Institute for Clinical and Experimental Medicine (IKEM) Prague, Czech Republic Presentation Brussels, October 19th, 2005 I. CARDIOCENTER 1) The Department of Cardiology is the most comprehensive cardiology department in the Czech Republic. It provides specialized health care for a broad spectrum of patients with cardiovascular diseases, being primarily involved with the diagnostics and management of coronary heart disease, heart failure, pulmonary hypertension and arrhythmias. A high volume of procedures (e.g. 16 000 of echocardiographic procedures, 4000 diagnostic coronary angiographies, 1500 of percutaneous coronary interventions, 400 catheter ablations, 130 implants of cardioverters-defibrillators, 35 heart transplants per year) allows us to conduct many clinical research projects. The department also provides specialized care for a cohort of more than 250 heart transplant patients. Current research programs are predominantly related to: a) non-pharmacological treatment of atrial fibrillation and ventricular arrhythmias (different catheter and surgical ablation strategies), b) novel imaging techniques in cardiology (CT, magnetic resonance imaging, tissue Doppler, etc), c) cardiac resynchronization therapy in patients with advanced heart failure, d) percutaneous interventions in coronary artery disease, e) immunosuppressive therapy in heart transplant recipients, and f) pulmonary arterial hypertension. Head: Josef Kautzner, PhD., FESC Assoc. Prof. of Medicine e-mail: josef.kautzner@ikem.cz 2) The Department of Cardiovascular Surgery is the largest cardiosurgical department in the Czech Republic performing around 1500 cardiosurgical procedures per year. It performs a wide scale of cardiac procedures in adult patients. Roughly 75%, includes operations for coronary heart disease and coronary artery bypass grafts using arterial or venons grafts or combined procedures with valve procedures and coronary artery bypass grafts or surgical ventricular restoration operations. The other routinely performed procedures include valve replacement or plastic operations, thoracic aortic surgery (deep hypothermia), orthotopic heart transplantation (approx. 600 by today), surgical treatment of cardiac arrhytmia (ventricular, atrial) and surgical treatment of congenital defects in adult patients. Since 2003, we have been using the Thoratec mechanical ventricular support system as a bridge to transplantion with great results. The results of clinical practice have been in the long term monitored and compared with the cardiac registry in Oregon, U.S.A. In comparison with this registry, our achievements are better than expected. The research mainly concentrates on the surgical treatment of chronical cardiac failure amd the surgical treatment of arrhytmia. We take part in international multicentric studies such as CARACASS (dealing with the long term follow-up patients with total arterial revascularization) or STICH (following the effect of surgical ventricular restoration procedures on patients survival). In the field of experimental cardiology surgeons have been carrying out various studies on the model of the Langendorf isolated rat,s heart. Head: Prof. Jan Pirk, MD, DSc. e-mail: jan.pirk@ikem.cz 3) The Department of Preventive Cardiology is a specialist outpatient clinic focused on the diagnosis and treatment of hypertension and dyslipidemia. There are about 5,000 patients registered with this outpatient clinic and being on follow-up care. The following methods are available to our patients at the Department of Preventive Cardiology: EKG; stress exercise test (bicycle); 24-hour ambulatory blood pressure monitoring; telephone-based blood pressure monitoring (transmission of home BP values to a PC in our department); carotid ultrasound; flow-mediated vasodilation (to evaluate endothelial function). The Department of Preventive Cardiology is also involved in epidemiology of cardiovascular disease; so far, there have been five cross-sectional population surveys (1985, 1988, 1992, 1997/98, and 2000/01) for screening of major cardiovascular risk factors. In 2000-01, a cohort study was initiated (re-examination of a population sample screened first in 1997-98). Therefore, we have longitudinal trends in the prevalence of major cardiovascular risk factors and, due to the cohort study, the first incidence data. Our population samples have served as control groups for many studies/analyses. Head: Renata Cífková, MD, PhD. Assoc. Prof. of Medicine e-mail: renata.cifkova@ikem.cz II. TRANSPLANTCENTER 1) The main task of the Department of Nephrology is to provide care to cadaveric or living-donor renal transplant recipients since the first postoperative day, immunosuppressive therapy management, management of post-transplant internal complications and regular ambulatory follow-up. The department is the largest center of its kind in the Czech Republic, carrying out about 180 transplant procedures each year, about half of this countrys total number of transplant procedures. Follow-up involves about 900 renal transplant recipients with all their post-transplant complications. The department provides supervision and counseling in this area. In addition, the department provides all-round comprehensive diagnosis and care of patients with renal disease: rapidly progressive and chronic glomerulonephritides including biopsy (50), interstitial nephritides, hereditary nephropathies, secondary nephropathies associated with systemic and other internal diseases. In renal failure patients, the department provides screening for metabolic disorders, dietary and conservative treatment 300 pts/yr as well as renal replacement therapy using hemodialysis, hemodiafiltration and peritoneal dialysis (5065/1649/165). The department has participated in multi-centric studies, particularly those involving new immunosuppressives. The research projects carried out there are related to the above clinical activities and for the potential of some specialist laboratories (lab of examination of renal function, lab of bone metabolism and hypertension) and for the experimental department carrying out animal experiments. These include, a) the study of gene polymorphisms as related to the development of renal disease and post-transplant complications, b) the effect of intrarenal expression of inflammation genes on the course of transplantation, c) the study of metabolic disorders and gene polymorfism in obesity after renal transplantation (adipokines in fat tissue, DNA and RAGE polymorfism), and its effect on renal failure progression and cardiovascular events, d) disorders in bone metabolism in transplant and chronic renal failure patients, e) renal and renovascular hypertension. Several experimental models of renal disease have been developed. Head: Prof. Vladimír Teplan, MD, PhD. e-mail: vladimir.teplan@ikem.cz 2) In the area of clinical medicine, the Department of Hepatogastroenterology provides background to the liver transplant program. It focuses in the selection of recipients, their follow-up and treatment while on the waiting list and after-transplantation care. It developed a system of protocol-based follow-up and prevention of post-transplant complications. The department pursues full-scale clinical practice in hepatogastroenterology: treatment of viral hepatitides, cholestatic and metabolic liver disease including management of their complications (portal hypertension). The department is also the regional supervisor of the national screening program of colorectal cancer providing also follow-up of patients with pancreatic and biliary duct disease including tumors, and those with inflammatory bowel disease. It provides the full range of endoscopic methods including capsule endoscopy and all kinds of metallic stent placement. Altogether, we perform approximately 6000 mostly advanced procedures annually. In research, the departments investigators carry out projects covering a variety of aspects of liver transplantation and the genetics of alcoholic liver disease and pathogenesis of fibrosis. Head: Julius Špičák, MD, PhD. Assoc. Prof. of Medicine e-mail: julius.spicak@ikem.cz 3) The Department of Transplant Surgery has three basic areas of activities transplantations, vascular surgery and abdominal surgery. Last year, the clinic showed the highest growth in the area of liver transplantations, while kidney and pancreas transplantations continued to be highly active and their results are comparable to those achieved by major European transplant centers. Experimental activities focus on intestinal transplantations and the development of perfusion solutions protecting transplanted organs. As to vascular surgery, the clinic offers a broad portfolio of reconstructive surgery. Lately, there has been an increasing number of operations which make use of allogenous veins. The department of abdominal surgery continues to develop hepatobiliar surgery and all operations and activities related to the extensive transplantation program. The broad spectrum of activities of the Department of Transplant Surgery, and especially its transplantation program, can surely offer topics that could be included in EU projects. Head: Miloš Adamec, MD, PhD. Assoc.Prof. of Medicine e-mail: milos.adamec@ikem.cz 4) The Department of Immunology is part of a modern complex of ISO 9001 accredited clinical labs and covers a complete range of routine immunological methods. The department is performing HLA typing for the organ and stem cell transplantation programs of the Czech Republic. The laboratory is accredited by the European Federation of Immunogenetics and serves as a national reference laboratory for HLA typing. Czech Bone Marrow Donor Registry (CBMD Prague) is a member of major international networks and registers 20 140 bone marrow (stem cells) donors including cord blood units. Over the last ten years, CBMD registry has found 270 donors who donated bone marrow (stem cells) for transplant. Recent research activities of immunologists are focused mainly to immune reactions associated with kidney allograft transplantation including the role of a) IL-18 upregulation in acute rejection, b) soluble CD30 and HLA antibodies as potential risk factors, c) cytokine gene polymorphisms in donor and recipient pairs, d) chemokine gene induction in epithelial cells, and e) sequence-based methods of HLA typing. Head: Ilja Stříž, MD, PhD. Assoc. Prof. of Medicine e-mail: ilja.striz@ikem.cz III. DIABETES CENTER The center provides complex multidisciplinary care of diabetic subjects including treatment of acute and chronic complications, education and implementation of progressive methods of diabetes management. Special attention is paid to the treatment of diabetic foot syndrome and kidney, pancreas and islet transplantation in diabetic subjects. Research projects are focused on 4 main areas: treatment of diabetes with transplantation of insulin producing tissue, identification and modification of main factors of insulin resistance, prevention and treatment of diabetic nephropathy and complex treatment of diabetic foot lesions. The total number of pancreas transplants (in combination with a kidney or alone) exceeded 270 in 2005 with long-term results comparable or better than those reported by the International Pancreas Transplant Registry. The center is involved in the European multicenter pancreas transplant study EUROSPK based in Bruxelles. Currently, the EUROSPK 02 study is underway. The center is open to other possible cooperation in this field. A clinical pancreatic islet transplant program has been started in 2005. Its Pancreatic Islet Laboratory has recently developed an original reproducible method for in vitro visualization of transplanted islets using magnetic resonance imaging. Insulin resistance is being studied both in humans and in experimental animals. Research projects primarily focus on the analysis of adipose tissue and skeletal muscle glucose transport, insulin signaling and free fatty acid utilization at the cellular, organ and whole body level. For this purpose various rat models of insulin resistance and diabetes are used. In humans, in vivo metabolic studies of insulin secretion, insulin action and glucose counterregulation in healthy and diabetic subjects are being performed. Methods used include hyperinsulinemic euglycemic, hyperglycemic and hypoglycemic clamp studies. In addition, indirect calorimetry to measure substrate oxidation, subcutaneous tissue biopsy to study the expression of regulatory molecules and magnetic resonance spectroscopy are available. Research on diabetic nephropathy is studying experimental disorders involved in insulin-signaling cascade and renin-angiotensin system at cellular level in experimental model of diabetes. Clinical research is focused on optimal management strategies in prevention and treatment of diabetic nephropathy Our foot clinic is participating in a multicenter observational study organized by EURODIALE, a European group of diabetic foot centers. Its first initiative was the development of a research program focused on the standardization of foot care in diabetic subjects. We would like to continue taking part in other EURODIALE projects aimed not only on optimal organization, but also on optimal management strategies. Head: Prof. Terezie Pelikánová, MD, PhD. e-mail: terezie.pelikanova@ikem.cz Contact person: František Saudek, MD, PhD. Assoc. Prof. of Medicine e-mail: frantisek.saudek@medicon.cz IV. CENTER FOR EXPERIMENTAL MEDICINE The Center for Experimental Medicine consists of four major research groups, namely: 1. Laboratory of Metabolism and Diabetes, 2. Laboratory for Atherosclerosis Research, 3. Laboratory of Experimental Hepatology, 4. Laboratory of Experimental Nephrology and Hypertension. The main field of research in the Laboratory of Metabolism and Diabetes are the pathophysiological mechanisms of insulin resistance and the metabolic consequence of impaired lipid and carbohydrate metabolism in relation to the development of type 2 diabetes mellitus and cardiovascular complications. Experiments are carried out on the unique experimental model, in the non-obese hereditary hypertriglyceridemic rats exhibiting all symptoms of the metabolic syndrome. Research projects primarily focus on the glucose and lipid transport, insulin signaling and contribution of oxidative stress. The Department has all the necessary equipment for metabolic studies at the cellular, organ and whole body level and for breeding of rat models. The Department is also involved in several collaborations on a national and international level with other research laboratories. Head: Ludmila Kazdová, PhD. e-mail: ludmila.kazdova@ikem.cz The Laboratory for Atherosclerosis Research is mainly focused on the role of menopause and atherogenity of lipid factors, mainly remnant-like particles; on the role of 204C allele of cholesterol 7alfa-hydroxylase gene on the lipid metabolism and on the role of vasa vasorum in the interaction of atherogenic plasma molecular factors with different vascular beds in perimenopause. Preclinical atherosclerosis is also intensively studied in various populations. Substantial part is focused on epidemiological genetics. A large DNA bank of the Czech population sample has been completed (n=10 000) together with the DNA bank of different pathologies (dialyzed patients, young MI survivals, heart TX, kidney TX, etc.). Epidemiological genetics is not only in the area of atherogenesis but also in the field of osteoporosis and inflammation is also performed. Head: Jan Piťha, MD, PhD. e-mail: jan.pitha@ikem.cz The Laboratory of Experimental Hepatology is focused on genetic factors involved in etiology/pathogenesis of cholestatic liver diseases and liver fibrosis. The most important recent result is the discovery of dual hereditary jaundice – a digenic disorder of bilirubin metabolism presenting with mixed type hyperbilirubinemia caused by simultaneous mutations in the UGT1A1 and ABCC2 genes. Our activities in the field of liver fibrosis involve development of a non-invasive scintigraphic technique for monitoring of antifibrotic therapy and characterization of genetic factors responsible for susceptibility to alcoholic liver disease. Head: Milan Jirsa, MD, Mgr., PhD. e-mail: milan.jirsa@ikem.cz The main field of interest in the Laboratory of Experimental Nephrology and Hypertension is focused on the role of the kidney in the development of hypertension. Specifically, the role of the interaction of the renin-angiotensin system and nitric oxide in the development of hypertension is investigated. Two experimental models of hypertension are employed, namely newly-bred rat strain with inducible hypertension, where physiological parameters could be correlated with the increase in blood pressure in a very short time, and the transgenic rat strain for the mouse Ren-2 renin gene, in which the development of hypertension is a result of insertion of the mouse Ren-2 renin gene into rat genome. Head: Luděk Červenka, MD, PhD. Assoc. Prof. of Medicine e-mail: ludek.cervenka@ikem.cz Contact person: Ivana Vaněčková, PhD. e-mail: ivana.vaneckova@medicon.cz V. COMPLEMENT The main research fields of the Department of Diagnostic and Interventional Radiology are in fields of Interventional Radiology and Magnetic Resonance. Head: Jan Peregrin, MD, PhD. Assoc. Prof. of Medicine e-mail: jan.peregrin@ikem.cz a) Interventional Radiology The Interventional Team is intensively doing research and clinical application in following fields: Endovascular treatment of renovascular hypertension and ischemic renal failures caused by ischemic nephropathy, percutaneous treatment of complications of transplanted liver and kidney, critical limb ischemia and treatment of hemodialysation port failure. The Interventional Team can also provide interventional experiments with animals in a specialized catheterization room that is a part of our experimental department of IKEM. A fully equipped seminar room with a control unit for live case transmission from the catheterization room for local and outdoor transmissions was constructed and is available for teaching and research purposes. b) Magnetic Resonance The main scope of MR spectroscopy and functional MR imaging research group is the development of new MR technologies and to bring these methods into clinical practice and research. Wide experience with MR “in vivo” spectroscopy was gained and this method is uniquely used as routine examination for patients from the entire Czech Republic. The priority in molecular imaging is focused on cell transplantation with the application of nanoparticles. This technique of molecular imaging is used for modeling of the transplantation process of either insulin isles or cells into the brain or spinal cord. 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IKEM is looking for cooperation in the areas: non-pharmacological treatment of arterial fibrillations and arrhythmias novel imaging techniques in cardiology cardiac resynchronization therapy of heart failure and its surgical treatment long-term follow up of patients with total coronary revascularization epidemiology of risk factors of ischemic heart disease (IHD) epidemiological genetics of IHD and its risk factors genetic determination of renal disease and the course of kidney transplantation gene and environmental influence of obesity after renal transplantation renovascular hypertension genetics and pathogenesis of liver fibrosis alcoholic and non-alcoholic liver disease - factors responsible to susceptibility cytokines and acute rejection after transplantation sequence-based methods of HLA typing diabetic nephropathy and insulin signaling – experimental and clinical diabetic foot clinical pancreatic islet transplantion program insulin resistance (glucose transport, insulin signaling, free fatty acid utilization) – experimental models and clamp techniques preclinical atherosclerosis determination techniques (ultrasound, IVUS, MR, CT) pathophysiology of hypertension, renin-angiotensin system and nitric oxide in transgenic models analysis of cell transplantations with application of nanoparticles experimental studies (both small and large animals) in newly established facility including: molecular biology, molecular genetics, microsurgery and operation theaters Prof. Rudolf Poledne, PhD Director IKEM Vídeňská 1958/9 140 21 Praha 4 Czech Republic tel. +420261364000 fax +420261362805, e-mail: rudolf.poledne@ikem.cz