able to penetrate cells. One of the Department’s important advances in this area has been the liposomal co-encapsulation of doxorubicin with bisphosphonates with and with- out targeting to the folate receptor under a proprietary technology of Shaare Zedek MC and the Hebrew University. In view of the expanding use of bisphosphonates in cancer, this novel formulation has attracted considerable interest since it may enable co-delivery of two antican- cer agents with different mechanisms of action and non-overlapping toxicities and appears to have additional immunotherapeutic properties, thus providing a potential added value over Doxil and other chemotherapy-only based nanomedicines. Representative Research The clinical trials unit is involved in a number of experimental studies with various chemo- therapy agents or supportive care agents at phase II and III levels. Most of these studies in- volve collaboration with pharmaceutical companies. These studies include the testing of ultra- lowmolecularweightheparinstopreventthrombosisincancerpatients,newchemotherapeutic, hormonal, and biological agents in the treatment of breast cancer, lung cancer, ovarian cancer, prostate cancer, and colon cancer. Of particular interest are studies with antibodies combined with chemotherapy in ovarian cancer and with a targeted cytotoxic agent conjugated to an anti-Her2 antibody (TDM1). In collaboration with Prof. David Kelsen, we have established a closecollaborationwiththeGastro-EnterologicalOncologyServiceoftheMemorialSloanKet- tering Cancer Center (New York, USA) which already has paved the way for the participation of the Institute in an epidemiological gastric cancer research program that originated in this institution. Research Report 2013 68
    • The Palliative Care Unit, under the leadership of Dr. Nathan Cherny, has continued to research areas associated with the quality of life of patients with curable and incurable cancer and is- sues in care development. The Cancer Pain and Palliative medicine services have become cen- tral players in collaborative research programs of the European Society of Medical Oncology (ESMO) and the European Association of Palliative Medicine (EAPC). The research focus of the unit has involved pain in mammography and the extent to which it influences compliance, the demographics of palliative care delivery in Europe (an EAPC study) and doctor-patient communication in advanced cancer. Dr. Cherny led and coordinated the ESMO survey that addressed the degree to which oncologists in Europe coordinate with palliative care clinicians inthecareofpatientswithadvancedcancer. Inthesphereofevidence-basedmedicine,thede- partment has taken a leadership role in the development of the EAPC experts’ working group reports on the use of opioids in the management of cancer pain, the management of opioid adverse effects, the measurement of pain and the management of breakthrough pain. Publications Experimental Oncology 1. Shmeeda H, Tzemach D, Mak L, and Gabizon A. “Her2-targeted pegylated liposomal doxorubicin: Retention of target-specific binding and cytotoxicity after in vivo passage.” Journal of Controlled Release 2009; 136(2):155-160. 2. Schroeder A, Honen R, Turjeman K, Gabizon A, Kost J, and Barenholz Y: “Ultrasound Triggered Release of Cisplatin from Liposomes in Murine Tumors.” Journal of Controlled Release 2009; 137(1):63-68. 3. Gabizon A, Tzemach D, Gorin J, Mak L, Amitay Y, Shmeeda H, and Zalipsky S. Improved therapeutic activity of folate-targeted liposomal doxorubicin in folate receptor-expressing tumor models. Cancer Chemotherapy and Pharmacology 2010; 66:43–52. 4. Shmeeda H, Amitay Y, Gorin J, Tzemach D, Mak L, Ogorka J, Kumar S, Zhang JA, Gabi- zon A. Delivery of zoledronic acid encapsulated in folate-targeted liposome results in po- tent in vitro cytotoxic activity on tumor cells. J Control Release 2010;146(1):76-83. 69 Oncology
    • 5. Gabizon A, Tzemach D, Gorin J, Mak L, Amitay Y, Shmeeda H, Zalipsky S. Improved therapeutic activity of folate-targeted liposomal doxorubicin in folate receptor-expressing tumor models. Cancer Chemother Pharmacol 2010 ;66(1):43-52. 6. Avnir Y, Turjeman K, Tulchinsky D, Sigal A, Kizelsztein P, Tzemach D, Gabizon A, Barenholz Y. Fabrication principles and their contribution to the superior in vivo therapeutic efficacy of nano-liposomes remote loaded with glucocorticoids. PLoS One 2011;6(10):e25721. 7. Szebeni J, Muggia F, Gabizon A, Barenholz Y. Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and preven- tion. Adv Drug Deliv Rev 2011;63(12):1020-30. 8. Gabizon A, Shmeeda H, Baabur H, and Satchi-Fainaro R: Liposomes and polymers in folate-targeted cancer therapeutics. In Targeted Drug Strategies for Cancer and Inflamma- tion (Jackman A., and Leamon C. Eds.), 2011; Springer Publishers, New York, 217-247. 9. Petersen AL, Hansen AE, Gabizon A, Andresen TL. Liposome imaging agents in personal- ized medicine. Adv Drug Deliv Rev 2012;64(13):1417-35. 10. Gabizon A, Amitay Y, Tzemach D, Gorin J, Shmeeda H, Zalipsky S. Therapeutic efficacy of a lipid-based prodrug of mitomycin C in pegylated liposomes: studies with human gastro- entero-pancreatic ectopic tumor models. J Control Release 2012 ;160(2):245-53. 11. Gabizon A, Shmeeda H, Grenader T. Pharmacological basis of pegylated liposomal doxo- rubicin: impact on cancer therapy. Eur J Pharm Sci 2012;45(4):388-98. Clinical Oncology 1. Grenader T, Goldberg A, Hadas-Halperin I, and Gabizon A: “Long-term response to pe- gylated liposomal doxorubicin in patients with metastatic soft-tissue sarcomas”. Anti-Can- cer Drugs 2009; 20(1):15-20. 2. Grenader T, Goldberg A, and Gabizon A: “Combination therapy with oxaliplatin and 5-fluo- rouracil in a patient with severe hepatic dysfunction associated with metastatic adenocar- cinoma of the large bowel.” Anti-Cancer Drugs 2009; 20(9):845-847. Research Report 2013 70
    • 3. Grenader T, Gabizon A. What is the right way to administer pegylated liposomal doxorubi- cin in breast cancer therapy? J Clin Oncol 2010; 28 (12):e193-4. 4. Grenader T, Goldberg A, Gabizon A. Monitoring long-term treatment with pegylated lipo- somal doxorubicin: how important is intensive cardiac follow-up? Anticancer Drugs 2010; 21 (9):868-71. 5. Safra T, Borgato L, Nicoletto MO, Rolnitzky L, Pelles-Avraham S, Geva R, Donach ME, Curtin J, Novetsky A, Grenader T, Lai WC, Gabizon A, Boyd L, Muggia F. BRCA muta- tion status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol Cancer Ther 2011; 10 (10):2000-7. 6. Grenader T, Vernea F, Reinus C, Gabizon A. Malignant epithelioid hemangioendothelioma of the liver successfully treated with pegylated liposomal doxorubicin. J Clin Oncol 2011; 29 (25):e722-4. 7. Lowery M, Shah MA, Smyth E, Epstein A, Segal A, Rosengarten O, Isacson R, Drukker L, Keinan A, Rachkiman M, Reissman P, Gabizon A, Kelsen D, O’Reilly EM. A 67-year-old woman with BRCA 1 mutation associated with pancreatic adenocarcinoma. J Gastroin- test Cancer 2011; 42 (3):160-4. 8. Kwa M, Baumgartner R, Shavit L, Barash I, Michael J, Puzanov I, Kopolovic J, Rosen- garten O, Blank S, Curtin JP, Gabizon A, Muggia F. Is Renal Thrombotic Angiopathy a Potential Problem in the Chronic Treatment of Ovarian Cancer? Oncologist 2012. [Epub ahead of print]. 9. Agnelli G, George DJ, Kakkar AK, Fisher W, Lassen MR, Mismetti P, Mouret P, Chaudhari U, Lawson F, Turpie AG; SAVE-ONCO Investigators. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 2012; 366 (7):601-9. 10. La-Beck NM, Zamboni BA, Gabizon A, Schmeeda H, Amantea M, Gehrig PA, Zamboni WC. Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in pa- tients. Cancer Chemother Pharmacol 2012; 69 (1):43-50. 11. 11. Grenader T, Rosengarten O, Isacson R, Plotkin Y, and Gabizon A. Pegylated liposomal doxorubicin and carboplatin combination therapy in recurrent ovarian cancer, progress- ing on single agent pegylated liposomal doxorubicin. World J Clin Oncol 2012. In press. 71 Oncology
    • T he Integrated Oncology and Palliative Medicine De- partment, directed by Professor Nathan Cherny, was founded in 1994 and is considered to be one of the finest examples of integrated oncology and palliative care in the world. The Interdisciplinary Palliative Care Service is based in the oncology day hospital where it serves the needs of patients presenting for routine care. The palliative care ser- vice provides consultative advice or a shared care program with the treating oncologist depending on the needs of the oncologist and the prevailing problems. When the severity of symptoms is such that patients need to be admitted, the pal- liative care team reviews the patient on a daily basis and coor- dinates the care plan with the oncologist responsible for over- seeing the care and inpatient ward. The department has a broad view of interdisciplinary palliative care. The palliative care team consists of palliative care physicians, nurses, social workers, mental health clinicians, chaplaincy, massage and complementary medicine and music. Many patients with very advanced cancer can benefit from the input from these clinicians. One of the key roles of the palliative care nurse is the close liaison and monitoring of patients known to have significant problems who are being cared for in the community. When problems are identified, patients may be treated at home, they may at present for pal- liative care needs in the oncology day hospital or they may be admitted for intensive inpatient palliative care in the joint oncology and palliative care ward, Our continuity of care does not end with the death of the patient and we maintain a fol- Integrated Oncology Department Research Report 2013 72
    • low-up relationship with the surviving family members to support them during the bereave- ment process and with any other follow-up needs. The Cancer Pain and Palliative Medicine Service at Shaare Zedek has been a national leader on many fronts: the first integrated oncology and palliative medicine in Israel, the first to introduce a chaplaincy training program in Israel, the first to introduce free integrative thera- pies including massage and reflexology, the first to introduce harp therapy and art therapy to routine cancer care. In addition to advanced clinical care programs the department has a very strong internation- ally renowned educational program. Professor Nathan Cherny is the senior coeditor of the Ox- ford textbook of palliative medicine as well as the chair of the palliative care working group for the European Society of Medical Oncology. The model of care developed at Shaare Zedek has been the basis for a program for the designation of centers of excellence in integrated oncology and palliative care by the European Society of Medical Oncology around the world. Research activity Over the last five years the department has played a leading role in major multinational re- search initiatives. These include evaluating the barriers to availability and accessibility of mor- phine and related drugs for the management of strong cancer pain in Europe, formulary avail- ability and regulatory barriers to accessibility of opioids for cancer pain in Europe: a report by the ESMO/EAPC Opioid Policy Initiative, a pan-European study of the communication prac- tices of medical oncologists evaluates how they discuss bad news in difficult diagnoses with their patients and the factors that make some physicians reluctant to talk honestly with their patientsandtheethicsandmethodologyof thebestsupportivecarestudies.Ahugecollabora- tive project was, led by Prof. Cherny, involving 19 international oncology and palliative care organizations with data from over 90 countries and states on the availability and accessibility of opioids in Asia, Africa, the Middle East, the Caribbean and Latin America. Representative Research The charts below from the collaborative study on the accessibility of opioids show data from countries covering almost 5 billion of the world’s population, and the degree to which national drug formularies comply with the essential drug lists for medicines to relieve strong cancer pain from the WHO and the International Association for Hospice and Palliative Medicine. 73 Integrated Oncology
    • Publications 1. Cherny NI. Controversies in oncologist-patient communication: a nuanced approach to autonomy, culture, and paternalism. Oncology (Williston Park). 2012;26(1):37-43, 6. 2. Zafar SY, Currow DC, Cherny N, Strasser F, Fowler R, Abernethy AP. Consensus-based standards for best supportive care in clinical trials in advanced cancer. Lancet Oncol 2012;13(2):e77-82. 3. Caraceni A, Hanks G, Kaasa S, Bennett MI, Brunelli C, Cherny N, et al. Use of opioid anal- gesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol 2012;13(2):e58-68. 4. Cherny N. Is oral methadone better than placebo or other oral/transdermal opioids in the management of pain? Palliat Med 2011;25(5):488-93. Research Report 2013 74
    • 5. Cherny NI. [Mitigating the moral risks of private medicine in public hospitals (SHARAP) through regulation and accountability]. Harefuah. 2011;150(5):426-31, 92. 6. Cherny N. Best supportive care: a euphemism for no care or a standard of good care? Semin Oncol 2011;38(3):351-7. 7. Ponizovsky AM, Marom E, Zeldin A, Cherny NI. Trends in opioid analgesics consumption, Israel, 2000-2008. Eur J Clin Pharmacol 2011;67(2):165-8. 8. Cherny N. The oncologist’s role in delivering palliative care. Cancer J 2010;16(5):411-22. 9. Cherny N. The role of the oncologist in palliative care: from the guest editor. Cancer J 2010;16(5):410. 10. Cherny NI. Factors influencing the attitudes and behaviors of oncologists regarding the truthful disclosure of information to patients with advanced and incurable cancer. Psy- chooncology 2011;20(12):1269-84. 11. Cherny N. Taxonomy distress: including spiritual suffering and demoralization. J Support Oncol 2010;8(1):13-4. 12. Cherny NI, Baselga J, de Conno F, Radbruch L. Formulary availability and regulatory bar- riers to accessibility of opioids for cancer pain in Europe: a report from the ESMO/EAPC Opioid Policy Initiative. Ann Oncol 2010;21(3):615-26. 13. Cherny N. Cancer pain--progress and ongoing issues in Israel. Pain Res Manag 2009;14(5):356-7. 14. Cherny NI, Radbruch L. European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care. Palliat Med 2009;23(7):581-93. 15. Cherny N, Catane R, Schrijvers D, Kloke M, Strasser F. European Society for Medical On- cology (ESMO) Program for the integration of oncology and Palliative Care: a 5-year review of the Designated Centers’ incentive program. Ann Oncol 2010;21(2):362-9. 16. Cherny NI, Abernethy AP, Strasser F, Sapir R, Currow D, Zafar SY. Improving the meth- odologic and ethical validity of best supportive care studies in oncology: lessons from a systematic review. J Clin Oncol 2009;27(32):5476-86. 75 Integrated Oncology
    • 17. Cherny N. The use of sedation to relieve cancer patients’ suffering at the end of life: ad- dressing critical issues. Ann Oncol 2009;20(7):1153-5. 18. Ferris FD, Bruera E, Cherny N, Cummings C, Currow D, Dudgeon D, et al. Palliative cancer care a decade later: accomplishments, the need, next steps -- from the American Society of Clinical Oncology. J Clin Oncol 2009;27(18):3052-8. 19. Urban D, Cherny N, Catane R. The management of cancer pain in the elderly. Crit Rev Oncol Hematol 2010;73(2):176-83. 20. Breivik H, Cherny N, Collett B, de Conno F, Filbet M, Foubert AJ, et al. Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes. Ann Oncol 2009;20(8):1420-33. 21. Cherny NI. Stigma associated with “palliative care”: getting around it or getting over it. Cancer 2009;115(9):1808-12. Research Report 2013 76
    • T he Adult Nephrology Unit, directed by Dr. Itzchak Slotki, is staffed by two specialists, Dr. Linda Shavit and Dr. Ezra Gabbay, and an associate, Dr. Jawad Atrash. The Unit, founded in 1971 by one of the original de- signers of the arteriovenous fistula for chronic hemodialysis, thelateDr.BaruchHurwich,hasalongrecordofclinicalexcel- lence. In addition to the chronic hemodialysis unit, there is an ambulatory peritoneal dialysis unit, one of the largest in Isra- el. The Unit provides a comprehensive in-patient consult ser- vice covering all areas of nephrology, an outpatient general nephrology clinic, a pre-dialysis clinic and a hypertension clinic managed jointly with cardiologists. Areas of Research Activity Clinical research is a central focus of the Adult Nephrology Unit, with in-hospital, national and international collabora- tive projects in progress. In addition to the Unit physicians, there is a part-time research nurse. Residents in Internal Medicine and medical students conduct projects as part of their training or qualification requirements. The main areas of research include the prevention and treatment of vascular access clotting (grafts and central venous catheters, CVC) in hemodialysis,protocolsforreducingacutekidneyinjury(AKI) aftercoronaryangiography,theearlyidentificationofAKIina variety of settings, methods to improve anemia management indialysispatients(internationalmulticenterstudy)andethi- cal issues related to the provision of dialysis to patients with multiple comorbidities and limited life expectancy. Nephrology Unit 77 Nephrology
    • The main outcomes from the most recent research work include a simple efficient protocol using urokinase for bedside declotting of CVC, enoxaparin for reducing the frequency of an- giographicprocedurestomaintainA-Vgraftpatency,anduseoftheurinarybiomarkerneutro- phil gelatinase associated lipocalin (NGAL) for early identification of AKI and as a prognostic marker after major non-cardiac surgery. Representative Research An important ongoing project is our participation (Dr. Slotki is the Principal Investigator) in an international multicenter randomized controlled phase 2- trial to examine the effect of a monoclonal antibody to TGF beta, the principal driver of kidney scarring, in slowing the progression of diabetic nephropathy (DN). DN is the main cause of end stage kidney disease both in Israel (50% of patients with chronic kidney disease, CKD) and the rest of the developed world. We are also looking at outcomes of octogenarians who have undergone cardiac surgery and who developed AKI post-operatively. In the field of medical ethics we are embarking on a study of outcomes following dialysis initiation in patients with AKI against a background of multiple acute and chronic comorbidities with a view to identifying patients who might not benefit from dialysis. Finally, we are also examining the effects of vitamin D deficiency on mortality and progression in patients with CKD. Given that a vitamin D deficiency is found in 90% of CKD patients, the ultimate aim of this work is to see whether repletion of vitamin D levels can improve outcomes in this group of patients. PUBLICATIONS 1. Shavit L, Korenfeld R, Lifschitz M, Butnaru A and Slotki I. Sodium bicarbonate versus sodium chloride and oral N-acetylcysteine for the prevention of contrast induced acute kidney injury in advanced chronic kidney disease. Journal of Interventional Cardiology 2009; 22:556-63. 2. Shavit L, Reinus C and Slotki I. Severe renal failure and microangiopathic hemolysis in- duced by malignant hypertension: case series and review of literature. Clinical Nephrology 2009; 73:147-52. 3. Gabbay E, Calvo-Broce J, Meyer KB,Trikalinos TA, Cohen J, Kent DM. The empirical basis for determinations of medical futility. J Gen Intern Med 2010; 25:1083-9. Research Report 2013 78
    • 4. Gabbay E, Meyer KB, Griffith JL, Richardson MM, Miskulin DC. Temporal trends in health- related quality of life among hemodialysis patients in the United States. Clin J Am Soc Nephrol 2010; 5:261-7. 5. Shavit L, Lifschitz M, Lee,S and Slotki I. Use of Enoxaparin to Diminish the Incidence of Vascular Access Procedures in chronic Hemodialysis Patients. Int Urol Nephrol 2011; 43: 499-505. 6. Shavit L, Lifschitz MD, Plaksin J, Grenader T and Slotki I. High dose Urokinase for restora- tion of patency of occluded permanent central venous catheters in hemodialysis patients. Clinical Nephrology 2011; 74:297-302. 7. Shavit L, Bar- Lev M, Lifschitz MD, Fink D, Rudensky B and Slotki I. Prevalence and clini- cal significance of heparin induced antibodies in chronic hemodialysis patients and cardiac surgery patients. Int J Artif Org 2011; 34:1172-8. 8. Shavit L, Dolgoker I, Ivgi H, Assous M, Slotki I. Neutrophil gelatinase-associated lipocalin as a predictor of complications and mortality in patients undergoing non-cardiac major surgery. Kidney Blood Press Res 2011; 34: 116-124. 9. Shavit L, Neykin D, Lifschitz M, Slotki I N. Effect of Eplerenone on Blood Pressure and the Renin-Angiotensin- Aldosterone System in Oligo-Anuric Hemodialysis Patients. Clinical Nephrology 2011; 76:388-95. 10. Shavit L, Lifschitz M, Slotki I. Hypothesis: Hypoparathyroidism in dialysis patients causes hypophosphatemia. Clinical Nephrology 2011, accepted for publication. 11. Shavit L, Tauber R, Lifschitz M, Bitran D, Slotki I, Fink D. Influence of minimal changes in preoperative renal function on outcomes of cardiac surgery. Kidney Blood Press Res 2011; 35: 400-406. 12. Slotki, I and Skorecki KL. Disorders of Sodium. In Brenner and Rector’s The Kidney, 9th edition, eds. Taal, M.W, Chertow G.M., Marsden, P.A., Yu, A.S.L. and Brenner, B, Elsevier, 2011. 13. Schumacher U, Nehmann N, Adam E, Mukthar D, Slotki IN, Horny HP, Flens MJ, Schlegelberger B, Steinemann D. MDR-1-overexpression in HT 29 colon cancer cells grown in SID mice. Acta Histochem 2012; 114(6):594-602. 79 Nephrology
    • 14. Gabbay E, Meyer KB. Kidney failure treatment: the freedom to choose. Am J Kidney Dis 2012; 60:5-7. 15. Shavit L, Grenader T, Slotki I. Pregabalin as a potential therapy for intractable itching in chronic hemodialysis patients. J Pain Symptom Manage 2012; accepted for publication. 16. Shavit L, Lifschitz M, Epstein, M. Aldosterone blockade and the mineralocorticoid receptor in the management of chronic kidney disease: current concepts and emerging treatment paradigms. Kidney Int 2012; 81: 955-68. Published Abstracts 1. Shavit L, Neykin D, Lifschitz M, Slotki, I. Effect of Eplerenone on Blood Pressure and the Renin-Angiotensin- Aldosterone System in Oligo-Anuric Hemodialysis Patients. J Am Soc Nephrol 2009; 20:592A. Research Report 2013 80
    • T he Neurology and Toxicology Service and Unit, headed by Professor Yoram Finkelstein, are directed indepen- dently, admitting patients to various hospital depart- ments when required. Ongoing services are provided in the neurology and IDF outpatient clinics. Neurological consulta- tions are provided in the hospital departments. Academic in- structionandresearchactivitiestakeplaceattheHebrewUni- versity of Jerusalem and other universities in Israel and abroad. Clinical activity in the field of neurology and neurotoxicology is combined with basic, clinical and epidemiological research. Neurotoxicology provides a for a better understanding of the relationships between exposure to toxic compounds, the amount of the compound that reaches the brain and other target tissues, and the development of clinical manifesta- tions of toxicity (e.g. Parkinsonism, dementia). Understand- ing the mechanisms of nervous system toxicity may enable better predictions of the toxic outcomes in different types of exposure situations. Neurobehavioral evaluation and tests of highercognitivefunctionsmayfindapplicationinriskassess- ment in both environmental and occupational settings. Use- ful tools are advanced imaging techniques (e.g. CT, MRI and fMRI) and electrophysiological assessment (e.g. EEG, Nerve Conduction Studies and Evoked Potentials). This combined approach of clinical neurology and basic neurotoxicology pro- motes the diagnosis, prevention and treatment of diseases of occupational toxicity in the individual patient. It also im- proves monitoring of environmental health hazards at the Is- Neurology and Toxicology Service and Unit 81 Neurology & Toxicology
    • raeli national level. Public medical activities include consulting community groups exposed to industrial pollution hazards, mainly in the Bay of Haifa and the Kishon River Basin. Areas of research activity Based on original clinical and basic research, the Neurology and Toxicology Service and Unit have established a widely-accepted standard clinical protocol for the treatment of severe acute cases of organophosphorous pesticide poisoning. Studies deal with the underlying nature of pesticides and their specific patterns of intoxication in the human brain. Other studies have examined lead poisoning in children and movement disorders, e.g. the possible association of mercury and manganese with Parkinson’s disease and the possible association of selenium, heavy metals and pesticides with motor neuron disease (Lou Gehrig’s disease). The Neurology and Toxicology Service and Unit carried out a project for re-assessing the neuro-behavioral status of a cohort of several hundred kibbutz workers, residents and their children who have continuously been exposed to pesticide drift. The same cohort was initially examined three decades ago. Genetic determinants of each individual were studied. Current exposures were assessed by measuring urinary metabolites of pesticides. Simultaneously, at- mospheric stations monitored the levels of pesticides and their degradation products in the air, in collaboration with the Technion – Israel Institute of Technology in Haifa. These three studies are pioneering in many repects. The techniques of clinical evaluation, neurobehavioral examination and didactic tests, electrophysiology, biochemistry, genetics, biological parameters of exposure and epidemiology were employed. We collected data and developed a unique and extensive database for three different populations living in this rural area, in addition to an additional population of children living in a rural area in which organic agriculture is employed. The studies were presented at two consecutive meetings of the American Academy of Neurol- ogy and were selected as “Highlights in the Field”. All of these complex projects have provided a firm scientific and institutional basis for clinical neurotoxicology in Israel. Prof. Finkelstein organized and chaired the 12th Meeting of the International Neurotoxicology Association on gene-environment interactions. This meeting in Jerusalem was a critical tipping point for ad- vancing neurobehavioral toxicology in Israel. Representative Research The Hula Valley has been extensively cultivated since 1957. Organophosphorous (OP) pesti- cides have been widely used for pest control in orchards and crop fields in the Hula. Previous Research Report 2013 82
    • studies in 1984-1991 showed in-season reversible neurobehavioral effects of low-level, long- term exposure to OP pesticides in a cohort of 214 residents and agricultural workers in several kibbutzim in the Hula Valley. The study assessed several health effects and neurobehavioral, cognitive, electrophysiological and genetic outcomes in: (a) Individuals in the original adult cohort (n=139). Eighty-seven (62.5%) of them are still residing in the valley; (b) A cross sec- tional study of cognitive and neurobehavioral functioning in 8-12 year-old “second genera- tion” schoolchildren (n=135) in families with 30-year exposures in these communities. Cognitive tests were conducted and subjective symptom questionnaires were administered. Questionnaire for exposures and health effects were employed as well. The school children’s study included the same cognitive tests, and psycho-didactic tests. Features of electrical activ- ity were measured along the neural pathways of both the Central and Peripheral Nervous Sys- tems in adults. Blood or saliva was sampled in both studies to measure Paraoxonase-1 (PON1) gene polymorphisms that may affect individual susceptibility to OP toxicity. Urinary samples were collected in both studies during and following the spraying seasons over a period of three years to measure the quantities of OP metabolites. The results showed neurotoxic effects of chronic exposure of adults and children to pesticides. Manual dexterity was more impaired in adults than in children. Implicit signs of polyneuropathy (impaired function of peripheral nerves) were observed in the adults. There were suggestions of environmental-susceptibility interactions mediating the risk for Attention Deficit Hyperactivity Disorder (ADHD) in chil- dren with low-level endemic exposure to pesticides. 02-6666034 83 Neurology & Toxicology
    • PUBLICATIONS 1. Fitsanakis VA, Finkelstein Y, Aschner M. Changes in Dietary Iron Levels Affect Brain Man- ganese Accumulation and Distribution. Cell Biol Toxicol 2009; 25:185-189. 2. Aschner M, Finkelstein Y. Manganese Transport: Relationship to Iron. In: M Szilágyi, K Szentmihályi, K (Eds.) 3rd International Symposium on Trace Elements in the Food Chain – Delivery or Excess of Trace Elements in the Environment as a Risk of Health. Working Committee on Trace Elements of the Hungarian Academy of Sciences (HAS), Institute of Material and Environmental Chemistry of the HAS, Budapest, Hungary, 2009; 397-401. 3. Finkelstein Y, Zhang N, Fitsanakis VA, Avison M J, Gore JC, Aschner M. Differential de- position of manganese in the rat brain following subchronic exposure to manganese: a T1-weighted MRI. Isr Med Assoc J 2009;10:793-798. 4. Finkelstein Y, Ophir A, Aschner M, Richter ED. Is there a consistent cognitive and neurobe- havioral pattern of toxicity following acute, delayed or chronic exposures to organophos- phates? Neurotoxicology, 2010; 31:608-612. 5. FinkelsteinY, Milatovic D, Lazarovici P, Ophir A, Richter ED, Aschner M, Lecht S, Mar- cinkiewicz C, Lelkes PI, Zaja-Milatovic S, Gupta RC, Brodsky B, Rosengarten A, Proscura E, Shapira E, Wormser U. Peaceful Use of Disastrous Neurotoxicants, Neurotoxicology 2010;31 :608-620. 6. Finkelstein Y, Fox DA, Aschner M, Boyes WK. Gene–environment interactions in neuro- toxicology: The 12th biennial meeting of the International Neurotoxicology Association. Neurotoxicology 2010; 31:543-544. 7. Mir DF, Finkelstein Y, Tulipano G. Impact of integrated pest management (IPM) training on reducing pesticide exposure in Illinois childcare centers. NeuroToxicology 2010; 31:621- 626. 8. Stein Y, Finkelstein Y, Levy-Nativ O, Bonne O, Aschner M, Richter, E D. Exposure and sus- ceptibility: schizophrenia in a young man following prolonged high exposures to organic Research Report 2013 84
    • solvents. Neurotoxicology 2010; 31:603-7. 9. 9. Finkelstein, Y., Richter, E.D. and Aschner, M. Epidemiological and Clinical Studies on Acute and Chronic Organophosphate-Induced Neurotoxicity in Israel. In: T Satoh and R C Gupta (Eds.) Anticholinesterase Pesticides: Metabolism, Neurotoxicity, and Epidemiology. Hoboken, N.J.: John Wiley & Sons, 2011; Chapter 31, pp. 447-456. 10. Zarfin Y, Yefet E, Abozaid S, Nasser W, Mor T, Finkelstein Y. Infant with Altered Conscious- ness after Cannabis passive Inhalation. Child Abuse and Neglect 2012; 36:81-3. 11. Vinceti M, Bottecchi I, Fan A, Finkelstein Y, Mandrioli J. Are environmental exposures to selenium, heavy metals and pesticides risk factors for amyotrophic lateral sclerosis? Rev Environ Health 2012; 27:19-41. 12. Wormser U, Brodsky B, Milatovic D, Finkelstein Y, Farina M, Rocha JB, Aschner, M. Pro- tective effect of a novel peptide against methylmercury-induced toxicity in rat primary astrocytes. Neurotoxicology 2012; 33:763-8. Published Abstracts 1. Finkelstein Y, Ophir A, Aschner M, Richter ED. Organophosphates-related neurobehav- ioral toxicology – the Israeli experience. International Conference on Preventing Emerging Occupational Risks in South Asia and Beyond, World Health Organization in collaboration with Collegium Ramazzini and Drexel University 2009; New Delhi, India. Abst. p. 42. 2. Finkelstein Y, Ophir A, Richter ED. Hazards of Low-Level Long-Term Exposure to Organo- phosphates: is Neurotoxicity Permanent? The 28th scientific meeting of Israel Society of Toxicology, Beer-Sheva, Israel. 2009;Abst. p. 9. 3. Finkelstein Y, Ophir A, Aschner M, Richter, ED. Low-level long-term exposure to organo- phosphates: what are the consequences after 30 years? The Annual Meeting of the Israel Neurological Association, Ein Bokek, Israel 2009;Abst. P. 44. 4. Ophir A, Richter ED, Wormser U, Finkelstein Y. Neurotoxicity of organophosphorous pes- ticides: lessons from three-decade study. Annual Symposium, Institute of Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Israel 2009;Abst. p. 71. 85 Neurology & Toxicology
    • 5. Finkelstein Y, Ophir A, Richter ED. Are the Neurotoxic Effects of Low-Level Long-Term Ex- posure to Organophosphates Permanent? INA-12, the 12th Meeting of the International Neurotoxicology Association, Jerusalem, Israel 2009; Abst. p. 26. 6. Bonne O, Cohen A, Levy-Nativ O, Stein Y, Finkelstein Y, Richter, ED. Exposure and sus- ceptibility: Schizophrenia in a young man following prolonged high exposure to organic solvents. INA-12, the 12th Meeting of the International Neurotoxicology Association, Je- rusalem, Israel 2009; Abst. p. 33 7. Mir DF, Tulipano GD, Rosenberg R, Kerzee R, Wagner J, Finkelstein Y. Impact of IPM train- ing in Illinois childcare centers. INA-12, the 12th Meeting of the International Neurotoxicol- ogy Association, Jerusalem, Israel 2009; Abst. p. 52. 8. Richter ED, Aschner M, Ophir A, Finkelstein Y. Work in progress - Long term community exposure to drift containing organophosphate pesticides (OP) – are there neurobehavioral effects after three decades? …and what about the children? Annual Ramazzini Days 2009 Carpi, Italy 2009;Abst. p. 10. 9. Finkelstein Y, Aschner M, Ophir A, Richter ED. Health Hazards of Exposures to Organo- phosphates. Symposium on Minimizing the Hazards of Toxic Substances and Pesticides in Agriculture (organized by the Chief Scientist, Israel Ministry of Environmental Protection) Bet Dagan, Israel 2010. 10. Finkelstein Y, Aschner M, Ophir A, and Richter ED. Cognitive effects induced by chronic exposure to sprayed organophosphorous pesticides. The Annual Meeting of the Israel Neurological Association, Eilat, Israel. J Isr Neurol Assoc 2010; 4:57. 11. Finkelstein Y, Dubowski Y, Ophir A, Zivan O, Aschner M, Segal-Rosenhaimer M, Bar-Ilan I, Doitsch E, Richter ED. Neurological changes in children induced by sprayed organo- phosphorous pesticides and the atmospheric variables contributing to it. Innovations and Future Directions in Health and Environment Research in Israel, Environment and Health Fund Symposium, Jerusalem, Israel 2010. 12. Ophir A, Richter ED, Aschner M, Wormser U, Finkelstein Y. Neurobehavioral effects of low-level exposure to organophosphorous pesticides after three decades. Annual Sym- posium, Institute of Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Israel. 2010;Abst. p. 46. 13. Finkelstein, Y., Aschner M, Ophir A, Wormser U, Richter ED. In-community study of long Research Report 2013 86
    • term low level exposure to organophosphate pesticides – are there neurobehavioral ef- fects after three decades? 49th Meeting of the Society of Toxicology (SOT), Salt Lake City, UT, USA. The Toxicologist 2010; 114: 269. 14. Finkelstein Y, Aschner, M., Ophir, A., and Richter, E.D. (2010) Long-term Community Ex- posure to Drift Containing Organophosphate Pesticides (OP) – are there Neurobehavioral Effects after Three Decades? Selected for presentation as a Highlight in the Field of Neuro-epidemiology at the 62nd Annual Meeting of the American Academy of Neurology, Totonto, Canada. Neurology (2010) 74 (Suppl. 2):A53. 15. Finkelstein Y. Impairment of the nervous system due to long-term low- Labor. Conference for Preventive Action, and Research in Health and Safety at Work, Maale Hachamisha, Israel 2010; Abst. pp. 20-21. 16. Richter ED, Berman T, Ophir A, Finkelstein Y. Pesticides: Toxicology, Cancer, Epidemiol- ogy and Preventive Strategies. The International Conference of Preventive Medicine and Public Health, Pécs University in conjunction with Collegium Ramazzini, Pécs, Hungary. 2010;Abst. p. 44. 17. Finkelstein Y, Ophir A, Aschner M, Doitsch E, Wormser U, Richter ED. Three decades of low-level exposure to sprayed organophosphates: neurobehavioral outcomes in agricul- tural workers and residents of rural communities. 50th Annual Meeting of the Society of Toxicology, Washington DC. The Toxicologist 2011; 120:258. 18. Finkelstein Y, Ophir A, Aschner M, Doitsch J, Abarbanel M, Wormser U, Richter ED. What can be learned over three decades on the cognitive changes induced by sprayed organophosphorous pesticides? Selected for presentation as a Highlight in the Field of Neuro-epidemiology at the 63rd Annual Meeting of the American Academy of Neurology, Honolulu, HI, USA. Neurology 2011; 76 (Suppl. 4):A470. 19. Finkelstein Y, Ophir A, Richter E, Doitsch E, Wormser U, Aschner M. Neurobehavioral exposure-effect gradient in schoolchildren chronically exposed to pesticides. The Annual Meeting of the Israel Neurological Association, Jerusalem, Israel. J Isr Neurol. Assoc 2011; 8:54. 20. Ophir A, Richter E, Doitsch E, Wormser U, Finkelstein Y. Neurobehavioral effects in school- children chronically exposed to environmental pesticides. First Annual Israel Graduate Stu- dent Symposium on Environmental Health, Technion, IIT, Haifa, Israel 2011. 87 Neurology & Toxicology
    • 21. Zarfin Y, Yefet E, Abozaid S, Nassaer W, Finkelstein Y. Gentamicin and Apnea in Neo- nates. Meeting of the Israel Society of Clinical Pharmacology, Zrifin, Israel 2011; Abst. p. 5. 22. Finkelstein Y, Ophir A, Wormser U, Doitsch E, Aschner M, Richter E. Exposure-effect gra- dient in schoolchildren chronically exposed to pesticides. Annual Ramazzini Days. Carpi, Italy 2011; Abst. p. 15. 23. Ophir A, Richter ED, Aschner M, Doitsch E, Wormser U, Finkelstein Y. Persistent neuro- logical effects in schoolchildren and adult after three decades of exposure to drift contain- ing organophosphorous pesticides. 23rd Annual Conference - International Society for Environmental Epidemiology, Barcelona, Spain. Environmental Health Perspectives 2011. 24. Finkelstein Y. Long-Term Community Exposure to Organophosphate Drift: Are There Neu- robehavioral Effects after Three Decades?  Preliminary Data from Israel. Organics Core Seminar, Harvard School of Public Health – National Institute of Environmental Health Sci- ences (HSPH-NIHES) Center, Boston, MA, USA. 2012. 25. Finkelstein Y, Ophir A, Richter E, Doitsch E, Wormser U, Aschner M. Neurobehavioral exposure-effect gradient in parents and children: three-decade study of exposure to or- ganophosphate drift. The Annual Meeting of the Israel Neurological Association, Jerusa- lem, Israel. J Isr Neurol Assoc 2012; 12:72. 26. Finkelstein Y. Parents and children: two generations of exposure to organophosphates in kibbutzim. Chief Scientist’s Lecture, Israel Ministry of Environmental Protection 2012. 27. Finkelstein Y, Ophir A, Richter E, Doitsch E, Wormser U, Aschner M. Neurobehavioral exposure-effect gradient in schoolchildren chronically exposed to pesticides. Society of Toxicology Annual Meeting, San Francisco, CA, USA. The Toxicologist 2012;126:84. 28. Ophir A, Doitsch E, Wormser U, Aschner M, Richter E, Finkelstein Y. Exposure-effect gra- dient in two generations of exposure to pesticides. 24th Annual Conference - International Society for Environmental Epidemiology, Columbia, South Carolina, USA. Epidemiology 2012; 23:S484. 29. Finkelstein Y, Ophir A, Doitsch E, Aschner M, Wormser U, Richter E. Exposure-effect gra- dient in the neurobehavior or schoolchildren endemically exposed to pesticides. 24th An- nual Conference - International Society for Environmental Epidemiology, Columbia, South Carolina, USA. Epidemiology 2012; 23: S371. Research Report 2013 88
    • 30. Wormser U, Aschner M, Finkelstein Y, Proscura E, Erlanger-Rosengarten A, Shapira E, Brodsky B. Transgenic mice constitutively expressing H2A histone fragment are resistant to chemical-induced bowel inflammation. 51st Annual Meeting of the Society of Toxicol- ogy. San Francisco, CA. The Toxicologist 2012;126:156. 31. Mir D, Finkelstein Y, Bar llan I, Doitsch E. Assessment of Young Children’s Exposure to Hazardous Chemicals especially Neurotoxicants, in Pre-Schools, Kindergartens and Homes in Northern Israel. Environment and Health Fund conference: From Science to Policy – Environment and Health in Israel. Tel Aviv, Israel 2012; Abst. p. 31. 32. Richter ED, Stein Y, Michael K, Finkelstein Y, Stanton GH. The Precautionary Principle and Genocide Prevention. Annual Ramazzini Days Carpi, Italy 2012;Abst. p. 23. 33. Finkelstein Y, Ophir A, Wormser U, Doitsch E, Aschner M, Richter E. Parents and children: exposure-effect gradient two generations of exposure to pesticides in Israeli kibbutzim Annual Ramazzini Days Carpi, Italy 2012;Abst. p. 12. 34. Finkelstein Y, Ophir A, Doitsch E, Wormser U, Aschner M, Richter E. Neurobehavioral exposure-effect gradient in schoolchildren chronically exposed to pesticides. The Annual Meeting of the Israel Neurological Association, Jerusalem, Israel. J Isr Neurol Assoc 2012; 8:55. 35. Mir D, Finkelstein Y, Bar llan I, Doitsch E, Rosen D. Assessment of Young Children’s Expo- sure to Hazardous Chemicals especially Neurotoxins, in Pre-Schools, Kindergartens and Homes in Northern Israel. 40th Annual Conference of the Israel Society of Ecology and Environmental Sciences, Tel Aviv, Israel 2012; Abst. pp. 3-4. 36. Finkelstein Y. Environmental exposure to organophosphate pesticides: neurobehavioral effects in adults and children. Centro di Ricerca in Epidemiologia Ambientale, Genetica e Nutrizionale (CREAGEN), Dipartimento di Scienze di Sanita Pubblica, Universita degli Studi di Modena e Reggio Emilia, Modena, Italy 2012. 37. Wormser U, Aschner M, Finkelstein Y, Proscura E, Brodsky B, Shapira E. A Novel anti- inflammatory peptide: Potential therapy of sepsis induced by bacterial endotoxin. Society of Toxicology Annual Meeting, San Antonio, TX, USA. The Toxicologist 2013. 38. Finkelstein Y, Ophir A, Wormser U, Doitsch E, Aschner M, Richter E. Neurotoxic hazards in schoolchildren – second generation of chronic exposure to organophosphorous drifts. International Commission on Occupational Health – Scientific Committee on Neurotoxicol- 89 Neurology & Toxicology
    • ogy and Psychophysiology, Cape Town, South Africa 2013. 39. Finkelstein Y. Attention deficit disorder in schoolchildren – second generation of expo- sure to organophosphorous drifts. Joint American-Israeli medical Toxicology Confrerence, Haifa, Israel 2013 (accepted). 40. Ophir A, Richter E, Finkelstein Y. 30-year study on effects of pesticides in human. Annual Meeting of Research and Development in Northern Israel. Kiriat Shmona, Israel 2013. Abst. p.5. Research Report 2013 90
    • T he Adult Pulmonary Institute, directed by Dr. Gabriel Izbicki, is staffed by four additional senior physicians - Dr. Nissim Arish, Dr. Abraham Bohadana, Dr. Clement Cahan and Dr. Ariel Rokach - and one associate- Dr. Chava Azulay. Two nurses, one bronchoscopy technician, two lung function technicians and six respiratory technicians complete the team. The Adult Pulmonary Institute deals with a broad range of pulmonary diseases. Pulmonary consulting is provided in the hospital five days a week. The physicians also work in com- munity pulmonary clinics. The services cover a broad range of pulmonary diseases: asthma, chronic obstructive pulmo- nary disease, bronchiectasis, chronic cough, infectious lung disease, inflammatory lung disease, interstitial lung disease, tumors, etc. We also run a special stop smoking clinic that provides group therapy and individual therapy for smokers interested in quitting. In this clinic we also treat smoking- related pulmonary diseases. The Pulmonary Institute runs a pulmonary function test lab- oratory for in and outpatients. The Pulmonary Institute has a bronchoscopy suite with advanced equipment for diagnos- tic and therapeutic procedures, including bronchial biopsies, lymph node, and lung tissue biopsies. Invasive procedures are performed with laser. Removal of foreign bodies from the re- spiratory tract is also performed. The bronchoscopy suite is equipped with advanced bronchoscopic ultrasound for medi- astinal lymph node biopsies (EBUS). Pulmonary Unit 91 Pulmonology
    • The unit provides assistance to all departments in the hospital, including recommendations on invasive and non-invasive ventilation and works in close collaboration with the Oncology Institute, the Radiology Department, the Thoracic Surgery unit and the Pathology Institute. Two meetings are held every week with the Radiology and Pathology Departments. The first, called the “Tumor-board”, discusses cases of thoracic tumors or other surgical cases currently under evaluation. The second deals with non-surgical patients and addresses differential diag- nosis issues. The Adult Pulmonary unit works closely with the Cardiology Department, espe- cially in the context of patients with pulmonary hypertension. The unit also works in tandem with the Institute of Physical Therapy, which runs pulmonary rehabilitation programs for 25 groups of patients diagnosed with COPD and other chronic lung diseases. During pulmonary rehabilitation, patients strengthen the skeletal and respira- tory muscles, and the cardiovascular system. Enrolled patients receive dietary advice, medical advice and psychological support. The Adult Pulmonary unit also works with the Pediatric Pulmonary unit. Together, we hold meetings and seminars that enrich our knowledge and allow better care for patients with com- plex problems. The Adult Pulmonary unit is part of the Internal Medicine Department. We teach medical students (fourth and sixth year students) and conduct independent studies. Research Report 2013 92
    • The Pulmonary Institute also runs a sleep laboratory directed by Dr. Clement Cahan and chief technician Edwina Swed RPSGT with two additional senior physicians: Dr. Shmuel Goldberg (a specialist in pediatric pulmonology) and Prof. Ruth Shalev (a specialist in pediatric neurol- ogy). The sleep laboratory, which is Health Ministry accredited, treats a wide range of sleep and sleep-breathing disorders. The tests performed in the Sleep Laboratory include full poly- somnograms, an ambulatory sleep test that controls for airflow, breathing effort, EKG and oxygen saturation, the NPT (Nocturnal Penile Tumescence) using a Rigiscan, tests for Erectile Dysfunction,the MWT (Maintenance of Wakefulness Test) a daytime test to examine the like- lihood of falling asleep/staying awake in conditions conducive to sleep, and the MSLT (Mul- tiple Sleep Latency Test) that tests for levels of drowsiness during the day and the diagnosis of Narcolepsy. The laboratory also carries out CPAP (continuous positive airway pressure) and BiPAP (Bi level positive airway pressure) titrations on patients with sleep apnea and/ or chronic lung disease. PUBLICATIONS 1. Hersch M, Einav S, Izbicki G. Accuracy and ease of use of a novel electronic urine output monitoring device compared with standard manual urinometer in the intensive care unit. J Crit Care 2009; 24:629 e13-7. 2. Izbicki G, Ben-Dor I, Shitrit D, Bendayan D, Aldrich TK, Kornowski R, Kramer MR.The prevalence of coronary artery disease in end-stage pulmonary disease: Is pulmonary fibro- sis a risk factor? Respir Med 2009; 103: 1346-9. 3. Rokach A, Nemet D, Dudkiewicz M, Albalansi A, Pinkert M, Schwartz D, Bar-Dayan Y. Advanced Rescue Techniques May Save Lives- Lesson Learned From Building Collapse in Nairobi Kenya. Disasters 2009; 33(2):171-9. 4. Rokach A, Cohen R, Shapira N, Einav S, Mandibura A, Bar-Dayan Y. Preparedness for Anthrax Attack- The effect of knowledge on willingness to Treat Patients. Disasters 2010; 34(3):637-43. 5. Goldberg S, Schwartz S, Mimouni F, Stankiewicz H, Izbicki G, Picard E. Does sweat vol- ume influence the sweat test result? Arch Dis Child 2010; 95: 377-81. 93 Pulmonology
    • 6. Oberbaum M, Spira RM, Lukasiewicz E, Armon Y, Samuels N, Singer SR, Barak V, Izbicki G, Einav S, Hersch M. Beneficial effect of Traumeel S on the course of CLP- induced sepsis in rats: A pilot study. Journal of Alternative and Complementary Medicine. 2010;. Oct;17(10):909-13 Banauch GI, Brantly M, Izbicki G, Hall C, Shanske A, Chavko R, San- thyadka G, Christodoulou V, Weiden MD, Prezant DJ. Accelerated spirometric decline in Alpha-1 Antitrypsin deficient New York City firefighters. Chest 2010; 138:1116-24. 7. Furer V, Raveh D, Picard E, Goldberg S, Izbicki G. Absence of leukocytosis in bacteremic pneumococcal pneumonia. Prim Care Respir J 2011; 20: 276-81. 8. Maayan H, Ashkenazi Y, Nagler A, Izbicki G. Sarcoidosis and lymphoma: Case series and literature review. Sarcoidosis Vasc Diffuse Lung Dis 2011; 28: 146-52. 9. Izbicki G, Grosman A, Weiler Z, Shulimzon T, Laxer U, Fink G. Nati Onal Asthma obser- vational survey of severe asthmatics in Israel: the NO-AIR study. The Allergy, Asthma, Clin Immunol 2012; in press. 10. Goldberg S, Mimouni F, Joseph L, Izbicki G, Picard E. Seasonal effect on exercise-chal- lenge tests for the diagnosis of exercise-induced bronchoconstriction. Allergy and Asthma Proceedings, 2012; in press. Research Report 2013 94
    • T he Neurology Department, directed by Dr. Isabelle Korn-Lubetzki, is staffed by five neurologists: Dr. Bettina Steiner Birmanns, Dr. Marina Dano, Dr. Yehuda Benasouli and Dr. Adel Misk. The services provided by the Department include care of patients with neurological diseases, neurological consultations for all patients with neu- rological problems hospitalized in the hospital, an outpatient neurological clinic and electrophysiological interventions performed in the Neurological Institute. The clinic deals in particular with the neurological problems of adolescents / young women, attention deficit hyperactivity disorders in adolescents/young adults, epilepsy, headaches, strokes, multiple sclerosis, and autoimmune neurological diseases. In the Neurological Institute about 1800 electrophysiological interventions are performed annually including digital EEG, evoked potentials, nerve conduction studies and electromyo- gram, repetitive stimulations. Research activity In recent years the Department has conducted studies on dif- ferent aspects of stroke/ ischemic stroke, in various settings suchasduringandaftercardiacproceduresorcardiacsurgery. The Department takes part in the tri-annual national acute stroke survey in Israel (NASIS). The database accumulated in the NASIS can provide answers to specific questions such as Neurology Department 95 Neurology
    • the prognosis of posterior fossa strokes. The Department takes part as well in multicenter prospective studies assessing the efficacy of medications used for multiple sclerosis. Representative Research AjointstudyconductedwiththeDepartmentofHeartSurgeryshowedthatstrokesafterheart surgery were mostly located in the right hemisphere and had a rather good prognosis. Sur- prisingly, while most of the patients after surgery receive anticoagulant therapy and suffer from vascular risk factors, none of them developed intra-cerebral hemorrhage. Furthermore we demonstrated that when reviewing all the heart surgeries performed over a 20 year period, and looking for a risk factor leading to post operative stroke, only intra-operative hypothermia was significant. Although hypothermia is routinely used to prevent neurological complica- tions, this study showed that lowering the temperature too much was not protective and was even associated with ischemic strokes. We are in the process of finishing a collaborative study with the Cardiology Department designed to identify ischemic neurological complications oc- curring after heart catheterization. The study includes all cardiac catheterizations performed over a 19 year period and includes 43350 procedures performed on 30907 procedure days. PUBLICATIONS 1. Koton S, Bornstein NM, Tsabari R, Tanne D, NASIS Investigators. Derivation and vali- dation of the prolonged length of stay score in acute stroke patients. Neurology. 2010; 11;74:1511-6. 2. Korn-Lubetzki I , Steiner I, Oren A, Tauber R, Steiner-Birmanns B, Bitran D.The possible risk for strokes complicating cardiac surgery in patients with intraoperative hypothermia. Cerebrovasc Dis 2010;30:602-605. 3. Korn-Lubetzki I , Oren A, Tauber R, Steiner-Birmanns B, Bitran D. No Symptomatic Intra- cerebral Hemorrhage after Cardiac Surgery. A 14-Year Retrospective Study. Eur Neurol 2010; 64:351-354. 4. Gelfin E, Kaufman Y, Korn-Lubetzki I , Bloch B, Kremer I, Javitt DC, Heresco-Levy U. D-SERINE adjuvant treatment alleviates behavioural and motor symptoms in Parkinson’s disease. Int J Neuropsychopharmacol. 2011; 7:1-7. Research Report 2013 96
    • 5. Korn-Lubetzki I, Steiner I. Common Movement Disorders in Children: Diagnosis, Patho- genesis and Management. Neuroscience & Medicine 2012;3, 90-100, 2012. 6. Korn-Lubetzki I , Molshatzki N, Benderly M, Steiner I . The Relatively Good Outcome of Cerebellum-brainstem Ischemic Strokes. Eur Neurol 2012. In press. PUBLISHED Abstracts 1. Heresco-Levy U, Javitt DC, Gelfin Y, Kaufman Y, Levin R, Korn-Lubetzki I, Bloch B, Wolo- sker H, Kremer I. D-serine adjuvant treatment alleviates motor and behavioural symptoms in idiopathic Parkinson’s disease. Eur Neuropsychopharm 2009;19 (suppl 3) :S255-256. 2. Korn-Lubetzki I, Steiner I, Oren A, Tauber R, Steiner Birmanns B, Bitran D .The Possible Risk of Intra Operative Hypothermia for Strokes Complicating Cardiac Surgery. Neurology 2010;74 (suppl 2): A498 3. Steiner I, Benderly M, Korn-Lubetzki I .Brain stem and cerebellar strokes are less car- dioembolic and less severe than hemispheric strokes. Prospective Data from the Na- tional Acute Stroke Israeli Surveys (NASIS). Neurology 2010; 74 (suppl 2): A139-140. 97 Neurology
    • T he Department of Geriatrics directed by Professor Moshe Sonnenblick consists of 4 sub-units: three acute geriatric units directed by Dr. Reuven Fried-mann, and a rehabilitation unit directed by Dr. Ezra Shapiro. Four of the five senior physicians have combined specialization in Geriatric and Internal medicine and the fifth specializes in rehabilitation.The acute geriatric unit that opened more than four decades ago was the first such unit in a general hospital in Israel. The department’s physicians pro- vide medical care in a long term care unit and a home for the elderly. The acute medical unit is highly reputed for treating elderly patients with a variety of acute medical problems including the need for mechanical ventilation (with a high weaning rate and with a relatively high in-hospital survival rate). The reha- bilitation unit has a multidisciplinary service serving patients with strokes, fractures of the femur and patients affected by long periods of inactivity. The unit has comprehensive fa- cilities including physiotherapy, occupational therapy and speech and swallowing therapy. The department has a long tradition of teaching geriatric and internal medicine in affilia- tionwiththeHebrewUniversityofJerusalembothtomedical students and nurses. The department is also affiliated with the Geriatric Institute directed by Professor Arnold Rosin and Lea Abramovitz. This institute offers approximately 15 different courses in geriatric medicine for physicians, nurses, physiotherapists, occupational therapists and social workers. Department of Geriatrics Research Report 2013 98
    • Areas of Research Activity Research in the Geriatrics Department is the direct consequence of clinical bedside needs and observations. A recent publication by Dr. I. Galperin, Dr. R. Friedmann, Dr. H. Feldman and Prof. M. Sonnenblick deals with the relationship between low sodium blood levels (hypona- tremia) in patients suffering acute urinary retention. This study resulted from the high rate of co-occurrence of these two events observed by staff in six patients. Dr. I. Alexandrowich is currently completing a study on the co-occurrence of high levels of protein excretion under the supervision of Dr. D.S. Shapiro from the Geriatric Department, together with Dr. L. Shavit from Nephrology. A joint study by Dr. R. Manilov from the Geriatrics Department and Dr. L. Shavit from Ne- phrology investigated excretion of the biomarker neutrophil gelantinase-associated lipocalin (NGAL) as an early marker of deterioration of kidney function. Many elderly patients are administered Colistin (an antibiotic agent) which is crucial for treating drug- resistant bacte- rial infections. This agent may however harm kidney function. Therefore, early detection of kidney deterioration by a new biomarker is imperative. Dr. A. Husseini, under the supervision of Dr. D.S. Shapiro and Prof. M. Sonnenblick together with Prof. A.M. Yinon from the Infection Control Division and Dr. A.M. Assous, Head of the Microbiology and Immunology Laboratory, are investigating procalcitonine levels as a diag- nostic parameter of clostridium difficile bacterial infections in the large bowel. This infection results from antibiotic treatment in many of our patients. An additional aspect of our publication work focuses on ethical issues. Treatment is often viewed as futile for elderly patients. Dr. R. Friedmann and Dr. D.S. Shapiro published an article entitled “Can prognostic predictors be used for making clinical decisions to withhold treat- ment in terminally ill elderly patients? to argue that prognoses are often uncertain in predict- ing death, and therefore cannot be invoked to withhold treatment. Representative Research In a recent study we determined the incidence, etiology, clinical characteristics and outcome of severe hyponatremia among hospitalized elderly patients. The prevalence of hyponatremia was 6.2% and was more common in women than in men (8.1% vs. 4.0% respectively). The leading cause of hyponatremia was inappropriate antidiuretic hormone secretion (SIADH). All patients with thiazide induced hyponatremia had other contributing factors (as shown in the Figure). Overall in-hospital mortality was 19% while only hypoalbuminemia was found as an independent risk factor for death. 99 Geriatrics
    • Causes of Hyponatremia in 86 patients. PUBLICATIONS 1. Rosin A. The long term consequences of exposure to lead. Isr Med Assoc J 2009; 11(11):689-94. 2. Friedmann R, Raveh D, Zartzer E, Rudensky B, Broide E, Attias D, Yinnon AM. Prospective evaluation of colonization with extended-spectrum beta-lactamase (ESBL)- producing enterobacteriaceae among patients at hospital admission and of subsequent colonization with ESBL-producing enterobacteriaceae among patients during hospitaliza- tion. Infect Control Hosp Epidemiol 2009; 30(6): 534-42. THIAZIDES 21 SIADH 39 DRUGSi 21 OTHERii 26 CHF 23 SODIUM LOSS WATER LOAD 10 4 7 3 9 3 1 8 i Drugs known to cause SIADH such as SSRI, narcotics etc even if strict criteria for SIADH are not met. ii Respiratory disease known to cause SIADH, malignancy, acute CVA even if strict criteria for SIADH are not met, Low sodium diet, renal failure. PUBLICATIONS 1. Rosin A. The long term consequences of exposure to lead. Isr Med Assoc J 2009; 11(11):689-94. 2. Friedmann R, Raveh D, Zartzer E, Rudensky B, Broide E, Attias D, Yinnon AM. Prospective evaluation of colonization with extended-spectrum beta-lactamase (ESBL)-producing enterobacteriaceae among patients at hospital admission and of subsequent colonization with ESBL-producing enterobacteriaceae among patients during hospitalization. Infect Control Hosp Epidemiol 2009; 30(6): 534-42. 3. Benenson S, Cohen MJ, Block C, Stern S, Weiss Y, Moses AE; JIRMI Group Collaborators: Azoulay D, Friedmann R, Goldstein I, Hammerman-Rozenberg R, Hayman S, Levi O, Marcus EL, Meyler L. Vancomycin-resistant Research Report 2013 100
    • 3. Benenson S, Cohen MJ, Block C, Stern S, Weiss Y, Moses AE; JIRMI Group Collabora- tors: Azoulay D, Friedmann R, Goldstein I, Hammerman-Rozenberg R, Hayman S, Levi O, Marcus EL, Meyler L. Vancomycin-resistant enterococci in long-term care facilities. Infect Control Hosp Epidemiol 2009; 30(8): 786-9. 4. Friedmann R, Shapiro DS. The oldest-old in the internal medicine wards – can prognostic predictors be used for making clinical decisions? Isr Med Assoc J 2010; 1: 42-44. 5. Shapiro DS, Sonnenblick M, Galperin I, Meldonyan L, Munter G. Severe heponatraemia in elderly hospitalized patients: prevalence, aetiology and outcome. Intern Med J 2010; 40(8): 574-80. 6. Sprung CL, Cohen R, Adini B et al: Introduction. Recommendations and standard op- erating procedures for intensive care unit and hospital preparations for and influenza epi- demic or mass disaster. Intensive Care Med 2010; 36 Suppl 1:S4-10. 7. Galperin I, Raznov E, Sonnenblick M. Anticoagulation treatment for progressing ischemic strokes in the elderly. Asian J Gerontol Geriatr 2011; 6: 100-102. 8. Winchester Behr T, Sonnenblick M, Nesher G, Munter G. Hyponatremia in older people as a sign of adrenal insufficiency: A case control study. Intern Med J 2012; 42(3): 306- 310. 9. Shavit L, Lifschitz M, Galperin I. Influence of enteric nutrition on blood urea Nitrogen (BUN) in very old patients with chronic kidney disease (CKD). Arch Gerontol Geriat 2012; 54 (1): 228-231. 101 Geriatrics
    • T he Rheumatology Unit is headed by Dr. Gabriel S. Breuer MD. Prof Gideon Nesher, the Head of the De- partment of Medicine A who is a rheumatologist founded the unit in the early 1990’s . Dr Pinchus Klahr who recently made “aliyah” from Pittsburgh is a rheumatologist as well as an allergiologist and works in the outpatient clinic. Prof P. Hashkes is in charge of pediatric rheumatology. All the physicians are involved in seeing out-patients as well as in- patients, and teaching students as well residents in training and research. The Unit evaluates and treats joint diseases, autoimmune conditions and soft tissue rheumatology The main speciality of the Unit is systemic sclerosis (scleroderma) and giant cell arteritis with and without polymyalgia rheuamatica. Towards the end of 2012 the clinics was reorganized so that there are designated times for various conditions including vasculitis, collagen diseases and spondyloarthropathy. In ad- dition to general rheumatology, soldiers are seen at specific hours to speed up their waiting time. A new unique clinic will be devoted for early arthritis, to provide optimal therapy be- fore any joint damage occurs. Areas of Research Activity Issues concerning temporal artery biopsies of giant cell arte- ritis have been studied extensively in the Unit. What should the optimal size of the biopsy be? Should the biopsy be unilat- Rheumatology Unit Research Report 2013 102
    • eral or bilateral? What diagnosis can be made when the biopsy is negative? Is there a correla- tion between the biopsy and the severity of the disease? Is there seasonal variation in disease presentation? The Unit has also recently collaborated with the Radiology Department regarding the utility of the dual energy CT (DECT) as a diagnostic tool for evaluating gout in different parts of the skeleton. The CT in the Radiology Dept is unique in its ability to make and establish diagnoses of gout. Research is currently being conducted regarding the utility of the DECT and its ability to support a diagnosis of gout during the inter-critical period when the patient is seen in the office with no apparent inflammation after the critical inflammation has subsided. Representative Research Dual-energy computed tomography (DECT) is a sensitive method for identifying uric acid de- posits in joints and periarticular soft tissues in patients suspected of having gout. Diagnosis of gout cannot be confirmed by polarized microscopy during asymptomatic (intercritical) pe- riods, as joint aspiration is not feasible in most cases. We estimated the yield of dual-energy computed tomography (CT) in detection of uric acid tissue deposits during intercritical peri- ods in patients suspected of having gout. 22 patients with a mean age of 57 with a history of recurrent short-lived mono- or oligo- arthralgia or arthritis, were included (18 men, four women). All had uric acid levels >6 mg/dl and were completely asymptomatic at the time of clinical and radiological evaluations. DECT screened the specific joints and periarticular soft tissues that were previously involved in each case. Articular or soft-tissue urate deposits were identified by DECT in 11 cases (50%). Uric acid lev- el did not differ significantly between the groups with or without deposits (8.5+2 and 8.7+1.2 mg/dl, respectively). The table shows the yield of DECT in various anatomic locations: Area screened feet knees elbows hands Number of cases 18 8 1 4 Cases with urate deposits 7 2 0 3 % with urate deposits 39% 25% 0 75% This study shows that in asymptomatic hyperuricemic patients with a history of recurrent 103 Rheumatology
    • short-lived mono- or oligo-arthralgia or arthritis, DECT can identify urate crystals in 50%, confirming a diagnosis of gout. DECT is thus a valuable tool in diagnosing gout during inter- critical periods. DECT of the hands showing uric acid deposits colored in green. This is diagnostic for gout. PUBLICATIONS 1. Breuer GS, Nesher G.What does imaging tell us about polymyalgia rheumatica? Rheuma- tology 2012; 51(1):5-6. Epub 2011 Jul 6. 2. Lawrence YR, Pokroy R, Berlowitz D, Aharoni D, Hain D, Breuer GS.Splenic infarction: an update on William Osler’s observations.Isr Med Assoc J 2010; 12(6):362-5. 3. Furer V, Hersch M, Silvetzki N, Breuer GS, Zevin S Nicotiana glauca (tree tobacco) intoxi- cation--two cases in one family. J Med Toxicol 2011;7(1):47-51. 4. Breuer GS, Nesher R, Nesher G.Effect of biopsy length on the rate of positive temporal artery biopsies.Clin Exp Rheumatol 2009;27(1 Suppl 52):S10-3. 5. Breuer GS, Nesher G, Nesher R Rate of discordant findings in bilateral temporal artery biopsy to diagnose giant cell arteritis.J Rheumatol 2009 ;36(4):794-6. Epub 2009 Feb 17. Area screened feet knees elbows hands Number of cases 18 8 1 4 Cases with urate deposits 7 2 0 3 % with urate deposits 39% 25% 0 75% This study shows that in asymptomatic hyperuricemic patients with a history of recurrent short-lived mono- or oligo-arthralgia or arthritis, DECT can identify urate crystals in 50%, confirming a diagnosis of gout. DECT is thus a valuable tool in diagnosing gout during intercritical periods. DECT of the hands showing uric acid deposits colored in green. This is diagnostic for gout. Research Report 2013 104
    • 6. Nesher G, Oren S, Lijovetzky G, Nesher R.Vasculitis of the temporal arteries in the young. Semin Arthritis Rheum 2009;39(2):96-107. 105 Rheumatology
    • T he Endocrine Unit is directed by Dr. Gabriel Munter assisted by Dr. Noa Silvetzki, a specialist in Endocrinology. The Endocrine Unit focuses on clinical activity. Consultations for endocrine problems in different departments of the hos- pital are provided every day. Outpatient clinics are an integral part of the Unit’s daily life. The clinic provides treatment for general endocrinology issues and diabetes, but focuses on thyroid, parathyroid and adrenal disorders. The Unit runs specialized clinics as well in osteoporosis and male endocri- nology. The thyroid cancer clinic will start in a few months as a multidisciplinary team directed by Dr. Munter in collabora- tion with the ENT, surgery, nuclear medicine and pathology departments. Diabetes management in a very important problem since 20-30 % of the patients that are admitted have a diagnosis of diabetes. A multidisciplinary team, including a dedicated nurse, dietitian, podiatrist and endocrinologist care for these patients and are designing guidelines for diabetes treatment for inpatients. Areas of Research Activity Research is an important activity in the Endocrine Unit. There are several areas of interest. One is endocrine diseases in hospitalized patients, including their management, diag- nosis and prognosis. This includes electrolyte abnormalities Endocrine Unit Research Report 2013 106
    • like hyponatremia and diabetic ketoacidosis (DKA). Hyponatremia is the most common elec- trolyte abnormality among elderly patients. Two important studies were published in col- laboration with the Geriatric Department. There is an ongoing retrospective study analyzing patients who were admitted with DKA, that was designed to determine the risk factors for rehospitalization and management failure. The Unit also studies vitamin D levels and their consequences on human health. A study conducted by the unit comparing vitamin D levels in Shaare Zedek and family physicians showed that doctors at the hospital suffer from severe vitamin D deficiency. Bone mineral density measurement among doctors is the next step in this project. The effects of Jewish halacha (dietary laws) observance on diabetes control is another field of interest. An ongoing study conducted by Dr. Silvetzki in collaboration with the nutrition ser- vice is evaluating the effect of Sabbath observance on glucose levels. The effect of Yom Kippur fasting on diabetic patients is also part of a future study. Ramadan fasting is also a challenging health problem. Licorice ingestion is common among Moslems during the Ramadan and can cause severe hypokalemia. The frequency, risk factors and prognosis of licorice induced hypo- kalemia is a topic for future study. The Unit is also investigating rare endocrine diseases. Understanding these pathologies can shed light on more common diseases. For example, a family suffering from a form of auto- somal dominant Cushing syndrome of adrenal origin is being evaluated. A multidisciplinary approach is being used in this case, including collaboration with an endocrine surgeon, pa- thologist and the Genetics Department. A study aimed at determining the genetic basis of this disease is currently in progress. Finally, the endocrine unit, in collaboration with the Cardiology Department, participates in international clinical trials of new drugs, mainly in the field of diabetes. Two studies evaluat- ing DPP4 inhibitors and aglp-1 agonist in a new formula are being conducted at SZMC. Representative Research Hyponatremia is the most common electrolyte abnormality among elderly hospitalized pa- tients. Inappropriate secretion of antidiuretic hormone is the most common reason for low levels of sodium. Hypoadrenalism is another cause of hyponatremia but its frequency among elderly patients is unknown. In the first study of this important clinical question, a stimulation test of cortisol secretion using ACTH was administered to 60 elderly patients, half of them with hyponatremia. Hypo- adrenalism was not found among the control patients admitted with low sodium levels. 107 Endocrinology
    • It was concluded that AI is an uncommon cause of hyponatraemia in older age. Based on this small cohort, AI may be present in 3% of elderly patients with hyponatraemia. AI cannot be excluded by baseline cortisol in a significant minority of hyponatremic patients and further testing with adrenocorticotropin hormone stimulation is needed. Research Report 2013 108
    • PUBLICATIONS 1. Melamud B, Shilo S, Munter G. Life-threatening hypoglycemia due to false measurement of glucose in a peritoneal dialysis patient. Isr Med Assoc J 2010;12(2):125-6. 2. Shapiro DS, Sonnenblick M, Galperin I, Melkonyan L, Munter G. Severe hyponatrae- mia in elderly hospitalized patients: prevalence, aetiology and outcome.Intern Med J 2010;40(8):574-80. 3. Ulbrichova D, Mamet R, Munter G, Martasek P, Schoenfeld N. Novel human pathologi- cal mutations. Gene symbol: HMBS. Disease: Acute intermittent porphyria. Hum Genet 2010;127(1):114. 4. Ben-Chetrit E, Munter G. Purple urine. JAM 2012;307(2):193-4. 5. Winchester Behr T, Sonnenblick M, Nesher G, Munter G. Hyponatraemia in older people as a sign of adrenal insufficiency: a case-control study. Intern Med J 2012;42(3):306-10. 6. 6 . Ben-Chetrit E, Chen-Shuali C, Zimran E, Munter G, Nesher G. A Simplified Scoring – in Tool for Prediction of Readmission in Elderly Patients Hospitalized in Internal Medicine Department IMAJ 2012. In press. 109 Endocrinology
    • T he Interventional Radiology Unit is directed by Dr. Anthony Verstandig and has 3 senior physicians: Dr. Danny Berlovitz, Dr. Ibrahim Zaghal and one fellow, Dr. Bashar Shamieh. The Unit provides dialysis access for both the residents of Jerusalem and for many patients who are referred from other parts of the country. We perform more than 1200 procedures a year to maintain patency of both grafts and fistulas by dilating stenoses and opening (de- clotting) total occlusions. Our aim is to provide rapid service to prevent progression from narrowing to total occlusion in a comforting environment. The Unit works closely with Dr. David Shemesh of the Vascular Access Unit. Another focus of the Unit is regional therapy for cancer, pri- marily of the liver. By inserting a catheter into the artery supplying the tumor, high dose therapy can be delivered with minimal side effects. This therapy can consist of chemothera- peutic drugs alone or be combined with blocking the artery to deprive the tumor of its blood supply, or radioactive particles. The Unit also specializes in treating male infertility caused by varicocele (dilated veins in the scrotum causing abnormal sperm production). More than 450 catheterization proce- dureshavebeenperformedtoblocktheseveins,thusavoiding the discomfort and loss of work days that result from surgery. Patients return to normal activity immediately after the pro- cedure, which is performed under local anesthesia. Similarly, in patients with severe internal bleeding from any cause or bleeding from the digestive system we can often identify the Angiography Unit – Interventional Radiology Unit Research Report 2013 110
    • bleeding site and block the supplying arterial branch, thus avoiding major surgery. Extensive thrombosis of the lower limb veins in young active people can cause permanent disability if treated only with anticoagulation. We are able to catheterize the blocked veins, dissolve the clots with lytic agents and place stents in narrowed segments to restore the leg to full function. In addition to these special techniques , the Unit performs the regular spectrum of catheter based interventional procedures including drainage, stricture dilation and stone removal in the kidneys and bile ducts, liver biopsies and therapies for portal hypertension, venous access catheter placement, etc. Areas of Research Activity The Unit conducted a study on central vein stent grafts in dialysis patients (in association with the Vascular Access Unit). It reported on the long term patency and reintervention rates of these stent grafts on 52 consecutive patients- the largest sample size ever studied. The Unit is also researchingcephalic arch stent grafts in dialysis patients. 111 Angiography
    • An ongoing study on long term patency rates and frequency of secondary interventions has developed a novel technique for increasing the accuracy of stent graft placement at the ce- phalic arch – axillary vein confluence. Current research involves examining AV graft venous anastomic stenosis dilatation compar- ing the results of different balloon sizes. Representative Research A study is in progress to reduce radiation dose rates for left varicocele embolization. The stan- dard procedure uses a technique where the patient’s body habitus is the main dependent vari- able affecting radiation dose. We have modified the procedural technique and used all available radiation reduction applications to reduce the radiation dose to a minimum, which is signifi- cantly less than any dose previously reported. This involved developing a method for body habitus compensation using CT data that corrects the dose rate for the body mass index. This enables auditing of dose rates over time. Dose parameters for 72 consecutive cases using state of the art equipment, low dose/low pulse rate fluoroscopy, stringent collimation and no digital acquisition images have been analyzed. Graph I - shows a definite reduction in corrected radiation dose over time Graph II - illustrates a “collimation index” calculated for 83 consecutive patients by dividing the area dependent Kerma air product Pka by the area independent skin area dose to audit de- gree of collimation over time. This demonstrated that more stringent collimation was a major factor in decreasing the overall dose. Research Report 2013 112
    • Graph I Graph II illustrates a “collimation index” calculated for 83 consecutive patients by dividing the area dependent Kerma air product Pka by the area independent skin area dose to audit degree of collimation over time. This demonstrated that more stringent collimation was a major factor in decreasing the overall dose. Graph II Publications R² = 0.0849 0 2 4 6 8 10 0 20 40 60 80 CorrectedRadiationDose Patient Number 0 2 4 6 8 10 12 14 16 18 0 20 40 60 80 100 CollimationIndex(Pka/SED) Patient Number Graph II illustrates a “collimation index” calculated for 83 consecutive patients by dividing the area dependent Kerma air product Pka by the area independent skin area do to audit degree of collimation over time. This demonstrated that more stringent collimation was a major factor in decreasing the overall dose. Graph II Publications R² = 0.0849 0 2 4 6 8 10 0 20 40 60 80 CorrectedRadiationDose Patient Number 0 2 4 6 8 10 12 14 16 18 0 20 40 60 80 100 CollimationIndex(Pka/SED) Patient Number Number of Patients Number of Patients PUBLICATIONS 1. Bala M, Almongy G, Klimov A, Rivkind AI, Verstandig A. Percutaneous “stepped” drainage 113 Angiography
    • technique for infected pancreatic necrosis.Surg Laparosc Endosc Percutan Tech 2009; Aug;19(4):e113-8. 2. Grenader T, Goldberg A, Verstandig A, Shavit L.Indwelling central venous access port insertion during bevacizumab-based therapy.Anticancer Drugs 2010;21(7):704-7. 3. Shemesh D, Goldin I, Zaghal I, Berelowitz D, Verstandig AG, Olsha O. Stent Graft Treat- ment for hemodialysis access aneurysms. Journal of Vascular Surgery 2011; 54:1088-94. 4. Verstandig AG. Berelowitz D, Zaghal I. Stent grafts for central venous occlusive disease in patients with ipsilateral hemodialysis access. Conditionally accepted for publication. Research Report 2013 114
    • T he Department of Cardiology has been under the di- rection of Prof. Dan Tzivoni for two decades. Over this period, the Department has grown and developed into a network of interacting units each with its special clinical contribution and research interests. The principal level of infrastructure is the Cardiology Ward. This 35-bed ward under the direction of Dr. Marc Klutstein provides the basis for most inpatient care. It provides sup- port and care for patients undergoing elective procedures as well as a step down unit for patients post heart attack after an initial stay in the coronary intensive care unit. However, the mainstay of activity is providing service to acutely ill patients presenting through the emergency room. The Coronary Intensive Care Unit is directed by Dr. Jonathan Balkin. This 6-bed unit provides the most critical patients with high-level care and interlinks with the cardiology ward and catheterization laboratory. The patients presenting with acute heart attacks are brought to this unit either directly by the ambulance service (MDA) or via the catheterization labo- ratories following angioplasty and stenting to arrest the heart attack. The Ambulatory Care Units directed by Dr. Mady Moriel are a mainstay of clinical practice for the entire department. The Unit offers a framework that services all the cardiologists and subspecialty units allowing for first point of call as well as on- going patient care within the community. This is effective for Department of Cardiology 115 Cardiology
    • the broad range of cardiology patients and specifically caters to pacemaker care, patients with pulmonary hypertension, structural and congenital heart disease pre and post interventions and the newly founded hypertension clinic for patients unsuccessfully controlled by their pri- mary or secondary physician. The Cardiac Rehabilitation and Prevention Unit is directed by Dr. Jacob Klein with the assis- tance of a team of cardiac nurses, exercise physiologists, nutritionists, social workers, medi- cal technicians, psychologists and psychiatrists. Together, this team works to rehabilitate pa- tients and bring them to their optimum mental and physical level. It also works to modify the risk factors wherever possible and therefore prevent recurrence of cardiac events.The program runs in three stages: during the period of hospitalization, after discharge for a period of four to six months, and finally a maintenance program which patients continue independently. It is designed for patients who have suffered myocardial infarction, blockages in their coronary arteries, undergone bypass surgery or have had angiograms with procedures to open arteries. The Unit of Non-Invasive Cardiology is directed by Dr. David Rosenmann. This Unit is com- prised of three principal laboratories. The Holter monitoring laboratory functions in conjunc- tion with Dr. Michael Ilan of the pacing and arrhythmia service. The stress testing laboratories offer a range of tests including simple stress testing as well as adjunctive testing with echocar- diography and in association with the Nuclear Medicine Department, isotope based perfusion testing. This laboratory, as well as providing a high-level outpatient service also serves inpa- tient departments and particularly the emergency room, allowing for triage of patients pre- senting with indeterminate chest pain. The Echocardiography Laboratory is involved in heart and valve function and allows the treating physician to diagnose the root cause of the patients' symptoms,aswellastheabilitytotailormedicaltherapyfarmorespecificallythaneverbefore. TheCardiacCatheterizationandInterventionalLaboratoriesareheadedbyDr.YaronAlmagor. has participated in leading investigations of new cardiac stents, and most recently was the first in Israel to introduce transcatheter aortic valve implantation (TAVI). This game chang- ing technology has provided a therapeutic avenue for patients unable to undergo surgery for valve replacement as well as a lower risk option for those with multiple comorbidities making open heart surgery a daunting prospect. The unit has transmitted live demonstration cases to multiple international meetings including the largest international interventional cardiology meeting in the USA. The Electrophysiology Unit represents a tertiary referral service for patients with complex rhythm disturbances that can be treated with interventional techniques. This Unit is headed by Dr. Aharon Medina. This extremely active service implants about 250 pacemakers and de- fibrillators annually. This includes cardiac resynchronization therapy whereby a specialized Research Report 2013 116
    • triple leaded pacemaker is implanted and used to improve cardiac function that has deterio- rated partially due to a failed electrical conduction system. The Structural and Congenital Heart Disease Unit under the direction of Dr. David Meerkin deals with a wide range of congenital conditions including closing intracardiac defects, such as atrial septal defects , patent foramen ovale, patent ductus arteriosus, congenital aortic and pulmonary valve stenosis, aortic coarctation and pulmonary arterial stenosis. The Cardiology Research Unit, led by Prof. Dan Tzivoni, and directed by Ms. Astrid Rojan- sky, MPH, has been extremely active for over 20 years, conducting clinical trials with leading pharmaceuticalcompaniesthathavechangedthetreatmentsofmoderncardiologyinmultiple conditions including prevention and treatment of heart attacks and angina, heart failure, ar- rhythmia, as well as developing novel stents and devices. Areas of Research Activity The Department is involved in a range of specialized research activities including studies on the risk of developing significant coronary artery disease (CAD) in patients with previously demonstrated normal (NCA) or near normal coronary arteries (NNCA), and the factors influ- encing this risk, studies involving acute heart attacks, anticoagulant and antiplatelet regimens as well as heart failure therapies, therapeutic hypothermia to cool the brain with a view to ap- plication to a variety of clinical conditions such as post cardiac arrest and ischemic and hemor- rhagic stroke, detection of Mitral Regurgitation (MR) which is often present in patients with severe aortic stenosis (AS) undergoing transcather aortic valve implantation (TAVI), and the introduction of novel imaging technologies, particularly for three-dimensional reconstruction allowing for improved quantitative vessel analysis. There is additional strong interest in the creation of animal models for assessment of novel devices and therapies and the establish- ment of stable models of chronic and acute heart failure using a combination of techniques including microsphere injection to coronary arteries, fluid loading, valvular incompetence and afterload creation with phenylephrine or balloons. Representative Research On the basis of strong evidence that the left atrial appendage (LAA) is the site of the majority of thrombus formations within the left atrium in patients with non-valvular atrial fibrilla- tion, non-pharmacological approaches to LAA exclusion have been developed and shown to be effective. Early studies showed a high complication rate (7-10%) with all techniques and devices to date. We assessed the cumulative experience of a single operator using a strict set of deploymentandreleasecriteriafortheAmplatzerCardiacPlugandtheimpactofthesecriteria 117 Cardiology
    • on procedural success and complications. One hundred consecutive patients with atrial fibril- lation and an extremely high stroke risk underwent occlusion of the LAA and their early out- comes assessed. Only two complications were noted, both of which were treated successfully and the patients were discharged with only a short delay. In this single operator report, LAA occlusion using the double element ACP was safely performed with excellent success rates. Using very specific deployment success, stability and release criteria, this device can achieve LAA occlusion with extremely low complication rates in an extremely frail oral anticoagulant ineligible population with multiple co-morbidities. The Amplatzer cardiac plug for left atrial appendage occlusion in anticoagulant ineligible pa- tients is shown below. Research Report 2013 118
    • Publications 1. Meerkin D, Balkin J, Klutstein MC. Rapid Transcatheter Occlusion of coronary cameral fistula using a three lobed vascular occlusion plug. J Invasive Cardiol 2009;21:E151-3. 2. Connolly SJ, et al. for the RE-LY steering committee and investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151. 3. Meerkin D. A Double Handed Approach to Anterior Ischemia. TCTMD. 2009; February 17. 4. Alexander JH, et al. for APPRAISE steering committee and investigators. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009;119:2877-2885. 5. Meerkin D. Transradial Use of a Combined Coronary Stent and Embolic Protection System for STEMI. TCTMD. 2009; July 6. 6. Stone GW, for the HORIZONS-AMI trial investigators. Paclitaxel-eluting stents versus bare metal stents in acute myocardial infarction. N Engl J Med 2009;360:1946-1959. 7. Mehran R, et al for the HORIZONS-AMI trial investigators. Bivalirudin in patients undergo- ing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1 year results of a randomized controlled trial. Lancet 2009;374:1149-1159. 8. Tzivoni D, Krucoff MW. Continuous ST-segment monitoring in contemporary acute coro- nary syndrome patients: the magic of MERLIN TIMI 36. J Am Coll Cardiol 2009;53:1422- 1424. 9. Tzivoni D, Balkin J, Bar FW, Hibberd M, Reiber JH, Cowing G. Effect of Caldaret on the incidence of severe left ventricular dysfunction in patients with ST-elevation myocardial infarction undergoing primary coronary intervention. Am J Cardiol 2009;103:1-4. 10. Colombo A, Almagor Y, Gaspar J, Vonderwalde C. The pericardium covered stent (PCS). EuroIntervention 2009;5(3):394-399. 11. Klutstein MK, Balkin J, Butnaru A, Ilan M, Lahad A, Rosenmann D. Tricuspid incompe- tence following permanent pacemaker implantation. PACE 2009;32:S135-S137. 119 Cardiology
    • 12. Guiliano RP, for the EARLY ACS investigators. Early versus delayed, provisional eptifiba- tide in acute coronary syndromes. N Engl J Med 2009;360:2176-2190. 13. Majidi M, Kosinkski AS, Al-Khatid SM, Lemmert ME, Smolders L, van Weert A, Reiber JH, Tzivoni D, Bat FW, Wellend HJ, Horgels AP, Krucoff MW. Reperfusion ventricular arrhythmia “bursts” predict larger infarct size despite TIMI 3 flow restoration with primary angioplasty for anterior ST-elevation myocardial infarction. Eur Heart J 2009;30:757-764. 14. Wallentin L, et al. for the PLATO investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-1057. 15. Liel-Cohen N, Tsadok Y, Beeri R, Lysyansky P, Agmon Y, Feinberg MS, Fehske W, Gilon D, Hay I, Kuperstein R, Leitman M, Deutsch L, Rosenmann D, Sagie A, Shimoni S, Vaturi M, Friedman Z, Blondheim DS. A new tool for automatic assessment of segmental wall mo- tion based on longitudinal 2D strain: a multicenter study by the Israeli Echocardiography Research Group. Circ Cardiovasc Imaging 2010; 3(1):47-53. Epub 2009 Nov 19. 16. Meerkin D, Balkin J, Shaheen J, Tzivoni D. The twin-pass dual access catheter for assess- ment of the no-reflow phenomenon. J Invasive Cardiol 2010;22:125-9. 17. Meerkin D, Farber B, Nir A. Initial Experience and Sizing Considerations Using the Novel Three Lobed Amplatzer Ductal Occluder 2. J Invasive Cardiol 2010;22:190-4. 18. Balkin J, Silberman S, Almagor Y. Buddy balloon for TAVI. Cathet and Cardiovasc Intv 2010, June 14, epub. Blondheim DS, Beeri R, Feinberg MS, Vaturi M, Shimoni S, Fehske W, Sagie A, Rosenmann D, Lysyansky P, Deutsch L, Leitman M, Kuperstein R, Hay I, Gilon D, Friedman Z, Agmon Y, Tsadok Y, Liel-Cohen N. Reliability of visual assessment of global and segmental left ventricular function: a multicenter study by the Israeli Echocar- diography Research Group. J Am Soc Echocardiogr 2010;23(3):258-64. 19. Rosenmann D, Lysyansky P, Deutsch L, Leitman M, Kuperstein R, Hay I, Gilon D, Fried- man Z, Agmon Y, Tsadok Y, Liel-Cohen N. Reliability of visual assessment of global and segmental left ventricular function: a multicenter study by the Israeli Echocardiography Research Group. J Am Soc Echocardiogr 2010;23(3):258-64. 20. Meerkin D, Marom H, Cohen-Biton O, Einav S. Three-dimensional vessel analyses pro- vide more accurate length estimations than the gold standard QCA. J Interv Cardiol 2010;23:152-9. Research Report 2013 120
    • 21. Weatherley BD, et al. for PROTECT steering committee, investigators and coordinators. Design and rationale of the PROTECT study: a placebo-controlled randomized study of the selective A1 adenosine receptor antagonist rolofylline for patients hospitalized with acute decompensated heart failure and volume overload to assess treatment effect on congestion and renal function. J Cardiac Fail 2010;16:25-35. 22. Massies BM, et al. for the PROTECT investigators and committees. Rolofylline, an ade- nosine A1-receptor antagonist in acute heart failure. N Engl J Med 2010;363:1419-1428. 23. Park JW, Bethencourt A, Sievert H, Santoro G, Meier B, Walsh K, Lopez-Minquez JR, Meerkin D, Valdés M, Ormerod O, Leithäuser B. Left atrial appendage closure with Am- platzer cardiac plug in atrial fibrillation: initial European experience. Catheter Cardiovasc Interv 2011;77:700-6. 24. Patel MR, et al. for the ROCKET AF steering committee and investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891. 25. Stone GW, et al for the HORIZONS-AMI trial investigators. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirubin monotherapy and paclitaxel-eluting stents versus bare metal stents in acute myocardial infarction (HORIZONS-AMI): final 3 year results from a multicenter, randomized controlled trial. Lancet 2011;377:2193-2204. 26. Gottlieb S, Behar S, Schwartz R, Harpaz D, Shotan A, Zahger D, Hod H, Tzivoni D, Moriel M. Age differences in the adherence to treatment guidelines and outcome in patients with ST-elevation myocardial infarction. Arch Geront and Geriatr 2011;52:118-124. 27. 4. Blondheim DS, Friedman Z, Lysyansky P, Kuperstein R, Hay I, Feinberg MS, Beeri R, Vaturi M, Sagie A, Shimoni S, Fehske W, Deutsch L, Leitman M, Gilon D, AgmonY, Tsadok Y, Rosenmann D, Liel-Cohen N. Use of an automatic application for wall motion classifica- tion based on longitudinal strain: is it affected by operator expertise in echocardiography? A multicentre study by the Israeli Echocardiography Research Group. Eur Heart J Cardio- vasc Imaging 2012;13(3):257-62. Epub 2011 Nov 6. 28. Cohen A, Bertrand OF, Meerkin D. Transradial angioplasty for ST elevation MI. Interv Car- diol. 2011;3:337-346. 29. BertrandOF,BélisleP,JoyalD,CosterousseO,RaoS,JollyS,MeerkinD,JosephL.Comparison of transradial and femoral approaches for percutaneous coronary interventions: A system- atic review and hierarchical Bayesian meta-analysis. Am Heart J 2012;163:632-648. 121 Cardiology
    • 30. Roe MT, et al. for the TRILOGY ACS investigators. Prasugrel versus Clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012;367:1297-1309. 31. Healey JS, et al. on behalf of the RE-LY investigators. Periprocedural bleeding and throm- boembolic events with dabigatran compared with warfarin. Circulation 2012;126:343-348. 32. Rosenmann D, Mogilevski Y, Amit G, Davrath LR, Tzivoni D. High-Frequency QRS Analy- sis Improves the Specificity of Exercise ECG Testing in Women Referred for Angiography Journal of Electrocardiology 2012; forthcoming. 33. Hijazi Z, et al. (RE-LY substudy). Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation. Circulation 2012;125:1605-1616. 34. Dvir D, Lavi I, Eltchaninoff H, Himbert D, Almagor Y, Descoutures F, Vahanian A, Tron C, Cribier A, Kornowski R. Multicenter evaluation of Edwards SAPIEN positioning during transcatheter aortic valve implantation with correlates for device movement during final deployment. JACC Cardiovasc Interv 2012;5(5):563-70. 35. Bertrand OF, Meerkin D. Vascular Access Site for Percutaneous Coronary Angiography and Intervention. In EAPCI Interventional Cardiology Textbook 2012. 36. Meerkin D. Interventional Cardiology and the Transradial Approach in Israel. J Invasive Cardiol 2012. 37. Weitzman T, Meerkin D. Primary percutaneous coronary intervention: devices to prevent no-reflow phenomenon. Interv Cardiol 2012. Research Report 2013 122
    • Pediatrics JeanGoldwurmInstituteforPediatricMedicine Eugen&JeanGluckPediatricPavilion FanyaGottesfeldHeller&JosephHellerPediatricCardiologyUnit VivienneWohlPediatricSurgeryCenter GlaubachDepartmentofPediatricEmergency StefanAdelipourShock,TraumaandBurnCenter KuppermannPediatricIntensiveCareUnit ZusmanDepartmentofPediatricNeurology Jean&JulaGoldwurmNeurologicalDiagnostic&ExaminationUnit Lesley&LeonBermanPaediatricDialysisUnit RothbergDepartmentofPediatricNephrology
    • T he Division of Pediatrics directed by Prof. Yechiel Schlesingerhasalongtraditionofexcellence.Founded in the early 60’s by Prof. Serem Freier in the original building of Shaare Zedek hospital, the division has expanded extensively, and now includes all subspecialties of Pediatrics. Thedivisioncomprisesof25residentsandmorethan40staff members, has a very active emergency room, 28 beds for hos- pitalizedpatients,apediatricsurgerydepartment,andapedi- atric intensive care unit. Along with the country’s largest de- livery room that currently performs around 15,000 deliveries per annum, there are three big well -baby nurseries as well as the country’s largest neonatal intensive care unit. Sub-spe- cialty units include pediatric cardiology, pediatric hematolo- gy-oncology, pediatric gastroenterology and nutrition, pedi- atric endocrinology, pediatric pulmonology, pediatric nephrology and dialysis, pediatric neurology and child devel- opment, pediatric rheumatology, pediatric immunology, pe- diatric infectious diseases, and medical genetics Areas of Research Activity The wide spectrum of experts in all aspects of modern pediat- rics is reflected in the hundreds of research papers published in top journals by the various departments and units of the DivisionofPediatrics.Theserangefrom clinicalstudiestoba- sic bench research and from large-scale studies sponsored by major pharmaceutical companies to molecular microbiology. Division of Pediatrics Research Report 2013 124
    • T he Pediatric Gastroenterology Unit, directed by Prof. Dan Turner is staffed by five specialists: Dr. Raffi Lev-Tzion, Dr. Oren Ledder, Dr. Elena Rachman, Prof. Etti Granot and Ms. Ronit Dadosh (Clinical Dietician), mak- ing this unit the largest of its kind in Jerusalem. The Unit has a long history of clinical and academic excellence. As early as the1960’s,theUnitservedasamajorreferralcenterfortreat- ing challenging cases. During the 1970’s parenteral nutrition was introduced, thus saving infants with intestinal failure who would not have survived. The first duodenal biopsy was performed in the 1970’s using a special capsule that was revo- lutionary at the time. Today’s advanced technology has made thesetestsmoreaccurateandsafe.Underdirectvisualization, biopsies are directed to the suspected areas of pathology, and intervention is possible by controlling bleeding, dilating nar- rowing bowel, removing polyps, and closing small tears. To- day, over 600 digestive system procedures are performed an- nually in children including endoscopies, colonoscopies, capsule endoscopy, insertion of inter-abdominal feeding tubes and esophageal Ph monitoring. Of the diverse and comprehensive services that the GI unit provides, three services deserve special mention. The Pedi- atric Inflammatory Bowel Diseases Center (headed by Prof. Dan Turner) cares for over 250 children with Crohn’s disease and ulcerative colitis from all over Israel based on a multi- disciplinary and holistic approach. The Pediatric Hepatology Service (headed by Prof. Etti Granot and Dr. Oren Ledder) treats children with diverse chronic and acute liver diseases, Pediatric Gastroenterology Unit 125 Pediatric Gastroenterology
    • including post transplant follow-up. Finally, Dr. Elena Rachman heads the clinic for nutrition and feeding disorders in infancy, assisted by a paramedical team. Areas of Research Activity Research is a major focus of activity at the Pediatric GI Unit, which is involved in numerous local, national and international projects both in clinical and basic science. The research staff of the Pediatric Gastroenterology Unit is composed of a team six including a research nurse, threeprojectmanagers,one researchcoordinatorandalabtechnician.Themajorresearcharea of the Unit is Pediatric Inflammatory Bowel Disease (IBD). These chronic inflammatory dis- eases of the gut are manifested by periods of remission and exacerbations. The incidence of IBD is rising in Israel and the therapeutic approach combines different medications that con- trol the immune system. Numerous IBD research projects are conducted at the unit, each tap- ping into a different aspect of the disease: etiology, epidemiology, diagnostic and intervention. The Unit serves as Israel’s coordinating center for the large Canadian GEM (Genetic, Environ- ment, Microbes) Project, in which 2500 healthy first degree relatives of IBD patients are being followed prospectively for 6 years in an attempt to unravel the pathogenesis of the disease. A randomized controlled trial of once-daily dosing in ulcerative colitis is being conducted in Is- rael and coordinated by the unit. We are working with the Healthcare Funds (Kupot Holim) on a collaborative administrative epidemiological study of the disease in Israel and to understand the geographic and environmental factors underlying the disease burden. Prof. Turner is the principal investigator on an international investigator-initiated study (27 sites from 11 coun- tries) to evaluate Crohn’s Disease activity and complications using MRI techniques. Children are recruited from several other European collaborative studies, including risk stratification to identify youngsters who require more aggressive treatment at disease onset. Other research interests include Celiac disease, which is an auto-immune disease of the gut in the presence of the grain protein gluten. The Unit has conducted several studies and bench substudiesafteritwasshownthatapproximatelyhalfofallchildrenwithCeliacdiseasearenot protected against Hepatitis B despite adequate vaccination. A new therapeutic intervention is currently being assessed for these children. In hepatology, we are exploring non-invasive interventions for children with hemolytic diseases who are at risk for developing bile stones (cholelithiasis). Finally, the Unit is involved in several industry initiated clinical trials on vari- ous GI related pathologies. Representative Research A translational project conducted in close collaboration with the Pediatric GI Unit, the Bio- chemical Service Lab and the Genetics Lab of Shaare Zedek, brings basic science and cutting Research Report 2013 126
    • edge research to the bedside to improve the safety of medications prescribed to IBD patients. One of the most common families of immune suppression medications used in IBD are the thiopurines (azathioprine (or imuran) and mercaptopurine (purinethol)). TPMT is a key en- zyme that deactivates thiopurines into their inactive metabolite. Low TPMT activity, a geneti- cally determined trait, often results in severe side effects (such as a reduced blood count and even cancer). The aim of this study was to determine TPMT activity and TPMT mutations for the first time among Jews to establish an evidence-based assay for this population before starting thiopurine treatment. First, TPMT biochemical activity was determined in 213 Jew- ish adult volunteers by a sophisticated assay developed in the biochemical lab. Known muta- tions were then explored by the genetic lab in 33 participants with low enzyme activity. Sur- prisingly, only six were carriers of the known mutations (see Figure). Sequencing the entire TPMT gene of the remaining 27 discordant cases did not reveal any novel “Jewish” mutations. The conclusion of that study was that unlike in Caucasians, genetic analysis for TPMT activity is of limited value among Jews and therefore a biochemical assay is a more useful tool in this population. A continuation 1- year study is now underway to correlate these findings with clinical outcomes in 100 children with IBD commenced on thiopurines at the Pediatric IBD Center at Shaare Zedek. 5 10 15 20 25 30 35 0 10 20 30 40 50 M S N n TPMT activity (nMol/mlPRBC)  TPMT activity among 227 Jewish volunteers N=33 (14%) ≤11mmol N=26 (11.5%) >20 mmol 127 Pediatric Gastroenterology
    • PUBLICATIONS 1. Turner D, Griffiths AM, Steinhart AH, Otley AR, Beaton DE. Mathematical weighting of a clinimetric index (Pediatric Ulcerative Colitis Activity Index) was superior to the judgmental approach. J Clin Epidemiol 2009; 62(7):738-744. 2. Turner D, Hyams J, Markowitz J, Lerer T, Mack DR, Evans J, Pfefferkorn M, Rosh J, Kay M, Crandall W, Keljo D, Otley AR, Kugathasan S, Carvalho R, Oliva-Hemker M, Langton C, Mamula P, Bousvaros A, LeLeiko N, Griffiths AM. Appraisal of the Pediatric Ulcerative Colitis Activity Index (PUCAI). Inflamm Bowel Dis 2009; 15(8):1218-23. 3. Turner D. Severe acute ulcerative colitis: the pediatric perspective. Dig Dis 2009; 27:322– 326. 4. Bousvaros A, Turner D, Vitito L: Monitoring disease activity in Pediatric IBD patients. A continuing medical education monograph series. NASPGHAN and CDHNF 2009. 5. Turner D, Beaton DE, Schunemann HJ, Griffiths AM, Kritch J, Griffith LE, Guyatt GH. The minimal detectable change cannot reliably replace the minimal important difference. J Clin Epidemiol 2010; 63(1):28-36. 6. Turner D, Griffiths AM, Mack D, Otley AR, Seow CH, Steinhart AH, Silverberg MS, Hyams J, Guyatt GH. Assessing disease activity in ulcerative colitis: patients or their physicians? Inflamm Bowel Dis 2010; 16(4):651-656. 7. Turner D, Ashkenazi S, Mimouni F, Shamir R. Recommendations for the diagnosis and management of pediatric acute gastroenteritis in Israel. Harefuah 2010; 149(1): 53-58. 8. Turner D, Guyatt G. Reflections on the minimal important difference: research is the ulti- mate goal, not the anchor. J Clin Epidemiol 2010; 63:806 (Letter). 9. Turner D, Griffiths AM, Walters TD, Seah T, Markowitz J, Pfefferkorn M, Keljo D, Otley A, Leleiko NS, Mack D, Hyams J, Levine A. Appraisal of the pediatric Crohn’s disease activity index on four prospectively collected datasets: recommended cutoff values and clinimetric properties. Am J Gastroenterol 2010; 105(9):2085-2092. 10. Turner D, Mack D, Leleiko N, Walters TD, Uusoue K, Leach ST, Day AS, Crandall W, Sil- verberg MS, Markowitz J, Otley AR, Keljo D, Mamula P, Kugathasan S, Hyams J, Griffiths AM. Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and Research Report 2013 128
    • predictors of response. Gastroenterology 2010; 138(7):2282-2291. 11. Hudara S, Mimouni F, Rachman Y, Dayan B, Silbermintz A, Turner D. Retrospective cohort study of a new infant formula during the first six months of life: reflections about growth curves, human milk and formula feeding. IMAJ 2010; 12:676-680. 12. Turner D, Levine A, Weiss B, Hirsh A, Shamir R, Shaoul R. Evidence-based recommenda- tions for bowel cleansing before colonoscopy in children: a report from a national working group, the Israeli Society of Pediatric Gastroenterology and Nutrition (ISPGAN). Endos- copy 2010; 42:1063-1070. 13. Russell RK, Turner D. Management of severe pediatric ulcerative colitis. Inflamm Bowel Dis Monit 2011; 11(4):139–44. 14. Turner D, Shah PS, Steinhart AH, Zlotkin S, Griffiths AM. Maintenance of remission in Inflammatory Bowel Disease using omega-3 fatty acids (fish oil): A systematic review and meta-analyses. Inflamm Bowel Dis 2011; 17(1):336-45 (revised from earlier work). 15. Turner D, Griffiths AM. Acute Severe Ulcerative Colitis in Children: A Systematic Review. Inflamm Bowel Dis; 2011 17(1):440-9 (invited manuscript). 16. Turner D, Travis SPL, Griffiths AM, Ruemmele FM, Levine A, Benchimol EI, Dubinsky M, Alex G, Baldassano RN, Langer JC, Shamberger R, Hyams JS, Cucchiara S, Bousvaros A, Escher JC, Markowitz J, Wilson DC, Assche G, Russell RK. Consensus for managing acute severe ulcerative colitis in children: a systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD working group of ESPGHAN. Am J Gastroenterol 2011; 106(4):574-88. 17. Levine A, Bachar L, Tsangen Z, Mizrachi A, Levy A, Dalal I, Kornfeld L, Levy Y, Zadik Z, Turner D, Boaz M. Screening criteria for diagnosis of infantile feeding disorders as a cause of poor feeding or food refusal. J Pediatr Gastroenterol Nutr 2011; 52(5):563-568. 18. Sylvester FA, Turner D, Draghi A, Uuosoe K, McLernon R, Kaproske K, Mack DR, Crandall WV, Hyams JS, LeLeiko NS, Griffiths AM. Fecal osteoprotegerin may guide the introduc- tion of second line therapy in hospitalized children with ulcerative colitis. Inflamm Bowel Dis 2011; 17(8):1726-30. 19. Levine A, Turner D. Combined azithromycin and metronidazole therapy is effective for inducing remission in pediatric Crohn’s disease. J Crohns Colitis 2011;5(3):222-6. 129 Pediatric Gastroenterology
    • 20. Levine A, Griffiths AM, Markowitz J, Wilson DC, Turner D, Russell RK, Fell J, Ruemmele FM, Walters TD, Sherlock M, Dubinsky M, Hyams JS. Pediatric modification of the Mon- treal classification for inflammatory bowel disease: The Paris classification. Inflamm Bowel Dis 2011;17(6):1314-21. 21. Muise AM, Walters T, Xu W, Shen-Tu G, Guo CH, Lam GY, Bennitz J, Van Limbergen J, Fattouh R, Renbaum P, Kasirer Y, Ngan BY, Turner D, Denson LA, Sherman PM, Du- err RH, Cho J, Satsangi J, Wilson DC, Paterson AD, Griffiths AM, Glogauer M, Silver- berg MS, Brumell JH. Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis. Gastroenterology 2011;141(2):633-641. 22. Turner D, Mack DR, Hyams J, LeLeiko N, Otley A, Markowitz J, Kasirer Y, Muise A, Seow CH, Silverberg MS, Crandall W, Griffiths AM. C-reactive protein (CRP), erythrocyte sedi- mentation rate (ESR) or both? A systematic evaluation in pediatric ulcerative colitis. J Crohn Colitis 2011;5(5):423-429. 23. Turner D, Griffiths AM, Walters TD, Seah T, Markowitz J, Pfefferkorn M, Keljo D, Waxman J, Otley A, Leleiko NS, Mack D, Hyams J, Levine A. Mathematical weighting of the pedi- atric Crohn’s disease activity index (PCDAI) and comparison with its other short versions. Inflamm Bowel Dis 2012;18(1):55-62. 24. Turner D, Griffiths AM. CRP, ESR and pediatric ulcerative colitis: authors’ reply. J Crohn Colitis 2012;6(2):260 (Letter to the editor) 25. Lev-Tzion R, Turner D. Is pediatric IBD treatment different than in adults? Minerva Gastro- enterol Dietol 2012;58(2):137-150. 26. Dayan B, Turner D. Pediatric Radiation Doses and IBD. Inflamm Bowel Dis 2012; In press. Invited commentary 27. Gana JC, Turner D, Mieli-Vergani G, Davenport M, Miloh T, Avitzur Y, Yap J, Morinville V, Brill H, Ling SC. Non-invasive diagnosis of esophageal varices in children: a prospective multicentre validation study. Gastroenterology 2012; In press. 28. Kasirer Y, Turner D. Management issues in adolescents with Crohn’s disease- current practice. World J Gastroenterol 2012; In press. 29. Shaoul R, Sladek M, Turner D, Paerregaard A, Veres G, Veereman-Wauters G, Escher Research Report 2013 130
    • J, Amil Dias J, Lionetti P, Staiano A, Kolho KJ, De Ridder L, Nuti F, Cucchiara S, Shevah O, Levine A. Limitations of fecal calprotectin at diagnosis in untreated pediatric Crohn’s disease. Inflamm Bowel Dis 2012; In press. 30. Judd TA, Day AS, Lemberg DA, Turner D, Leach ST. An update of faecal markers of in- flammation in inflammatory bowel disease. J Gastroenterol Hepatol 2012; In press. 31. Michail S, Durbin M, Turner D, Griffiths AM, Mack D, Hyams J, Leleiko N, Kenche H, Stolfi A, Wine E. Alterations in the gut microbiome of children with severe ulcerative colitis. In- flamm Bowel Dis 2012; In press. 32. Turner D. Collaboration and networking- the name of the game in Pediatric IBD (Editorial). J Pediatr Gastroenterol Nutr 2012; In press 33. Kolho KL, Turner D, Veereman-Wauters G, Sladek M, de Ridder L, Shaoul R, Paerregaard A, Amil Dias J, Koletzko S, Nuti F, Bujanover Y, Staiano A, Bochenek K, Finnby L, Levine A, Veres G. Rapid test for fecal calprotectin levels in children with Crohn´s disease. J Pediatr Gastroenterol Nutr 2012; In press 34. Moran CJ, Walters TD, Guo CH, Kugathasan S, Klein C, Turner D, Wolters VM, Bandsma RH, Mouzaki M, Langer JC, Cutz E, Benseler SM, Roifman C, Silverberg MS, Griffiths AM, Snapper SB, Muise AM. IL-10R polymorphisms are associated with very early-onset ulcerative colitis. Inflamm Bowel Dis 2012; In press. 35. Dayan B, Turner D. The role of surgery in severe ulcerative colitis in the era of medical rescue therapy. World J Gastroenterol 2012; In press. 36. Koslowsky B, Turner D. The Role of Infliximab in Pediatric Ulcerative Colitis. Int J Clin Rev 2012; In press. 37. Turner D, Levine A, Escher JC, Griffiths AM, Russell RK, Dignass A, Dias JA, Bronsky J, Braegger CP, Cucchiara S, de Ridder L, Fagerberg UL, Hussey S, Hugot JP, Kolacek S, Kolho KL, Lionetti P, Pærregaard A, Potapov A, Rintala R, Serban DE, Staiano A, Sweeny B, Veerman G, Veres G, Wilson DC, Ruemmele FM. Management of Pediatric Ulcerative Colitis: A Joint ECCO and ESPGHAN Evidence-Based Consensus Guidelines. J Pediatr Gastroenterol Nutr 2012. In press. 38. Levine A, de Bie CI, Turner D, Cucchiara S, Sladek M, Murphy MS, Escher JC; and the EUROKIDS Porto IBD Working Group of ESPGHAN. Atypical disease phenotypes in pe- 131 Pediatric Gastroenterology
    • diatric ulcerative colitis: 5-year analyses of the EUROKIDS Registry. Inflamm Bowel Dis 2012. In press. Published abstracts 1. Turner D, Seow CH, Silverberg MS, Greenberg GR, Griffiths AM, Steinhart AH. Which Non-Invasive Disease Activity Index Should Be Used in Ulcerative Colitis? A Systematic Head-to-Head Psychometric Comparison. Gastroenterology 2009;136 (5 Suppl 1):A-161 (Abst 1050). 2. Kabakchiev B, Turner D, Hyams JS, Mack DR, LeLeiko NS, Crandall W, Markowitz J, Otley AR, Xu W, Hu P, Griffiths AM, Silverberg MS. Gene Expression Profiles Associated with Lack of Response to Intravenous Corticosteroids in Children with Severe Ulcerative Colitis. Gastroenterology 2009;136 (5 Suppl 1):A-172 (Abst 1107). 3. Turner D, Mack DR, Uusoue K, Hyams JS, Leleiko N, Leach S, Walters TD, Day AS, Crandall W, Markowitz J, Silverberg MS, Otley AR, Mamula P, Griffiths AM. Prospective multicenter study of outcomes and predictors of response in severe pediatric ulcerative colitis. Gastroenterology 2009;136 (5 Suppl 1):A-571 (Abst T1745). 4. Gana JC, Turner D, Avitzur Y, Ling SC. Prediction of Esophageal Variceal Bleeding in Chil- dren. Gastroenterology 2009;136 (5 Suppl 1):A-825 (Abst S1832). 5. Turner D, Wine E, Kolho K, Mack D, Hyams J, Silverberg MS, Otley AR, Markowitz J, Crandall W, Leleiko N, Leach, Griffiths AM. Determinants of corticosteroid-resistance in severe pediatric ulcerative colitis. Inflamm Bowel Dis 2009; 15 (12 Suppl):S16 (Abstr P-38). 6. Turner D, Mack D, Wine E, Hyams JS, Otley AR, Markowitz J, Crandall W, Mamula P, Leleiko N, Griffiths AM. Infliximab in steroid-refractory pediatric UC: predictors of response in a prospective multicenter study. JCC 2010; 4 (1):S63 (Abst P125). 7. Turner D, Mack DR, Wine E, Hyams JS, Otley AR, Markowitz J, Crandall W, Mamula P, LeLeiko NS, Griffiths AM. A prospective multicenter study: outcomes and predictors of response to infliximab given as a rescue therapy in severe pediatric ulcerative colitis. Gas- troenterology 2010; 138 (5), Suppl 1: S-29 (Abst 149). Research Report 2013 132
    • 8. Sylvester FA, Turner D, Draghi A, Uuosoe K, MacLernon RA, Griffiths AM. Fecal Osteo- protegerin predicts the need for second line therapy in hospitalized children with ulcerative colitis. Gastroenterology 2010; 138 (5), Suppl 1: S-358 (abst M1226). 9. Durbin M, Wine E, Turner D, Griffiths AM, Kenche H, Stolfi A, Michail S. The gut micro- biome in children with severe ulcerative colitis. Gastroenterology 2010; 138 (5), Suppl 1: S-28 (abst 148). 10. Levine A, Griffiths AM, Markowitz J, Wilson DC, Turner D, Russell RK, Fell J, Ruemmele FM, Walters TD, Sherlock M, Dubinsky M, Hyams JS. Pediatric modification of the Mon- treal classification for inflammatory bowel disease: The Paris classification. J Crohn Colitis 2011; 5(1): S5(abst 6). 11. Turner D, Griffiths AM, Walters TD, Seah T, Markowitz J, Pfefferkorn M, Keljo D, Waxman J, Otley A, Leleiko NS, Mack D, Hyams J, Levine A. Mathematical weighting of the pedi- atric Crohn’s disease activity index (PCDAI) and comparison with its other short versions. J Ped Gastroenterol Nutr 2011;52(Suppl 1):E17 (abst PA-G-0029). 12. Weiss B, Egbaria R, Lerner A, Suchar I, Broide E, Turner D, Pinsk V, Bujanover Y. Inflam- matory bowel disease in children under 2 years of age: clinical characteristics and out- come. J Ped Gastroenterol Nutr 2011;52(Suppl 1):E146 (abst PO-G-0110). 13. De Bie1 C, Levine A, Turner D, Cucchiara S, Sladek M, Murphy S, Escher J, for the EUROKIDS Porto IBD Working Group of ESPGHAN. Atypical disease phenotypes in paediatric ulcerative colitis: 5-year analyses of the EUROKIDS registry. J Crohn Colitis 2012;6(Suppl 1):S43 (abst P083). 14. Shaoul R, Turner D, Sladek M, Veres G, Veerman-Wauters G, Escher J, Paerregaard A, Amil Dias J, Lionetti P, Levine A. Limitations of fecal calprotectin at diagnosis in untreated pediatric Crohn’s disease. J Crohn Colitis 2012;6(Suppl 1):S48 (abst P096). 15. Church P, Turner D, Walters T, Greer ML, Amitai M, Griffiths A. A systematic review of MR enterography signs of inflammation and damage in Crohn’s disease. J Crohn Colitis 2012;6(Suppl 1):S84 (abst P188). 16. Levine A, Sladek M, Shaoul R, Veres G, Amil Dias J, Escher J, Turner D. Exclusive enteral nutrition is superior to corticosteroids and mesalamine for achieving remission with nor- malization of CRP in new onset pediatric Crohn’s disease. J Crohn Colitis 2012;6(Suppl 1):S111 (abst P255). 133 Pediatric Gastroenterology
    • 17. Kasirer Y, Segel R, Renbaum P, Algur N, Mevorach R, Rachman Y, Turner D. Biochemical assay to determine thiopurine S-methyltransferase (TPMT) activity should be used in the Jewish population, rather than genotyping. J Crohn Colitis 2012;6(Suppl 1):S146 (abst P343). Research Report 2013 134
    • T he Pediatric Infectious Diseases Unit in the Division of Pediatrics is directed by Prof. Yechiel Schlesinger. Dr. Maskit Bar-Meir and Dr. Orli Megged, both board-cer- tified in Pediatrics as well as Infectious Diseases, are the other two members of the unit. The team provides care for children with infectious diseases, from diagnosis through treat- ment.  The Unit provides consultation to children in all pedi- atric units including the pediatric emergency room, hospital- ized patients, pediatric surgery, pediatric day hospital, neonatology/neonatal intensive care and the patients treated by sub-specialty units. Consultations are also provided by telephone to primary pediatricians in the community. The members of the unit play an important role in student and intern instruction Areas of Research Activity In addition to clinical work, the Pediatric Infectious Diseases Unit also operates a research laboratory, directed by Prof. Schlesinger. The laboratory focuses mainly on molecular di- agnosis of infectious diseases, in particular viral infections in children. Another area of interest is Cytomegalovirus (CMV) infection in pregnant women, which centers on immune mechanisms involved in the control of maternal-fetal trans- mission of the virus. Studies are also conducted in epidemiology, diagnosis, clini- cal manifestations and treatment of common and rarer infec- tious diseases in children. Pediatric Infectious Diseases Unit 135 Infectious Diseases
    • The Unit also takes part in international studies run by the pharmaceutical industry, mainly pertaining to innovative immunizations combating a range of pediatric diseases. Representative Research The unit recently published an article on the current status of infection by the bacterium Hae- mophilus influenza, with a specific emphasis on the strain. Years ago, this bacterium was the leading cause of invasive, dangerous and even fatal bacterial infection in children up to 2 years of age. A revolution in pediatric infectious diseases occurred about 20 years ago when a very effective vaccine became available, and nearly, but not completely, eliminated this infection. In this article (Megged O, Bar-Meir M, Schlesinger Y. Haemophilus influenzae activity in a single medical center in Israel in the post-vaccine era. Isr Med Assoc J. 2012; 14:410-4), the authors describethecumulativeexperiencewiththisbacteriuminthepost-vaccineera(1997-2010),in a single medical center (Shaare Zedek Medical Center). The authors outline all the epidemio- logical and clinical characteristics of the 104 patients (57 children, 47 adults) with either Hae- mophilus or non- Haemophilus influenza infection (Figure and Table 1). Overall, 21 (20%) of the infections were due to serotype B. The children had shorter hospitalizations (6 vs. 12 days, P = 0.005) and a lower mortality rate (5% vs. 28%, P = 0.003) compared to the adults. Pneumo- nia was the most common diagnosis in adults (45% vs. 28% in children, P = 0.08) while men- ingitis was more common in children (17% vs. 3.5%, P = 0.09).There was a seasonal pattern, with infections more common during the winter and spring. The authors conclude that inva- sive H. influenzae disease is uncommon but still exists in both children and adults, and that even in the global vaccination era, serotype B constitutes a significant portion of invasive disease. Research Report 2013 136
    • Publications 1. Megged O, Schlesinger Y. Varicella zoster infection in adults: a preventable disease. Isr Med Assoc J 2009;11(5):306-7. 2. Schwartz S, Raveh D, Toker O, Segal G, Godovitch N, Schlesinger Y. A week-by-week analysis of the low-risk criteria for serious bacterial infection in febrile neonates. Arch Dis Child 2009;94(4):287-92. 3. Wiener-Well Y, Raveh D, Schlesinger Y, Yinnon AM, Rudensky B. Cefuroxime for empiric treatment of community-acquired pneumococcal pneumonia: is there a generation gap? Chemotherapy 2009;55(2):97-104. 4. Megged O, Schlesinger Y, Attias D, Rudensky B. [Gastrointestinal carriage of Pseudomo- nas aeruginosa in children residing in chronic care institutes in Jerusalem: high prevalence and high rates of antibiotic resistance]. Harefuah 2009;148(11):766-8, 793. 5. Eidelman AI, Megged O, Feldman R, Toker O. The burden of respiratory syncytial virus bronchiolitis on a pediatric inpatient service. Isr Med Assoc J 2009;11(9):533-6. 137 Infectious Diseases
    • 6. Baneth G, Harrus S, Ohnona FS, Schlesinger Y. Longitudinal quantification of Eh- rlichia canis in experimental infection with comparison to natural infection.Vet Microbiol 2009;12:136(3-4). 7. Schlesinger Y, Ben-Shalom E, Raveh DP, Yinnon AM, Miskin H, Rudensky B. [Vibrio vulni- ficus infection outside of the fish ponds in northern Israel:acquisition in the “Einot Tzukim” springs near the Dead Sea]. Harefuah 2009;148(11):772-4, 792. 8. Megged O, Shalit I, Yaniv I, Fisher S, Livni G, Levy I. Outcome of antibiotic lock technique for persistent central venous catheter-associated coagulase-negative Staphylococcus bacteremia in children. Eur J Clin Microbiol Infect Dis 2010;29(2):157-61. 9. Bar-Meir M, Tan TQ. Staphylococcus aureus skin and soft tissue infections: can we antici- pate the culture result? Clin Pediatr (Phila) 2010;49(5):432-8. 10. Toker O, Schwartz S, Segal G, Godovitch N, Schlesinger Y, Raveh D. A costly covenant: ritual circumcision and urinary tract infection. Isr Med Assoc J 2010;12(5):262-5. 11. Dubnov-Raz G, Ephros M, Garty BZ, Schlesinger Y, Maayan-Metzger A, Hasson J, Kassis I, Schwartz-Harari O, Yagupsky P. Invasive pediatric Kingella kingae Infections: a nation- wide collaborative study. Pediatr Infect Dis J 2010; 29(7):639-43. 12. Wiener-Well Y, Rudensky B, Yinnon AM, Kopuit P, Schlesinger Y, Broide E, Lachish T, Raveh D. Carriage rate of carbapenem-resistant Klebsiella pneumoniae in hospitalised patients during a national outbreak. J Hosp Infect 2010;74(4):344-9. 13. Carbonell-Estrany X, Simões EA, Dagan R, Hall CB, Harris B, Hultquist M, Connor EM, Losonsky GA; Motavizumab Study Group. Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: a noninferiority trial. Pediatrics 2010;125:e35-51. 14. Wiener-Well Y, Fink D, Schlesinger Y, Raveh D, Rudensky B, Yinnon AM. Q fever endocar- ditis; not always expected. Clin Microbiol Infect 2010;16(4):359-62. 15. Miron D, Horovitz Y, Luder A, Ohnona FS, Schlesinger Y. Age-related immunoglobu- lin G seroprevalence of human parvovirus B-19 in Israeli children. Isr Med Assoc J 2010;12(5):277-9. 16. Stein M, Tasher D, Glikman D, Shachor-Meyouhas Y, Barkai G, Yochai AB, Leibovitz E, Hausman-Kedem M, Hess A, Megged O, Kassis I, Gresario G, Somekh E. Hospitaliza- Research Report 2013 138
    • tion of children with influenza A(H1N1) virus in Israel during the 2009 outbreak in Israel: a multicenter survey. Arch Pediatr Adolesc Med 2010;164(11):1015-22. 17. Megged O, Schlesinger Y. Down syndrome and respiratory syncytial virus infection. Pedi- atr Infect Dis J 2010;29(7):672-3. 18. Megged O, Schlesinger Y. Down syndrome and streptococcus group A disease in hospi- talized children. Acta Paediatr 2010;99(6):796-7. 19. Feltes TF, Sondheimer HM, Tulloh RM, Harris BS, Jensen KM, Losonsky GA, Griffin MP; Motavizumab Cardiac Study Group. A randomized controlled trial of motavizumab versus palivizumab for the prophylaxis of serious respiratory syncytial virus disease in children with hemodynamically significant congenital heart disease. Pediatr Res 2011;70:186-91. 20. Wiener-Well Y, Galuty M, Rudensky B, Schlesinger Y, Attias D, Yinnon AM.Nursing and physician attire as possible source of nosocomial infections. Am J Infect Control 2011;39(7):555-9. 21. Bar-Meir M, Haklai Z, Dor M. Kawasaki disease in Israel. Pediatr Infect Dis J 2011; 30(7):589-92. PubMed PMID: 21343843. 22. Bar-Meir M, Haklai Z, Dor M. Kawasaki disease in Israel. Pediatr Infect Dis J 2011; 30(7): 589-92. 23. Hauser AR, Jain M, Bar-Meir M, McColley SA. Clinical significance of microbial infection and adaptation in cystic fibrosis. Clin Microbiol Rev 2011;24(1):29-70. 24. Megged O, Argaman Z, Kleid D. Purulent pericarditis in children: ispericardiotomy need- ed? Pediatr Emerg Care 2011;27(12):1185-7. 25. Megged O, Stein J, Ben-Meir D, Shulman LM, Yaniv I, Shalit I, Levy I.BK-virus-associated hemorrhagic cystitis in children after hematopoietic stem cell transplantation. J Pediatr Hematol Oncol 2011;33(3):190-3. 26. Megged O, Navon-Elkan P, Anikster Y, Kleid D. Recurrent fever, arthritis,lymphadenopathy, and hepatosplenomegaly. Pediatr Infect Dis J 2011;30(2):182-5. 27. Megged O, Bar-Meir M, Schlesinger Y. Haemophilus influenzae activity in a single medical center in Israel in the post-vaccine era. Accepted for publication Isr Med Assoc J. 139 Infectious Diseases
    • 28. Ben-Ami R, Olshtain-Pops K, Krieger M, Oren I, Bishara J, Dan M, Wiener-Well Y, Wein- berger M, Zimhony O, Chowers M, Weber G, Potasman I, Chazan B, Kassis I, Shalit I, Block C, Keller N, Kontoyiannis DP, Giladi M; Israeli Candidemia Study Group. Collabo- rators: Orni-Wasserlauf R, Moses A, Elinav H, Rahav G, Maor Y, Goldshmidt-Reuven A, Sheba C, Finkelstein R, Sprecher H, Paul M, Levi I, Samra Z, Goldberg E, Gottesman T, Schwartz-Harari O, Yinon A, Megged O, Lazarovitch T, Harofeh A, Ciobotaro P, Gottes- man B, Paz A, Raz R, Miron D, Riesenberg K, Saidel L, Sheva B, Halperin E, Hassin D, Yafe H, Soboh S. Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection. Antimicrob Agents Chemother 2012;56(5):2518-23. 29. Ashkenazi L, Bar-Meir M, Schlesinger Y, Megged O. Invasive pneumococcal disease in infants younger than 60 days. Clin Pediatr (Phila) 2012;51(5):478-82. 30. Rave O, Assous MV, Hashkes PJ, Lebel E, Hadas-Halpern I, Megged O. Pantoea agglom- erans Foreign Body Induced Septic Arthritis. Pediatr Infect Dis J 2012; Aug 24. 31. Megged O, Assous M, Weinberg G, Schlesinger Y. Inducible clindamycin resistance in beta hemolytic streptococci and Streptococcus pneumoniae. Accepted for publication Isr Med Assoc J. Research Report 2013 140
    • T he Pediatric Rheumatology Unit, established in 2009, is headed by Prof. Philip Hashkes. Ms. Shoshana Berg, the only physical therapist in Israel with formal train- ing in treating children with rheumatic conditions, is part of the unit. The Unit works with the nursing and other staff of the Pediatric Day Hospital. The Unit collaborates with other services involved in multisystem diseases, such as ophthal- mology,orthopedics,nephrology,gastroenterologyandinfec- tious disease. Services include the diagnosis and management of pediat- ric rheumatology diseases and conditions, particularly juve- nile idiopathic arthritis. Procedures include corticosteroid intraarticular injections (often utilizing sedation and ultra- sound guidance) and infusions of anti-inflammatory medica- tions, including novel biological agents developed in recent years. Prof. Hashkes was instrumental in introducing some of these new medications to the Israeli “Health Basket” so thesemedicationscouldbefundedforchildren.Prof.Hashkes is considered an international authority in the treatment of juvenile arthritis, primary vasculitis diseases in children and autoinflammatory syndromes, including familial Mediterra- nean fever. Areas of Research Activity As most pediatric rheumatology conditions are rare, the Unit’s research is mostly conducted as part of international collaborations. Much of the research is related to projects Pediatric Rheumatology Unit 141 Pediatric Rheumatology
    • started by Prof. Hashkes in the United States. Prof. Hashkes specializes in clinical research and publications related to his research have appeared in leading journals and textbooks of rheumatology.The most important research projects are related to new treatments for familial Mediterranean fever (FMF), a genetic disease causing recurrent attacks of fever, abdominal, chest pain, arthritis and rash, particularly in populations living near the Mediterranean Sea. The number of FMF patients in Israel is estimated to be between ten and fifteen thousand. Most patients respond well to treatment with colchicine. Colchicine also prevents the long- term complications of FMF, mainly the development of kidney failure related to the accumu- lation of a protein called amyloid in the kidney. However, about 10% of FMF patients do not respond or do not tolerate colchicine and currently there is no adequate alternative for these patients.Prof.HashkesdirectedamulticenterstudyconductedintheUnitedStates,fundedby theUSFoodandDrugAdministration,usingrilonacept,asolublereceptorofinterleukin1(IL- 1) which is a pivotal protein involved in the inflammatory process of FMF. We were also part of a local multicenter research project sponsored by Novartis, using canakinumab, an antibody to IL-1β, for these patients. The unit also collaborates (mainly with Meir Hospital in Kfar Saba) on studying the very com- mon phenomenon of childhood “growing” pains. These refer to episodes of primarily lower limb pain occurring in young children late in the day and often awaking the child at night without major abnormal physical, laboratory and imaging findings. Our research (with nearly 10 publications) has found that these pains are often related to overexertion in children with a low pain threshold and possibly low bone strength. The long-term outcome of these pains is generally good, although many children continue to complain of these pains even as teenagers. The unit also conducts epidemiological and outcome studies in pediatric rheumatology, utiliz- ing large databases. In the first large study on mortality in pediatric rheumatology diseases we showed that mortality has decreased in recent years although there is still increased mor- tality, particularly systemic lupus erythematosus, dermatomyositis and primary vasculitis. In other outcome projects we showed that the use of non-steroidal anti-inflammatory drugs for the treatment of juvenile arthritis as well as the need for joint replacement surgery have de- creased, most likely related to the earlier use of more effective medications, including metho- trexate and biological disease modifiers. Representative Research In a multicenter randomized controlled study performed at 6 sites (including the National In- stitutes of Health) in the United States and funded by the United States Food and Drug Ad- ministration we examined whether rilonacept is effective in decreasing the number of FMF attacks in children and adults who do not respond to or do not tolerate colchicine. Rilonacept, Research Report 2013 142
    • a soluble receptor of IL-1 (see above for background), is given once weekly by subcutaneous injection. Since FMF is very rare in the United States and we studied only the ~10% of FMF patients not responsive or intolerant of colchicine, we devised a unique trial and statistical design to obtain the maximal data and effect from each of the 14 patients who participated in thistrial.WefoundthatrilonaceptsignificantlydecreasedthenumberofFMFattacks(butnot the length of attacks) when compared to placebo, particularly in children, although there were several patients, all adults, who did not respond to rilonacept. There was also a marked im- provementinthephysicalhealth-relatedqualityoflifeduringrilonacepttreatmentwhencom- pared to placebo. There were no clinically significant safety differences between rilonacept and placebo although the size of the trial was not sufficient to fully study safety issues. Therefore, in this first controlled study we found that using rilonacept is an option for most FMF patients who are not responsive or intolerant to colchicine. An example of the course of one patient (a responder) in the FMF rilonacept trial. PUBLICATIONS 1. Hashkes PJ, Hong S, Reiff A, Lehman TGA. Responsiveness of Simple Measure of Impact of Lupus Erythematosus in Youngsters A multicenter prospective study. Lupus 2009;18:622-629. 2. Cabral DA, Uribe AG, Benseler S, O’Neil KM, Hashkes PJ, Higgins G, Zeft AS, Lovell DJ, Kingsbury DJ, Stevens A, McCurdy D, Chira P, Abramson L, Arkachaisri T, Campillo S, Eberhard A, Hersh AO, Huber AM, Kim S, Klein-Gitelman M, Levy D, Li SC, Mason T, DeWitt EM, Muscal E, Nassi L, Reiff A, Schikler K, Singer NG, Wahezi D, Woodward attacks attack attack attack Pt 1 length of treatment course day of escape visit Rilonacept Placebo (d) 31 within course length of treatment course (d) 78 79 89 89 25 35 59 8 15 22 29 day of attack start day of attack start day of attack start within treatment course within treatment course within treatment course Escape 143 Pediatric Rheumatology
    • A, for the ARChiVe investigator’s Network. Classification, presentation and initial treat- ment of Wegener’s Granulomatosis in childhood: an ARChiVE project. Arthritis Rheum 2009;60:3413-3424. 3. Montaleagre Sanchez G, Hashkes PJ. Neurologic manifestations of the Mendelian inher- ited autoinflammatory syndromes. Develop Med Child Neurol 2009;51:420-428. 4. Uziel Y, Zifman E, Hashkes PJ. Osteoporosis in children: pediatric and pediatric rheuma- tology perspective: a review. Pediatr Rheumatol 2009;7:16. 5. Hashkes PJ. Rheumatic disorders. In Intensive Review of Pediatrics, 3rd edition. Sabella C, Cunningham RJ III, eds. Lippincott Williams and Wilkins, Philadelphia, PA, 2010:430- 443. 6. Hashkes PJ, Laxer RM. Management of juvenile idiopathic arthritis. In Rheumatology 5th edition. Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Elsevier, Philadelphia, PA, 2010:1017-1027. 7. Saad-Magalhães C, Pistorio A, Ravelli A, Filocamo G, Viola S, Brik R, Mihaylova D, Ten Cate R, Andersson Gare B, Ferriani VP, Minden K, Hashkes PJ, Rygg M, Sauvain MJ, Venning H, Martini A, Ruperto N. Does removal of AIDS/devices and help make a differ- ence in the Childhood Health Assessment Questionnaire Disability Index? Ann Rheum Di. 2010;69:82-87. 8. Hashkes PJ, Wright B, Lauer MS, Worley SE, Tang AS, Roettcher PA, Bowyer SL. Mortali- ty outcomes in pediatric rheumatology in the United States. Arthritis Rheum 2010;62:599- 608. 9. Uziel Y, Chapnich G, Jaber L, Nemet D, Hashkes PJ Five-year outcome of children with “growing-pains”: Correlations with pain threshold. J Pediatr 2010;156:838-840. 10. Kashikar-Zuck S, Flowers SR, Verkamp E, Ting T, Lynch-Jordan AM, Graham TB, Passo M, Schikler KN, Hashkes PJ, Spalding S, Banez G, Richards MM, Powers SW, Arnold LM, Lovell D. Actigraphy-based physical activity monitoring in adolescents with juvenile primary fibromyalgia syndrome. J Pain 2010;11:885-993. 11. Kashikar-Zuck S, Johnston M, Ting TV, Graham TB, Lynch-Jordan AM, Verkamp E, Passo M, Schikler KN, Hashkes PJ, Spalding S, Banez G, Richards,MM, Powers SW, Arnold LM, Lovell D. Relationship between school absenteeism and depressive symptoms among Research Report 2013 144
    • adolescents with juvenile fibromyalgia. J Pediatr Psychol 2010;35:996-1004. 12. Ruperto N, Pistorio A, Ravelli A, Rider L, Pilkington C, Oliveira S, Wulffraat N, Espada G, Garay S, Cuttica R, Hofer M, Quartier P, Melo-Gomes J, Reed AM, Wierzbowska M, Feld- man BM, Harjacek M, Huppertz HI, Nielsen S, Flato B, Lahdenne P, Michels H, Murray KJ, Punaro L, Rennebohm R, Russo R, Balogh Z, Rooney M, Pachman LM, Wallace C, Hashkes P, Lovell DJ, Giannini EH, Martini A, for the Pædiatric Rheumatology International Trials Organisation (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG). The PRINTO criteria for the evaluation of response to therapy in juvenile derma- tomyositis. Arthritis Care Res 2010;62:1533-1541. 13. Ruperto N, Lovell DJ, Li T, Sztajnbok F, Goldenstein-Schainberg C, Scheinberg M, Calvo Penades I, Fischbach M, Orozco J, Hashkes PJ, Hom C, Jung L, Lepore L, Oliveira S, Wallace C, Alessio M, Quartier P, Cortis E, Eberhard A, Simonini G, Lemelle,I, Chalom E, Sigal HH, Block A, Covucci A, Nys M, Martini A, Giannini EH, for the Paediatric Rheuma- tology International Trials Organization (PRINTO) and the Pediatric Rheumatology Col- laborative Study Group (PRCSG). Abatacept improves health-related quality of life, pain, sleep quality and daily participation in subjects with juvenile idiopathic arthritis. Arthritis Care Res 2010;62:1542-1551. 14. Mehta BM, Hashkes PJ, Avery R, Deal CL. A 21 year old man with Still’s disease, fever, rash and pancytopenia. Arthritis Care Res 2010;62:575-579. 15. Toker O, Hashkes PJ. Critical appraisal of the role of canakinumab in the treatment of adults and children with cryopyrin-related periodic syndrome (CAPS). Biologics 2010;4:131-138. 16. Hashkes PJ, Uziel Y, Laxer RM. The safety profile of novel biologic therapies for juvenile idiopathic arthritis. Nat Rheumatol Rev 2010;6:561-571. 17. Hashkes PJ. Autoinflammatory disorders. In Rudolph’s Textbook of Pediatrics, 22 edi- tion, Rudolph CD, Rudolph AM, Lister GE, First LR, Gershon AA, eds. McGraw Hill, New York,NY, 2011:832-837. 18. Hashkes PJ, Wright B, Lauer MS, Worley SE, Tang AS, Roettcher PA, Bowyer SL. Survival rates of children with acute lymphoblastic leukemia presenting to a pediatric rheumatolo- gist in the United States. J Pediatr Hematol Oncol 2011;33:424-428. 19. Kochar R, Kyle M, Jain A, Spalding S, Hashkes PJ. Decrease in the use of non-ste- roidal anti-inflammatory drug for the treatment of juvenile idiopathic arthritis in the 145 Pediatric Rheumatology
    • era of modern aggressive treatment. Rheumatol Int 2011 (Epub). 20. Hashkes PJ, Sagi E. Tefillin-related contact dermatitis Harefuah 2011;150:700-702. 21. Mehta BM, Hashkes PJ. Macrophage activation syndrome: why and what should a gas- troenterologist know. J Clin Gastroenterol 2011;45:210-214. 22. Goldzweig O, Hashkes PJ. Abatacept in the treatment of polyarticular juvenile idiopathic arthritis: development, clinical utility and place in therapy. Drug Design, Development and Therapy 2011;5:61-70. 23. Hashkes PJ. Strengths and challenges of a new guide for treating JIA [editorial]. Nat Rheu- matol Rev 2011;7:377-378. 24. Uziel Y, Hashkes P. An era of international collaboration in pediatric rheumatology. Harefuah 2011;150:737-741. 25. Uziel Y, Perl L, Barash J, Hashkes PJ. Post streptococcal reactive arthritis in children: how does it relate to acute rheumatic fever. Pediatr Rheumatol 2011;9:32 (electronic publica- tion). 26. Hashkes PJ, Toker O. Autoinflammatory syndromes. Pediatr Clin North Am 2012;59:447- 470. 27. Hashkes PJ, Villa-Forte, A. Henoch Schonlein purpura. In Inflammatory Diseases of Blood Vessels, 2nd edition. Hoffman GS, Weyand C, Langford C, Goronzy JJ, eds. Wiley-Black- well, Oxford, UK, 2012:205-216. 28. Kashikar-Zuck S, Ting TV, Arnold LM, Bean J, Powers SW, Graham TB, Passo M, Schikler KN, Hashkes PJ, Spalding S, Lynch-Jordan AM, Banez G, Richards MM, Lovell D. A randomized clinical trial of cognitive behavioral therapy for the treatment of juvenile fibro- myalgia. Arthritis Rheum 2012;64:297-305. 29. Uziel Y, Chapnik G, Oren-Ziv A, Jaber L, Nemet D, Hashkes PJ. Bone strength in children with growing pains: long term follow-up. Clin Exp Rheumatol 2012;30:137-140. 30. Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O’Neil KM, Zeft AS, Szer IS, Ringold S, Brunner HI, Schanberg LE, Sundel RP, Milojevic D, Punaro MG, Chira P, Gottlieb BS, Higgins GC, Ilowite NT, Kimura Y, Hamilton S, Johnson A, Huang B, Lovell DJ, for the Research Report 2013 146
    • Childhood Arthritis Rheumatology Research Alliance (CARRA). Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum 2012;64:2012-2021. 31. Ting TV, Hashkes PJ, Schikler K, Desai AM, Spalding S, Kashikar-Zuck S The role of be- nign joint hypermobility in the pain experience in Juvenile Fibromyalgia: an observational study. Pediatr Rheumatol 2012;10:16. 32. Morishita K, Guzman J, Chira P, Muscal E, Zeft A, Klein-Gitelman M, Uribe AG, Abramson L, Benseler SM, Eberhard A, Ede K, Hashkes PJ, Hersh AO, Higgins G, Imundo LF, Jung L, Kim S, Kingsbury DJ, Lawson EF, Lee T, Li SC, Lovell DJ, Mason T, McCurdy D, O’Neil KM, Punaro M, Ramsey SE, Reiff A, Rosenkranz M, Schikler KN, Scuccimarri R, Singer NG, Stevens AM, van Mater H, Wahezi DM, White AJ, Cabral, DA, for the ARChiVe Inves- tigators Network. Do Adult Disease Severity Subclassifications Predict Use of Cyclophos- phamide in Children with ANCA-Associated Vasculitis? An Analysis of ARChiVe Study Treatment Decisions. J Rheumatol 2012 Epub. 33. Ben-Pazi H, Hashkes PJ, Kroyzer N. Sydenham’s chorea: Long Term Immunosuppression for Psychiatric Symptoms. J Pediatr Neurol 2012. 34. Rave O, Assous MC, Hashkes PJ, Lebel E, Halpern IH, Megged O. Pantoea Agglomerans foreign body induced septic arthritis. Ped Infect Dis J 2012. 35. Hashkes PJ, Spalding SJ, Giannini EH, Huang B, Johnson A, Park G, Barron KS, Weis- man MH, Pashinian N, Reiff AO, Samuels J, Wright DA, Kastner DL, Lovell DL. Rilonacept for colchicine resistant or intolerant familial Mediterranean fever: a randomized controlled trial. Ann Intern Med 2012. 147 Pediatric Rheumatology
    • T he Neuropediatric Unit, directed by Prof. Ruth Shalev, is staffed by five specialists (Prof. Varda Gross Tsur, Dr. Adi Aran, Dr. Tal Gilboa and Dr. Hila Ben Pazi), a resident (Dr. Gideon Winter), 4 psychologists (Dr. Yehuda Pollak, Dr. Julie Segal-Rosenman, Raya Wertman and Tzila Nir-Shamir) and a physiotherapist (Ms. Nava Gelkop). The Unit also has an EEG unit reserved for examinations of chil- dren with neurological and neuro-psychiatric disorders. The staff treats over 8,300 children annually, many of whom are seen at the specialized multidisciplinary clinics for Tourette’s Syndrome,PraderWilliSyndrome,epilepsy,andattheNeuro- logic-Genetic and Movement Disorder Clinics. The Unit was established in 1965 by Professor Naomi Amir and has a his- tory of innovation and excellence in the field. The philosophy of the Unit is to expand treatment horizons beyond diagnosis and pharmacological treatment and search for innovative ways to maximize the abilities and participation of children with neurological deficits. Since the 1970s the Unit has run a specialeducationkindergartenforchildrenwithdevelopmen- tal neurological disorders which today is housed in a state-of- the-art building providing services for children from birth to age seven. The unit organizes an annual symposium for pro- fessionals and parents providing up-to-date medical and sci- entific information on pediatric neurological conditions and attracts audiences of over 1000 every year. Each physician has an area of expertise: Prof. Gross-Tsur, To- urette Syndrome, Prader Willi Syndrome; Dr. Tal Gilboa epi- lepsy; Dr. Ben Pazi movement disorders (particularly cerebral Neuropediatric Unit Research Report 2013 148
    • palsy); Dr. Adi Aran sleep disorders and complex metabolic and degenerative neurological dis- orders, and Prof. Ruth Shalev, learning disabilities and attention deficit hyperactivity disorder. Areas of research activity The Unit’s physicians are pioneers in exploring the clinical ramifications of developmental dyscalculia, a learning disability impairing the normal acquisition of arithmetic skills. They also contributed to developing the concept of non-verbal learning disabilities and defining its clinical features. Although it seems apparent that children and adolescents with attention deficit hyperactivity disorder can make poor decisions, the characteristics of decision making in this disorder are unclear and are a focus of intense research headed by Dr. Pollak. Multiple aspects of Prader Willi syndrome, a genetic disorder affecting the brain and body, are being studied by the multidisciplinary team headed by Prof. Gross-Tsur; these include cognitive fea- tures, predilection for epilepsy and the unique hormonal and reproductive features of the syn- drome. Dr. Aran deals with the neurocognitive deficits associated with sleep deficiency. He is also studying narcolepsy, a lifelong, disabling neurological disorder characterized by daytime sleepiness. Dr.Aranalsoresearchesthelateonseteffectsofinfections,particularlystreptococ- cal disorders and their ability to cause or contribute to illnesses via immune mediated mecha- nisms. Dr. Gilboa’s research focus is pediatric epilepsy and its expression in neonates, patients with genetic syndromes and otherwise healthy children. Dr. Ben-Pazi’s research interests are mainlyintheareaofdiagnosisandtreatmentofpediatricmovementdisorders.Sheisinvolved in etiological studies of congenital movement disorders such as cerebral palsy and Sydenham’s chorea. Treatment innovations are an important research avenue and she is conducting ongo- ing trials to evaluate the efficacy of pharmacological agents such as dopamine and trihexiphe- nidyl for dystonia, and baclofen and botulinum toxin for spasticity. Representative Research This series of studies on the inhibiting effects of post-streptococcal auto-antibodies on protein disulfide isomerase and associated insulin resistance investigated the long term auto-immune effects of ordinary bacterial infections. This translational research was conducted in close col- laboration with the Stanford University Basic Science Sleep Laboratory and the Wisconsin University Sleep Cohort Study. One study showed that streptococcal throat infections can trigger an immune mediated process that results in narcolepsy. A new auto-antibody, present in ~8% of the population in the context of post-streptococcal immunity, may play a role in the emergence of diabetes and obesity. This novel autoantibody targets the important pleiotropic enzyme Protein Disulfide Isomerase (PDI) which is involved in the metabolism of a variety of proteins, including insulin; the mere presence of this antibody impairs PDI enzymatic activity in vitro. In a large population- based cohort, increased insulin levels and indicators (HOMA) 149 Neuropediatric
    • of increased insulin resistance were found in subjects with the anti PDI autoantibody. These resultsareconsistentwiththegrowingbodyofresults linkinginfections,immunityandmeta- bolic abnormalities. Streptococcal infection leads to insulin resistance Higher insulin levels in subjects with anti-PDI Research Report 2013 150
    • Higher insulin resistance in subjects with anti-PDI PUBLICATIONS 1. Ben-Pazi H, Ishihara A, Kukke S, Sanger TD. Increasing viscosity and inertia using a ro- botically controlled pen improves handwriting in children. J Child Neurol 2009; 25:674-80. 2. Ben-Pazi H, Adi- Japha E, Lossos A. Primary and secondary writing disorders in children Harefuah 2009;148:515-519. 3. Mignot E. Aran A. The immune system, the brain and narcolepsy. Future Neurology. 2009;4:683-687. 4. Eldar-Geva T, Hirsch HJ, Rabinowitz R, Benarroch F, Rubinstein O, Gross-Tsur V. Primary ovarian dysfunction contributes to the hypogonadism in women with Prader-Willi Syn- drome. Hormone Research 2009;72:153-150. 151 Neuropediatric
    • 5. van der Meere J, Shalev RS, Borger N, Wiersema JR. Methylphenidate, inter-stimulus- interval and reaction time performance of children with attention-deficit/hyperactivity dis- order: a pilot study. Child Neuropsychology 2009;15:554-566. 6. Pollak Y, Weiss PL, Rizzo AA, Weizer M, Shriki L, Shalev RS, Gross-Tsur V. The utility of a continuous performance test embedded in virtual reality in measuring ADHD-related deficits. J Dev Behav Pediatr 2009;30:2-7. 7. Hirsch HJ, Geva-Eldar T, Benarroch F, Rubinstein O, Gross-Tsur V. Primary testicular dysfunction is a major contributor to abnormal pubertal development in males with Prader- Willi Syndrome.   J Clinic Endocrinol & Metabolism 2009; 94:2262-2268. 8. Pollak Y, Benarroch F, Kanengisser L, Shilon Y, Ben Pazi H, Shalev RS, Gross-Tsur V. To- urette syndrome-associated psychopathology: roles of comorbid attention-deficit hyper- activity disorder and obsessive-compulsive disorder. J Dev Behav Pediatr 2009;30:413- 419. 9. Aran A, Nevsimalova S, Plazzi G, Hong SC, Weiner K, Zeitser J, Mignot E. Elevated anti- streptococcal antibodies in patients with recent narcolepsy onset. Sleep 2009;32:979- 983. 10. Aran A , Weiner K , Lin L, Finn LA, Greco MA, Peppard P, Young T, Ofran Y , Mignot E. Post-streptococcal auto-antibodies inhibit protein disulfide isomerase and are associated with insulin resistance. PLoS ONE 2010;5:e12875. 11. Aran A; Einen M; Lin L; Plazzi G; Nishino S; Mignot E. Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children. Sleep 2010; 33:1457-1464. 12. Eldar-Geva T, Hirsch HJ, Benarroch F, Rubinstein O, Gross-Tsur V. Hypogonadism in females with Prader-Willi syndrome from infancy to adulthood: variable combinations of a primary gonadal defect and hypothalamic dysfunction. Eur J Endocrinol 2010;162:377- 384. 13. Shriki L, Weizer M, Pollak Y, Weiss PL, Rizzo AA, Gross-Tsur V. Utility of continuous per- formance test embedded in virtual reality in measuring ADHD related deficits. Harefuah 2010;149:18-23, 63. 14. Pollak Y, Shomaly HB, Weiss PL, Rizzo AA, Gross-Tsur V. Methylphenidate ef- Research Report 2013 152
    • fect in children with ADHD can be measured by an ecologically valid continuous performance test embedded in virtual reality. CNS Spectrum 2010;15:125-130. 15. Sanger T, Chen C, Fehlings DL, Hallett M, Lang AE, Mink JW, Singer H, Alter K, Ben-Pazi H, Butler E, Chen R, Collins A, Dayanidhi S, Forssberg H, Fowler E, Gilbert DL, Gor- man SL, Gormley ME, Jinnah HA, Kornblau B, Krosschell K, Lehman LK, MacKinnon C, Malanga CJ, Mesterman R, Barry Michaels M, Pearson TS, Rose J, Russman B, Sternad D, Swoboda K, Valero-Cuevas F. Definition and Classification of Hyperkinetic Movements in Childhood. Mov Disord 2010;25:1538-1549. 16. Ben-Pazi H. Motor skill acquisition following trihexyphenidyl treatment in children with dys- tonia. J Child Neurol 2011;26:810-816. 17. Ben-Pazi H, Sadan O, Offen D. Striatal microinjection of Sydenham’s chorea antibodies in rats failed to induce behavioral changes. J Mol Neurosci 2011; 46:162-166. 18. Shilon Y, Aran A, Pollak Y, Gross-Tsur V. Accidental injuries are more common in children with Attention Deficit Hyperactivity Disorder compared to their non-affected children. Child Care Health Dev 2011;38:366-370. 19. Ben-Pazi H, Jaworowski S, Shalev RS. Cognitive and psychiatric phenotypes of move- ment disorders in children: a systematic review. Dev Med Child Neurol 2011;53:1077- 1084. 20. Han F; Lin L; Li J; Aran A; Dong SX; An P; Zhao L; Li M ; Li QY; Yan H; Wang JS; Gao HY; Li M; Gao ZC; Strohl KP; Mignot E. Presentations of primary hypersomnia in Chinese children. Sleep 2011;34:627-632. 21. Aran A, Lin L, Finn LA, Weiner K, Peppard P, Young T, Mignot E. Post-streptococcal anti- bodies are associated with metabolic syndrome in a population-based sample of healthy adults. PLoS ONE. 2011;6(9):e25017. 22. Han F, Lin L, Li J, Aran A, Dong SX, An P, Zhao L, Li QY, Yan H, Wang JS, Gao HY, Li M, Gao ZC, Strohl KP, Mignot E. TCRA, P2RY11, and CPT1B/CHKB associations in Chinese narcolepsy. Sleep Med 2012;13:269-272. 23. Aran A, Shors I, Lin L, Mignot E, Schimmel M. CSF levels of hypocretin-1 (Orexin-A) peak during early infancy in humans. Sleep 2012;35:187-191. 153 Neuropediatric
    • 24. Weiner Lachmi K, Lin L, Kornum BR, Rico T, Lo B, Aran A, Mignot E. DQB1*06:02 al- lele-specific expression varies by allelic dosage, not narcolepsy status. Hum Immunol 2012:73:405-410. 25. Mórocz IA, Janoos F, van Gelderen P, Manor D, Karni A, Breznitz Z, von Aster M, Kushnir T, Shalev R. Time-resolved and spatio-temporal analysis of complex cognitive process- es and their role in disorders like developmental dyscalculia. Int J Imaging Syst Technol 2012;22:81-96. 26. Artzi M, Ben Sira L, Bassan H, Gross-Tsur V, Berger I, Marom R, Leitner Y, Bental Y, Shiff Y, Geva R, Weinstein M, Ben Bashat D. Brain diffusivity in infants with hypoxic ischemic encephalopathy following whole body hypothermia: preliminary results. J Child Neurol 2011;26:1230-1236. 27. Gross-Tsur V, Eldar-Geva T, Benarroch F, Rubinstein O, Hirsch HJ. Body image and sex- ual interests an adolescents and young adults with Prader Willi syndrome. J Pediatr Endo- crinol Metabolism 2011;24:469–475. 28. Gilboa T. Emotional stress-induced seizures: another reflex epilepsy? Epilepsia 2012; 53;e29-32. 29. Ben-Pazi H, Kroyzer N, Hashkes PJ. Sydenham’s chorea: Long-term immunosuppression for psychiatric symptom. J Pediatr Neurol 2012. In press. 30. Scharf JM, Yu D, Mathews CA, Neale BM, S. Stewart E, Fagerness JA, Evans P, Gamazon E, Service S,Tikhomirov A, Osiecki L, Illmann C, Pluzhnikov A, Konkashbaev A, Davis L, Gross-Tsur V, Benarroch F, Pollak Y. et al. Genome-wide association study of Tourette Syndrome. Mol Psychol 2012. In press. 31. Gross-Tsur V, Hirsch HJ, Benarroch F, Eldar-Geva T. The FSH-inhibin axis in Prader-Willi Syndrome: heterogeneity of gonadal dysfunction. Reprod Prod Biol Endocrin 2012. In press. 32. Aran A, Shalev R, Arnulf I , Mignot E. Reçurent hypersomnia: Kleine-Levin syndrome sub- type. In: UpToDate, Rose, BD (Ed). UpToDate, Waltham, MA. 2012. In press. 33. Hirsh HJ, Eldar-Geva T, Gross-Tsur V. Management of hypogonad- ism in Prader-Willi Syndrome. In: C. Hoybee (Ed). The Management of Research Report 2013 154
    • Prader-Willi Syndrome. Nova Science publishers. 2013.In press. 34. Gilboa T, Gross-Tsur V, Nuoman R, Ettinger AB. Mental retardation / Intellectual disabil- ity. In: AB Ettinger AB, DM Weisbrot (Eds.).. Neurological Differential Diagnosis; A Case- Based Approach. Cambridge University Press. 2013. In press. 155 Neuropediatric
    • T he Department of Neonatology, headed by Professor Michael Kaplan, operates 3 regular nurseries and a large neonatal intensive care unit. In 2011, 14,813 babies were treated, making the Unit the largest neonatal de- partment in the country. Unit heads include Professor Mi- chael Schimmel (intensive care unit) and Professor Cathy Hammerman (regular newborn nurseries). In addition to the neonatal specialists, we are complemented by residents from the Department of Pediatrics. The Unit also provides a ser- vice for high risk babies, many of whom are admitted to the neonatal intensive care unit. The Unit has a good record of saving the lives of even the smallest premature babies, and has discharged babies whose birth weights were as little as 500 grams. The Unit is equipped with advanced newborn life support devices to manage even the smallest babies with the most complex problems including baby incubators, neonatal respirators, monitors, X-ray machines and ultrasound. Al- most all investigations and treatment can be provided to the babies at bedside, without having to risk taking them to other areas of the hospital. The staff is composed of nurses who are specially trained in the field of neonatal nursing, as well as physiotherapists, occupational therapists, respiratory thera- pists and many other paramedical specialists. The Unit also runs a follow up clinic for babies who have been discharged from the nursery to make sure that they are developing normally. Areas of Research Activity The Department has conducted extensive research on neo- natal jaundice, a common, yet potentially dangerous condi- tion. The G-6-PD deficiency is a red cell enzyme deficiency Department of Neonatology Research Report 2013 156
    • prevalent in some subsets of the Israeli population. This condition is associated with a high incidence of neonatal jaundice . Other studies in the Department have focused on necrotizing enterocolitis, a condition as- sociated with severe damage to the bowel in premature infants. Findings have demonstrated the beneficial effect of probiotics (“good” bacteria) in preventing this potentially serious con- dition. Patent ductus arteriosus is a condition often encountered in premature infants. A re- cent observation in the Department suggested that paracetamol, a frequently used headache and fever medication, may be of use in treating this condition. A randomized trial comparing paracetamol with conventional drug treatment is now under way. In cooperation with the University of Pennsylvania, studies of babies’ sucking abilities are in progress using a special computerized device for measuring sucking characteristics of newborn and premature infants. Epidemiological studies include the impact of advanced maternal age on neonates, the asso- ciation between in vitro fertilization and prematurity, and the mortality and morbidity of low birth weight infants. PUBLICATIONS 1. Kaplan M, Na’amad M, Kenan A, Rudensky B, Hammerman C, Vreman HJ, Wong RJ, Ste- venson DK. Failure to predict hemolysis and hyperbilirubinemia by IgG subclass in blood group A or B infants born to group O mothers. Pediatrics 2009; Jan123(1):e132-137. 2. Kaplan M and Hammerman C. Exchange transfusion for neonatal hyperbilirubinemia with Glucose 6 Phosphate Deficient Blood. Pediatric Health 2009; 3:119-123. 3. Kaplan M and Hammerman C. The need for neonatal glucose-6-phosphate dehydroge- nase screening: A global perspective.  J Perinatol 2009;29 Suppl 1:S46-52. 4. Kaplan M, Na’amad M, Kenan A, Rudensky B, Hammerman C,  Vreman HJ, Wong RJ, Stevenson DK. Failure to Predict Hemolysis and Hyperbilirubinemia by IgG Subclass in Blood Group A or B Infants Born to Group O Mothers. Pediatrics 2009; 123:e132–e13. 5. Kaplan M and Hammerman C. Glucose-6-phosphate dehydrogenase deficiency and severe neonatal hyperbilirubinemia: A complexity of interactions between genes 157 Neonatology
    • and environment. Semin Fetal Neonatal Med 2010; 15:148-156. 6. Godfrey ME, Schimmel MS, Hammerman C, Farber B, Glaser J and Nir A. Incidence of Congenital Heart Defects in Very Low Birth Weight and Extremely Low Birth Weight In- fants. Isr Med Assoc J 2010;12:36-8. 7. Sanders ME, Akkermans L, Constable A, Haller D,  Hammerman C, Heimbach J, Hör- mannsperger G, Huys G, Levy D, Lutgendorff F, Mack D, Phothirath P,  Solano-Aguilar G, Vaughan E. Safety Assessment of Probiotics for Human Use. Gut Microbes 1:164-185, 2010.8. 8. Kaplan M, Hammerman C, Vreman HJ, Wong RJ, Stevenson DK. Hemolysis and hyper- bilirubinemia in antiglobulin positive, direct ABO blood group heterospecific neonates. J Pediatr 2010;157:772-777. 9. Hammerman C, Shchors I, Schimmel MS, Bromiker R, Kaplan M, Nir A. N-terminal-pro- B-type natriuretic peptide in premature patent ductus arteriosus: a physiologic biomarker, but is it a clinical tool? Pediatr Cardiol 2010;31:62-65. 10. Grisaru-Granovsky SPI, Gordon EC, Haklai ZC, Samueloff AC, Schimmel MSPI. Effect of interpregnancy interval on adverse perinatal outcomes – A national study. Contraception 2010;80: 512-518. 11. Hammerman C, Shchors I, Schimmel MS, Bromiker R, Kaplan M, Nir A.N-terminal-pro- B-type natriuretic peptide in premature patent ductus arteriosus: a physiologic biomarker, but is it a clinical tool? Pediatr Cardiol 2010;31:62-65 12. Joseph L, Nir A, Hammerman C, Goldberg S, Ben Shalom E, Picard E. N-terminal pro-B- type Natriuretic Peptide as a Marker of Bronchopulmonary Dysplasia in Premature Infants. Am J Perinatol 2010; 27:381-6. 13. Fadeev API, Ioscovich AC, Rivlis A, Grisaru-Granovsky SC, Samueloff AC, Schimmel MSC, Elstein DPI. Prospective study of maternal and neonatal outcome in great-grand multiparous women (≥10 births) and in aged-matched women with lesser parity. Archives of Gynecology and Obstetrics 2011;284:799-805. 14. Hammerman C, Bin-Nun A, Markowitz E, MD, Schimmel MS, Kaplan M and Fink D. In- advertent Ductal Closure with Paracetamol Presents Unexpected Potential for a New Ap- proach to PDA Treatment. Pediatrics 2011; 128:e1618-21. Research Report 2013 158
    • 15. Kaplan M and Hammerman C. Neonatal Screening for Glucose-6-Phosphate Dehydro- genase Deficiency: Biochemical Versus Genetic Technologies. Seminars in Perinatology 2011; 35:155-161. 16. Kaplan M, Bromiker R and Hammerman C: Severe Neonatal Hyperbilirubinemia and Ker- nicterus: Are These Still Problems in the Third Millennium? Neonatology 2011 100:354- 362. 17. Joseph LJ, Bromiker R, Toker O, Schimmel MS, Goldberg S, Picard E. Unilateral Lung Intubation for Pulmonary Air Leak Syndrome in Neonates: A Case Series and a Review of the Literature. Am J Perinatol 2011;28:151-156. 18. Ioscovich A, Shen O, Sichel JY, Lajos Y, Orkin D, Bromiker R, Briskin A.Remifentanil-nitro- glycerin combination as an anesthetic support for ex utero intrapartum treatment (EXIT) procedure. J Clin Anesth 2011;23:142-4 19. Einav S, Bromiker R, Weiniger CF, Matot I. Mathematical modeling for prediction of survival from resuscitation based on computerized continuous capnography: proof of concept. Acad Emerg Med 2011;18:468-75. 20. Grisaru-Granovsky S, Altarescu G, Finci  S, Weintraub A, Tevet A Samueloff  A and  Schim- mel M. Prostanoid DP Receptor (PTGDR) variants in mothers with post-coital associated  preterm births - Preliminary Observation. J of Perinatology 2012;30:33-37. 21. Aran  A, Shors I, Lin L, Mignot E, Schimmel M. CSF Levels of Hypocretin-1 (Orexin-A) Peak during Early Infancy in Humans. SLEEP 2012;35:187-191. 22. Bromiker R, Kasinetz Y, Kaplan M, Hammerman C,  Schimmel M, Medoff-Cooper B. Sucking Improvement Following Blood Transfusion for Anemia of Prematurity. Arch Pedi- atr Adolesc Med 2012;4:1-5. 23. Algur N, Avraham I, Hammerman C, Kaplan M. Quantitative neonatal glucose-6-phos- phate dehydrogenase screening: distribution, reference values, and classification by phe- notype. J Pediatr 2012;161:197-200. 24. Bromiker R, Bin Nun A, Schimmel MS, Hammerman C, Kaplan M. The low intermediate risk category on the bilirubin nomogram: a hidden risk for neonatal hyperbilirubinemia. Pediatrics, 2012. In press. 159 Neonatology
    • 25. Schimmel MSPI, Wasserteil NPI, Perry ZHC, Erlichman MPI. Parents’ compliance with specific medical instructions in newborn discharge letters. Accepted for publication Cana- dian Paediatr & Child Health 26. Bromiker R, Ernest N, Bar Meir M, Kaplan M, Schimmel MS, Hammerman C, Schlesinger Y. Correlation of Bacterial Type and Antibiotic Sensitivity in Early-Onset Neonatal Sepsis with Maternal Antibiotic Exposure. Neonatology 2012;103(1):48-53. 27. Grisaru-Granovsky S  Reichman B, lerner-Geva L, Hamerman C, Samueloff A, Schimmel MS and in collaboration with the Israel neonatal Network. Preterm small for gestational age infants- mortality and morbidity: a population-based study. Accepted for publication in the American J of  Obstet Gynecolog 2012. 28. Kaplan M and Hammerman C. Hemolytic Disorders and their Management. In: Care of the Jaundiced Neonate. Stevenson DK, Maisels MJ and Watchko JF eds. 2012; 145-175. 29. Hammerman C, Bin-Nun A and Kaplan M: Managing the Patent Ductus Arteriosus: A New Look at What We Thought We Knew. Seminars in Perinatology 2012; 36:130-138. Research Report 2013 160
    • T he Division of Pediatric Nephrology treats children with a wide variety of congenital as well as acquired kidney diseases, from birth to adulthood. It is headed by Prof. Yaacov Frishberg with 4 additional attending physi- cians: Dr. Sofia Feinstein (Director of the Clinical Pediatric Nephrology Unit), Dr. Rachel Becker-Cohen, Dr. Choni Rinat and Dr. Efrat Ben-Shalom. A sizeable portion of resources is devoted to treating children whose kidneys have failed and require replacement therapy which includes kidney trans- plantation or chronic dialysis.  The Division of Pediatric Nephrology comprises three units: 1. The Pediatric Hemodialysis Unit provides dialysis at the hospital at least three times a week for each patient. It was the first unit in Israel to provide dialysis to children with end-stage renal disease and remains the largest of its type. In 2011, 2,605 dialysis sessions were performed. 2. The Pediatric Peritoneal Dialysis Service, administered by parents at home, supported by ongoing instruction and close monitoring at our center. 3. The Pediatric Nephrology Day-Hospital and Clinic over- sees intravenous medical treatments, clinical diagnostic in- vestigations and follow-ups of children who require multidis- ciplinary care. The unit treats children who have undergone kidney transplantation, children suffering from chronic kid- ney disease at varying degrees of severity and children with Division of Pediatric Nephrology 161 Pediatric Nephrology
    • inflammatory kidney diseases.  Special emphasis is placed on identification of kidney diseases with a genetic background as well as the diagnosis and treatment of children with high blood pressure and kidney stones. The Institute provides 24-hour ambulatory blood pressure moni- toring, analysis of the results and recommendations regarding diagnosis and treatment alter- natives. Children with structural malformations of the kidney and urinary tract, diagnosed before or after birth, undergo evaluation and follow-up at the clinic. Areas of Research Activity The Pediatric Nephrology Research Laboratory is directed by Dr. Ruth Belostotsky. Studies focus on identification of the genetic basis of kidney diseases in children, to help develop therapeutic modalities. In addition to the detection of mutations in known genes and genetic variants that may govern the ultimate severity of kidney disease, this lab has launched several projects to define the genetic basis of new clinical entities. The new multi-systemic HUPRA syndrome was first described by physicians in the Unit. This acronym refers to the combi- nation of the clinical characteristics of this disease; namely, hyperuricemia, pulmonary hy- pertension, renal failure in infancy and metabolic alkalosis. Affected infants succumb to this syndrome within their first year of life. Genetic studies have successfully identified the gene responsibleforthisdisease(SARS2encodingthemitochondrialseryl-tRNAsynthase).Further research demonstrated that 1 in 10-15 inhabitants of a village within the greater Jerusalem area is a carrier of this mutation, which enabled the implementation of targeted screening in this village. The referral of an affected child from Turkey enabled the team to detect a novel mutation in the same gene and better understand the clinical scope of this syndrome. A number of projects focus on various genetic aspects of childhood nephrotic syndrome, including those who respond to steroids and reach remission and those who are resis- tant to steroid therapy and may progress to end-stage kidney disease. Several clinical stud- ies are currently under way at the division to explore the unique aspects of chronic kid- ney diseases in children and those who have undergone renal transplantation, including: risk factors for cardiovascular disease among children suffering from chronic kidney disease and those who have undergone kidney transplants, heart function and vascular conditions of children and young adults suffering from chronic kidney diseases calcium, phosphate and vitamin D disorders in children with chronic kidney diseases risk factors and management of infections in infants and children who undergo chronic hemodialysis and long-term follow-up of children who were diagnosed prenatally with congenital kidney diseases. Research Report 2013 162
    • Representative Research A new inherited disease that manifests as kidney stone formation during early childhood was described by the Unit’s pediatric nephrologists. These children tend to form kidney stones due to excessive production of oxalate by the liver and the precipitation of calcium-oxalate insolu- ble crystals in the kidney. This new kidney disease was dubbed Primary Hyperoxaluria Type III (PH3). Genetic studies performed in the pediatric nephrology research lab headed by Dr. Ruth Belostotsky yielded a novel gene (now known as HOGA1) and its predicted metabolic pathway which explains this abnormality.This clinical entity has been identified among various ethnic groups around the world but there is a founder mutation among Ashkenazi Jews. Further studies have led to the development of a relatively simple urinary diagnostic test as depicted in the figure. The metabolic defect results in the accumulation of three metabolites. Itisestimatedthatapproximately11%ofallmenand6%ofallwomenwilldevelopatleastone symptomatic kidney stone by the age of 70. The most prevalent cause is stones composed of calcium-oxalate crystals. Current studies are now testing whether a portion of this population carries mutated copies of the HOGA1 gene. This project allows the team to explore the possi- bility that there is an interaction between genetic and environmental factors which determine 163 Pediatric Nephrology
    • the rate of stone formation. This may imply that dietary modifications may prevent further stone formation. PUBLICATIONS 1. Becker-Cohen R, Belostotsky R, Ben-Shalom E, Feinstein S, Rinat, C, Frishberg Y. Con- genital analbuminemia with acute glomerulonephritis – a diagnostic challenge. Pediatr Nephrol 2009; 24:403-406. 2. Tory K, Rousset-Rouviere, C, Gubler MC, Moriniere V, Pawtowski A., Becker C., Guyot C, Gie S, Frishberg Y, Nivet U, Deschenes G, Cochat P, Gagnadoux MF, Saunier S, Antignac C, Salomon R. Mutations of NPHP2 and NPHP3 in infantile nephronophthisis. Kidney Int 2009; 75:839-847. 3. Frishberg Y, Dinour D, Belostotsky R, Becker-Cohen R, Rinat C, Feinstein S, Navon-Elkan P, Ben-Shalom E. Dent’s disease manifesting as focal glomerulosclerosis – Is it the tip of the iceberg? Pediatr Nephrol 2009; 24:2369-2373. 4. Bargal R, Cormier-Daire V, Ben-Neriah Z, Le Merrer M, Sosna J, Melki J, Zangen DH, Smithson SF, Borochowitz Z, Belostotsky R, Raas-Rothschild A). Am J Hum Genet 2009; 81:80-84. 5. Schlesinger,Y. Ben-Shalom,E. Raveh,DP. Yinnon,AM. Miskin,H. Rudensky B.Vibrio vulnifi- cus infection outside of the fish ponds in northern Israel: acquisition in the “Einot Tzukim” springs near the Dead Sea. Harefuah 2009; 148:772-774. 6. Bargal R, Cormier-Daire V, Ben-Neriah Z, Le Merrer M, Sosna J, Melki J, Zangen DH, Smith- son SF, Borochowitz Z, Belostotsky R, Raas-Rothschild A. Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications. Am J Hum Genet 2009;84(1):80-4. 7. Rinat,C. Becker-Cohen R, Nir A, Feinstein S, Shemesh D, Algur N, Ben-Shalom E, Farber B, Frishberg Y. A comprehensive study of cardiovascular risk factors, cardiac function and vascular disease in children with chronic renal failure. Nephrol Dial Transplant 2010; 25:785-793. 8. Belostotsky R, Seboun E, Idelson GH, Milliner DS, Becker-Cohen R, Rinat C, Monico Research Report 2013 164
    • CG, Feinstein S, Ben-Shalom E, Magen D, Weissman I, Charon C, Frishberg Y. Muta- tions in DHDPLS are responsible for primary hyperoxaluria type III. Am J Hum Genet 2010;87:392-399. 9. Even-Or,E. Becker-Cohen,R. Miskin H. Deferasirox treatment may be associated with re- versible renal Fanconi syndrome. Am J Hematol 2010; 85:132-134. 10. Daugirdas,JT. Hanna MG, Becker-Cohen R, Langman CB. Dose of dialysis based on body surface area is markedly less in younger children than in older adolescents. Clin J Am Soc Nephrol 2010; 5:821-827. 11. Joseph L, Nir A, Hammerman C, Goldberg S, Ben-Shalom E, Picard E. N-terminal pro-B- type natriuretic peptide as a marker of broncho pulmonary dysplasia in premature infants. Am J Perinatol 2010; 27:381-386. 12. Chernin G, Vega-Warner V, Schoeb DS, Heeringa SF, Ovunc B, Saisawamat P, Cleper R, Ozaltin F, Arbeiter A, Bakkaloglu A, Benz M, Bockenhauer D, Bogdanovic R, Chandha V, Ettenger R, Ghossein C, Goldberg A, Heiliczer J, Hooper D, Jenkins R, Kaplan B, Kemper MJ, Konrad M, London R, Mache C, Mansoor O, Mayr M, Neuhaus T, Plank C, Reusz G, Rinat C, Seeman T, Strecker M, Taranta-Janusz K, Weigel F, Zlotnitskaya A, Hildebrandt F. Genotype-phenotype correlation in nephrotic syndrome caused by WT1 mutations. Clin J Am Soc Nephrol 2010; 5:1655-1662. 13. Belostotsky R, Ben-Shalom E, Rinat C, Becker-Cohen R, Feinstein S, Zeligson S, Segel R, Elpeleg O, Nassar S, Frishberg Y. Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis (HUPRA syndrome). Am J Hum Genet 2011; 88:193-200. 14. Monico CG, Rossetti S, Belostotsky R, Cogal AG, Herges RM, Seide BM, Olson JB, Bergstrahl EJ, Williams HJ, Haley WE, Frishberg Y, Milliner DS. Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clin J Am Soc Nephrol 2011; 6:2289-2295. 15. Belostotsky R, Frishberg Y, Entelis N. Quality control of human mitochondrial tRNA in health and disease: A channeling mechanism? RNA Biol 2012;9:33-39. 16. Rinat C, Becker-Cohen R, Nir A, Feinstein S, Algur N, Ben-Shalom E, Farber B, Frishberg Y. B-type natriuretic peptides are reliable markers for cardiac strain in CKD pediatric pa- tients. Pediatr Nephrol 2012; 27:617-625. 165 Pediatric Nephrology
    • 17. Becker-Cohen R, Rinat C, Ben-Shalom E, Feinstein S, Ivgy H, Frishberg Y. Vitamin A de- ficiency associated with urinary retinol binding protein wasting in Dent’s disease. Pediatr Nephrol 2012; 27:1097-1102. 18. Cleper R, Ben-Shalom E, Landau D, Weissman I, Krause I, Konen O, Rahamimov R, Mor E, Bar-Nathan N, Frishberg Y, Davidovits M. Post-transplantation lymphoproliferative dis- order in pediatric kidney transplant recipients – A national study. Pediatr Transplant 2012. In press. 19. Belostotsky R, Pitt JJ, Frishberg Y. Primary hyperoxaluria type III – A model for studying perturbations in glyoxylate metabolism. J Mol Med 2012; 90:1497–1504. Research Report 2013 166
    • T he pediatric pulmonology unit is staffed by three pedi- atric pulmonologists: Prof. Elie Picard (director), Dr. Shmuel Goldberg (sleep specialist) and Dr. Leon Joseph. Two ear nose and throat specialists are associated with the unit: Dr. Anat Shatz and Dr. Pierre-David Attal. The unitalsohas asecretary,SaritKoresh,twopulmonarytechni- cians, Ronit Hammami-Belisha and Ahuva Tessama, 2 nurses: Yael Greenberg (day-care) and Esther Tennenhaus (bronchos- copy suite), a respiratory physiotherapist Rena Huri, and a dietetician, Dorit Forer. Thepediatricpulmonologyunitoffersawiderangeofpediat- ric pulmonary facilities including: • A general pulmonary clinic that treats common pediatric respiratory problems including BPD (chronic lung disease of prematurity), asthma, recurrent pneumonia, chronic lung diseases such as Cystic Fibrosis and Ciliary dyskinesis and congenital lung malformations. • A day care hospital pulmonary service for patients with respiratory problems. There they can benefit from consul- tations with other pediatric specialists and receive intra- venous treatment or other procedures including some of those requiring light sedation. • A pediatric sleep center: This is the only pediatric sleep center in Jerusalem. It houses a pediatric sleep laboratory and a sleep clinic. In the sleep laboratory polysomnograph- Pediatric Pulmonology Unit 167 Pediatric Pulmonology
    • icstudiesareperformedonchildren.Inthesleepclinic,alltypesofsleepdisordersincluding babies at high risk for cot death, snoring and obstructive sleep apnea (prolonged pauses in breathing) are treated. The sleep clinic is a multi-disciplinary clinic staffed by a pulmonolo- gist, ENT surgeon, nurse and sleep lab technician. • A pediatric lung function test laboratory: The lung function lab provides lung function tests, lung challenge tests, infant lung challenge tests and lung volume measurements. • A bronchoscopy suite: The Pediatric Pulmonology Unit has been performing pediatric bronchoscopic examinations for the past 20 years. This is a fiberoptic examination of the airway used to visualize the airways during breathing. This experience and advances in ex- amination techniques have enabled us to perform lung biopsies without the need for a ma- jor operation. The pulmonary team works hand in hand with the ENT team to treat a wide range of upper and lower airway diseases. Areas of Research Activity Research is an important part of activities of the pediatric pulmonology unit. Our focus is clinical research as reflected by recent projects. One line of research involves the usefulness of the oxygen saturation probe in ascertaining severity of respiratory disease. We have also conducted studies to quantify which bacteria are present in children with complicated pneu- monias. In a separate project, we created an assessment score for children with complicated pneumonia that can predict the need for more aggressive treatment. We are currently investi- gating the cause of the recent increase in complicated pediatric pneumonias and are planning a study to examine how treatment at home prior to the diagnosis affects the progression of pneumonia. Asthma treatment has some long- term side effects and we have measured bone density us- ing a technique based on ultrasound in a patient cohort. We are also involved in several proj- ects on the epidemiology of asthma. Finally we are investigating the use of anti inflamma- tory medications to prevent side effects related to broncho-alveolar lavage performed during bronchoscopies. Representative Research The diagnostic test for cystic fibrosis involves measuring chloride concentration in sweat. A less accurate screening test measures the overall conductivity of the sweat. Sweat samples of low volume are considered unreliable, given that sweat conductivity and chloride are thought to be reduced at lower sweating rates. We designed a study to re-evaluate the relationship be- Research Report 2013 168
    • tween sweat volume and test results. We reviewed all sweat tests performed in our institution to assess the relationship between sweat volume and conductivity, and between sweat volume and sweat chloride. We also compared results between pairs of sweat tests taken simultane- ously from a single patient, one with sweat volume below and the other above the currently accepted minimum volume (15µl). A weak inverse relationship between sweat volume and sweat conductivity was found. There was no correlation between sweat volume and sweat chloride. In paired tests from a single child, one below and one exceeding the accepted mini- mum volume, the mean test result in the low volume sample was slightly higher than its coun- terpart. We concluded that normal sweat conductivity and/or chloride value from a sweat volume of less that 15µl in a patient whose clinical symptoms are not very suggestive of CF renders this diagnosis unlikely. In contrast, elevated sweat chloride or conductivity measured from a sample whose volume is below 15µl may represent an artefact related to the low volume. The relationship between sweat volume and sweat conductivity in 2994 sweat tests. Lower sweat volumes are associated with increased sweat conductivity. 0 20 40 60 80 100 120 140 0 20 40 60 80 100 120 Sweat Volume (µl) Conductivity (mmol/L) 169 Pediatric Pulmonology
    • Publications 1. Joseph L, Goldberg S, Picard E. CO2 treatment for apnea. J Pediatr 2009; 154: 627-8. 2. Joseph L, Nir A, Hammerman K, Goldberg S, Ben-Shalom E, Picard E. N-terminal pro-B- type Natriuretic Peptide as a Marker of Bronchopulmonary dysplasia in Premature Infants. American Journal of Perinatology 2010; 27(5): 381-6. 3. Joseph L, Shahroor S, Fisher D, Goldberg S, Picard E. Conservative treatment of a large post-infectious pneumatocele. Pediatrics International 2010; 52(5): 841-3. 4. Picard E, Joseph L, Goldberg S, Mimouni F, Deeb M, Kleid D, Raveh D. Predictive Factors of Morbidity in Childhood Parapneumonic Effusion-Associated Pneumonia: A Retrospec- tive Study. Pediatric Infectious Diseases Journal 2010; 29(9): 840-3. 5. Goldberg S, Schwartz S, Mimouni F, Stankiewicz H, Izbicki G, Picard E. Does sweat vol- ume influence the sweat test result? Arch Dis Child 2010; 95 (5): 377-381. 6. Joseph L, Bromiker R, Toker O, Schimmel MS, Goldberg S, Picard E. Unilateral Lung Intubation for Pulmonary Air Leak Syndromes in neonates: A Case Series and a review of the literature. American Journal of Perinatology 2011; 28: 151-156. 7. Furer V, Raveh D, Picard E, Goldberg S, Izbicki G. Absence of leukocytosis in bacteremic pneumococcal pneumonia. Prim Care Respir J 2011; 20(3):276-81. 8. Joseph L, Goldberg S, Picard E. Dexamethasone in community-acquired pneumonia. Lancet 2011; 378(9795):980. 9. Joseph L, Goldberg S, Shahroor-Karni S, Gomori JM, Picard E. Sinus vein thrombosis as presenting finding in the congenital central hypoventilation syndrome: an insight on the pathophysiology of the association. Pediatric Pulmonology 2011 Aug; 46(8): 826-8. 10. Goldberg S, Buhbut E, Mimouni FB, Joseph L, Picard E. Effect of Moderate Elevation above Sea Level on Blood Oxygen Saturation in Healthy Young Adults. Respiration 2012; 84(3):207-1120. 11. Goldberg S, Mimouni F, Joseph L, Izbicki G, Picard E. Seasonal Effect on Exercise Chal- lenge Tests for the Diagnosis of Exercise-Induced Bronchoconstriction. Allergy Asthma Proc 2012; 33(5):416-20. Research Report 2013 170
    • 12. Picard E, Goldberg S, Joseph L. Selective unilateral lung ventilation in preterm infants with acquired bullous emphysema: Pediatr Pulmonol 2012 Jul 6. 13. Samuel T, Bromiker R., Mimouni FB, Picard E, Goldberg S. Oxygen saturation on day 2-3 of life at mild altitude versus sea level: implication for neonatal screening. Submitted 2012 14. Picard E, Wilk M, Mimouni FB, Joseph L, Goldberg S. Tibial bone ultrasound velocity is not affected by prolonged inhaled steroid therapy in children. Submitted 2012. 15. Cohen S, Berkman N, Springer C, Avital A, Picard E, Goldberg S. Asthma Co-morbidities in teenagers - a large cohort Study. Submitted 2012. 16. Cohen S , Berkman N, Avital A, Springer C, Kordova l, Goldberg S, Picard E. A decrease in asthma prevalence and severity paralleled by decrease environmental factors and in- crease preventive therapy. Submitted 2012. 17. Joseph L, Picard E, Dayan B, Goldberg S. Methacholine challenge tests results in children are season dependent. Submitted 2012. 18. Joseph L, Brickner-Braun I, Pinshow B, Goldberg S, Miskin H, Picard E. A child with asthma and hemoglobinopathy – At which oxygen saturation level is supplemental oxygen required? Submitted 2012. 171 Pediatric Pulmonology
    • T he Pediatric Hematology-Oncology Unit is directed by Dr. Hagit Miskin, assisted by Dr. Dan Harlev and a third rotating intern from pediatrics. The unit was formally established about twenty years ago by Prof. Ayala Abrahamov. Since then, it has earned a reputation for excel- lence in diagnosis and treatment. The unit specializes in he- matological diseases of pediatric patients from birth to late adolescence, often including young adults. It diagnoses and treats acquired and inherited anemias, coagulation diseases including platelet and coagulation protein defects and leuko- cyte abnormalities and provides regular blood transfusions and iron chelation treatments. Theambulatoryclinicisoneofthelargestofthepediatricsub- specialties in the hospital. This is due to the volume of benign hematological disease seen in pediatric patients although many patients have life-long diseases requiring prolonged treatment and may suffer life threatening events which de- mand immediate hospitalization and treatment. This often makes the unit their de facto primary care physician. Treat- ing benign disease requires a strong interface with the com- munity; this is achieved by encouraging telephone and clinic consultations from primary care physicians, and continuing reciprocal dialogue with community-based hematologists. The Unit has established a unique group of multi-disciplinary collaborative specialized clinics to treat and prevent stroke and cerebral bleeding, diagnose and treat heavy menstrual bleeding and hyper-coagulability, prevent fetal platelet disor- Pediatric Hematology- Oncology Research Report 2013 172
    • ders causing catastrophic bleeding in the fetus and newborn,diagnose and treat various au- toimmune diseases and prevent pregnancies with serious inherited hematological disorders. Areas of Research Activity Research at the pediatric hematology-oncology unit is clinically oriented. We participate in national and international clinical protocols; these provide us with the opportunity to be part of up-to-date laboratory investigations and cutting edge medical treatment. We register our patients in the appropriate national registries; these include the pediatric oncology registry, the inherited bone marrow failure registry and the inherited thrombocytopenia registry. Par- ticipation in the creation of these registries enables us to take part in large scale epidemio- logical research and participate in national projects. Part of the research undertaken in the Pediatric Hematology Unit involves collaboration with other research groups at the hospital. A recent example of this is our work with the Pediatric Gastroenterology Unit; together with the pediatric hepatologists we are investigating a non-invasive method to prevent and treat bile-stone formation in children with hemolytic anemia. Research in the Pediatric Hematology Unit concentrates on Thalassemia syndrome and its side effects. Thalassemia is an inherited disruption of the production of the main molecule in red blood cells, hemoglobin, whose main function is to deliver oxygen to the body. In affected individuals, one of the protein chains that constitute the hemoglobin, usually the beta-globin chain, is not produced. Complete inability to produce this protein causes severe anemia and requires life-long blood transfusions every few weeks in order to survive. These transfusions cause a net transfer of iron, resulting in massive iron overload. The iron precipitates into vital organs, such as the heart, liver, pancreas and the endocrine system, disrupting their function and causing severe morbidity and death. The only proven method of removing iron from the body is by conjugating it to a chemical called an iron chelator, given by mouth or parenterally. This binds the iron and is secreted via the urine or feces. The chelator has to be taken regularly on a lifetime basis. Due to the inconvenience and the side effects of these medications there is a high rate of non-compliance in patients. We investigated the effect of group psychological intervention in adult patients and its effect on their quality of life; we assessed compliance to treatment in general and to iron chelation in particular. The interim results appear to be promising and we are about to conclude the trial and await the final results to assess the long term effects. Representative Research Ironchelationpatientscansufferfromakidneyproblem;morespecifically,arenaltubulardys- function known as renal Fanconi syndrome. This condition developed in three of our patients 173 Pediatric Hemato - Oncology
    • receiving a new oral iron chelator, Deferasirox. We noted that the dysfunction was reversed after stopping the treatment. A literature search returned only a single article describing this problem: a case report of renal Fanconi syndrome and renal failure in an elderly patient suf- fering from diabetes mellitus. As there were no previous reports of Deferasirox-related renal Fanconi syndrome in younger adult patients, we investigated the relation of this condition to the new chelation drug. We re-challenged one patient who had recovered after cessation of Deferasirox. Renal impairment recurred shortly after restarting the treatment. All the non- affected patients receiving various chelation therapies were followed up on a regular basis for signs of this syndrome. There were no cases in which this condition developed. We published our results and we were among the first to actively investigate this condition and relate it to the new drug. Since our publication, various other groups have reported similar adverse effects and it is now accepted that Fanconi syndrome may be caused by treatment with Deferasirox. PUBLICATIONS 1. Eldar AH, Futerman B, Abrahami G, Attias D, Barak AB, Burstein Y, Dvir R, Gabriel H, Horovitz J, Kapelushnik J, Kaplinsky H, Miskin H, Sthoeger D, Toren A, Vilk-Revel S, Wein- traub M, Yaniv I, Linn S, Arush MB. Burkitt lymphoma in children: the Israeli experience. J Pediatr Hematol Oncol 2009; 31(6):428-36. 2. Revel-Vilk S, Varon D, Shai E, Agmon Y, Hyam E, Daas N, Miskin H, Weintraub M. Evalu- ation of children with a suspected bleeding disorder applying the Impact-R [Cone and Plate(let) Analyzer]. J Thromb Haemost 2009; 7(12):1990-6. 3. Schlesinger Y, Ben-Shalom E, Raveh DP, Yinnon AM, Miskin H, Rudensky B. Vibrio vulni- ficus infection outside of the fish ponds in northern Israel: acquisition in the “Einot Tzukim” springs near the Dead Sea. Harefuah 2009; 148(11):772-4. 4. Even-Or E, Becker-Cohen R, Miskin H. Deferasirox treatment may be associated with reversible renal Fanconi syndrome. Am J Hematol 2010; 85(2):132-4. 5. Harlev D, Zaidman I, Sarig G, Ben Arush MW, Brenner B, Elhasid R. Prophylactic therapy with enoxaparin in children with acute lymphoblastic leukemia and inherited thrombophilia during L-asparaginase treatment. Thromb Res 2010; 126(2):93-7. 6. Aviner S, Miskin H, London D, Horowitz S, Schlesinger M. Mycoplasma pneumonia infec- Research Report 2013 174
    • tion: A possible trigger for immune thrombocytopenia. Indian J Hematol Blood Transfusion 2011; 27(1):46-50. 7. Altarescu G, Eldar-Geva T, Grisaru-Granovsky S, Bonstein L, Miskin H, Varshver I, Mar- galioth EJ, Levy-Lahad E, Renbaum P. Preimplantation genetic diagnosis for fetal neonatal alloimmune thrombocytopenia due to antihuman platelet antigen maternal antibodies. Ob- stet Gynecol 2012; 119(2):338-43. 8. Megged O, Assous MV, Miskin H, Peleg U, Schlesinger Y. Neurologic Manifestations of Fusobacterium infections in children. Eur J Pediatr 2012 (Epub ahead of print). 175 Pediatric Hemato - Oncology
    • T he Pediatric Endocrinology Unit, directed by Dr. Floris Levy-Khademi, was founded in April 2010. The unit has grown tremendously over the last 2 years and treats almost 1000 children per year with different endocrine diseases. These include children with short stature, pubertal problems, hypoyhyroidism and diabetes. One of the special interests of the clinic is the care of adolescent girls with endo- crineproblemsspecificto thisgroup.Dr.HarryHirsch,oneof the most senior and experienced pediatric endocrinologists in Israel, is an advisor to the unit and is in charge of children with kidney problems needing endocrine treatment, and works with Prof. Varda Gross to make the Unit the largest center for Prader Willi Syndrome in Israel. The unit runs a pediatric juvenile diabetes clinic staffed by a physician, a specialized diabetic nurse, a nutritionist, so- cial worker, psychologist and an educational team. The clinic provides multi- disciplinary treatment for children and their parents and helps them cope. Since there has been a constant increase in the prevalence of type I diabetes, especially among young children, the clinic has been growing constantly and is currently treating approximately 100 diabetic children and adolescents. The clinic provides additional services to sick children and their families including educational workshops, scientific conferences and constant 24hr support. This sup- port solves many urgent issues and helps avoid their hospital- ization in the emergency room, thus improving their quality of life. Pediatric Endocrinology Unit Research Report 2013 176
    • Areas of Research Activity • The Unit is conducting ongoing research on a rare condition- hypothalamic amenorrhea – in an attempt to characterize the clinical and biochemical features of the disorder and outcome. This study is being conducted jointly with the Gynecology Unit. • A new study dealing with growth patterns of children and young adults with Gaucher disease has just begun. This study will be conducted in the Gaucher Unit, in association with Prof. Zimran. • The Unit has recently completed a study with other diabetic clinics in Jerusalem on the nutritional habits of diabetic patients from different ethnic backgrounds and compari- sons to their healthy siblings. PUBLICATIONS 1. Abu-Libdeh A, Levy-Khademi F, Abdulhadi-Atwan M, Bosin E, Korner M, White P, Zan- gen D. Autosomal recessive familial neurohypophyseal diabetes insipidus - onset in early infancy. Eur J Endocrinol 2009; 162:221-6. 2. Rekhtman D, Wolf DG, Levy-Khademi F, Averbuch D, Kerem E, Wexler ID. Influenza A infection in young infants. Arch Dis Child 2010;96 (11),1085-7. 3. Tenenbaum A, Malkiel S, Wexler ID, Levy-Khademi F, Revel-Vilk S, Stepensky P. Anemia in children with down syndrome. Int J Pediatr 2011;:813541. Epub 4. Levy-Khademi F, Brooks R, Maayan C, Tenenbaum A, Wexler ID. Dead sea water Intoxica- tion. Pediatr Emerg Care 2012; 28(8),815-6. 5. Tenenbaum A, Malcah Y, Wexler ID, Brooks R, Shulman C, Levy-Khademi F Obesity and the metabolic syndrome characteristics in children with down syndrome. Down Syndrome quarterly, accepted for publication. 177 Pediatric Endocrinology
    • Research Report 2013 178
    • Obstetrics, Gynecology & IVF JozefNatansohnIVFUnit Cheryl&HaimSabanMicromanipulationUnit ZOHARLaboratory WilfWoman&InfantCenter AdeleKanarekGynecologicalCareUnit KuppermannDepartmentofGynecologyandHighRiskPregnancy DeleciaEsformesGynecology-OncologyOutpatientUnit BrachfeldFamilyDepartmentofObstetrics Erna&HenryLeirOperatingComplex Marcos&AdinaKatz&ChildrenMotherandInfantA Frances&SamuelSchreiberMother&InfantB HochsteinMother&InfantC LincolnDavidAbrahamWellBabyNurseryComplex
    • T he In Vitro Fertilization (IVF) Unit, directed by Prof. Ehud J. Margalioth, is one of the most advanced in Is- rael. IVF is the process of fertilizing oocytes (eggs) outside of a woman’s body, in the laboratory, culturing the embryos in the incubator and transferring them into a wom- an’s uterus. IVF is most commonly used when there are low sperm counts or viability (male factor infertility), mechanical reasons, such as blocked fallopian tubes impeding ovulation, or unexplained infertility. The medical staff includes 5 fertili- ty specialists (Prof. Talia Eldar-Geva, Dr. Michael Gal, Dr. Avi Tsafrir, Dr. Avraham Ben Chetrit, and Dr. Rachel Babayof) and 1-2 residents, 3 ultrasound technicians, and 8 specifically trainednurses.Fiveembryologistsperformeggretrievalfrom the follicular fluid, the inseminations and intracytoplasmic sperm injections (ICSI) using micromanipulation, culturing the embryos in the incubators and freezing the surplus em- bryos for cryopreservation (Dr. Oshrat Shoenberger, Irit Var- shaver, Aharon Peretz, Nava Dekel and Esther Rubinstein). Men with no sperm cells in the semen (Azoospermia) due to obstructive or testicular pathologies may have epididimal or testicular sperm extraction (TESE) and as a result of this treatment over 50% will be able to father a child. A new ser- vice provided by the unit includes egg freezing for single women aged 30-41 for fertility preservation. Preimplantation Genetic Diagnosis (PGD) services are provided by the Repro- ductive Endocrinology and Genetics Unit (directed by Prof. Talia Eldar-Geva), a subdivision of the IVF Unit. In Vitro Fertilization (IVF) Unit Research Report 2013 180
    • Areas of Research Activity Research is a major focus of activity in the IVF Unit, in particular identifying the best methods for improving outcomes (higher pregnancy and live-birth rates) and reducing complications (ovarian hyperstimulation syndrome and multiple pregnancies). The use of ultrasonic and biochemical markers of ovarian reserve and the influence of contraceptive use on these mark- ers are being investigated. Treatment of advanced age infertile women is a topic of ongoing research in the Unit. Other research interests include the association between the causes of infertility and preg- nancy and neonatal outcome, the influence of embryo freezing on IVF treatment outcome, the effect of adding GnRH-agonist in frozen-thawed embryo transfer, and the use of complemen- tary medical therapies by IVF patients, in collaboration with other IVF Units in Israel. Representative Research Is IVF per-se associated with an increased rate of prematurity and low birth rates? To deter- mine whether infertility etiology or IVF per-se are associated with prematurity or low birth weight, we conducted a retrospective cohort study of 1,252 women who underwent IVF and gave birth to a live singleton infant. The control group was 3,124 mothers matched for age and parity, who conceived spontaneously. The IVF group was analyzed for male factor (MF), tubal factor (TF), polycystic-ovary syndrome (PCOS), pre-implantation genetic diagnosis (PGD), un- explained fertility, combined male & PCOS or tubal factors. Weak of delivery for each subgroup - Single Neonate 181 Ivf
    • WefoundthatneonatesconceivedbyIVFwereborn3.1daysearlierandwere160gramslighter (P<0.0001)comparedtothecontrolgroup.Theirriskofbeingborn<37wksincreasedbyO.R.1.92 (95%CI1.57-2.36)and<33wksby2.63(95%CI1.52-4.54).TheirriskforIUGRwas2.5(95%CI 1.65-3.83).IUGRprevalencewashigher,asfewerembryosweretransferred(p.015).Significant- ly more cases of prematurity followed fresh embryo transfer than following cryopreservation. Increased maternal age was found to be another risk factor for birth <37 wks, 1.05 (95% CI 1.01-1.08). However IUGR was found in association with young age (p=0.041). ,Couples that underwent IVF due to MF or TF abnormalities presented poorer outcomes com- pared to the control. We concluded that IVF per- se did not increase neonatal morbidity; nevertheless various infertility etiologies, maternal age, fresh /cryopreserved embryo transfer and single/multiple embryo transfer may influence the neonatal morbidity rate. Publications 1. Pront RH, Margalioth EJ, Green R, Eldar-Geva T, Maimoni Z, Zimran A, Elstein D. Preva- lence of low serum cobalamin in infertile couples. Andrologia 2009; 41, 46–50. 2. Tsafrir A, Simon A, Margalioth EJ, Laufer N. What should be the first-line treatment for unexplained infertility in women over 40 years of age - ovulation induction and IUI, or IVF? Reprod Biomed Online 2009;19 Suppl 4:4334. 3. Liberty G, Hyman JH, Eldar-Geva TC, Latinsky B, Gal M, Margalioth EJ. Ovarian hem- orrhage after transvaginal ultrasonographically guided oocyte aspiration: a potentially catastrophic and not so rare complication among lean patients with polycystic ovary syn- drome. Fertil Steril 2010;93:874-9. 4. Humaidan P, Kol S, Papanikolaou EG; Copenhagen GnRH Agonist Triggering Workshop Group. GnRH agonist for triggering of final oocyte maturation: time for a change of prac- tice? Hum Reprod Update 2011;17(4):510-24. 5. Ben-Yosef D, Amit A, Malcov M, Frumkin T, Ben-Yehudah A, Eldar I, Mey-Raz N, Azem F, Altarescu G, Renbaum P, Beeri R, Varshaver I, Eldar-Geva TC, Epsztejn-Litman S, Levy-Lahad E, Eiges R. Female Sex Bias in Human Embryonic Stem Cell Lines. Stem Cells Dev 2012 Feb 10;21(3):363-72. Research Report 2013 182
    • T he Pediatric Genetics Unit directed by Dr. Reeval Segel is part of the Medical Genetics Institute and the Pedi- atric Wing. The Unit operates a referral clinic for chil- dren with multiple congenital anomalies, mental retardation, autism spectrum disorder and other congenital disorders. Pa- tients are referred for evaluation by pediatricians, pediatric neurologists and other pediatric disciplines from the entire Jerusalem area. The Neurogenetics clinic, run jointly with Pe- diatric Neurology, diagnoses and treats pediatric patients with complex neurological disorders. The Unit also provides consultations on neonates with congenital anomalies in the nursery and the Neonatal Intensive Care Unit and complex cases in the entire Pediatric Wing. The Unit attracts students and residents interested in the rapidly evolving field of Medi- cal Genetics. Areas of Research Activity Research in the Unit is translational, and focuses on under- standing the genetic basis of human diseases. Discovery of novel correlations between genotypes and disease pheno- types is a key tool in understanding the function of the genes involved. Major research areas include: • Detection of novel genes causing autosomal recessive Diseases - Polyarteritis nodosa (PAN) is a systemic necro- tizing vasculitis affecting medium and small sized mus- cular arteries. In collaboration with Dr. Pnina Navon, a senior Pediatric Rheumatologist at the hospital, we are Pediatric Genetics Unit 183 Pediatric Genetics
    • working on elucidating the molecular basis of the disease in a specific pediatric popula- tion. This will hopefully lead to a better understanding of the disease mechanism in the general population, and eventually may lead to better treatment of vasculitis. • Mental retardation and obesity in the Muslim population - We identified a Muslim family with 3 siblings who suffer from mental retardation and obesity. One of them also has renal failure. In collaboration with the Pediatric Nephrology Unit and the Pediatric Endocrinol- ogy Unit, we delineated the patients' clinical status, and by methods of genomic research (homozygositymappingandwholeexomesequencing),wewereabletofindthegenewhose mutation caused the disorder. We plan to test other patients with a similar clinical presen- tation for mutations in this gene. By identifying the affected gene we will be able to better understand the molecular basis of mental retardation, and to give genetic counseling to the families for their next pregnancies. • Genotype-phenotype correlation of thiopurine S-methyltransferase (TPMT) – testing be- fore thiopurine treatment in inflammatory bowel diseases. This research is being conduct- ed in collaboration with Prof. Dan Turner, head of the Pediatric GI unit in SZMC and with theBiochemicalServiceLab.TheaimofthisstudyistodetermineTPMTactivityandTPMT mutations for the first time among Jews in order to establish an assay for this population before starting thiopurine treatment. Representative Research Cerebral palsy (CP) is an “umbrella term” for a complex pediatric neurological phenotype, and is the major cause of physical disability in children, although the etiology is unclear. Recent studies have shown that Copy Number Variations (CNVs) are an important cause of a number of complex pediatric disorders, including mental retardation and autism. CNVs are identified by microarray technology. As pathogenic CNVs usually arise de novo, most CNV-associated cases are sporadic, not familial. We hypothesized that CNVs play a role in the etiology of cere- bral palsy, and we are attempting to identify genomic rearrangements in subjects with CP by microarray analysis, and then to correlate the neurological and dysmorphological phenotype with the genotype. We have recruited 50 CP patients born at term and detected genomic rear- rangements in 13 samples in regions known to cause diseases. Our data support the hypoth- esis that CNVs play a role in the pathogenesis of CP. Therefore, we believe that patients with a diagnosis of CP should undergo CNV analysis as part of the workup of their disease. This has implications both for their diagnostic process, as well as for genetic counseling to the parents. Scientifically, it has a major impact on our understanding of this disorder, and may help iden- tify specific genes associated with CP. Research Report 2013 184
    • An example of a deletion detected in patient no. 15040. Deletion is marked in red. The deletion is not inherited from the parents. PUBLICATIONS 1. SegelR,Levy-LahadE,PasuttoF,PicardE,RauchA,AlterescuG,SchimmelMS.Pulmonary hypoplasia-Diaphragmatic hernia-Anophthalmia-Cardiac defect (PDAC) syndrome due to STRA6 Mutations - What are the minimal criteria? Am J Med Genet 2009; 149A(11):2457- 63. 2. Zeharia A, Shaag A, Pappo O, Mager-Heckel AM, Saada A, Beinat M, Karicheva O, Man- del H, Ofek N, Segel R, Marom D, Rötig A, Tarassov I, Elpeleg O. Acute infantile liver failure due to mutations in the TRMU gene. Am J Hum Genet. 2009; Sept.85(3):401-7. 3. Renbaum P, Kellerman E, Jaron R, Geiger D, Segel R, Lee M, King MC, Levy-Lahad E. Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene. Am J Hum Genet 2009; 85(2):281-9. 4. Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, Müller L, Ze- 185 Pediatric Genetics
    • schnigk C, Botti C, Rabinowitz R, Uyanik G, Crocq MA, Kraus U, Degen I, Faes F. New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet 2010; May 26. 5. Belostotsky R,Ben-Shalom E, Rinat C, Becker-Cohen R, Feinstein S, Zeligson S, Segel R, Elpeleg O, Nassar S, and Frishberg Y. Mutations in the mitochondrial seryl-tRNA synthe- tase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, (HUPRA syndrome). Am J Hum Genet 2011; Feb 11;88(2):193-200. 6. Segel R, Anikster Y, Zevin S, Steinberg A, Gahl WA, Fisher D, Staretz-Chacham O, Zimran A and Altarescu G. A Safety Trial of High Dose Glyceryl Triacetate for Canavan Disease. Mol Genet Metab 2011; Mar 15. 7. Saada A, Edvardson S, Shaag A, Chung WK, Segel R, Miller C, Jalas C, and Elpeleg O. Combined OXPHOS complex I and IV defect, due to mutated complex I assembly factor C20ORF7. J Inherit Metab Dis 2012; Jan;35(1):125-31. PUBLISHED Abstracts 1. Segel R, Zeligson S, Falik-Zaccai T, Perlberg T, Neufeld M, Cohen P, Renbaum P, Zucker- man S, Nir A, Levi-Lahad E. Homozygosity Mapping is an efficient strategy for mutation identification  in Consanguineous Families with a Genetically Heterogenous Disease. Am J Hum Genet Am J Hum Genet 2010; 82: A2390. Research Report 2013 186
    • T he Reproductive Endocrinology and Genetics Unit, es- tablished in 2009 as a subdivision of the IVF Unit, is directed by Prof. Talia Eldar-Geva. The unit provides wide-ranging diagnosis and treatment services in two main areas: reproductive endocrinology and preimplantation ge- netic diagnosis (PGD). The first includes a referral clinic deal- ing with complicated reproductive pathologies, such as pre- mature ovarian failure (POF), polycystic ovary syndrome (PCOS) and Turner’s syndrome. In collaboration with the en- docrine laboratory, comprehensive analysis of ovarian and testicular function using blood tests for the ovarian reserve markers anti-Mullerian hormone (AMH) and inhibin B is pro- vided. In addition, Prof. Eldar-Geva is part of the multidisci- plinary Prader-Willi syndrome (PWS) clinic. This national clinic treats almost all individuals in Israel with this rare syn- drome. Many of the symptoms of PWS, including delayed and incomplete puberty, dysmorphic features, short stature and osteoporosis are related to abnormalities in the reproductive and endocrine systems. The Unit is also part of the multidisciplinary PGD division that consists of the Zohar PGD Unit. Couples that are car- riers or affected with genetic disorders and wish to prevent the risks of pregnancy termination are offered the alternative of a PGD. Following hormonal ovarian stimulation and IVF, a biopsy of one or two embryonic cells is performed in the Unit and the cell is transferred to the Zohar PGD laboratory for genetic diagnosis. Only unaffected embryos are transferred to the uterus. The Unit is among a select few in the world that Reproductive Endocrinology and Genetics Unit 187 Reproductive Endocrinology And Genetics
    • performs all types of biopsies – polar body, blastomere and blastocyst – using mechanical and otherspecialbiopsytechniquestopreventpotentialinjuriestotheoocytesandembryos.More than 230 healthy babies have been born following this treatment, the largest number in Israel, due to tailoring the treatment to case and disease-specific criteria and the excellent treatment outcome (pregnancy rate per embryo transfer >40%). The embryologists at the IVF-PGD lab are Dr. Oshrat Shuenberger, Irit Varshaver, Aharon Peretz, Nava Dekel and Esther Rubinstein. Areas of Research Activity Research and teaching are a major focus of activities in the Reproductive Endocrinology and Genetics Unit, involving numerous local and international projects in both clinical and ba- sic science. One major research area is the continuous study of markers of ovarian function and reserves in normal and pathological conditions. The in-depth study of the reproductive system in individuals with PWS in the national multidisciplinary clinic has enabled a better understanding of the hypothalamic-pituitary-gonadal axis in Prader-Willi syndrome. The pub- lication showing that primary ovarian dysfunction contributes to the hypogonadism in wom- en with Prader-Willi Syndrome won the prize for the best original paper published in 2009 in Pediatric Endocrinology from the European Society of Pediatric Endocrinology. Ongoing longitudinal studies of the causes and spectrum of hypogonadism in females and males with Prader-Willi syndrome, from infancy to adulthood, and the FSH-inhibin axis in this syndrome are being conducted. Other research interests in reproductive endocrinology include the relationships between FSH, inhibin B, AMH, and androgens in polycystic ovary syndrome (PCOS), in women with diminishedovarianreservesandinmen,toidentifyformodulatorsofAMHsecretioninphysi- ological and pathological conditions. Finally, basic and clinical studies on ovarian function in women with Myotonic Dystrophy and Fragile-X premutation carriers, in collaboration with the Zohar PGD Unit, as well as projects on PGD treatment outcome are ongoing. Representative Research Poor response to ovarian stimulation for IVF treatment is a clinical challenge, with expected pregnancy rates as low as 2-10% per cycle. No particular treatment has a clear benefit, or can be recommended. It was suggested that supplementation of Dehydroepiandrosterone (DHEA, a weak androgen secreted mainly from the adrenal gland) could improve IVF treatment out- comes in women with diminished ovarian reserves. Dr. Jordana Hyman conducted a prospec- tive self controlled study to investigate the impact of DHEA supplementation on IVF treat- Research Report 2013 188
    • mentoutcometofindatwhichstageoffolliculogenesisDHEAinfluencesovarianresponse.An enhanced response was found, including increased peak estradiol (E2) levels, number of folli- cles, oocytes, mature (M2) oocytes and embryos. There was a significant increase in the num- ber of very small follicles (antral follicles count, AFC), without significant changes in the base- line biochemical parameters AMH, inhibin B or FSH. Our data suggest that the mechanism responsible for the improvement in IVF treatment out- come following DHEA supplementation does not include recruitment of more pre-antral or very small antral follicles - no change in AMH and inhibin B – but rather the rescue from atre- sia of small antral follicles - increased AFC. It is possible that in young women with premature reproductive ageing, DHEA has the potential to improve deteriorating oocyte function and return it, at least partially, to more age-appropriate reproductive function. 02-6666034 Representative Research Poor response to ovarian stimulation for IVF treatment is a clinical challenge, with expected pregnancy rates as low as 2-10% per cycle. No particular treatment offers clear benefit, or can be recommended. It was suggested that supplementation of Dehydroepiandrosterone (DHEA, a weak androgen secreted mainly from the adrenal gland) could improve IVF treatment outcome in women with diminished ovarian reserve. Dr. Jordana Hyman conducted a prospective self controlled study to investigate the impact of DHEA supplementation on IVF treatment outcome to find at which stage of folliculogenesis DHEA influences ovarian response. An enhanced response was found, including increased peak estradiol (E2) levels, number of follicles, oocytes, mature (M2) oocytes and embryos. There was a significant increase in the number of very small follicles (antral follicles count, AFC), without significant changes in the baseline biochemical parameters AMH, inhibin B or FSH. A. Markers of ovarian reserve Pre-DHEA Post-DHEA * Missing legends on figures and what is the histogram on the far right? Our data suggest that the mechanism responsible for the improvement in IVF treatment outcome following DHEA supplementation does not include recruitment of more pre-antral or very small antral follicles - no change in AMH and inhibin B – but rather the rescue from atresia of small antral follicles - increased AFC. It is possible that in young women with premature reproductive ageing, DHEA has the potential to improve deteriorating oocyte function and return it, at least partially, to more age-appropriate reproductive function. Publications 1. Li Y, Altarescu G, Renbaum P, Eldar-Geva T, Levy-Lahad E, Margalioth EJ, Zhong X, Hahn S, Holzgreve W. Non-invasive prenatal diagnosis using cell-free fetal DNA in maternal plasma from PGD pregnancies. Reprod Biomed Online. 2009; 19:714-20. 2. Hirsch HJ, Eldar-Geva T, Benarroch F, Rubinstein O, Gross-Tsur V. Primary testicular dysfunction is a major contributor to abnormal pubertal development in males with Prader- Willi syndrome. J Clin Endocrinol Metab 2009; 94:2262-8. 3. Altarescu G, Eldar-Geva T, Varshower I, Brooks B, Haran EZ, Margalioth EJ, Levy-Lahad E, Renbaum P. Real-time reverse linkage using polar body analysis for preimplantation genetic diagnosis in female carriers of de novo mutations. Hum Reprod 2009; 24:3225-9. 4. Eldar-Geva T, Hirsch HJ, Rabinowit R, Benarroc F, Rubinstein O, Gross-Tsu V. Primary B. Outcome parameters * ** ** * * 189 Reproductive Endocrinology And Genetics
    • Publications 1. Li Y, Altarescu G, Renbaum P, Eldar-Geva T, Levy-Lahad E, Margalioth EJ, Zhong X, Hahn S, Holzgreve W. Non-invasive prenatal diagnosis using cell-free fetal DNA in maternal plasma from PGD pregnancies. Reprod Biomed Online. 2009; 19:714-20. 2. Hirsch HJ, Eldar-Geva T, Benarroch F, Rubinstein O, Gross-Tsur V. Primary testicular dys- function is a major contributor to abnormal pubertal development in males with Prader- Willi syndrome. J Clin Endocrinol Metab 2009; 94:2262-8. 3. Altarescu G, Eldar-Geva T, Varshower I, Brooks B, Haran EZ, Margalioth EJ, Levy-Lahad E, Renbaum P. Real-time reverse linkage using polar body analysis for preimplantation genetic diagnosis in female carriers of de novo mutations. Hum Reprod 2009; 24:3225-9. 4. Eldar-Geva T, Hirsch HJ, Rabinowit R, Benarroc F, Rubinstein O, Gross-Tsu V. Primary ovarian dysfunction contributes to the hypogonadism in women with Prader-Willi Syn- drome. Horm Res 2009; 72:153-9. 5. Altarescu G, Eldar-Geva T, Brooks B, Zylber-Haran E, Varshaver I, Margalioth EJ, Levy-La- had E, Renbaum P. Preimplantation genetic diagnosis (PGD) for nonsyndromic deafness by polar body and blastomere biopsy. J Assist Reprod Genet 2009; 26:391-7. 6. Eldar-Geva T, Liberty G, Chertin B, Fridmans A, Farkas A, Margalioth EJ, Spitz IM. Rela- tionships between FSH, inhibin B, anti-Mullerian hormone, and testosterone during long- term treatment with the GnRH-agonist histrelin in patients with prostate cancer. Eur J Endocrinol 2010; 162:177-81. 7. Eldar-Geva T, Hirsch HJ, Benarroch F, Rubinstein O, Gross-Tsur V. Hypogonadism in fe- males with Prader-Willi syndrome from infancy to adulthood: variable combinations of a primary gonadal defect and hypothalamic dysfunction. Eur J Endocrinol 2010;162:377- 84. 8. Liberty G, Ben-Chetrit A, Margalioth EJ, Hyman JH, Galoyan N, Eldar-Geva T. (2010) Does estrogen directly modulate anti-müllerian hormone secretion in women? Fertil Steril. 94:2253-6. 9. Tsafrir A, Altarescu G, Margalioth E, Brooks B, Renbaum P, Levy-Lahad E, Rabinowitz R, Varshaver I, Eldar-Geva T. PGD for fragile X syndrome: ovarian function is the main deter- minant of success. Hum Reprod 2010; 25:2629-36. Research Report 2013 190
    • 10. Altarescu G, Renbaum P, Eldar-Geva T, Varshower I, Brooks B, Beeri R, Margalioth EJ, Levy-Lahad E, Elstein D, Zimran A. Preimplantation genetic diagnosis (PGD) for a treat- able disorder: Gaucher disease type 1 as a model. Blood Cells Mol Dis 2011; 15;46:15-8. 11. Almog B, Shehata F, Suissa S, Holzer H, Shalom-Paz E, La Marca A, Muttukrishna S, Bla- zar A, Hackett R, Nelson SM, Cunha-Filho JS, Eldar-Geva T, Margalioth EJ, Raine-Fenning N, Jayaprakasan K, McIlveen M, Wunder D, Freour T, Nardo LG, Balasch J, Peñarrubia J, Smeenk J, Gnoth C, Godehardt E, Lee TH, Lee MS, Levin I, Gamzu R, Tulandi T. Age-related normograms of serum antimüllerian hormone levels in a population of infertile women: a multicenter study. Fertil Steril 2011; 95:2359-63, 2363.e1. 12. Altarescu G, Renbaum P, Eldar-Geva T, Brooks B, Varshaver I, Avitzour M, Margalioth EJ, Levy-Lahad E, Elstein D, Epsztejn-Litman S, Eiges R. Preventing mucopolysaccharidosis type II (Hunter syndrome): PGD and establishing a Hunter(46, XX) stem cell line. Prenat Diagn 2011 Jun 27. [Epub ahead of print] 13. Altarescu G, Barenholz O, Renbaum P, Beeri R, Levy-Lahad E, Margalioth EJ, Brooks B, Varshaver I, Eldar-Geva T. Preimplantation genetic diagnosis (PGD)--prevention of the birth of children affected with endocrine diseases. J Pediatr Endocrinol Metab 2011; 24:543-8. 14. Gross-Tsur V, Eldar-Geva T, Benarroch F, Rubinstein O, Hirsch HJ. Body image and sexual interests in adolescents and young adults with Prader-Willi syndrome. J Pediatr Endocrinol Metab 2011; 24:469-75. 15. Altarescu G, Barenholz O, Renbaum P, Beeri R, Levy-Lahad E, Margalioth EJ, Brooks B, Varshaver I, Eldar-Geva T . Preimplantation genetic diagnosis (PGD)--prevention of the birth of children affected with endocrine diseases. J Pediatr Endocrinol Metab 2011; 24:543-8. 16. Ben-Yosef D, Amit A, Malcov M, Frumkin T, Ben-Yehudah A, Eldar I, Mey-Raz N, Azem F, Altarescu G, Renbaum P, Beeri R, Varshaver I, Eldar-Geva , Epsztejn-Litman S, Levy- Lahad E, Eiges R. Female Sex Bias in Human Embryonic Stem Cell Lines. Stem Cells Dev 2012; ;21(3):363-72. 17. Altarescu G, Eldar Geva T, Grisaru-Granovsky S, Bonstein L, Miskin H, Varshver I, Mar- galioth EJ, Levy-Lahad E, Renbaum P. Preimplantation genetic diagnosis for fetal neonatal alloimmune thrombocytopenia due to antihuman platelet antigen maternal antibodies. Ob- stet Gynecol 2012; 119(2 Pt 1):338-43. 191 Reproductive Endocrinology And Genetics
    • 18. Gross-Tsur V, Hirsch HJ, Benarroch F, Eldar-Geva T. The FSH-inhibin axis in prader-willi syndrome: heterogeneity of gonadal dysfunction. Reprod Biol Endocrinol 2012; 10:39. 19. Altarescu G, Beeri R, Eldar-Geva T, Varshaver I, Margalioth EJ, Levy-Lahad E, Renbaum P. PGD for germline mosaicism. Reprod Biomed Online 2012; 25(4):390-395. 20. Hirsch HJ, Eldar-Geva T, Gross-Tsur V, Benarroch F, Roger M, Lahlou N. Normal Insulin- Like Peptide-3 Levels Despite Low Testosterone in Adult Males with Prader-Willi Syn- drome: Variations in Leydig Cell Function from Infancy through Adulthood. J Clin Endocri- nol Metab 2012 Nov 12. [Epub ahead of print] 21. Hyman JH, Margalioth EJ, Rabinowitz R, Tsafrir A, Gal M, Alerhand S, Algur N, Eldar-Geva T. DHEA supplementation may improve IVF outcome in poor responders: a proposed mechanism. Eur J Obstet Gynecol Reprod Biol. Research Report 2013 192
    • T he Zohar Preimplantation Genetic Unit (PGD) is a multidisciplinary division that consists of the Medical Genetic and an In-Vitro Fertilization (IVF) subdivi- sions.PGDGeneticsisdirectedbyProf.GheonaAltarescuand isstaffedbythreePh.D.molecularspecialists:Dr.P.Renbaum, Dr. R. Beeri and Dr. D. Zeevi, four laboratory biologists: Elina Farhi, Hagit Elharar, Shira Shaviv, and Merav Ben Shlomo, two cytogenetic specialists: Dr. Y. Nevo and Dr. O. Loebel and one microarray specialist: Sharon Zeligson. The PGD IVF sub- division is directed by Dr. Talia Geva and includes Prof. Ehud Margalioth (Head of the IVF unit), Dr. A. Tzafrir, Dr. M. Gal, Dr. E. Ben Shitrit , the embryologists A. Perez, I. Varshaver, O. Shonberger, E. Rubinstein, N. Biton, N. Dekel and the nurses of the IVF unit. The Zohar PGD Unit specializes in the genetic diagnosis of in-vitro fertilized oocytes and embryos, a technique that is implemented to prevent at-risk couples from transmitting genetic diseases to their progeny. PGD is an alternative to pregnancy termination for parents who are carriers or af- fected with genetic disorders. The Unit has performed PGD for more than 150 different genetic disorders including single gene (for example Tay Sachs) and cytogenetic (for example, chromosomal translocations) related abnormalities. The Unit reports a very high pregnancy rate (nearly 140% higher than that of several PGD centers in Europe) and is constantly implementing the latest in cutting edge technology to im- prove the speed and quality of its service. Since its inception in 2004, the PGD Unit has performed over 1000 PGD cycles Zohar Preimplantation Genetic Unit (PGD) 193 Pga
    • and more than 200 healthy children have been born. Today, the Unit is the largest of its kind in Israel and the first to pioneer polar body-based PGD in the Middle East. In addition, the PGD Unit is among a select few in the world that performs all types of biopsies and analyses that are tailored to case and disease-specific criteria. Areas of Research Activity The PGD unit specializes in various areas of research, including both clinical and basic science. In the realm of clinical research, the Unit was the first in the world to successfully perform PGD for a woman affected with achondroplasia (dwarfism) even though her small pelvic area posed a challenge to oocyte retrieval, pregnancy, and childbirth. In addition, the PGD Unit has expanded the gamut of genetic changes (mutations) that can be diagnosed by PGD to include heritable de novo mutations (mutations that occur in a single individual, that do not appear in immediate family members, but can be passed down to the next generation). Such muta- tions are common in heritable forms of cancer, neurofibromatosis, polycystic kidney disease, and other debilitating genetic disorders. Prior to the development of novel methodological approaches by the PGD Unit, it was impossible to accurately diagnose these disorders by con- ventional PGD methods. The PGD Unit has also conducted a follow-up study on the neurological, behavioral and physi- cal development of children born after PGD. The PGD Unit has been distinguished on the in- ternational level. It was recently selected for a multi-center international study to investigate the effects of oocyte chromosomal content on pregnancy rates. In the realm of basic science, the PGD Unit is constantly innovating and adapting the speed, accuracy and availability of tools for early stage prenatal diagnostics. The Unit has now implemented a rapid and univer- saltechnologyforPGDbycombiningmicroarray(microchip)analysiswithone-shotamplifica- tion of all genetic material from a single cell. The Unit now offers a clinical service for embryo sex determination at week 7 of gestation. In the future, the Unit aims to provide this service for a wide range of genetic disorders. Representative Research Development of PGD assays for molecular disorders based on analysis of a familial mutation together with polymorphic genetic markers is lengthy and requires the identification of mul- tiple informative markers prior to PGD analysis. The aim of this study was to validate simulta- neous familial haplotyping and blastomere analysis during PGD cycles (instant haplotyping to eliminate time-consuming pre-case preparations for each family. Wild type and mutant paternal haplotypes were assigned based on the affected mother. Out of Research Report 2013 194
    • 4844totalSNPprobesonchromosome17,sixhundredfortyninewereidentifiedaspaternally informative, and 378 SNPs remained informative for the wild type or mutant allele when the maternal genotype was introduced. After unique informative allele selection, 103 to 137 SNPs were available for haplotype mapping in blastocyst and 97 to 109 SNPs in blastomere biopsies. This analysis of entire chromosome haplotypes in blastomere and blastocyst biopsies clearly showedthatbothembryosreceivedthemutantpaternalchromosome,reconfirmingtheinitial diagnosis. This is the first report to apply the ‘unique informative allele selection’ algorithm to microarray-based PGD for a monogenic disorder. The methodology is universal, can eliminate pre-case haplotype preparation, and allows couples to start PGD immediately following ge- netic counselling. Characterization of DM1- affected HESC lines. 02-6666034 Characterization of DM1- affected HESC lines. Expression of undifferentiated cell specific markers by immunostaining for OCT4 (red, merged onto Hoechst (blue)), for the cell surface marker Tra 1-60 (red, merged onto Hoechst (blue)) and for alkaline phosphatase activity, in all DM1 HESC lines. 195 Pga
    • Bibliography 1. Altarescu G, Eldar-Geva T, Brooks B, Zylber-Haran E, Varshaver I, Margalioth EJ, Levy- Lahad E, Renbaum P. Preimplantation genetic diagnosis (PGD) for nonsyndromic deaf- ness by polar body and blastomere biopsy. J Assist Reprod Genet 2009; 26(7):391-397. 2. Altarescu G, Eldar-Geva T, Varshower I, Brooks B, Haran EZ, Margalioth EJ, Levy-Lahad E, Renbaum P. Real-time reverse linkage using polar body analysis for preimplantation ge- netic diagnosis in female carriers of de novo mutations. Hum Reprod 2009; 24(12):3225- 3229. 3. Li, Altarescu, Renbaum, Eldar-Geva, Levy-Lahad, Margalioth E, Zhong, Hahn, Holzgreve . Non-invasive prenatal diagnosis using cell-free fetal DNA in maternal plasma from PGD pregnancies. Reprod Biomed Online 2009; 19(5):714-720. 4. Tsafrir A, Altarescu G, Margalioth E, Brooks B, Renbaum P, Levy-Lahad E, Rabinowitz R, Varshaver I, Eldar-Geva TP. PGD for fragile X syndrome: ovarian function is the main determinant of success. Human Reprod 2010; 25(10): 2629-36 5. Reish O, Huber C, Altarescu G Chapman-Shimshoni D Levy-Lahad E , Renbaum P Ma- shevich M, Munnich A, Cormier-DaireV. Mosaic compound heterozygosity of SHOX re- sulting in Leri-Weill dyschondrosteosis with marked short stature: implications for disease mechanisms and recurrence risks. Am J Med Genet A 2010; 152A(9):2230-5. 6. Altarescu G, Renbaum P, Eldar-Geva T, Varshower Brooks B, Beeri B, Margalioth EJ, Levy-Lahad E, Elstein D, Zimran A. Preimplantation genetic diagnosis (PGD) for a treatable disorder: Gaucher diseasetype 1 as a model. Blood Cells Mol Dis 2011; 46(1):15-18. 7. Altarescu G, Reish O, Renbaum P, Levy-Lahad E, Ron El R.Preimplantation genetic diag- nosis (PGD) for SHOX-related haploinsufficiency in conjunction with trisomy 21—detection by molecular analysis. J Assist Reprod Genet 2011;28(3):233-238. 8. Altarescu G, Renbaum P, Eldar-Geva T, Brooks B, Varshaver I, Margalioth EJ, Levy-Lahad E, Elstein D, Epsztejn-Litman S, Eiges R. Preventing mucopolysaccharidosis type II (Hunt- er syndrome): preimplantation genetic diagnosis (PGD) and establishing a Hunter (46,XX) stem cell line. Prenat Diagn 2011; 31(9):853-860 9. Altarescu G, Barenholtz O, Renbaum P, Beeri R, Levy-Lahad E, Margalioth EJ, Brooks B, Varshaver I, Eldar-Geva T. Preimplantation genetic diagnosis: prevention of the birth of Research Report 2013 196
    • children affected with endocrine diseases. J Pediatr Endocr Met 2011; 24(7-8):543-548 10. Ben-Yosef D, Frumlin T, Malcov M, Eldar Cohen T, Altarescu G, Renbaum P, Geva-Eldar T, Epsztejn-Litman S, Eiges R. Female sex bias in human embryonic stem cell lines. Stem Cells Dev 2012; 21(3):363-372. 11. Altarescu G, Geva TE, Grisaru-Granovsky S, Bonstein L, Miskin H, Varshver Margalioth EJ, Levy-Lahad E, Renbaum P. Preimplantation genetic diagnosis for fetal neonatal alloim- mune thrombocytopenia due to antihuman platelet antigen maternal antibodies. Obstet Gynecol 2012; 119(2 Pt 1):338-343. 12. Altarescu G, Beeri R, Eldar-Geva T, Varshaver I, Margalioth EJ, Levy-Lahad E, Renbaum P. Preimplantation Genetic Diagnosis (PGD) for germline mosaicism. 2012. In Press. RBM Online 197 Pga
    • T he Department of Obstetrics and Gynecology oper- ates the most active maternity in the country as well as being a prestigious center for Gynecologic Surgery, OncologyandReproductiveEndocrinology.Thestaffconsists of over twenty senior physicians and close to twenty house officers. The director, Prof. Uzi Beller, is a specialist in Gyne- cologic Oncology and Surgery and is currently the Editor in Chief of the International Journal of Gynecological Cancer. The head of the Obstetrics Department is Prof. Arnon Samuelof and the Infertility unit is run by Prof. Ehud Margalioth. Three of the senior staff members have a Ph.D. degree - Drs. Gal, Geva and Grisaru - an outstanding achieve- ment unparalleled by any clinical department in Israel. TheDepartmentisinvolvedinthecareofover14,000women in labor annually, performs 900 major surgical procedures, more than 1,200 fertility treatments as well as dealing with thousands of clinic visits, emergency room admissions and non surgical admissions for high-risk pregnancy and gyneco- logical problems. Areas of Research Activity Research in clinical medicine as well as basic science is re- garded as a top priority. The diversity of clinical activity is re- flected in the Department’s research efforts and publications. The major areas of research include studies and analysis of obstetrical practices, infertility treatments and In Vitro Fer- tilization (IVF) combined with Pre-gestational Genetic Diag- Department of Obstetrics and Gynecology Research Report 2013 198
    • nosis (PGD). We also concentrate our efforts, jointly with the Department of Human Genetics, on studying the epidemiology and clinical outcome of women at high risk for breast and ovar- ian cancer due to their inherited mutation in the BRCA1/2 genes, so common (2.5%) among Ashkenazi Jews.The PGD unit, led by Prof. T. Geva, is a leader in clinical applications of this high-tech cutting edge fertility treatment and is also a pioneer in research on the management of families with inherited highly lethal conditions. Representative Research In collaboration with a group of Israeli gynecology surgeons the Department has recently analyzed the use of radiation therapy for women who have undergone radical surgery for can- cer of the cervix. This large scale analysis of over 600 patients was led by Dr. O. Gemmer and showed that these women receive additional radiation therapy almost 60% of the time. This number, higher than commonly found in Western countries, should be taken into account by gynecological oncologists in Israel when counseling newly diagnosed women with cervical cancer. The selection of patients for surgical treatment is of paramount importance and this study provides retrospective data that are crucial for our daily activities. A surgical specimen of the uterus and parametria removed during a radical hysterectomy procedure. 199 Obstetrics & Gynecology
    • Publications 1. Reichman O, Akins R, Sobel JD. Boric acid addition to suppressive antimicrobial therapy for recurrent bacterial vaginosis. Sex Transm Dis 2009;36(11):732-4. (3.268; 19/58; 3:3). 2. Auslender R, Shen O, Kaufman Y, Goldberg Y, Bardicef M, Lissak A, Lavie O. Doppler and gray-scale sonographic classification of adnexal torsion. Ultrasound Obstet Gynecol 2009; 34(2):208-211. 3. Chertin B, Pollack A, Koulikov D, Rabinowitz R, Shen O, Hain D, Hadas Halpren I, Farkas A. Does renal function remain stable after puberty in children with prenatal hydronephrosis and improved renal function after pyeloplasty? J Urol 2009; 182(4 Suppl):1845-1848. 4. Shen O, Yagel S. The added value of 3D/4D ultrasound imaging in fetal cardiology: has the promise been fulfilled? Ultrasound Obstet Gynecol 2010;35(3):260-262. 5. Shen O, Rabinovitz R, Geist RR, Shafir E. Effect of background case characteristics on decisions in the delivery room. Med Decision Making 2010; 30(4):518-22. 6. Yagel S, Kivilevitch Z, Cohen SM, Valsky DV, Messing B, Shen O, Achiron R. The fetal ve- nous system, part I: normal embryology, anatomy, hemodynamics, ultrasound evaluation and Doppler investigation. Ultrasound Obstet Gynecol 2010; 35(6):741-50. 7. Yagel S, Kivilevitch Z, Cohen SM, Valsky DV, Messing B, Shen O, Achiron R. The fetal ve- nous system, part II: ultrasound evaluation of the fetal venous system the fetus with con- genital venous system malformation or developing circulatory compromise. Ultrasound Obstet Gynecol 2010; 36(1):93-111. 8. Sobel JD, Reichman O, Misara D, Yoo W. Prognosis and treatment of Desquamative Inflammatory Vaginitis. Obstet Gynecol 2011; 117(4): 850-5. 9. Shen O, Valsky DV, Messing B, Cohen SM, Lipschuetz M, Yagel S. Shunt diameter in agenesis of ductus venosus with extrahepatic portosystemic shunt impacts prognosis. Ultrasound Obstet Gynecol 2011;37(2):184-90. 10. Yagel S, Cohen SM, Rosenak D, Messing B, Lipschuetz M, Shen O, Valsky DV. Added value of 3D/4DUS in the offline analysis and diagnosis of congenital heart disease. Ultra- sound Obstet Gynecol 2011; 37(4):432-7. Research Report 2013 200
    • 11. Shen O, Rabinowitz R, Yagel S, Moran G. Absent gallbladder on fetal ultrasound: prenatal findings and postnatal outcome. Ultrasound Obstet Gynecol 2011; 37(6):673-7. 12. Ioscovich A, Shen O, Sichel JY, Lajos Y, Orkin D, Bromiker R, Briskin AJ. Remifentanil-ni- troglycerin combination as an anesthetic support for ex utero intrapartum treatment (EXIT) procedure. J Clin Anesth 2011; 23(2):142-4. 13. Messing B, Cohen SM, Valsky DV, Shen O, Rosenak D, Lipschuetz M, Yagel S.Fetal heart ventricle mass obtained by STIC acquisition combined with inversion mode and VOCAL. Ultrasound Obstet Gynecol 2011; 38(2): 191-7. 14. Shen O, Yagel S, Valsky DV, Rabinowitz R, Zalel Y. Sonographic examination of the fetal vermis: tricks for obtaining the narrow midline target with 3-dimensional volume contrast imaging in the C plane. J Ultrasound Med 2011; 30(6):827-31. 15. Avnet H, Shen O, Mazaki E, Yagel S, Daniel-Spiegel E. Four vessel umbilical cord. Ultra- sound Obstet Gynecol 2011; 38(5):604-6. 16. Shen O, Rabinowitz R , Yagel S , Avnet H . Omega-shaped anomaly of the umbilical artery: association with chromosome 18q deletion. J Ultrasound Med 2011; 30(4):581-2. 17. Shen O, Rabinowitz R , Yagel S, Gal M .Reply to Prenatal non- visualization of fetal gall- bladder: beware of biliary atresia. Ultrasound Obstet Gynecol 2011; 38(2) 238-40. 18. Shen O, Rabinowitz R, Yagel S, Gal M Correspondence: Relationship of non-visualization of the fetal gallbladder and amniotic fluid digestive enzymes analysis to outcome. Prenatal Diagnosis 2012. In press. 19. Shen O, Rabinowitz R , Malinger G , Mazaki E, Tsafrir A. Omega shaped variant of the umbilical artery. Prenatal diagnosis and outcome. J Ultrasound Med 2012. In press. 201 Obstetrics & Gynecology
    • T he department of Obstetrics and Maternal Fetal Med- icine is a largest in the Jerusalem area and the largest in Israel with over 15,000 births a year. The Depart- ment faculty provide the full spectrum of clinical care to women of all ages, participate in research, and provide educa- tion to students and residents.  The Director and his staff are as follows: A. Samueloff, MD Prof. Chairman Dept. Obstetrics & Maternal Fetal Medicine; S. Grisaru Granovsky, Prof. MD Ph. D. ,Head of the Mater- nal Fetal Medicine Unit MD, E. Gdansky, Head of the Deliv- ery Room, R. Rabinovitz, MD , Head of the U.S. Unit, Y. Yakel Melamed MD, V. Plotkin MD, O. Reichman MD, B Latinsky MD, O. Chen MD, E. Mazaaky MD, T. Halevy Shalem MD. The Department’s maternal-fetal medicine specialists are specifically involved in the care of women experiencing high- risk pregnancies. These patients include women with seri- ous medical conditions such as asthma, high blood pressure, kidney transplants, and diabetes. They also care for women whose pregnancies are complicated by multiple gestations, premature labor, or other high-risk conditions. The Depart- ment runs specific outpatient clinics where these specialists examine, counsel, and help in planning the future pregnan- cies of women who have medical conditions that might com- plicate their pregnancies and women who have had previous pregnancies with unfavorable outcomes.  Department of Obstetrics and Maternal Fetal Medicine Research Report 2013 202
    • Areas of Research Activity Our research programs are extensive and diverse. The Department conducts clinical as well as basic science studies involving women’s health and the early origins of health and disease. Recent research has focused on the growth and development of the fetus, normal and compli- cated obstetrics, and surgical and medical diseases of the female reproductive system, opera- tive obstetrics and early placenta formation. The Department is actively involved in numerous national maternal- neonatal epidemiologic studies. A recent study identified several genetic fingerprints for preterm birth and habitual abortions. PUBLICATIONS 1. Grisaru-Granovsky S, Maoz M, Barzilay O, Yin YJ, Prus D, Bar-Shavit R. Protease acti- vated receptor-1, PAR1, promotes placenta trophoblast invasion and beta-catenin stabili- zation. J Cell Physiol 2009; 218(3):512-521. 2. Ioscovich A, Mirochnitchenko E, Halpern S, Samueloff A, Grisaru-Granovsky S, Go- zal Y, Einav S. Perioperative anaesthetic management of high-order repeat caesarean section: audit of practice in a university-affiliated medical centre. Int J Obstet Anesth 2009;18(4):314-319. 3. Ioscovich AM, Goldszmidt E, Fadeev AV, Grisaru-Granovsky S, Halpern SH. Peripartum anesthetic management of patients with aortic valve stenosis: a retrospective study and literature review. Int J Obstet Anesth 2009; 18(4):379-386. 4. Zimran A, Morris E, Mengel E, Kaplan P, Belmatoug N, Hughes DA, Malinova V, Heitner R, Sobreira E, Mrsic M, Granovsky-Grisaru S, Amato D, vom Dahl S. The female Gaucher patient: the impact of enzyme replacement therapy around key reproductive events (men- struation, pregnancy, and menopause). Blood Cells Mol Dis 2009;43(3):264-288. 5. Grisaru-Granovsky S, Ethel-Sherry G, Haklai Z, Samueloff A, Schimmel M. Effect of inter- pregnancy interval on adverse perinatal outcomes—a national study. Contraception 2009; 80(6):512-518. 6. Grisaru-Granovsky S, Rabinowitz R,Ioscovich A, Elstein D, Schimmel M. Congenital diaphragmatic hernia: review of the literature in reflection of 203 Obstetrics
    • unresolved dilemmas. Acta Paediatr 2009 ;98(12):1874-81. Epub 2009 Jul 20. 7. Grisaru-Granovsky S, Altarescu G, Finci S, Weintraub A, Tevet A, Samueloff A, Schimmel MS. Prostanoid DP receptor (PTGDR) variants in mothers with post-coital associated preterm births: preliminary observations. J Perinatol 2009; 30(1):33-37. 8. Yinon Y, Grisaru-Granovsky S, Chaddha V, Windrim R,Gareth P, Seaward R, Kelly EN, Beresovska O, Ryan G. Perinatal outcome following fetal chest shunt insertion for pleural effusions. Ultrasound Obstet Gynecol 2010; 36(1):58-64. 9. Cohen I, Maoz M, Turm H, Grisaru-Granovsky S, Maly B, Uziely B, Weiss E, Abramovitch R, Gross E, Barzilay O, Qui Y, Bar-Shavit R. Etk/Bmx regulates proteinase–activated re- ceptor 1 (PAR1) in breast cancer invasion: signaling partners, hierarchy, and physiological significance. PloS One 2010; 5(6):e11135. 10. Turm H, Grisaru-Granvosky S, Maoz M, Offerman S, Bar-Shavit R. DVL as a scaffold pro- tein capturing classical GPCRs. Commun Integr Biol 2010;3(6):495-8. Epub 2010 Nov 1. 11. Fadeev A, Ioscovitch A, Rivlis A, Grisaru-Granovsky S, Samueloff A, Schimmel MS, Elstein D. Prospective study of maternal and neonatal outcome in great-grand mulitparous wom- en and aged-matched women with lesser parity. Arch Gynecol Obstet 2011; 284(4):799- 805. Epub 2011 Oct 30. 12. Grisaru-Granovsky S, Belmatoug N, vom Dahl S Mengel E, Morris E, Zimran A. The man- agement of pregnancy with Gaucher Disease. Eur J Obstet Gynecol Reprod Biol 2011; 156(1):3-8. Epub Jan 26. 13. Bar-Shavit R, Turm H, Salah Z, Maoz M, Cohen I, Weiss E, Uziely B, Grisaru-Granovsky S. PAR1 plays a role in epithelial malignancies: transcriptional regulation and novel signaling pathway. IUBMB Life 2011; 63(6):397-402. doi: 10.1002/iub.452. Epub May 9. 14. Michaelson-Cohen R, Elstein D, Ioscovich A, Armon S, Schimmel MS, Butnaru A, Samu- eloff A,C Grisaru-Granovsky S.PI Severe heart disease complicating pregnancy does not preclude a favourable pregnancy outcome: 15 years’ experience in a single centre. J Obstet Gynecol 2011;31(7):597-602. 15. Grisaru-Granovsky S, Reichman B, Lerner-Geva L, Boyko V, Hammerman C, Samueloff A, Schimmel MS. Israel Neonatal Network. Mortality and morbidity in preterm small-for- gestational-age infants: a population-based study. Am J Obstet Gynecol 2011;Aug 27. Research Report 2013 204
    • 16. Tevet A, Grisaru-Granovsky S, Samueloff A, Ioscovich A. Peripartum use of cell salvage: a university practice audit and literature review. Arch Gynecol Obstet. 2011;285(2):281-4. 17. Schimmel MS, Altarescu G, Grisaru S. Preterm birth following marital relations. Assia, 2011Issue pei-tet; tzadik: 137-138. 18. Ioscovich AM, Barth D, Samueloff A, Grisaru-Granovsky S, Halpern S. Anesthetic man- agement of a patient with cleidocranial dysplasia undergoing various  obstetric proce- dures. Int J Obstet Anesth 2010; 19(1): 106-108. 19. Ioscovich A, Grisaru-Granovsky S, Halpern S, Shapiro Y.Peripartum anesthetic manage- ment of a patient with brittle cornea syndrome. Arch Gynecol Obstet 2011; 283 Suppl 1:49-52. 20. Altarescu G, Eldar-Geva T, Grisaru-Granovsky S, Bonstein L, Miskin H, Varshver I, Mar- galioth EJ, Levy-Lahad E, Renbaum P. Preimplantation genetic diagnosis for fetal neonatal alloimmune thrombocytopenia due to antihuman platelet antigen maternal antibodies. Ob- stet Gynecol 2012;119(2 Pt 1):338-43. PUBLISHED Abstracts 1. Grisaru-Granovsky S , Elstein O, Tevet A,Altarescu G, Schimmel MS, Samueloff A .As- sociation of vitamin D receptor (VDR) gene polymorphisms  with idiopathic preterm birth (IPTB). American Journal of Obstetrics & Gynecology. Society  For Maternal – Fetal  Medi- cine, The 29th Annual Meeting, San Diego, CA 2009, Sup.# 108. 2. Michaelson-Cohen R , Armon R, Ioscovich A, Schimmel MS, Klein Y, Samueloff A, Gris- aru-GranovskyS. Severe heart disease (HD) complicating pregnancy does not preclude a favorable pregnancy outcome: 15 years experience in a single center .American Journal of Obstetrics & Gynecology. Society  For Maternal – Fetal Medicine, The 29th Annual Meet- ing, San Diego, CA 2009, Sup # 520. 3. Halevy-ShalemT, Michaelson-Cohen R, Cohen R, Shaya M, ShenO, Samueloff A.Uterine rupture of “The Laboring  unscarred uterus”: Is it really that rare?  American Journal of  Obstetrics & Gynecology. Society  For Maternal – Fetal Medicine, The 29th Annual Meeting, San Diego, CA 2009,  Sup # 536. 205 Obstetrics
    • 4. Tevet A , Armon S , Schimmel MS , Samueloff A, Grisaru-Granovsky S . The premature neonate “Tolerates” preeclamptic toxemia (PET) better than the idiopathic spontaneous preterm birth (ISPB). American Journal of Obstetrics & Gynecology. Society  For Maternal – Fetal Medicine, The 30th Annual Meeting, Chicago, IL 2010,  Sup # 185. 5. Bas-Lando M, Rabinowitz R, Shen O, Samueloff A, Schimmel MS,Grisaru-Granovsky S.The prenatal diagnosis of isolated varix of the fetal intra- abdominal umbilical vein (VFI- UV): Iatrogenic prematurity is not obligatory American Journal of  Obstetrics & Gynecology. Society  For Maternal – Fetal Medicine, The 30th Annual Meeting, Chicago, IL 2010,  Sup # 354. 6. Tevet A , Armon S, Altarescu G , Samueloff A, Grisaru-Granovsky S. Protease activated receptor 1 (PAR1) genetic variants: key susceptibility factors for idiopathic spontaneous preterm births (ISPB) American Journal of Obstetrics & Gynecology. Society  For Maternal – Fetal Medicine, The 30th Annual Meeting, Chicago, IL 2010, Sup # 502. 7. Gdansky E, Plotkin V, Baruch S, Latinsky B, Grisaru-Granovsky S, Samueloff A. External Cephalic Version: our experience and predicting factors for success. The 21st European Congress of Obstetrics and Gynecology (EBCOG). Facts, Views & Vision. Book of ab- stracts 2010: 175. 8. Tevet A, Armon S, Khatib F, Grisaru-Granovsky S, Samueloff A. Vaginal delivery of the second non-cephalic presenting twin by internal podalic version and total breech extrac- tion versus cesarean delivery: comparable for neonates superior for mothers. American Journal of  Obstetrics & Gynecology. Society  For Maternal – Fetal Medicine, The 31st Annual Meeting, San Francisco,CA 2011,  Sup # 90. 9. Melamed Yekel Y, Helman S, Cohen M, Farkash R, Samueloff A. Late OGTT follow- ing normal GCT among women with  suspected macrosomia or polyhydramion in late pregnancy is not predictive of  Gestational Diabetes. American Journal of  Obstetrics & Gynecology.  Society  For Maternal – Fetal Medicine, The 31st Annual Meeting, San Francisco,CA 2011,  Sup # 282. 10. Halevy-Shalem T, Michaelson-CohenR, CohenM, Gdansky E, Samueloff A. Induction of labor due to term anhydramnios versus oligohydramnios: same approach? Gestational Diabetes. American  Journal of  Obstetrics & Gynecology. Society  For Maternal – Fetal Medicine,  The 31st Annual Meeting, San Francisco,CA 2011,  Sup # 321. 11. Armon S, Tevet A, Rabinowitz R, Grisaru-Granovsky S, Samueloff A, Lebel E. Isolated club- Research Report 2013 206
    • foot: is it really isolated? American  Journal of  Obstetrics  & Gynecology. Society  For Ma- ternal – Fetal Medicine, The 31st Annual  Meeting, San Francisco, CA 2011,  Sup # 379. 12. Gdansky E, Reichman O, Grisaru-Granovsky S, Farkash R, Samueloff A. Women in labor with male fetuses has an increased risk for obstetric and neonatal complications. The 22nd European Congress of Obstetrics and Gynecology (EBCOG). The book of abstracts FC24.02 (p. 111), May 2012. 13. Grisaru-Granovsky S, Reichman B, Lerner-Geva L,  Boyko V, Hammerman C, Samueloff A, Schimmel MS. Mortality and morbidity among preterm growth restricted infants: a pop- ulation-based study . American  Journal of  Obstetrics& Gynecology. Society  For Mater- nal – Fetal Medicine, The 31st Annual   Meeting, San Francisco, CA 2011,  Sup # 454. 14. Armon S, Tevet A, Khatib F, Grisaru-Granovsky S,Samueloff A. Vacuum  extraction failure: can we predict it? American  Journal of  Obstetrics&  Gynecology. Society  For Maternal – Fetal Medicine, The 31st Annual  Meeting, San Francisco, CA 2011,  Sup # 683. 15. Bas-Lando M, Srebnik N , Farkash R, Samueloff A, Grisaru-Granovsky S. Induction at term for women with gestational diabetes mellitus (GDM):safe for the mother, questionable for the neonate. American  Journal of   Obstetrics& Gynecology. Society  For Maternal – Fetal Medicine, The 32nd  Annual Meeting, Dallas,TE 2012,  Sup # 265. 16. Avitan T, Rabinovitz R, Algor N, Kovo M, Screiber L, Schimmel MS, Samueloff A,    Grisaru- Granovsky S.Reduced Fetal Urine Production Rate   (FUPR) in Preterm Premature Rup- ture of Membranes (PPROM) predicts adverse neonatal outcome ) ANO). Society  For Ma- ternal – Fetal Medicine, The 32nd  Annual Meeting, Dallas,TE 2012,  Sup # 530. 17. Armon S, Tevet A, Avitan T, Rosen H, Grisaru- Granovsky S,  Samueloff A . Oxytocin use during trial of labor after cesarean delivery (TOLAC)- is it really that dangerous? Soci- ety  For Maternal – Fetal Medicine, The 32nd  Annual Meeting, Dallas,TE 2012, Sup # 664. 207 Obstetrics
    • Research Report 2013 208
    • Surgery and Anesthesia MauriceWohlSurgicalComplex VivienneWohlPediatricSurgicalCenter MansteinDepartmentofPlasticandMaxillofacialSurgery RuthandHymanMatloffDepartmentofCardioThoracicSurgery
    • T he Department of General Surgery headed by Profes- sor Petachia Reissman has 9 attending surgeons and 12 residents. With over 60 admission beds, the Unit performs more than 3000 operations annually. In addition, 400+ patients undergo ambulatory surgery and roughly 7000 patients are seen in the clinic every year. These figures make the Department the largest in Jerusalem and one of the most active in Israel. The Department of General Surgery is a cen- ter of excellence for the treatment of various breast patholo- gies, thyroid diseases and colorectal surgery. It is also the leader country- wide in minimally invasive surgery for vari- ous abdominal diseases and pathologies including Inflamma- tory Bowel Disease (IBD), neuro-endocrine and pancreatic tumors. Patients from all over Israel are referred to the Unit for surgical treatment. The Department also houses the Di- gestive Disease Institute which was inaugurated in 2011. Aside from its year- round clinical activities, the Department invests heavily in training the next generation of surgeons andphysicians.Thedepartmentmaintainsalarge6-yearresi- dency program. In addition, 5th year students affiliated with the Hebrew University School of Medicine rotate through the department during their internships. IBD and pelvic floor fo- rumsareconstantlybeingheldtodefineclinicaldecisionsand therapeutic plans. Other cooperative fields include the ‘IBD Mom’ project that deals with high risk pregnancy in IBD pa- tients, and basic science projects carried out in the live animal laboratory that opened in 2004. Department of General Surgery Research Report 2013 210
    • Areas of Research Activity The Department of General Surgery has always been active in surgical research and educa- tion. Since the merger of the surgical departments in 2003 under new leadership, research has become a major priority. The focal areas include Crohn’s disease, breast cancer, hemodialysis access and endocrine surgery. Currently there are several studies investigating laparoscopic surgery for complicated Crohn’s disease and total laparoscopic colectomy. Retrospective studies on laparoscopic splenectomy for massive splenomagaly, laparoscopic resection of pancreatic neuro-endocrine tumors and laparoscopic adrenalectomy for large adrenal tumors are currently under way. Future studies include the effect of hand-assisted laparoscopic surgery on stress response, and animal studies on the effect of different protective measures on port site metastasis in laparoscopic surgery forcancer.Aprospectiverandomizedstudyassessingtheoptimallengthofintravenousantibi- otics for the treatment of abdominal infections will be initiated in the near future. TheBreastHealthCenterisinvolvedinstudyingestrogenandprogesteronereceptorvs.tumor receptorstatusinlymphnodesinbreastcancerpatients,andthenon-identificationofsentinel lymphnodesasafunctionofaxillarytumorload.Alargescaleassessmentinvolvingareviewof 20,000 screened patients and their outcomes is also in progress to determine whether manual screening of women is effective in early detection of breast cancer. A comparative study ex- amines the characteristics of Arab breast cancer patients and stage of diagnosis vs. Jewish patients in Jerusalem. The recently opened Hemodialysis Access Unit has rapidly become a national referral cen- ter for the creation of hemodialysis access (areteriovenous fistula for purifying the patient’s blood in an artificial kidney machine). The head of the Unit, Dr. David Shemesh, has devel- oped techniques for keeping the access open far beyond its expected lifetime, preserving the patient’s “lifeline” and minimizing the number of operations these unfortunate patients have to undergo. We are a national referral center for endocrine surgery including adernalectomy, neuro-endocrine tumors of the pancreas and carcinoid of the intestine. The unit integrates advanced endoscopic techniques as well as laparoscopic intraopereative ultrasounds, together with advanced thyroid and parathyroid surgery. Representative Research The Breast Unit and Pathology Departments are collaborating with the Hebrew University on viral involvement in the pathogenesis of breast cancer. Recent work on DNA sequences in the mice model of breast tumor virus MMTV shows that 20-40% of premalignant and malignant 211 General Surgery
    • breast lesions express the virus. This viral signal peptide, known as p14, is localized in cells infected with MMTV viruses. Using novel antibodies against p14 developed by Prof. Hochman at the Hebrew University our research shows that the viral peptide occurs in human breast cancer. We are now determining the rate of virus-associated breast cancer in Israel. The next step is to correlate the occurrence of viral proteins with the morphological type and hormonal status of the breast cancer tissue, and determine whether the viral status is identical in prima- ry and recurrent tumors, and in primary and metastatic tumors. These results will determine whether the MMTV analog can serve as a target for testing potential immunotherapies in humans,orwhetherbreastcancerassociatedwithviralinfectionshouldbeviewedasadistinct disorder. PUBLICATIONS 1. Shemesh D, Goldin I, Zaghal I, Berelowitz D, Raveh D, Olsha O. Angioplasty with stent- graft vs. bare stent for recurrent cephalic arch stenosis in autogenous arteriovenous ac- cess for hemodialysis: a prospective randomized clinical trial. J Vasc Surg 2009; 50:472-4. 2. Ashkenazi I, Olsha O, Schechter WB, Kessel B, Khashan T, Ricardo A. Inadequate mass casualty knowledge base adversely affects treatment decisions by trauma care providers. Prehosp Disaster Med 2009; 24:342-7. 3. Wexner SD, Edden Y. NOTES/NOSE/NOSCAR/LATAS: What does it all mean? Tech Co- loproctol. 2009; 13(1):1-3. 4. Edden Y, Wexner SD. Therapeutic devices for fecal incontinence: dynamic graciloplasty, artificial bowel sphincter and sacral nerve stimulation. Expert Rev Med Devices. 2009; 6(3):307-12. 5. Lavi E, Rivkin L, Carmon M, Reissman P. Clozapine-induced colonic obstruction requiring surgical treatment. Isr Med Assoc J 2009; 11(6):385-6. 6. Sachar DB, Lemmer E, Ibrahim C, Edden Y, Ullman T, Ciardulo J, Roth E, Greenstein AJ, Bauer JJ. Recurrence patterns after first resection for stricturing or penetrating Crohn’s disease. Inflamm Bowel Dis 2009;15(7):1071-5. 7. Kolodkin-Gal D, Edden Y, Hartshtark Z, Ilan L, Khalaileh A, Pikarsky AJ. Pikarsky E, Rabkin Research Report 2013 212
    • SD, Panet A, Zamir G. Herpes simplex virus delivery to orthotopic rectal carcinoma results in an efficient and selective anti-tumor effect. Gene Ther 2009; 16(7):905-15. 8. Einav S, Schecter WP, Matot, I, Horn JK, Hersch M, Reissman P, Spira RM. Case managers in multiple casualty incidents. Ann Surg 2009; 249(3):496-501. 9. Edden Y, Shih SS, Wexner SD. Solitary rectal ulcer syndrome and stercoral ulcers. Gastroenterol Clin North Am 2009; 38(3):541-5. 10. Edden Y, Wexner SD. The role of alvimopan in reducing morbidity rates and patient recovery times after laparoscopic and bowel resection surgery. US Gastroent and Hep 2009; 16-17. 11. Chertin B, Benjamin S, Reissman P, Khefets A, Prat O, Shenfeld O, Tsivian A.Transperitoneal laparoscopic radical nephrectomy is an effective procedure for large (more than 7cm) renal masses. Surg Laparosc Endosc Percutan Tech 2009;19(4):353-5. 12. Gavish L, Rubinstein C, Bulut A, Berlatzky Y, Beeri R, Gilon D, Gavish L, Harlev M, Reiss- man P, Gertz SD. Low-level laser irradiation inhibits abdominal aortic aneurysm progres- sion in apolipoprotein E- deficient mice. Cardiovasc Res 2009; 83(4):785-92. 13. Dagan A, Reissman P. Giant secretory villous adenoma of the rectum and sigmoid pre- senting as McKittrick-Wheelock syndrome. Int J Colorectal Dis 2010; 25(7):909-10. 14. Wexner SD, Hull T, Edden Y, Coller JA, Devroede G, McCallum R, Chan M, Ayscue JM, Shobeiri AS, Margolin D, England M, Kaufman H, Snape WJ, Mutlu E, Chua H, Pettit P, Nagle D, Madoff RD, Lerew DR, Mellgren A. Infection rates in a large investigational trial of sacral nerve stimulation for fecal incontinence. J Gastrointest Surg 2010;14(7):1081-9. 15. Olsha O, Korotchenko I, Dagan A. Prosthetic mesh repair for incarcerated recurrent ingui- nal hernia containing an acutely inflamed appendix. Internet J Surg 2010; 22:2. 16. Shemesh D, Goldin I, Olsha O. Banding between dialysis puncture sites to treat severe ischemic steal syndrome in low flow autogenous arteriovenous access. J Vasc Surg 2010; 52:495-8. 17. Lowery M, Shah MA, Smyth E, Epstein A, Segal A, Rosengarten O, Isac- son R, Drukker L, Keinan A, Rachkiman M, Reissman P, Gabizon A, Kelsen D, O’Reilly EM. A 67-Year-Old Woman with BRCA 1 Mutation Associated with 213 General Surgery
    • Pancreatic Adenocarcinoma. J Gastrointest Cancer 2011; 42(3):160-4. 18. Armon Y, Reissman P. Laparoscopic Management of Crohn’s Disease. Harefuah Journal of the Israeli Medical Society 2011. 19. Olsha O, Shemesh D, Carmon M, Sibirsky O, Abu Dalo R, Rivkin L, Ashkenazi I. Resection margins in ultrasound guided breast conserving surgery. Ann Surg Oncol 2011; 18:447- 52.   20. Olsha O, Lijovetzky G, Grenader T. Localized bullous pemphigoid following radiotherapy for breast cancer. Breast J 2011; 17:204-205. 21. Ashkenazi I, Olsha O, Kessel B, Krausz MM, Alfici R. Uncommon acquired fistulae involv- ing the digestive system: summary of data. Eur J Trauma Emerg Surg 2011; 37:259-267. 22. Pinto RA. Ruiz D. Edden Y. Weiss EG. Nogueras JJ. Wexner SD. How reliable is laparo- scopic colorectal surgery compared with laparotomy for octogenarians? Surg Endosc 2011;25(8):2692-8. 23. Shemesh D, Goldin I, Zaghal I, Berlowitz D, Verstandig A, Olsha O. Stent graft treatment for hemodialysis access aneurysms. J Vasc Surg 2011; 54:1088-94. 24. Olsha O, Carmon M. Re: Axillary Staging in the Neoadjuvant Setting. Ann Surg Oncol 2011; 18 Suppl 3:S276. 25. AshkenaziI, Ohana A, Azaria B, Gelfer A, Nave C, Deutch Z, Gens I, Fadlon M, Dahan Y, Rapaport L, Kishkinov D, Bar A, Tal-Or E, Vaknin N, Blumenfeld A, Kesse B, Alfici R, Olsha O, Michaelson M. 26. Edden Y, Wexner SD, Berho M. The use of molecular markers as a method to predict the response to neoadjuvant therapy for advanced stage rectal adenocarcinoma. Colorectal Dis 2012; 14(5):555-61. 27. Olsha O, Ashkenazy I. Minimizing length of hospital stay for patients undergoing unilateral mastectomy: a subtle balance between costs and quality of care. Eur J Surg Oncol 2012; 38:4-5. 28. Olsha O, Goldin I, Man V, Carmon M, Shemesh D. Ipsilateral hemodialysis access after axillary dissection for breast cancer. Breast Cancer Res Treat 2012; 132(3):1173-6. Research Report 2013 214
    • 29. Olsha O, Ashkenazy I. Minimizing length of hospital stay for patients undergoing unilateral mastectomy: a subtle balance between costs and quality of care. Eur J Surg Oncol 2012; 38:4-5. 30. Ashkenazi I, Ohana A, Azaria B, Gelfer A, Nave C, Deutch Z, Gens I, Fadlon M, Dahan Y, Rapaport L, Kishkinov D, Bar A, Tal-Or E, Vaknin N, Blumenfeld A, Kesse B, Alfici R, Olsha O, Michaelson M. Assessment of hospital disaster plans for conventional mass casualty incidents following terrorist explosions using a live exercise based upon real data of actual patients. Eur J Trauma Emerg Surg 2012; 38:113-7. 31. Olsha O, Goldin I, Man V, Carmon M, Shemesh D. Ipsilateral hemodialysis access after axillary dissection for breast cancer. Breast Cancer Res Treat 2012; 132:1173-6. 32. Schwartz S, Edden Y, Orkin B, Erlichman M. Perforated peptic ulcer in an adolescent girl. Pediatr Emerg Care 2012; 28(7):709-11. 33. Drukker L, Edden Y, Reissman P. Adenocarcinoma of the small bowel in a patient with oc- clusive Crohn’s disease. World J Gastrointest Oncol 2012; 4(7):184-6. 34. Argov S, Levandovsky O, Kerner H, Ben-Yizhak O, Klinehouse U, Reissman P. Alertness is its own reward: adult type Hirschprung’s disease – clinical description of the first two cases in Israel. Harefuah 2012; 151(1):18-19. 215 General Surgery
    • T he Department of Cardiothoracic Surgery is nearing 20 years of activity at Shaare Zedek. The Department is headed by Prof. Dani Bitran, and includes four se- nior surgeons: Dr. Shuli Silberman, Dr. Daniel Fink, Dr. Ofer Merin and Dr. Maher Deeb. The clinical spectrum covers all facets of adult cardiac surgery: coronary disease, valve repair and replacement, and aortic surgery. In addition, there is a dedicated unit for thoracic surgery which works in close con- tact with the Pulmonology, Oncology and Radiology Departments. Since its inception, the Department has been active in clinical research. A patient data base was established from the start, so that all patient data are prospectively collected and ana- lyzed. This valuable tool has enabled a high level of quality control as well as a portal for research. The Department is af- filiated with the Hebrew University of Jerusalem and makes teaching a priority. Numerous students attend a clinical ro- tation in cardiothoracic surgery every year, and a number of them also do their MD thesis in this field. Students rate the Department annually as one of the best internships. Areas of Research Activity Despite the heavy burden of daily clinical obligations, re- search has always received special attention and covers myo- cardial preservation, coronary disease, valvular disease and aortic surgery. Department of Cardiothoracic Surgery Research Report 2013 216
    • In particular, the unit has done extensive research on valve surgery. One study examined the hemodynamic performance of different valve types in the aortic position, and found non- stented valves the most beneficial. Other studies examined various interventions on the mi- tral valve. One study showed mitral valve repair had better outcomes than replacement in prolonging life in patients with poor cardiac function. The introduction of trans-catheter valve implantation has prompted studies comparing it to surgically implanted valves. Other areas of research deal with quality control. Established scoring systems such as Eu- roscore, assess the risk for patients about to undergo heart surgery. However these scoring systems do not accurately predict outcomes for any particular center, especially when dealing with high risk patients. The Euroscore was modified to more accurately predict outcomes in cardiac surgery at Shaare Zedek. This model was presented at the annual meeting of the Israel Cardiac Society, and received the young investigator’s award. The Unit is currently researching outcomes of patients in the intensive care unit. Complete follow-ups have shown that even patients at high risk, requiring prolonged a stay in the intensive care unit, have good chances of long term survival. Representative Research One research project in particular examined the hemodynamic profile of prosthetic valves in the aortic position. Prosthetic valves ideally should function as close as possible to nor- mal native valves. By default, prosthetic valves are not as efficient as a normal valve, due to the inherent structure of the prosthesis. Most biological prostheses are mounted on a stent which enables simple, problem free implantation. However the presence of the supporting rigid stent impairs hemodynamic performance. Although not always apparent at rest, dur- ing exercise with higher blood flows, there may be impedance to the blood flow through the valve. Non-stented valves are available for implantation, but the surgical technique is much more demanding and many surgeons avoid their use. This study examined the behavior of different valve types in the aortic position, and found that non-stented valves behave just like normal native valves under exercise conditions, while the more common stent mounted valves develop some degree of impedance to flow as measured by trans-valvular gradients during exercise. Similar behavior was seen in the more recently available catheter based valves, which may prove to be hemodynamically superior to conventional stented valves. 217 Cardiothoracic Surgery
    • In the figure, the solid lines show gradients of normal and non-stented values; dotted lines show gradients in conventional mechanical valves. Stentless valveStent mounted valve Research Report 2013 218
    • Publications 1. Merin O, Ilan M, Fink D, Oren A, Deeb M, Bitran D, Silberman S. Permanent pacemaker implantation following cardiac surgery: indications and long term follow up. PACE 2009; 32:7-12. 2. Silberman S, Klutstein M, Sabag T, Oren A, Fink D, Merin O, Bitran D. Repair of ischemic mitral regurgitation: Comparison between flexible and rigid annuloplasty rings. Ann Thorac Surg 2009; 87:1721-27. 3. Wiener-Well Y, Fink D, Schlesinger Y, Raveh D, Rudenski B, Yinnon AM. Q Fe- ver Endocarditis; not always expected. Clin Microbiol Infect. June 2009. 4. Korn-Lubetzki I, Steiner I, Oren A, Tauber R, Steiner-Birmanns B, Bitran D. The Possible Risk for Strokes Complicating Cardiac Surgery in Patients with Intraoperative Hypother- mia. Cerebrovasc Dis 2010;30:602-605. 5. Korn-Lubetzki I, Oren A, Tauber R, Bitran D, Steiner-Birmanns B. No Symptomatic Intra- cerebral Hemorrhage after Cardiac Surgery: A 14-Year Retrospective Study. Eur Neurol 2010;64:351-354. 6. Merin O, Ash N, Levy G, Schwaber MJ, Kreiss Y. The Israeli field hospital in Haiti--ethical dilemmas in early disaster response. N England J Med 2010; 362 (11):e38. 7. Kriess Y, Merin O, Peleg K, Levy G, Vinker S, Sagi R, Abargel A, Bartal C, Lin G, Bar A, Bar-On E, Schwaber MJ, Ash N. Early Disaster Response in Haiti: The Israeli Field Hospital Experience. Ann Intern Med. 2010 July; 153(1): 45-8. 8. Lin G, Lavon H, Gelfond R, Abargel A, Merin O. Hard times call for creative solutions: Medical improvisations at the Israel Defense Forces field hospital in Haiti. Am J Disaster Med 2010; 5(3):188-92. 9. Levy G, Blumberg N, Kreiss Y, Ash N, Merin O. Application of information technology within a field hospital deployment following the January 2010 Haiti earthquake disaster. J Am Med Inform Assoc 2010; 17(6):626-30.  10. Merin O, Blumberg N. Clinical and Ethical dilemmas of medical support during a mass casualty event. JIMM 2010; 7(2):79-81. 219 Cardiothoracic Surgery
    • 11. Blumberg N, Merin O. Integration of active duty and reserve medical personnel at the IDF- MC field hospital in Haiti. JIMM 2010; 7(2): 87-89. 12. Miskin IN, Nir-Paz R, Block C, Merin O, Burshtein S, Pirogovsky S, Halperin T, Schwartz D, Schwaber MJ.Antimicrobial therapy for wound infections after catastrophic earthquakes. N England J Med 2010; 363(26):2571-3. 13. Lebel E, Blumberg H, Gil A, Merin O, Bar-On E. External fixator frames as interim damage control for limb injuries: experience in the 2010 Haiti earthquake. J Trauma 2011;71(6):E128-E131. 14. Bar-On E, Lebel E, Kreiss Y, Merin O, Benedict S, Gill A, Lee E, Pirotsky A, Shirov T, Blumberg N. Orthopaedic management in a mega mass casualty situation. The Israel Defense Forces Field Hospital in Haiti following the January 2010 earthquake. Injury 2011; 42(10):1053-9. 15. Silberman S, Eldar O, Oren A, Tauber R, Fink D, Klutstein MW, Bitran D. Surgery for Ischemic Mitral Regurgitation: Should the Valve be Repaired? The Journal of Heart Valve Disease 2011;20:129-135. 16. Shavit L, Tauber R, Lifschitz M, Bitran D, Slotki I, Fink D. Influence of minimal changes in preoperative renal function on outcomes of cardiac surgery. Kidney & Blood Pressure Research 2012;35:400-406. 17. Merin O, Miskin IN, Lin G, Wiser I, Kreiss Y. Triage in Mass-Casualty Events: The Haitian Experience. Prehosp Disaster Med 2012 (27):1-5. 18. 11.Yitzhak A, Sagi R, Bader T, Assa A, Farfel A, Merin O,   Kreiss Y. Pediatric ventilation in a disaster - clinical and ethical decision making. Crit Care Med 2012; 40(2):603-7. 19. 12. Merin O, Blumberg N, Raveh D, Bar A, Nishizawa M, Cohen-Marom O. Global re- sponsibility in mass casualty events: the Israeli experience in Japan. Am J Disaster Med 2012;7(1):61-4. Research Report 2013 220
    • PUBLISHED Abstracts 1. Silberman S, Eldar O, Oren A, Tauber R, Merin O, Fink D, Deeb M, Bitran D. Surgery for ischemic mitral regurgitation: should the valve be repaired? In: Progress in Coronary Artery Disease, proceedings of the 8th international congress on coronary artery disease. Medi- mond publishing, 2009; 471-476, Lewis, Ongen, Flugelman, Halon editors. 2. Silberman S, Eldar O, Oren A, Tauber R, Merin O, Fink D, Deeb M, Bitran D. Surgery for ischemic mitral regurgitation: should the valve be repaired? Cardiology, 2010;115:251-293. 3. Silberman S, Ofir S, Butnaru A, Tauber R, Bitran D, Merin O. In: Coronary Artery Disease Update: from Prevention to Intervention. 9th International Congress on Coronary Artery Disease. Medimond Publishing, 2011; 449-454, Lewis, Flugelman, Halon editors. 4. Silberman S, Abu Akr F, Bitran D, Fink D, Almagor Y, Balkin J, Tauber R, Merin O. Severe aortic stenosis in high risk patients: Comparison between TAVI and surgical AVR. Cardiol- ogy 2012;121:137-8. 221 Cardiothoracic Surgery
    • T he Department of Plastic Surgery is one of the oldest such departments in Israel. The Department was founded by Professor Ben-Hur, is currently headed by Dr. David Mendes, and is staffed by five additional attending specialist surgeons: Dr. Yitzhak Tuchman, Dr. Natan Sternberg, Dr. Anat El-Ami, Dr. Rami Binenboym, and Dr. Yoav Gronovich. Dr. Michael Abrishami performs Moh’s sur- gery under the auspices of the Department. Plastic and Reconstructive Surgery is one of the broadest fields in medicine. The specialty is based on technique, and thus the plastic surgeon consults patients in every depart- ment of the hospital. The specialty of Plastic and Recon- structive Surgery is comprised of the fields of reconstructive plastic surgery and esthetic or cosmetic plastic surgery. The distinction between these two disciplines is characterized by significant overlap, as reconstructive surgical procedures de- mand a high esthetic sensibility on the part of the surgeon. The department surgeons have many years of experience in both reconstructive as well as esthetic plastic surgery. The clinical activity of the Department includes treatment of breast reconstruction following treatment for breast cancer. This involves immediate breast reconstruction, breast recon- struction with tissue expanders and implants, autologous breast reconstruction with myocutaneous flaps (e.g. TRAM, Latissimus dorsi). The Department also deals with benign skin lesions, skin cancer, including basal cell carcinoma, squa- mous cell carcinoma, and malignant melanoma and performs Department of Plastic Surgery Research Report 2013 222
    • Moh’s surgery for skin cancer, as well as surgery for soft tissue trauma. It also is specialized in reconstructive surgery following burns (treatment of scars, post-traumatic deformities such as contractures) and birth defects and congenital anomalies (cleft lip and palate, treatment of various craniofacial anomalies and syndromes, facial clefts, ear reconstruction for microtia). The Department physicians participate in the activity of the prenatal clinic, providing pre- natal consultation in the ultrasound suite in cases of cleft or craniofacial deformities. The Department is also involved in the reconstruction of post-traumatic facial deformities or facial fractures, facial and nasal reconstruction following surgery for cancer or fractures, corrective surgery of patients born with cleft lip or palate, body contouring following massive weight loss (e.g. bariatric surgery) , lower extremity reconstruction, and wound care for dif- ficult and chronic wounds, pressure ulcers, diabetic ulcers. The Department physicians also carry out esthetic surgery including plastic surgery of the eyelids, brow and face lifts, nose and ear plastic surgery, breast augmentation, reduction and lifts, body contouring (liposuction, abdominoplasty, thigh lift), fat grafting, laser surgery for treatment of vascular lesions and scars, soft tissue filler injection, and Botox treatments. Es- thetic surgery is performed through the Harmonia Esthetic Center. Areas of Research Activity Research activity in the Department of Plastic Surgery is focused on breast reconstruction and the effects of radiation therapy in breast reconstruction, autologous fat grafting, tissue expan- sion, new treatment for burns, as well as broader issues in medical ethics. PUBLICATIONS 1. Zilinsky I, Liran A, Winkler E, Orenstein A, Mendes D. How to avoid eyebrow pull-up in forehead reconstruction. Dermatol Surg 2008;34(2):240-2. Epub 2007 Dec 17. 2. Sokolov M, Mendes D, Ophir D. Madelung’s Disease. IMAJ 2010; 12. 3. Gronovich Y, Tuchman I, Binenboym R, Eizenman N, Elami A, Sternberg N, Go- lan J. Osmotic Tissue Expander - Experience in Ten Consecutive Pediatric Cases. Plastic & Reconstructive Surgery 2010;126:83-84. 223 Plastic Surgery
    • 4. Gronovich Y, Tuchman I, Binenboym R, Eizenman N, Golan J. Reconstruction with Osmotic Tissue Expander in Pediatric Patients. Plastic & Reconstructive Surgery 2012; 129(5):863-865. Research Report 2013 224
    • T he Department of Anesthesiology, Perioperative Medi- cineandPainTreatmentdirectedbyProf.YaacovGozal is staffed by 23 specialists and 12 residents. The Department is made up of a talented group of physicians dedicated to providing the very best anesthesia and pain medicine care for our patients. We focus on excellence in all areas of our practice, clinical care, research and education. In the operating room, our department provides anesthesia for more than 22,000 operations a year from general surgery to cardiovascular surgery, urology, gynecology, orthopedic sur- gery, ear-nose-throat and neck surgery, plastic surgery, eye surgery to pediatric surgery. The obstetric anesthesia service in Shaare Zedek provides clinical support for 13.5 thousand pre- and peripartum analgesic and anesthetic interventions annually. Although our main activity is in the operating room, anesthe- sia enables the provision of other services such as obstetrics, gastroenterology, radiology, angiography, cardiology, cath. lab, etc. In addition, we operate a pain clinic, specialized in interventional pain treatment. The Regional Anesthesia and Pain Management Unit concentrates its efforts on provid- ing a variety of anesthetic and analgesic modalities for better intra- and postoperative pain treatment and prophylaxis of chronic pain syndromes. The priority is given to the develop- ment of innovative interventions such as ultrasound guided peripheral nerve blocks. Department of Anesthesiology - Perioperative Medicine and Pain Treatment 225 Anesthesiology
    • Areas of Research Activity The unit conducts clinical research, in particular in the field of peripartum treatment of pa- tients with uncommon diseases, high rates of cesarean sections, grand and grand-grand multi- parity, and anesthetic approaches to high risk obstetric patients. These studies are conducted in close collaboration with medical centers in Israel and abroad . Research in pain management is presented regularly at international symposia such as the European Society of Regional Anesthesia (ESRA), the NWAC World Anesthesia Congress, and the European Anesthesiology Congress (Euroanaesthesia) The unit is also researching myocardial pre- and postconditioning. In collaboration with re- searchers outside of Israel, these studies examine the mechanisms of ischemic and anesthesia- induced myocardial pre- and postconditioning. Publications   1. Ioscovich A, Mirochnitchenko E, Halpern S, Samueloff A, Grisaru-Granovsky S, Gozal Y,  Einav S. Perioperative anaesthetic management of high-order repeat caesarean section: audit of practice in a university-affiliated medical centre. Int J Obst Anesth 2009; 18:314- 319. 2. Ioscovich AM, Goldszmidt E, Fadeev AV, Grisaru-Granovsky S, Halpern SH. Peripartum anesthetic management of patients with aortic valve stenosis: a retrospective study and literature review. Int J Obstet Anesth. 2009;18:379-86. 3. Grisaru-Granovsky S, Rabinowitz R, Ioscovich A, Elstein D, Schimmel MS. Congenital diaphragmatic hernia: review of the literature in reflection of unresolved dilemmas. Acta Paediatr. 2009; 98:1874-81. 4. Grisaru-Granovsky S, Hersch M,  Ioscovich A. Fetal outcomes of critically ill pregnant women. Crit Care Med. 2009 Mar; 37:1180-1 5. Halpern SH, Soliman A, Yee J, Angle P, Ioscovich A. Conversion of epidural labour an- algesia to anaesthesia for Caesarean section: a prospective study of the incidence and determinants of failure. Br J Anaesth. 2009 ;102:240-3. Research Report 2013 226
    • 6. Raphael J, Gozal Y, Navot N, Zuo Z. Hyperglycemia inhibits anesthetic-induced post- conditioning in the rabbit heart via modulation of phosphatidylinositol-3-kinase/Akt and endothelial nitric oxide   synthase signaling. J Cardiovasc Pharmacol 2010; 55:348-357. 7. Gozal Y, Nussmeier NA et al for the Multicenter Study of Perioperative Ischemia Research Group. Predictive value of the National Institute of Health stroke scale and the mini-mental state examination for neurologic outcome after coronary artery bypass graft surgery. J Cardiothorac Vasc Surg 2010; 139:901-912. 8. Marks A, Greenstein J, Berger MT, Shapiro J, Elstein D, Ioscovich A. Peripartum an- esthesia in grand-grand multiparous women (≥ 10 births). Health Care Women Int. 2010; 31:938-45. 9. Weiniger CF, Ivri S, Ioscovich A, Grimberg L, Evron S, Ginosar Y. Obstetric anesthesia units in Israel: a national questionnaire-based survey. Int J Obstet Anesth. 2010; 19:410-6. 10. Ioscovich A, Barth D, Samueloff A, Grisaru-Granovsky S, Halpern S. Anesthetic management of a patient with cleidocranial dysplasia undergoing various obstetric procedures. Int J Obstet Anesth. 2010; 19:106-8. 11. Gozal Y, Möhnle P et al for the Multicenter Study of Perioperative Ischemia Research Group. Postoperative red blood cell transfusion and morbid outcome in uncomplicated cardiac surgery patients. Intensive Care Med 2011; 37:97-109.  12. Gozal Y, Szekely A et al for the Multicenter Study of Perioperative Ischemia Research Group. Impact of hyperglycemia on perioperative mortality after coronary artery bypass graft surgery. J Thorac Cardiovasc Surg 2011; 142:430-437. 13. Gozal Y, Szekely A et al for the Multicenter Study of Perioperative Ischemia Research Group. A multinational study of the influence of health-related quality of life on in-hospital outcome after coronary artery bypass graft surgery. Am Heart J 2011; 161:1179-1185. 14. Gozal Y, Schwann NM et al for the Multicenter Study of Perioperative Ischemia Research Group. Lack of effectiveness of the pulmonary artery catheter in cardiac surgery. Anesth Analg 2011; 113:994-1002.  15. Michaelson-Cohen R, Elstein D, Ioscovich A, Armon S, Schimmel MS, But- naru A, Samueloff A, Grisaru-Granovsky S. Severe heart disease complicat- ing pregnancy does not preclude a favourable pregnancy outcome: 15 years’ 227 Anesthesiology
    • experience in a single centre. J Obstet Gynaecol. 2011;31:597-602. 16. Ioscovich A, Fadeev A, Rivilis A, Elstein D. Requests and usage of epidural analgesia in grand-grand multiparous and similar-aged women with lesser parity: prospective obser- vational study. J Perinat Med. 2011; 39:697-700. 17. Ioscovich A, Shen O, Sichel JY, Lajos Y, Orkin D, Bromiker R, Briskin A. Remifentanil-ni- troglycerin combination as an anesthetic support for ex utero intrapartum treatment (EXIT) procedure. J Clin Anesth. 2011; 23:142-4. 18. Ioscovich A, Grisaru-Granovsky S, Halpern S, Shapiro Y. Peripartum anesthetic manage- ment of a patient with brittle cornea syndrome. Arch Gynecol Obstet. 2011; 283 Suppl 1:49-52. 19. Lebel E, Ioscovich A, Itzchaki M, Zimran A, Elstein D. Hip arthroplasty in patients with Gaucher disease. Blood Cells Mol Dis. 2011 Jan 15; 46:60-5. 20. Fadeev A, Ioscovitch A, Rivlis A, Grisaru-Granovsky S, Samueloff A, Schimmel MS, El- stein D. Prospective study of maternal and neonatal outcome in great-grand multiparous women (≥10 births) and in aged-matched women with lesser parity. Arch Gynecol Obstet. 2011 Oct; 284:799-805. 21. Drenger B, Fontes ML, Miao Y, Mathew JP, Gozal Y, Aronson S, Dietzel C, Mangano DT  Patterns of Use of Perioperative ACE Inhibitors in CABG Surgery with Cardiopulmonary Bypass: Effects on In-Hospital Morbidity and Mortality Circulation 2012; 126:261-269. 22. Kocherov S, Prat D, Koulikov D, Ioscovich A, Shenfeld OZ, Farkas A, Chertin B. Outcome of hypospadias repair in toilet-trained children and adolescents. Pediatr Surg Int. 2012 Apr; 28:429-33. 23. Tevet A, Grisaru-Granovsky S, Samueloff A, Ioscovich A. Peripartum use of cell salvage: a university practice audit and literature review. Arch Gynecol Obstet. 2012; 285:281-4. 24. Raikhinshtein Y., Orkin D. An unusual appearance of the three brachial plexus cords on the ultrasound view in the infraclavicular fossa. Europ J Anaesth. 2012 June 29: 120-1. 25. Kocherov S, Arafeh WA, Zeldin A, Ostrovsky IA, Ioscovich A, Farkas A, Chertin B. Down- gradingofhigh-gradevesicoureteralrefluxisareliableoptioninthetreatmentofchildrenwith grade IV‒V reflux accompanied by breakthrough infections. J Pediatr Urol. 2012 (in press) Research Report 2013 228
    • 26. Lev A, Korn-Lubezki I, Steiner-Birmanns B, Samueloff A, Gozal Y, Ioscovich A. Prolonged propriospinal myoclonus following spinal anesthesia for cesarean section: case report and literature review. Arch Gynecol Obstet. 2012 (in press). 27. Zigelman CZ, Edelstein PM. Aortic valve stenosis. Anesthesiology Clin 2009; 27:519-532 28. Gindes L, Weissmann-Brenner A, Zajicek M, Weisz B, Shrim A, Tzadikevitch Geffen K, Mendes D, Kuint J, Berkenstet M, Achiron, R.3-Dimensional Ultrasound Demonstration of the Fetal Palate – In High Risk Patients: The accuracy of Prenatal Visualization. Prenat Diagn 2013;33(5):436-41. 229 Anesthesiology
    • T he Department of Otolaryngology-Head and Neck SurgeryisdirectedbyProfessorJean-YvesSichelandis staffed by 3 full time specialists (J.Y. Sichel, R. Perez and U. Peleg), 6 part time specialists (P. Friedman, I. Hoch- man, Y. Nazarian, A. Edri, D. Attal, Y. Gurwich) and 5 resi- dents. The Otology Unit in the Department which focuses on ear surgery and diseases is directed by Dr. Ronen Perez. The department specializes in the full spectrum of diseases and surgical procedures including complex ear, head and neck and sinus surgery as well as routine procedures such as tonsil- lectomy, adenoidectomy and ventilation tube insertion. The Departmentisamajorreferralcenterforallthesubspecialties of otolaryngology and particularly for otology and head and neck surgery. The Department also specializes in pediatric otolaryngology and deals with complex cases such as severe infection, lymphatic malformations or airway abnormalities in children. Cochlear implants are devices that restore hearing to infants born with hearing defects and adults who lost their hearing at a later stage. The Department’s cochlear implant program wasfounded4yearsagoanddealswithimplantationsincom- plex cases including revision surgery, surgery in children with ear anomalies and loss of hearing as a sequel to meningitis. The program is directed by Dr. Perez and Prof. Sichel, and Ms. Salomon who is in charge of the audiology section. The pro- gram works in close collaboration with Dr. Thomas J. Roland, Chief of Otolaryngology at New York University. In addition, Department of Otolaryngology - Head and Neck Surgery Research Report 2013 230
    • the department is the one of the leading centers in branchial anomalies and fistulas and per- forms many of the most complex cases in the country. Areas of Research Activity The Department sets a high priority on clinical and basic research. Clinical research topics include a clinical trial for the treatment of tinnitus (described in detail below), exploration of new treatment modalities for branchial anomalies, intratympanic steroids for treatment of sudden sensorineural hearing loss, comparison of new surgical techniques for tonsillectomy, and obstructive sleep apnea in pregnancy. Basic research is conducted extensively by members of the Department in collaboration with the Department of Physiology at the Hebrew University Medical School to which the depart- ment is affiliated. The two main areas of basic research involve studies on : a) an innovative theory for the mechanism of inner ear hearing; b) a new mode of hearing conduction (soft tissue conduction) which supplements the two known modes of conduction (air and bone conduction). Representative Research Tinnitus(ringingintheears)isaverycommoncomplaint,affecting10-20%oftheadultpopu- lation and in its severe form, about 1-3% of the population. To date, there is no effective treat- ment and specifically no treatment directed at reducing the loudness of the phantom noise. In this clinical study, conducted in collaboration with an Israeli startup company, the effect of electro-stimulation in the middle ear on patients with severe tinnitus was assessed. The pa- tients were electrically stimulated with a needle electrode through the ear drum into the inner wall of the middle ear three times every other day. Half of the patients experienced significant improvement in their tinnitus symptoms. The study is a preliminary stage for the develop- ment of a miniature implant located in the middle ear for the treatment of tinnitus. 231 Otolaryngology
    • Publications 1. Perez R, Adelman C, Sichel JY, Sohmer H. Occluding the round window causes no change in threshold but an increase in hearing loss following noise exposure. J Basic Clin Physiol Pharmacol 2009; 20: 159-172. 2. Perez R, deAlmeida J, Nedzelski JM, Chen J. Variations in the Carhart Notch and Over- closure Following Laser Assisted Stapedotomy in Otosclerosis. Otol Neurotol; 30:1033-6. 3. Tamir S, Schwartz Y, Peleg U, Perez R, Sichel JY. Acute mastoiditis in children: is com- puted tomography always necessary? Ann Otol Rhinol Laryngol 2009;118: 565-569. 4. Gavriel H, Kessler A, Perez R, Eviatar E. Evaluation and treatment of facial palsy in acute versus chronic otitis media- Could prognosis be altered? J Int Adv Otol 2009; 5: 370-375. 5. Sichel JY, Perez R, Adelman C, Sohmer H. Can a passive mechanical traveling wave be generated in superior canal dehiscense syndrome, cochlear implant, otosclerosis or atre- sia of windows? J Int Adv Otol 2009;5: 246-252. 6. Even-Or E, Sichel JY, Perez R, Minouni FB. Pediatric and adult otorhinolaryngological pub- lications: Trend over 15 years (1993-2007). Int J Pediatr Otorhinolaryngol 2009;73:1737- 41. 7. Cohen D, Raveh D, Peleg U, Nazarian Y, Perez R. Ventilation and clearance of the middle ear. J Laryngol Otol 2009;123:1314-20. 8. Ginsburg I, Koren E, Horani A, Mahamid M, Doron S, Muhanna N, Amer J, Safadi R. Amelioration of hepatic fibrosis via Padma Hepaten is associated with altered NKT lym- phocytes. Clinical & Experimental Immunology 2009;157:155-64. 9.  Sohmer H, Sichel JY, Perez R, Adelman C. When an air-bone gap is not a sign of a middle ear conductive hearing loss. Ear Hear 2009; 30: 147-148. 10. Perez R, Adelman C, Sichel JY, Freeman S, Sohmer H. The effect of noise on ears with a hole in the vestibule. Acta Oto-Laryngologic 2010; 30:659-64. 11. Adelman C, Perez R, Nazarian Y, Weinberger J, Freeman S, Sohmer HFurosemide Before Noise Exposure Can Protect the Ear. Ann Otol Rhinol Laryngol 2010; 119: 342-9. Research Report 2013 232
    • 12. Tamir S, Shwartz Y, Peleg U, Shaul C, Perez R, Sichel JY. Shifting trends: mastoiditis from a surgical to a medical disease. Am J Otolaryngol 2010; 31:467-71. 13. Perez R, Adelman C, Sohmer H. Several Mechanical Manipulations of the Wall of the Inner Ear Do Not Affect Air and Bone Conduction Auditory Thresholds. Ann Otol Rhinol Laryngol 2011;120: 66-70. 14. Muhanna N, Tair LA, Doron S, Amer J, Azzeh M, Mahamid M, Friedman S, Safadi R. Ame- lioration of hepatic fibrosis by NK cell activation Gut 2011; 60: 90-98. 15. Gavriel H, Eviatar E, Perez R, Sohmer Colchicine Prolongs Patency of Myringotomy in an Animal Model. Int J Pediatr Otorhinolaryngol 2011; 75: 554-557. 16. Perez R, Adelman C, Sohmer H. Bone conduction activation through soft tissues following complete immobilization of the ossicular chain, stapes footplate and round window. Hear- ing Research 2011; 280: 82-85. 17. de Jong M, Perez R, Adelman C , Chordekar S, Rubin M, Kriksunov L, Sohmer, H. Ex- perimental confirmation that vibrations at soft tissue conduction sites induce hearing by way of a new mode of auditory stimulation. Journal of Basic and Clinical Physiology and Pharmacology 2011; 22: 55-58. 18. de Jong M, Perez R, Adelman C, Sohmer, H. Experimental exploration of the Soft Tissue Conduction pathway from skin stimulation site to inner ear. Ann Otol Rhinol Laryngol 2012; 121: 625-628 19. Peleg U, Cohen D, Perez R. Ventilation and clearance of the middle ear and the Eustachian tube function. Otorinolaringologia 2012;62:131-140. 20. Perez R, Nazarian Y, Sohmer H, Sichel JY. The Effect of Topically Applied Antimycotic Agents on Inner Ear Vestibular and Cochlear Function. Laryngoscope 2012. In Press 21. Megged O, Assous MV, Miskin H, Peleg U, Schlesinger Y. Neurologic manifestations of Fusobacterium infections in children. European Journal of Pediatrics 2012. In Press. 22. Shaul C, Rodriguez M, Schwarz Y, Muahnna N, Peleg U, Sichel JY. Treatment and Long Term Follow-up of Peritonsillar Abscess. 2012. Submitted. 23. Muahnna N, Sichel JY, Shwartz Y, Peleg U, Shaul H, Perez R. Intratympanic steroid treat- 233 Otolaryngology
    • ment for sudden sensorineural hearing loss. 2012. Submitted. 24. Muahnna N, Doron S, Amer J, Safadi R, Sichel JY. The immune interplay between thyroid papillary carcinoma & hepatic fibrosis 2012. Submitted. 25. Adelman C, Sohmer H, Perez R. Mutual masking in the cochlea by bone conduction stim- ulation and by soft tissue conduction stimulation in an animal model. 2012. Submitted. 26. Sichel JY, Shaul C, Schwarz Y, Peleg U, Perez R. Second Branchial Sinus. A Rare Entity. Description and Treatment.2012. Submitted. 27. Adelman C, Perez R, Sohmer H. Effect on auditory threshold of air and water pockets in the pathway between soft tissue conduction sites and the cochlea. 2012. Submitted. 28. Perez R, Adelman C, Sohmer H. Auditory responses to stimulation at soft tissue sites be- fore and after fixation of mobile components of the middle ear. 2012 Submitted. 29. Perez R, Vardi M, Shaul C, Muhanna N, Kileny PR, Sichel JY. Electro-stimulation to the promontory for treatment of tinnitus 2012 Submitted. Research Report 2013 234
    • T he Department of Pediatric Urology, directed by Prof. Boris Chertin, has a long history of clinical and aca- demic excellence. The Pediatric Urology Unit was cre- ated as part of the Department of Urology in 1978 by Prof. Amicur Farkas, who is considered the pioneer of modern pe- diatric urology in Israel. The unit was an integral part of the Department of Urology until 2010 when it became an auton- omous department, and the only one of its kind in Israel. The Department serves as a major referral center for the treat- ment of congenital anomalies, challenging endocrine cases, and disorders of sexual differentiation that require surgical intervention on the external genitals. The Department spe- cializes in minimal interventions and laparoscopic surgery. The first endoscopic correction of vesicoureteral reflux in Is- rael was performed in 1988. Of the many comprehensive ser- vices provided by the Department a number deserve special mention. The Center for Dysfunctional Voiding is staffed by pediatric urologists, pediatric gastroenterologists, pediatric psychiatrists and urotherapists and treats children with dif- ferent aspects of voiding disturbances. Today most renal sur- gery, plastic surgery in congenital pathology, and advanced laparoscopic procedures are performed on a daily basis. Over 200 patients with various endocrine pathologies from all over Israel have undergone genital reconstruction in the department. Areas of Research Activity Clinical research is a major focus of activity in the Depart- Department of Pediatric Urology 235 Pediatric Urology
    • ment of Pediatric Urology and involves a number of national and international projects. The main research orientation is congenital anomalies of the urogenital tract, such as congenital obstructions,andvesicoureteralreflux(backflowofurinefromtheurinarybladdertowardthe kidneys). Since renal dilatation is one of the frequent findings in prenatal ultrasounds, clini- cal recommendations on ways to deal with these children following delivery is of paramount importance. More than 1000 children with congenital renal dilatations have been followed in the outpatient department over the last 30 years. The results serve as guidelines for the treatment of children with congenital obstruction in the international urological community. Vesicoureteral reflux is another area of research interest. Up to 60% of children with urinary tract infections have vesicoureteral reflux and often require surgical intervention. For years opensurgerytoconnecttheuretertothebladderandcreationofanantirefluxmechanismwas the main type of surgical intervention. Although open surgery enjoyed a high success rate it requiredprolongedhospitalization,accompaniedbyseverepostoperative discomfortandpain andleftsurgicalscarring.Nowwiththeadventofendoscopiccorrectionweareabletoperform a 10 minute outpatient procedure, with success rates that are practically equivalent to open surgery, cause no pain and leave no scarring. Prof. Chertin is the chief investigator on an international multicenter study including more than 10 centers from Europe, Asia and South America on the use of Vantris, a new tissue aug- menting substance for the treatment of reflux. Representative Research Endoscopic correction of reflux has become a first line of the treatment and has replaced open surgery in the majority of the centers worldwide. The Department of Pediatric Urology is a leading center in the development of this technology. Over the last 3 years we have utilized a new tissue augmenting substance for the treatment of vesicoureteral reflux called Vantris. Vantris is a non- biodegradable substance thaqt provides a high short term success rate and long term durability. More than 110 children (over 165 refluxing kidneys) have undergone endoscopic correction of reflux with Vantris. The overall success rate with a single injection of Vantris is 94% of reflux resolution ( Figure 1) with no recurrence during follow ups. Vantris thus appears to be an ideal material for the endoscopic correction of vesicoureteral reflux. Research Report 2013 236
    • OutcomeEndoscopic injection 153 (92.7%)Correction after 1st injection 7 (4.2 %)Correction after 2nd injection 5 (3.1%)Downgrading of VUR PUBLICATIONS 1. Bibliography Chertin B, Natsheh A, Fridmans A D, Shenfeld OZ, Farkas A. Renal scarring and UTI following successful endoscopic correction of vesicoureteral reflux. J Urol 2009; 182(4 Suppl):1703-1706. 2. Chertin B, Pollack A, Koulikov D, Rabinowitz R, Shen O, Hain D, Hadas-Halpren I, Farkas A. Does renal function remain stable after puberty in children with antenatal hydronephro- sis who showed improvement in renal function following pyeloplasty? J Urol 2009; 182(4 Suppl):1845-1848. 3. Spitz I, Chertin B, Fridmans A, Farkas A, Belanger A, Hartman H, Labrie F. Partial andro- gen suppression consequent to increased secretion of adrenal androgens in a patient with prostate cancer treated with long-acting GnRH agonists. Prostatic Cancer and Prostatic Diseases 2009; 12(1):100-103. 4. Chertin B, Benjamin S, Reisssman P, Kheifets A, Shenfeld OZ, Prat O, Sidi A, Tsivian A. Transperitoneal Laparoscopic Radical Nephrectomy Is an Effective Procedure for Large (More than 7 cm) Renal Masses. Surgical Laparoscopy, Endoscopy and Percutaneous Technique 2009; 19(4):353-355. 5. Chertin B, Golomb J, Mor Y Surgical and non surgical treatment options for pediatric neurogenic bladder. Future medicine 2009; 6(2):151-155. 6. Golomb J, Chertin B, Mor Y. Anatomy of urinary continence and neurogenic incontinence. Future medicine 2009; 6(2):157-164. 237 Pediatric Urology
    • 7. Chertin B. Editorial comments on the paper entitled Primary Ablation of Posterior Urethral Valves in Low Birth Weight Neonates by a Visually Guided Fogarty Embolectomy Catheter J Urol 2009; 181(5): 2289. 8. Chertin B, Koucherov S. Long Term results of endoscopic treatment of VUR using a differ- ent tissue augmenting substances. J Ped Urol 2010; 6(3):251-256. 9. Eldar-Geva T, Liberty G, Chertin B, Fridmans A, Farkas A, Margalioth EJ, Spitz IM. Rela- tionships between FSH, inhibin B, anti-Mullerian hormone, and testosterone during long- term treatment with the GnRH-agonist histrelin in patients with prostate cancer. Eur J Endocrinol 2010; 162(1):177-181. 10. Natsheh A. Shenfeld, OZ. Farkas, A. Chertin B. Endoscopic treatment of vesicoureteral reflux in adult population. Can we teach our adult urology colleagues? J Ped Urol 2010; 6(6):600-604 11. Hirsch HJ, Lahlou N, Gillis D, Strich D , Rosenberg-Hagen B, Chertin B I Farkas A, Hart- man H Spitz IM .(2010) Free {alpha}-Subunit Is the Most Sensitive Marker of Gonado- tropin Recovery after Treatment of Central Precocious Puberty with the Histrelin Implant; 95(6):2841- 2844. 12. Chertin B, Arafeh WA, Zeldin A, Kocherov S. Preliminary data on endoscopic treatment of vesicoureteric reflux with polyacrylate polyalcohol copolymer (Vantris(®)): Surgical out- come following single injection. J Pediatric Urology 2011; 7(6):654-657. 13. Chertin B, Prosolovich K, Aharon S, Nativ O, Halachmi S Surgical Reimplantation for the Correction of Vesicoureteral Reflux following Failed Endoscopic Injection. Adv Urol 2011; 352716. 14. Chertin B, Kocherov S, Chertin L, Natsheh A, Farkas A, Shenfeld OZ, Halachmi S. Endo- scopic bulking materials for the treatment of vesicoureteral reflux: a review of our 20 years of experience and review of the literature. Adv Urol 2011; 309626. 15. Kocherov S, Lev G, Shenfeld OZ, Chertin B Laparoscopic single site surgery: initial ex- perience and description of techniques in the pediatric population. J Urol 2011; 186(4 Suppl):1653-1657. 16. Chertin B, Prat D, Shenfeld OZ. The outcome of the hypospadias surgery in the adult life. Open Access Journal of Urology 2011. Research Report 2013 238
    • 17. Chertin B. Editorial comments J Urol 2011; 186(4 Suppl):1703-1704. 18. Chertin B. Editorial comment Urology, 2012; 79(6):1354. 19. Gnessin E, Chertin L, Chertin B. Current management of paediatric Nephrolithiasis. PSI 2012; 28(7):659-665. 20. Prat D, Natasha A, Polak A, Koulikov D, Prat D, Zilberman M, Abu Arafeh W, Moriel E Z, Shenfeld O Z, Mor Y, Farkas A, Chertin B Surgical outcome of different types of primary hypospadias repair over 3 decades in single center. Urology 2012; 79(6):1350-1354. 21. Kocherov S, Prat D, Koulikov D, Ioscovich A, Shenfeld OZ, Farkas A, Chertin B. Outcome of hypospadias repair in toilet trained children and adolescents. PSI 2012; 28(4):429-433. 22. Kocherov S, Arafeh WA, Zeldin A, Ostrovsky IA, Ioscovich A, Farkas A, Chertin B. Down- grading of high-grade vesicoureteral reflux is a reliable Option in the treatment of children with grade IV‒V reflux accompanied by breakthrough infections. J of Pediatric Urology. In press. 23. Chertin L, Mimouni F B, Chertin B. Pediatric and adult urological publications: trend over the last 15 years (1996-2010). Current Urology. In press. 239 Pediatric Urology
    • T he Department of Orthopedic Surgery, headed by Pro- fessor Amos Peyser, operates 8 specific services cover- ing the full spectrum of surgical and medical orthopedics. The joint-reconstruction service treats degenerative and post-traumatic joint problems, especially knee and hip re- placement. The Unit also specializes in the treatment of in- fected arthroplasties. The spine surgery service treats acute problems (disc hernia, fractures, etc.) as well as long- standing and developmental diseases (scoliosis and kyphosis, where innovative corrective surgery techniques are used) and degenerative problems of the spine (degenerative spinal stenosis). The hand surgery service is specialized in congenital hand and forearm deformities, and uses advanced vascularized bone grafting techniques for reconstructive hand surgery. The foot and ankle surgery service deals with a large array of foot trauma, bunion and total-toe arthroplasty surgeries, and runs a diabetic-foot service. The sports and arthroscopy service covers all type of joint in- juries, arthroscopic treatment of the shoulder, hip, knee and ankle, cruciate ligament reconstruction, cartilage repair and other advanced procedures. Department of Orthopedic Surgery Research Report 2013 240
    • The pediatric-orthopedic service covers traumatic injuries in children, reconstructive surgery for the pelvis and hip-joint, knee deformity, and clubfoot. Thetumorservicetreatsbenignandmalignanttumorsofboneandsofttissue,metastaticbone disease, and CT-guided tumor ablation The trauma service is the busiest. The Department performs all types of fracture-reconstruction surgery using the most advanced techniques and equipment. It specializes in fractures of the knee, wrist and the ankle, as well as all types of geriatric-trauma cases. The Department has a program for orthopedic surgery residency, which currently hosts 10 residents. Two surgeons have taken part in humanitarian missions abroad. Prof. Peyser served as a visit- ing orthopedic-surgeon in the city of Gondar in Ethiopia in 2012. Dr. Lebel served as a pedi- atric orthopedic surgeon with the Israeli military mission to Haiti after the 2010 earthquake. Areas of Research Activity Research is conducted in several areas: • CT-guided tumor surgery: improved methods of tumor ablation, improved rates of cure, shorter procedure and radiation-exposure times, and greater diagnostic accuracy. • Neurological aspects of patients with Legg-Calve-Perthes disease that affects the head of the femur in children. • Advances in the treatment of congenital clubfoot (serial casting techniques, limited surgical procedures, etc.) • Advanced techniques for knee ligament repair or replacement: a new concept of cruciate ligament repair (using a new synthetic material) is being evaluated. • Outcome of proximal humerus fracture surgery, and survival rates of 90+patients who sus- tain hip fractures. • Skeletal problems in Gaucher’s disease (a storage disease). • Evaluation of outcomes of orthopedic interventions, and quality of life of patients before and after interventions. 241 Orthopedic Surgery
    • PUBLICATIONS 1. Peyser API, Applbaum YPI, Simanovsky N C, Safran O C, Lamdan RPI. CT guided radio frequency ablation of pediatric osteoid osteoma utilizing a water-cooled tip. Annals of Surgical Oncology 2009; 16(10):2856. 2. Lebel E, Elstein D, Zimran A, Itzchaki M. Cementless total hip arthroplasties in Gaucher disease: long-term follow-up. Am J Orthop 2009; 38(3):130-2. 3. Safran OPI, Goldman V C, Applbaum Y C, Milgrom C C, Bloom R C. Peyser A C, Kis- selgoff D C.Posttraumatic Painful Hip Sonography as a Screening Test for Occult Hip Fractures. J Ultrasound Med 2009; 28(11):1447-52. 4. Elstein D, Gellman A, Altarescu G, Abrahamov A, Hadas-Halpern I, Phillips M, Margalit M, Lebel E, Itzchaki M, Zimran A. Disease severity in sibling pairs with type 1 Gaucher disease. J Inherit Metab Dis 2010; 33(1):79-83. 5. Lebel E, Karasik M. Massive allograft of the tibia for a child with McCune-Albright syn- drome: case presentation and surgical intervention. J Pediatr Orthop B 2010; 19(2):177- 80. 6. Lebel E, Ioscovich A, Itzchaki M, Zimran A, Elstein D. Hip arthroplasty in patients with Gaucher disease. Blood Cells Mol Dis 2011;46(1):60-5. 7. Atesok KI, Alman B A., Schemitsch E H, Peyser A B, Mankin H J. Osteoid Osteoma and Osteoblastoma. Journal of American Academy of Orthopedic Surgeons. J Am Acad Or- thop Surg 2011;19(11):678-89. 8. Lebel E, Karasik M, Shahroor-Karni S, Peyser A. Necrotizing upper limb fasciitis in a new- born: an uncommon life-threatening event. J Pediatr Orthop B 2011. 9. Bar-On E, Lebel E, Kreiss Y, Merin O, Benedict S, Gill A, Lee E, Pirotsky A, Shirov T, Blumberg N. Orthopaedic management in a mega mass casualty situation. The Israel Defense Forces Field Hospital in Haiti following the January 2010 earthquake. Injury 2011;42(10):1053-9. 10. Lebel E, Blumberg N, Gill A, Merin O, Gelfond R, Bar-On E. External fixator frames as in- terim damage control for limb injuries: experience in the 2010 Haiti earthquake. J Trauma 2011; 71(6):E128-31. Research Report 2013 242
    • 11. Samuels N, Elstein D, Lebel E, Zimran A, Oberbaum M. Acupuncture for symptoms of Gaucher disease. Complement Ther Med 2012;20(3):131-4. 12. Schroeder JE, Liebergall M, Raz I, Egleston R, Ben Sussan G, Peyser A, Eldor R. Benefits of a simple glycaemic protocol in an orthopaedic surgery ward: a randomized prospective study. Diabetes Metab Res Rev.2012;28(1):71-5 13. Lebel E, Karasik M, Bernstein-Weyel M, Mishukov Y, Peyser A. Achilles tenotomy as an office procedure: safety and efficacy as part of the Ponseti serial casting protocol for club- foot. J Pediatr Orthop.2012;32(4):412-5. 14. Ben-Chetrit E, Amir G, Lebel E, Hasharoni A. A compression fracture as the sole mani- festation of Gaucher disease. Blood Cells Mol Dis.2011;46(1):73-4. Epub 2010 Jul 14. PubMed PMID: 20634112. 15. Lebel E, Karasik M, Bernstein-Weyel M, Mishukov Y, Peyser A. Achilles tenotomy as an office procedure: safety and efficacy as part of the Ponseti serial casting protocol for club- foot. J Pediatr. Orthop 2012;32(4):412-5. 243 Orthopedic Surgery
    • Research Report 2013 244
    • Imaging, Emergency, ICU and Pathology JosephLevine(ForscheimFoundation)CatheterizationLaboratoryUnit JeanandJulaGoldwurmImagingCenter WilliamandFredaFingerhutInstituteofRadiology Dr.MoniqueC.KatzInterventionalRadiologyUnit RachelandSelimBeninDepartmentofPathology WeinstockDepartment ofEmergencyMedicine GeraldLeighTraumaandResuscitationCenter MarjorieShermanOBEDiagnosticImagingUnit
    • T he 9-bed General Intensive Care Unit (ICU) headed by Dr. Moshe Hersch and assisted by Dr. Sharon Einav-Bromiker and Dr. Lev Shmulovich provides ex- cellent multidisciplinary medical care to critically ill adults with a myriad of surgical and non-surgical problems. Patients are admitted from the operating room, the Department of Emergency Medicine and from the wards. The Unit is equipped with state-of-the-art equipment and has recently updated both its monitors and mechanical ventilators. Pa- tients are given individual 24-hour, specialized care provided by doctors and nurses who are graduates of formal intensive care training. The ICU personnel are not only highly qualified professionals, but also highly sensitive to human integrity and needs. The staff also includes trained respiratory thera- pists, physiotherapists and dieticians who are all part of the large ICU team.   TheIntensiveCareUnitisacademicallyaffiliatedwiththeHe- brew University of Jerusalem. It is engaged in teaching medi- cal students in the Internal Medicine, Surgical and Anesthe- siology wards. We also instruct many students from all over the world who come for an elective extra exposure to the art of Critical Care Medicine. Areas of Research Activity The ICU has a research laboratory where Dr. Hersch and his colleaguesarestudyingthepathophysiologyandtreatmentof sepsis. The research is conducted in a rat model, and recent Intensive Care Unit (ICU) Research Report 2013 246
    • work focuses on mitochondrial injury (the sub-cellular organs for energy production). The re- sults show that mitochondrial oxygen consumption of rats with sepsis caused by CLP –cecal ligature and puncture - surgery is reflected in three variables (Oxygen/min/mg, RCI-radiocon- trast induced kidney failure and Phosphate/Oxygen ratio), all of which can account for de- creased energy production. Future research will concentrate on mitochondrial therapy. Publications 1. Einav S, Hersch M, Steinberg A. Online featured comment to “Care of an Unresponsive Patient with a Poor Prognosis” by Slutsky AS and Hudson LD (Comment ID: 1AEBEA) New Eng J Med 2009;360:527-531. 2. Hersch MPI, Einav SC, Izbicki GC. Accuracy and ease of use of a novel electronic urine output monitoring device compared to standard manual urinometer in the intensive care unit. J Crit Care Dec 2009;24(4):629.e13-7. 3. Hadary API, Schecter WC, Embon OMC, Einav SPI. Impact of military conflict on a civilian receiving hospital in a war zone. Ann Surg 2009; 249(3):502-9. 4. Einav SPI, Schecter WPPI, Matot IC, Horn JKC,Hersch MC, Reissman PC, Spira RMPI. Case managers in mass casualty incidents. Ann Surg 2009; 249(3):496-501. 0 20 40 60 80 100 120 140 160 O2/min/mg RCI P/O % OXYGEN CONSUMPTION SHAM CLP 6h CLP 12h CLP 24h 247 Intensive Care
    • 5. Ioscovich API, Mirochnitchenko EC, Halpern SC, Samueloff AC, Grisaru-Granovsky SC, Gozal YC, Einav S. Perioperative anaesthetic management of high order repeat casesar- ian section: audit of practice in a university-affiliated medical centre. Int J Obst Anesth 2009;18(4):314-9 6. Weiniger CFPI, Yaghmour HC, Nadjari MC, Einav SC, Elchalal UC, Ginosar YC, Matot IPI. Walking reduces the post-void residual volume in parturients with epidural analgesia for labor: a randomized-controlled study. Acta Anaesthesiol Scand 2009;53(5):665-72. 7. Grisaru-Granovsky S, Hersch M, Ioscovich A. Fetal outcomes of critically ill pregnant women. Crit Care Med 2009; 37(3):1180-1. 8. Hersch M, Raveh D, Izbicki G. Effect of intravenous propacetamol on blood pressure in febrile critically ill patients. Alternative Viewpoints, Author’s Reply. Pharmacotherapy 2009; 29(3):140e-141e. 9. Chermesh I, Azoulay O, Alpert E, Anbar R, Berner I, Barak N, Chochrin E, Cohen M E,Fargan R, Freund H, Ganon M, Hadad S, Hersch M, Kairi M, Korzetsm A, Lang A, Levi Y, Niv E, Poraz I, Theilla M, Vaisman N, Singer P. Parenteral nutrition – Guidelines of the Israeli Society for Clinical Nutrition e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 2009;4: e270-e288. 10. Helviz Y, Einav S, Biderman P, Medalion B, Hersch M .The timing to initiate ECMO in H1N1 ARDS. Crit Care Med 2010; 38(12):2427-8. 11. Meerkin D, Marom H, Cohen-Biton O, Einav S. (2010) Three-dimensional vessel analyses provide more accurate length estimations than the gold standard QCA. J Interv Cardiol. Apr; 23(2):152-9. 12. Martin-Loeches I, Lisboa T, Rhodes A, Moreno RP, Silva E, Sprung C, Chiche JD, Bara- hona D, Villabon M, Balasini C, Pearse RM, Matos R, Rello J,Hersch M. Use of early corticosteroid therapy on ICU admission in patients affected by severe pandemic (H1N1) v influenza A infection. Intensive Care Med 2010; 37(2):272-83. 13. Cohen J, Kagan I, Hershcovici R, Bursztein S, Makhoul N, Samkohvalov A, Hersch M, Einav S, Berezovsky V, Jakobson DJ, Singer P. Red blood cell transfusions-are we nar- rowing the evidence-practice gap? An observational study in 5 Israeli intensive care units. Journal of Critical Care 2011; 26(1):106. Research Report 2013 248
    • 14. Sela HY, Weiniger CF, Hersch M, Smueloff A, Laufer N, Einav S. The pregnant motor ve- hicle accident casualty: adherence with basic workup and admission guidelines. Ann Surg 2011; 254(2):346-52. 15. Oberbaum M, Samuels N,Shapira R, Roe C, Einav S, Hersch M. Effect of Traumeel S on cytokine profile in a Cecal Ligation and Puncture (CLP) sepsis model in rats. J Altern Complement Med 2011; 17(10):909-913. 16. Einav S, Alon G, Kaufman N, Braunstein R, Carmel S ,Varon J, Hersch M. To resuscitate or not to resuscitate: a logistic regression analysis of physician-related variables influencing the decision. Emergency Medicine Journal 2011; eprint. 17. Valentin A, Ferdinande P. ESICM Working Group on Quality Improvement- Hersch M. Recommendations on basic requirements for intensive care units: structural and organi- zational aspects. 2011; 37(10):1575-87. 18. Furer V, Hersch M, Silvetzki N, Breuer GS, Zevin S. Nicotiana glauca (Tree Tobacco) Intox- ication-Two Cases in One Family. J Med Toxicol 2011;7(1):47-51. 19. Helviz Y, Hersch M, Shmuelevitz L, Atrash J, Einav S. Symmetrical peripheral gangrene complicating septic shock. Am J Med 2011;124(3):215-7. 20. Einav S, Bromiker R, Weiniger CF, Matot I. Mathematical modeling for prediction of survival from resuscitation based on computerized continuous capnography: proof of concept Acad Emerg Med 2011;18(5):468-75. 21. Dreiher J, Almog Y, Sprung C, Codish S, Klein M, Einav S, Bar-Lavie Y, Singer P, Nimrod A, Sachs J, Talmor D, Friger M, Greenberg D, Olsfanger D, Hersch M, Novack V. Temporal trends in patient characteristics and survival of intensive care admissions with sepsis: A multicenter analysis. Crit Care Med 2012; 40(3):855-860. 22. Einav S., Grisaru- Granovski S, Varon J. Maternal Resuscitation and Perimortem Cesarian Delivery. In: Anesthesia and the Fetus (Ginosar Y, Halpern S, Reynolds F, Weiner CP Eds.) 2012. Wiley Blackwell. 23. Einav S, Kaufmann N, Algur N, Kark JD. Modeling serum biomarkers S100B and NSE as predictors of a poor neurological outcome following cardiac arrest: an aid to clinical decision-making. J Am Coll Cardiol 2012;24;60(4):304-11 (accompanied by an editorial and also published as a Cardiosource article of special interest). 249 Intensive Care
    • 24. DeKeyser Ganz F, Kaufman N, Israel S, Einav S. Resuscitation in General Medical Wards: Who Decides? J Clin Nurse 2012; Accepted. 25. Einav S, Sela HY. Maternal cardiac arrest and Perimortem Cesarean Delivery: evidence or expert based? Resuscitation 2012;May 18. [Epub ahead of print] 26. Predictors of mortality of mechanically ventilated patients in Internal Medicine wards Hersch M,Izbicky G, Dahan D, Breuer G, Nesher , Einav S. 2012; Accepted to JCC, pending revision. 27. Einav S., Sela H, Weinieger CF. Trauma and the pregnant woman. In: Anesthesiology Clin- ics. 2012. Elsevier Inc. In press. 28. Meerkin D. Interventional Cardiology and the Transradial Approach in Israel. J Invasive Cardiol 2012. 29. Weitzman T, Meerkin D. Primary percutaneous coronary intervention: devices to prevent no-reflow phenomenon. Interv Cardiol 2012. Research Report 2013 250
    • T he Imaging Department is directed by Prof. Irith Hadas-Halpern and includes the pediatric radiology unit directed by Dr. Fisher, the interventional radiol- ogy unit directed by Dr. Verstandig, the MRI unit directed by Dr. Appelbaum, a CT unit directed by Dr. Bereolowich, a mammography unit currently under construction that will be directed by Dr. Strano, and an ultrasound unit directed by Irith Hadas. Thereare16seniorphysicians intheDepartment:Dr.Naama Bogot, Thoracic Imaging specialist, Dr. Yaacov Appelbaum, Muskolo-skeletal Imaging specialist, Dr.Yoram Segev, Neu- roimaging specialist, Dr. Verstandig, Interventional Radi- ology specialist, Dr. Strano, Breast Imaging specialist, Dr. Berelowich, Head & Neck Imaging specialist, Dr. Fisher, Pe- diatric Radiology Imaging specialist, Dr. Hadas, Ultrasound specialist, Dr. Zaghal, Dr. Nikitin, Dr. Yofeh, Dr. Balkum, Dr. Shamieh,Dr.Arazi-KleinmanDr.GechtmanandProf.Bar-Ziv. There also 9 residents in the department. The department is equipped with the most advanced equipment including state of the art CT (dual source), MRI and a modern angiography suite. The Department provides services covering X-ray, fluo- roscopy including GI examinations, VCUG, salpingography and ERCP, ultrasound, and a range of CT examinations in- cluding Cardiac CT, CT enterography, Dual Energy CT, and low dose CT especially for children. The MRI unit provides MR arthrography, Breast MR, Prostate MR, Cardiac MR, Body, MSK, Neuro MRI and pediatric MRI with sedation. Imaging Department 251 Imaging
    • Many invasive procedures are done in the Department, such as image guided biopsy, image guided drainage and image guided tumor ablations of different organs. Today, over 600 such procedures are performed annually under ultrasound or CT guidance. The Imaging Depart- ment is active in teaching medical students from the Hebrew University and involves most of the radiologists. Areas of Research Activity The Department is involved mainly in clinical research. Studies have been conducted on the useandeffectivenessofnon-radiationexaminationssuchasMRIinsteadofCTincertainclini- cal problems. A comparison was made of suspected pulmonary embolism and suspected acute appendicitis. A study was also conducted to examine possible causes of fetal death, including bone abnor- malities and fractures using CT. This study is complementary to prenatal US (in many cases) and can be used in lieu of a conventional post-mortem particularly when no permission for P.M. is obtained. PUBLICATIONS 1. Grenader T, Goldberg A, Hadas-Halpern I and Gabizon A. Long-term response to pegylat- ed liposomal doxorubicin in patients with metastatic soft tissue sarcomas. Anti-Cancer Drugs 2009; 20:15-20. 2. Peyser A, Applbaum Y, Simanovsky N, Safran O, Lamdan R. CT-guided radiofrequency ablation of pediatric osteoid osteoma utilizing a water-cooled tip. Ann Surg Oncol 2009; 16(10):2856-61. 3. Schonberg T, O’Doherty JP, Joel D, Inzelberg R, Segev Y, Daw ND. Selective impair- ment of prediction error signaling in human dorsolateral but not ventral striatum in Par- kinson’s disease patients: evidence from a model-based fMRI study. Neuroimage 2010; ;49(1):772-81. Epub 2009 Aug 12. 4. Safran O, Goldman V, Applbaum Y, Milgrom C, Bloom R, Peyser A, Kisselgoff D. Post- traumatic painful hip: sonography as a screening test for occult hip fractures. J Ultrasound Med 2009; 28(11):1447-52. Research Report 2013 252
    • 5. Willems PW, Willinsky RA, Segev Y, Agid R.Aggressive intracranial dural arteriovenous fistula presenting with cerebrospinal fluid rhinorrhea: case report.Neurosurgery 2009; 65(6):E1208-9; discussion E1209. 6. Ben-Chetrit E, Applbaum YH. Synovial osteochondromatosis of the hip. J Rheumatol 2010;37(3):668-9.7. 7. Hadas-Halpern I, Deeb M, Abrahamov A, Zimran A, Elstein D. Gaucher disease: spectrum of sonographic findings in the liver. J Ultrasound Med 2010. 8. Applbaum Y.H., Imaging of the Skeleton and the Joints in Chronic Kidney Disease. In: Olgaard K., Silver J., Salusky I.B., (Ed.) The Spectrum of Mineral and Bone Disorders in Chronic Kidney Disease: Second Edition. 2010. Oxford University Press Oxford, Chapter 12, pp. 199-216. 9. Esayag Y, Nikitin I, Bar-Ziv J, Cytter R, Hadas-Halpern I, Zalut T, Yinnon AM. Diagnostic value of chest radiographs in bedridden patients suspected of having pneumonia. Am J Med 2010. 10. Elstein D, Gellman A, Altarescu G, Abrahamov A, Hadas-Halpern I, Phillips M, Margalit M, Lebel E, Itzchaki M, Zimran. Disease severity in sibling pairs with type 1 Gaucher disease. J Inherit Metab Dis 2010. 11. Carmeli G, Artzi Z, Kozlovsky A, Segev Y, Landsberg R. Antral computerized tomography pre-operativeevaluation:relationshipbetweenmucosalthickeningandmaxillarysinusfunc- tion.Clin Oral Implants Res. 2011;22(1):78-82. doi: 10.1111/j.1600-0501.2010.01986.x. Epub 2010 Oct 13. 12. Lawrence Y, Pokroy R, Berelowitz D, Aharoni D, Hain D, Breuer GS. Splenic infarc- tion: An Update on William Osler’s observations. Israel Medical Association Journal 2010; 12:362-365. 13. Elstein D, Tiomkin M, Hadas-Halpern I, Zimran A. Organ volume by computed tomog- raphy correlates with longitudinal axis on ultrasound in patients with Gaucher disease. Ultrasound Q 2011. 14. Samuels N, Applbaum YH, Esayag Y. Paraneoplastic necrotizing myopathy and dermato- myositis in a patient with rectosigmoid carcinoma Rheumatol Int 2011. 253 Imaging
    • 15. Joseph I, Shahroor S, Fisher DC, Goldberg S, Picard E. Conservative treatment of a large, post-infections. Pneumatocoele, Pediatrics International 2011; 53.(6). 16. Schwartz SB, Fisher D, Reinus C, Shahroor S.Infectious Aortitis. A Rare Cause of Chest Pain in a Child. Pediatric Emergency Care 2011; 27(7) . 17. Segel R, Anikster Y, Zevin S, Steinberg A, Gahl WA, Fisher D, Staretz-Chacham O, Zimran A, Altarescu G. A safety trial of high dose glyceryl triacetate for Canavan disease. Molecu- lar Genetics and Metabolism 2011; 103:203-206. 18. Shihada R, Brand R, Segev Y, Luntz M. Spontaneous Regression of Petrous Apex Cho- lesterol Granuloma. Otol Neurotol 2011. 19. Cohen Y, Gekhtman D, Strano S. Mammography- sonography concordance AJR Am J Roentgenol, 2011;197(3):765. 20. Rave O, Assous MV, Hashkes PJ, Lebel E, Hadas-Halpern I, Megged O. Pantoea agglo- merans Foreign Body Induced Septic Arthritis. ; 2012. 21. Elstein D, Altarescu G, Maayan H, Phillips M, Abrahamov A, Hadas-Halpern I, Tiomkin M, Zimran A. Booster-effect with velaglucerase alfa in patients with Gaucher disease switched from long-term imiglucerase therapy: early Access Program results from Jerusalem. Blood Cells Mol Dis 2012. 22. Milgrom C, Constantini N, Milgrom Y, Lavi D, Appelbaum Y, Novack V, Finestone A. The effect of high versus low loading on bone strength in middle life. Bone 2012; 50(4):865-9. 23. Emanuel N, Rosenfeld Y, Cohen O, Applbaum YH, Segal D, Barenholz Y. A lipid-and-poly- mer-based novel local drug delivery system--BonyPid™: from physicochemical aspects to therapy of bacterially infected bones. J Control Release 2012;160(2):353-61. Research Report 2013 254
    • T he Ultrasound Unit of the Obstetrics and Gynecology Department is directed by Dr. Ron Rabinowitz and is staffed by five specialists: Dr. Ori Chen, Prof. Dan Turner, Dr. Tamar Shalem, Dr. Boris Latinsky and Dr. Eial Mazaki. The intense activity in the gyneco-oncology depart- ment and high risk pregnancy unit, together with the busiest delivery ward in Israel results in an extremely active ultra- sound unit revealing a wide variety of OBGYN– related prob- lems. Our unit collaborates with the infertility unit (mostly IVF) in ovarian antral follicle counts, a project led by Prof. Eldar-Geva, Director of the Shaare Zedek Pre-Implantation Genetic Diagnosis (PGD) project which helps to tailor treat- ment protocol per patient and predict the success of each cy- cle of treatment. Due to the rapidly increasing activity of the Genetics Depart- ment, we perform a growing number of invasive procedures including amniocentesis, placental biopsy (CVS) and fetal blood sampling for genetic analysis and fetal infections. Re- cently, we established the first “Anomaly Clinic” in Jerusa- lem (one of a very few in Israel) where patients diagnosed in community ultrasound units as having fetal structural anom- alies are referred for further evaluation. These women are examined in our unit by at least two ultrasound specialists. The case is then reviewed by a panel of advising specialists including geneticists, pediatric orthopedics, nephrologists, urologists, and cardiologists. The summary is presented to the couple together with recommendations for further evalu- ation and management. Ultrasound Unit 255 Ultrasound
    • All of these activities also contribute to the enhancement of our academic environment. Areas of Research Activity The Unit works to integrate ultrasound into routine use in labor and delivery. Studies conduct- ed by Dr. Rabinowitz showed the value of the use of ultrasound for evaluation of fetal position in the birth canal. Ultrasound studies were shown to be superior to manual examination for the position of the fetal head, thus enabling early decisions regarding the need for mechanical delivery, such as vacuum extraction. The Unit collaborates with Professor Eldar-Geva, Director of the Reproductive Endocrinol- ogy and Genetic Unit to determine whether there is a correlation between antral follicle count (AFC) and fertility. This team has shown that in women under 38, the AFC or basal anti-mullerian hormone (AMH) and stimulated inhibin B predict ovarian response to IVF, and AMH was shown to be superior in predicting pregnancy. In a separate study in young women with Prader-Willi syndrome, at the special outpatient clinic under the direction of Prof. Varda Gross-Tsur, it was found that unique follicular stage-specific insult leading to primary ovarian dysfunction is a major component of hypogonadism. Representative Research Our interest in making the ultrasound examination an integral component in the evaluation of the pregnant patient right before birth, during and following delivery prompted the unit to study the use of a trans - abdominal ultrasound examination before uterine exploration as a predictor of retained placental fragments following vaginal deliveries. Examination was followed by surgical-pathological confirmation of our findings. Ultrasound examination was performed in the labor suite right after delivery, in patients suspected of having retained pla- cental tissue. We were blind to the placental appearance. Ultrasound was found to be accurate in the de- tection of women with high suspicion of retained placental tissue. Results of this study have enabled us to avoid unnecessary invasive surgical procedures. Research Report 2013 256
    • Retained Placental Tissue Ultrasound PUBLICATIONS 1. Eldar-Geva T, Hirsch HJ, Rabinowitz R, Benarroch F, Rubinstein O, Gross-Tsur V. Primary ovarian dysfunction contributes to the hypogonadism in women with Prader-Willi Syn- drome. Horm Res 2009; 72(3):153-159. 2. Chertin B, Pollack A, Koulikov D, Rabinowitz R, Shen O, Hain D, Hadas-Halpren I, Farkas A. Does renal function remain stable after puberty in children with prenatal hydronephrosis and improved renal function after pyeloplasty? J Urol 2009;182(4 Suppl):1845-1848. 3. Grisaru-Granovsky S , Rabinowitz R, Ioscovich A, Elstein D, Schimmel MS. Congenital diaphragmatic hernia: review of the literature in reflection of unresolved dilemmas. Acta Paediatr 2009; 98(12):1874-1881. 4. Shen O, Rabinowitz R, Geist RR, Shafir E. Effect of background case characteristics on decisions in the delivery room. Med Decis Making 2010; 30(4)518-22 5. Tsafrir A, Altarescu G, Margalioth E, Brooks B, Renbaum P, Levi-Lahad E, Rabi- nowitz R, Varshower I, Eldar-Geva T. PGD for fragile X syndrome: Ovarian function is 257 Ultrasound
    • the main determinant of success. Hum Reprod 2010; 25(10):2629-36. 6. Morris-Rosendahl DJ, Segal R, Born AP, Conrad C, Loeys B, Brooks SS, Muller L, Ze- schnigk C, Botti C, Rabinowitz R, Crocq MA, Kraus U, Degen I, Faes, F. New RAB3GAP1 mutations in patients with Werburg Micro Syndrome from different ethnic backgrounds effect in the Danish. Eur J Hum Genet 2010;18(10):1100-6. 7. Shen O, Rabinowitz R, Yagel S,Moran G. Absent Gallbladder on fetal ultrasound : prenatal findings and postnatal outcome. Ultrasound Obstet Gynecol 2011; 37(6):673-7. 8. Shen O, Rabinowitz R, Yagel S, Avnet H . Omega-shaped anomaly of the umbilical artery : association with chromosome 18q deletion. J Ultrasound Med 2011; 30(4):581-2. 9. Shen O, Yagel S, Valsky DV, Rabinowitz R, Zalel Y. Sonographic examination of the fetal vermis : tricks for obtaining the narrow midline target with 3-dimentional imaging in the C plane. J Ultrasound Med 2011; 30(6):827-31. Research Report 2013 258
    • T he Institute of Pathology directed by Dr. Constantin Reinus is comprised of a core Department of Pathol- ogywithsix seniorpathologists,threeresidentphysi- cians and six laboratory personnel, a Cytology Unit directed by Dr. S. Gottschalk-Sabag and, jointly with the Institute of Medical Genetics, a Molecular Pathology service under Dr. E. Golomb. The Institute performs approximately 30,000 diag- nostic procedures annually, a figure that is constantly on the rise given the growth of the hospital and the rapid progress in surgery and invasive radiology at Shaare Zedek. Areas of Research Activity The Institute is actively involved in basic and clinical research Basic research is conducted in the fields of molecular pathol- ogy and toxicological pathology. In molecular pathology, the Unit is studying human and viral oncogenes involved in the development of breast cancer, in collaboration with the Breast Health Unit. Representative Research The Institute of Pathology developed the concept of “occult cardiotoxicity” as an outcome of its studies on toxicological pathology. The Institute’s findings show that the outcome of ischemic events depends not only on the extent and duration of the ischemic stimulus, but also on myocardial ischemic tol- erance. Drugs and exogenous agents may impair the ability to withstand ischemia, with no obvious adverse effect on the Institute of Pathology 259 Pathology
    • structure or function of the heart in oxygenated conditions. This is the phenomenon of “occult cardiotoxicity”.Itmayleadtosevereischemicsideeffectsofdrugs,thatsometimescauseacute suffering to patients, and withdrawal of drugs from markets. On the basis of these data, the Institute has developed means to assess occult cardiotoxicity, and is working to better assess the potential adverse cardiac effects of drugs.   Publications 1. Ariel I, Boldes R, Weintraub A, Reinus C, Beller U, Arbel R. Chorangiocarcinoma: a case report and review of the literature. Int J Gynecol Pathol 2009;28:267-271. 2. Golomb E, Nyska A, Schwalb H. Occult cardiotoxicity--toxic effects on cardiac ischemic tolerance. Toxicol Pathol 2009;37:572-593. 3. Shavit L, Reinus C, Slotki I. Severe renal failure and microangiopathic hemolysis induced by malignant hypertension - case series and review of literature. Clin Nephrol 2010;73:147- 152. 4. Grenader T, Vernea F, Reinus C, Gabizon A. Malignant epithelioid hemangioendothelio- ma of the liver successfully treated with pegylated liposomal doxorubicin. J Clin Oncol 2011;29:e722-724. 5. Schwartz SB, Fisher D, Reinus C, Shahroor S. Infectious aortitis: a rare cause of chest pain in a child. Pediatr Emerg Care 2011;27:654-656. 6. Grenader T, Golomb E, Goldberg A. Lymph node collision tumor of non-small cell lung carcinoma and chronic lymphocytic leukemia. Onkologie 2011;34:329-331. 7. Golomb E, Matza D, Cummings CA, Schwalb H, Kodavanti UP, Schneider A, Houminer E, Korach A, Nyska A, Shapira OM. Myocardial mitochondrial injury induced by pulmonary exposure to particulate matter in rats. Toxicol Pathol 2012;40:779-788. Research Report 2013 260
    • T he Emergency Department has been directed by Dr. Todd Zalut, M.D., Israel’s first residency- trained emer- gency medicine specialist, since September 2002. He has created a department that emphasizes expeditious as- sessment, high quality warm, personalized care. The senior staff consists of Dr. Debra West, a specialist in Internal Medi- cine and Emergency Medicine, Dr. Bezalel Perl, a specialist in InternalMedicine,Dr.OanaLevi,aspecialistinInternalMed- icine and Geriatrics, Dr. Ella Leshinsky, a specialist in Internal Medicine, Dr. Chana Mayaan,a specialist in Internal Medicine and Hematology, Dr. Yaacov Asayag, a specialist in Internal Medicine and Dr. Moshe Figdor, a specialist in Internal Medicine. The nursing staff is headed by Ms. Naama Bagrish, R.N., and consists of some 40 full and part time nurses, nursing aides, secretaries and volunteers. The Department cares for adults with acute medical prob- lems, as well as adults and children with acute injuries. The staff also cares for an average of forty admitted patients on a daily basis, waiting to be accepted to the various inpatient wards. Areas of Research Activity The staff is involved in various research projects. These in- clude a study comparing the use of ultrasound to CT in the diagnosis of appendicitis in the Emergency Department, use Emergency Department 261 Emergency
    • oftheEmergencyDepartmentbyurgentcarecenters,and theuseofArcoxiaintheprevention of fasting headaches during Yom Kippur and Ramadan. Representative Research Patients presenting with possible appendicitis can undergo various imaging studies to assist the physician in making the diagnosis before surgery. The gold standard is CT scanning of the abdomen. However this is a very time- consuming test, as well as one which exposes the patient to significant radiation. Ultrasound, however, is an excellent way to diagnose appendi- citis if and when the appendix can be visualized. In cases where the appendix is not seen, the clinician must decide to pursue the diagnosis further with CT or not. This study investigated patients in Emergency Departments in Israel as well as in the US to assess the use of ultra- sound for diagnostic purposes. PUBLICATIONS 1. Esayag Y, Nikitin I, Bar-Ziv J, Cytter R, Hadas-Halpern I, Zalut T, Yinnon A. Diagnostic Value of Chest Radiographs in Bedridden Patients Suspected of Having Pneumonia. Am J Med 2010; 123(1): 88.e1-88.e5. 2. Esayag Y, Nikitin I, Bar-Ziv J, Cytter R, Hadas-Halpern I, Zalut T, Yinnon A. The Reply. Am J Med. 2010; 123(8): e15. 3. Drescher M, Alpert A, Zalut T, Torgovicky R, Wimpfheimer Z. Research Submission: Pro- phylactic Etoricoxib Is Effective in Preventing Yom Kippur Headache: A Placebo-Con- trolled Double-Blind and Randomized Trial of Prophylaxis for Ritual Fasting Headache. Headache: The Journal of Head and Face Pain. 2010;50(8):1328-1334 4. Samuels N, Appelbaum YH, Esayag Y. Paraneoplastic necrotizing myopathy and derma- tomyositis in a patient with rectosigmoid carcinoma. Rheumatol Int. 2011 DOI: 10.1007/ s00296-011-2304-1 Online First. 5. Esayag Y, Brautbar A, Popov A, Wiener-Well Y. Necrotizing soft tissue infection: an un- usual and devastating complication of pressure sores Isr Med Assoc J 2011; 13(7):442-3. 6. Maayan H, Ashkenazi Y, Nagler A, Izbicki G. Sarcoidosis and lymphoma: case series and Research Report 2013 262
    • literature review. Sarcoidosis Vasc Diffuse Lung Dis 2011 ;28(2):146-52. 7. Elstein D, Altarescu G, Maayan H, Phillips M, Abrahamov A, Hadas-Halpern I, Tiomkin M, Zimran A. Booster-effect with velaglucerase alfa in patients with Gaucher disease switched from long-term imiglucerase therapy: Early Access Program results from Jerusalem. Blood Cells Mol Dis. 2011 Oct 31. 8. Alpert E and Peleg K. Rural Approaches. In: Oxford American Handbook of Disaster Medi- cine, R A Partridge, L Proano, and D Marcozzi (Eds.) 2012. New York: Oxford University Press: 375-378. 9. Alpert E and Peleg K. Urban Approaches. In: Oxford American Handbook of Disaster Medicine, RA Partridge, L Proano, and D Marcozzi (Eds.) 2012.  New York: Oxford Uni- versity Press: 379-386. 10. Kamenetsky Z, Da’as N, Esayag Y, Kleinman Y, Samuels N. Valproic acid-induced eo- sinophilic pleural effusion: a case report and review of the literature. Neurologist 2012; 18(1):39-40. Published abstracts 1. Shimoni A, Rand A, Shem-Tov N, Hardan I, Volchek Y, Maayaan H, Yerushalmi R, Nagler A. Second Allogeneic Hematopoietic Stem-Cell Transplantation Using Fludarabine Treo- sulfan Conditioning Regimen in Patients Previously Treated with Busulfan-Based Regi- mens; Myeloablation with Acceptable Toxicity. Blood (ASH Annual Meeting Abstracts) 2009; 114: 2255. 2. Shimoni A, Rand A, Shem-Tov N, Hardan I, Volchek Y, Maayaan H, Yerushalmi R, and Nagler A.Long-Term Survival and Late Events After Allogeneic Stem-Cell Transplantation with Reduced-Intensity Conditioning (RIC) for AML and Mds; Comparable Results with Myeloablative Conditioning.Blood (ASH Annual Meeting Abstracts), 2009; 114: 518 263 Emergency
    • Research Report 2013 264
    • Nursing and Complementary Care
    • T he Medical Ethics Unit is headed by Prof. Avraham Steinberg, MD. The Unit is a consulting service on medical, ethical and medical Halakhic issues for all de- partments in the hospital, and also serves individual physi- cians, patients and families. The Unit is engaged in research on medical ethics and medi- cine and Halakhah, as well as research related to the formu- lation of national policies and legislation by the Knesset on theseissues onawiderangeoftopics:end-of-lifeissues,brain death and organ transplantation, new fertility technologies, wrongful life malpractice lawsuits, circumcision, compilation of all issues related to medical ethics and Halakhah and medi- cine in an encyclopedic format. Savinglivesbyvitalorgantransplantationiscertainlyahighly noble act. The rate of organ donation in Israel is one of the lowest in the Western world. One of the major causes is the religious notion of the moment of death. We have launched a national campaign to convince a great number of rabbis to ac- cept the concept of brain death and to come out with a state- ment to promote organ donations. This campaign is based upon ethical and Halachic considerations. Medical Ethics Department Research Report 2013 266
    • PUBLICATIONS 1. Gesundhait B, Steinberg A, Blazer S, Jotkowitz A. The Groningen Protocol – The Jewish Perspective. Neonatology 2009; 96:6-10. 2. Steinberg A. The use of PEG in demented patients: A Halachic view. Jewish Medical Eth- ics 2009; 7(1): 41-42. 3. Steinberg A. Stem Cell Research. B’Or Ha’Torah 2009; 19:9-17. 4. Steinberg A. The dilemma of scarce resources. In: Israel Medical association Refuah Bein Ha’shurot 2009: 104-108. (Hebrew) 5. Steinberg A. Disclosure of information and informed consent: Ethical and practical consid- erations. J Child Neurol 2009: 24:1568-1571. 6. Steinberg A. Esistono contraddizioni tra tora e scienza? Segulat Israel 2009; 8:27-38. (Italian) 7. Steinberg A. Live kidney donation – halakhic aspects. Yeshurun 2010;22:570-583. (He- brew) 8. Steinberg A. Definition of a human being – halakhic implication. Techumin 30:122-128 9. Steinberg A (2010), The theory of evolution – A Jewish perspective. Rambam Maimonides Medical Journal 2010; 1(1)e0008:1-10. 10. Loike J, Gillick M, Mayer S, Prager K, Simon JR, Steinberg A, Tendler MD, Willig M, Fisch- bach RL. The critical role of religion: Caring for the dying patient from an orthodox Jewish perspective. J Palliative Med 2010; 13:1267-1271. 11. Steinberg A. Health legislation in Israel – Halakhic perspectives. B’or Ha’Torah 2010; 20:127-138. 12. Steinberg A. A Jewish perspective of the Theory of Evolution – A response. Rambam Maimonides Medical Journal 2011; 2(2)e0045:1-5. 13. Steinberg A. Designing babies – halakhic perspectives. B’Or Ha’Torah 2011; 21:13-23. 267 Medical Ethics
    • 14. Steinberg A. La legislation de la santé en Israel – perspectives halakh’iques, BeOr Ha- Torah 1 2012; 28-41. (French) 15. Steinberg A.Who is the father in modern times? Techumin 2012; 32:348-358. (Hebrew) Research Report 2013 268
    • T he Consultation/Liaison Psychiatry Unit, headed by Dr. Cornelius Gropp, is staffed by Dr. Joseph Mergui (Senior Adult Psychiatrist ), Dr. Sol Jaworowski (Se- nior Adult , Adolescent and Child Psychiatrist ) and Yedida Ponger (secretary). The Unit provides psychiatric consulta- tion to the Emergency Room (ER), the inpatient wards and outpatient clinics (Cardiac Rehabilitation, Oncology, Memory Clinic, Pediatric Neurology Clinic, etc.) as well as to the community. The Unit provides specialized assessment and treatment pro- grams including medical hypnosis, ultra-orthodox psychiatric care, psychopharmacology consultations and a psycho-oncol- ogy clinic. Areas of Research Activity The Unit conducts epidemiological research. This includes studies on including Alcohol Use Disorder (Alcohol Abuse and Alcohol Dependence) in the general hospital amongst hospital patients and in particular, the early identification of alcohol withdrawal states, and research on persons suffering from Cluster B Personality Disorder in the general hospital. These patients often present as “the difficult patients” with related alcohol and substance abuse, behavioral difficulties and suicidal ideation. As a result of these management dif- ficulties, significant allocation of resources such as constant observation are required. We plan to develop appropriate pro- active management guidelines to reduce the level of critical Consultation - Liaison Psychiatry Unit 269 Psychiatry
    • incidents involving these patients during their hospital stay. Representative Research Alcohol use disorders are currently recognized by the WHO as being the third highest threat to world health. This problem is also manifest in Israel particularly in young people. The “culture of drinking” in Israel has developed over the last 20 years, and medical training has not kept pace with these changes. To facilitate changes in the medical school curriculum, a question- naire measuring Knowledge of Psychiatric Aspects of Alcohol (KPAAQ) was developed and reliability and validity constructs were established using a medical student population. This questionnaire is currently used to quantify medical students’ retention of knowledge about clinical aspects of alcohol after small group lectures combined with involvement in workshops on early intervention of at- risk drinking and the intervention of a former alcoholic who lec- tures on his life story. The Unit is involved in a bi-national project with colleagues in Sydney, Australiatoestablishbothnationalandinternationalbenchmarksforteachingthismaterialto medical students and the possible influence of cultural and geographic factors on training. Dr. Jaworowski is also using this questionnaire to evaluate knowledge of the psychiatric features of alcohol among doctors in the Departments of Internal Medicine, Surgery and Pediatrics as part of a program to heighten awareness of this subject among the medical staff in general. KPAAQ results before and after lecture: significant improvement in information retained about the clinical aspects of alcohol Research Report 2013 270
    • PUBLICATIONS 1. Mergui J, Jaworowski S, Greenberg D, Lerner V. Shared obsessive-compulsive disorder: broadening the concept of shared psychotic disorder. Australian & New Zealand Journal of Psychiatry 2010; 44: 859-62. 2. Korn-Lubetzki, Steiner-Birmans, Jaworowski S. Anxiety as initial diagnosis in opsoclonus myoclonic syndrome. Arrchives Neurology 2010; 67( 9): 1154. 3. Ben-Pazi H, Jaworowski S, Shalev RS. Cognititve and psychiatric phenotypes of movement disorders in children: a systematic review. Developmental Medicine & Child Neurology 2011; 53: 1077-84. 4. Forrest DV, Chessick RD, Cohen MA, Davidson LA, Fyer MR, Gropp C, Kalman TP, Per- man G, Scarcella E, Halevi Spero M, Stine J, Waldron S, Zaphiropolous M. How if ever should psychiatric patients be solicited for charitable donations? The Journal of the Ameri- can Academy of Psychoanalysis and Dynamic Psychiatry 2011; 39: 610-32. 5. Oberbaum M, Lysy J, Gropp C. From Nebuchadnezzar to the randomized controlled trial- milestones in the development of clinical research. Harefuah (Hebrew) 2011; 686: 668-71. 6. Jaworowski S, Raveh D, Golmard JL, Gropp C, Mergui J. Alcohol use disorder in an Israeli general hospital. Israel Medical Association Journal 2012; 14: 294-98. 7. Jaworowski S, Raveh D, Golmard JL, Gropp C, Mergui J. Israel Medical Association Jour- nal. Invited response to letter “Removing financial barriers to medical treatment of alcohol dependence in Israel”. In Press. 271 Psychiatry
    • T he Center for Integrated Complementary Medicine, headed by Dr. Menachem Oberbaum, was founded in 1999 with the mission to explore complementary and alternative methods (CAM) for their therapeutic value and set up a clinic for CAM therapeutic services The Center has a homeopathic unit , which employs two ho- meopaths, and a traditional Chinese medical (TCM) unit, headed by Dr. Revital Shabi, which employs five TCM prac- titioners. Recently a CAM has been set up in in the Obstet- rics and Gynecology Unit headed by gynecologist Dr. Avishai Malkiel. This clinical entity, which is the first of its kind in Israel and probably one of the first in the world, combines Chinese medicine and homeopathy with conventional medi- cal treatment. Areas of Research Activity Complementary and Alternative Medicine is still considered the “fringe” of conventional medicine, and as such, very few institutes worldwide invest efforts in CAM research. We conduct cell culture research on the anti- viral activity of ho- meopathic medication. This study is being run jointly with the Unit of Clinical Virology of Hadassah Medical Center and the US Army Medical Research and Material Command, Wal- ter Reed Army Institute of Research, on a US- Army grant. Another field of research is basic science evaluating anti-in- flammatory activities of CAM agents. Our clinical research is focused into two main directions. We conduct clinical trials Center for Integrated Complementary Medicine Research Report 2013 272
    • using specific methodologies such as homeopathic treatment or acupuncture for Gaucher Dis- ease bone pain and weakness. We also assess combinations of different CAM treatments with allopathic medical systems. We are involved in a planned clinical trial, which will be conducted together with the Dept. of Cardio-Thoracic Surgery where the added value of several CAM methodologies on post operative recovery will be evaluated. Recently we published a method of appraising  model validity of randomized controlled trials of homeopathic treatment. We arealsoinvestigatingthefieldofhormesis,anareaoftoxicologythatevaluatesthestimulatory effect of low concentrations of substances, which in high concentrations have an inhibitory effect. Efforts are also being directed toward researching ethics and CAM. Representative Research Since most of the CAM professions regard any person as suffering from his own illness, typical experiments used in conventional medicine where one therapy/drug is tested against a place- bo or the best available treatment is not a suitable method to evaluate CAM. In order to avoid this problem, a clinical trial is being planned at the Dept. of Cardio-Thoracic Surgery at SZMC where all the patients hospitalized in the department during the coming year will be asked to participate. They will be divided into two groups: one group will receive either homeopathic treatment, acupuncture, reflexology or osteopathy or a combination of these treatments. The other group will serve as a control group. We will assess whether CAM treatment can lead to significant improvement in recovery time, pain and analgesic consumption, stress, costs, com- plication rate and patient satisfaction. This type of randomized controlled trial will be the first of its kind in Israel and most probably also the first in the world. PUBLICATIONS 1. Samuels N, Gropp C, Oberbaum M. Acupuncture for Psychiatric Illness. Behavioral Medi- cine 2009; 34: 55-64. 2. J Gnaiger–Rathmanner, A Schneider, B Loader, M Böhler, M Frass, SR Singer, M Ober- baum. (2009) Petroleum: a series of 25 cases, Homeopathy 2009; 97:83-88. 3. Singer SR and Oberbaum M. Traumeel S for pain relief following Hallux Valgus surgery: a randomized controlled trial. BMC Clinical Pharmacology 2010;12:10:9. 4. Samuels N, Zisk RY, Singer SR, Oberbaum M. Use of and Attitudes Toward Complementary 273 Complementary Medicine
    • and Alternative Medicine Among Nurse-Midwives in Israel. Am J Obstet Gynecol 2010; 203:341.1-7. 5. Oberbaum M, Singer SR, Samuels N. Hormesis and Homeopathy: Bridge over Troubled Waters. Hum Exp Toxicol 2010; 29:567-71. 6. Fisher PA, Mathie RT, Oberbaum M. Editorial ignores evidence. BMJ 2010; 340:c594. 7. Oberbaum M. Thomas Hobbs’s teaching do exhaust all possible means for the personal and financial advancement of the medical director. Harefuah 2011; 150:747 8. Oberbaum M, Gropp C (2011). Complementary medicine- other facts. Harefuah 2011; 150:767. 9. Fisher P,. Oberbaum M, Zacharias C. Homeopathy. BMJ 2011. http://www.bmj.com/con- tent/343/bmj.d5960/reply#bmj_el_270981 10. Oberbaum M, Spira RM, Lukasiewicz A, Armon Y, Samuels N Singer SR, Barak V, Izbicki G, Einav S, Hersch M. Effect of Traumeel S on cytokine profile in a cecal ligation and puncture (CLP) sepsis model in rats. J Altern Complement Med 2011;17: 909-13. 11. Samuels N , Oberbaum M , Singer RS . Zisk JR . Validation of a Hebrew translation of the Gastroparesis Cardinal Symptom Index (GCSI). Harefuah 2010; 149:83-6. 12. Oberbaum M , Samuels N, Ben-Arye E, Amitai Y, Singer SR. Apparent Life-Threatening Events in Infants and Homeopathy: An Alternative Explanation. Human and Experimental Toxicology 2011; 31:3-10. 13. Samuels N, Sagi E, Singer SR, Oberbaum M. Hypnosis and acupuncture (hypnopuncture) for prurigo nodularis: a case report. Am J Clin Hypn 2011; 53:283-92. 14. Oberbaum M, Lysy L, Gropp C . From Nebuchadnezzar to the Randomized Controlled Trial- Milestones in the development of clinical research. Harfuah 2011; 150:668-71. 15. Sencer SF, Zhou T, Freedman LS, Ives JA, Jonas WB, Oberbaum M. Randomized, dou- ble-blind, placebo-controlled trial of the homeopathic remedy Traumeel S given to prevent or ameliorate stomatitis in children following myeloablative stem cell transplantation. BMT 2012; April 16. 2012; 50(4):865-9. Research Report 2013 274
    • 16. Samuels N, Grbic JT, Saffer AJ, Wexler ID, Williams RC. Effect of an herbal mouth rinse in preventing periodontal inflammation in an experimental gingivitis model: a pilot study. Compend Contin Educ Dent. 2012;33:204-6, 208-11. 17. Mathie RT Oberbaum M Fisher P. Method for appraising model validity of randomised controlled trials of homeopathic treatment: multirater concordance study. BMC Med Res Methodol. 2012 Apr 17;12:49. 18. Samuels N, Elstein D, Lebel E, Zimran A, Oberbaum M. Acupuncture for symptoms of Gaucher disease. Complement Ther Med. 2012;20:131-4. 19. Samuels N, Saffer AJ, Wexler ID, Oberbaum M. Localized Reduction of Gingival Inflamma- tion Using Site- specific therapy with a topical Gingival Patch. J Clin Dent 2012; 23:64–67. 20. Samuels N, Zisk-Rony RY, Zevin S, Becker EL, Yinnon AM, Oberbaum M. Use of non- vitamin, non-mineral (NVNM) supplements by hospitalized internal medicine patients and doctor-patient communication, Patient Educ Couns 2012. (Accepted for publication) 275 Complementary Medicine
    • T he nursing division is directed by Mrs. Gali Weiss, the Deputy General and Head nurse. There are five nurse- supervisors who work jointly with her in the nursing office. Ms. Sara Goldberg, her assistant, ensures the hospital’s preparedness for emergencies, terror attacks as well as natu- ral disasters. There are 14 nurse -coordinators with various specialties including infectious diseases, pain management, organ donation, diabetes, colostomy care, IBD, research, etc. In total, the nursing force is comprised of about 1000 nurses and nursing assistants, the majority of whom have a BSN, as well as upper level courses in the various specialty areas of nursing. SZMC is known for its traditional excellent patient care. The current nursing management believes that academ- ic enhancement ensures a far superior quality and safer pa- tientcare.Nursesareencouragedtoseekfurthernursingedu- cation and professional courses. There are various forums withinSZMCwherenursesshareideas,treatmentmodalities, new protocols, etc. This leadership goes along with its mis- sion statement to lead, strive for professionalism and excel- lence while providing direct patient care and staying close to the patient. Areas of Research Activity Evidence based practice is the pillar of nursing practice. Re- search is a tool that directly impacts patient care. Efforts have been made in the last two years towards enabling nurses to conduct independent research in the various nursing practice areas. Nurses obtaining an MA degree are associated with a Nursing Division Research Report 2013 276
    • designated research group. Currently the Division is working on a qualitative analysis of past and present perceptions of the nursing profession. In March, these nurses will become GCP certified so that they will be able to submit an independent request to the Helsinki committee as PI. Last year, about 15 studies were presented at various conferences as oral presentations as well as posters. All dealt with nursing clinical practice such as Root Cause Analysis in nurs- ing, Stitch without a Stick (application of a topical anesthetic on lacerations to avoid a local anesthetic injection), etc. Other studies included work on cultural diversity and perceptions of post-partum pain, the issue of whether nurses’ cultural background impacts pain man- agement, and exposure of non-medical personnel to traumatic sights and experiences in the emergency department. Representative Research Arecentstudyentitled“Caringtoknow,knowingtocareforhostedpatients”examinedhosted patients, namely patients who have been admitted to one department, but physically placed in a different one. Lack of hospital beds leads to “patient hosting”:1-3% of total admissions are placed in alternate departments; mostly surgical and orthopedic patients hosted in sub- specialty surgical wards such as eye, urology, etc. This practice raises concerns as to whether hosted patients are getting the proper holistic care by the hosting departments and most crucially whether symptoms of developing complications are recognized. In addition, hosted patients are often not seen by their doctors during regular rounds, and nurses must take the initiative to ensure proper care. A 3- part questionnaire was distributed to nurses in hosting 277 Nursing
    • departments in SZMC including: Urology, E.N.T, and Thoracic & Plastic surgery to identify specificneedsmissinginthehostingdepartments.Statisticalanalysisrevealedalackofknowl- edge as the parameter most needed to improve hosted patients’ care. In particular, statistical analysis highlighted the lack of knowledge regarding care for hosted surgical and orthopedic patients vs. non hosted patients. Recommendations include courses for nurses on the typical, common conditions of hosted patients so as to enhance confidence and improve the care for hosted patients. Publications 1. Lebeau M, Lepage B, Migeot V, Silvain C, Robert, R. Use of a risk analysis method to improve care management for outlying inpatients in a university hospital, Qual Saf Health Care 2009; 18 441-445. 2. Schwarz A, Spitz A, Weiss G. Introducing Pico-salax in the surgical department – nurse- initiated change 2012. 3. Greenberger C, Mor P. Is Presence of a family member at the bedside of a critically ill pa- tient an issue of Pikuach Nefesh? Assia: Journal of Halacha, Ethics, and Medicine 2012; 23(3-4):81-103. 4. Mayslish N, Posner G, Abramov G, Levin E, Zebrasky Y, Spitz A. A comparison between nurses working in a hospital setting and those working in the community setting 2012. 5. Mor P, Oberle K, Greenberger C. The Power of PA R. Using Participatory Action Research Techniques, Healthy BRCA Mutation Carriers Design a Model of Care. Submitted to Jour- nal of Action Research 2012. Research Report 2013 278
    • Index
    • Anesthesiology225 Angiography110 Cardiology115 Cardiothoracic Surgery 216 Complementary Medicine 272 Digestive Diseases  41 Emergency261 Endocrine106 Endocrinology176 Gaucher disease 45 General Surgery 210 Geriatrics98 Hematology21 Imaging251 Infectious Diseases 135 Integrated Oncology 72 Intensive Care 246 Internal Medicine 14 IVF180 Medical Ethics 266 Medical Genetics 54 Neonatology156 Nephrology77 Neurology95 Neurology & Toxicology 81 Neuropediatric148 Nursing276 Obstetrics & Gynecology 198 Research Report 2013 280
    • Obstetrics & Maternal 202 Oncology67 Orthopedic Surgery 240 Otolaryngology230 Pathology259 Pediatric Gastroenterology 125 Pediatric Genetics 183 Pediatric Hematology-Oncology 172 Pediatric Nephrology 161 Pediatric Pulmonology 167 Pediatric Rheumatology 141 Pediatrics124 Pediatric Urology 235 Plastic Surgery 222 Preimplantation193 Psychiatry269 Pulmonary91 Reproductive Endocrinology and Genetics Unit  187 Research & Development 8 Rheumatology102 Stem Cell Research  64 Ultrasound255 281 Index
    • Research Report 2013 282