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42 Časopis Društva doktora medicine Republike Srpske Journal of the Medical Society of the Republic of Srpska Godina: 42. • Broj 2 • Oktobar 2011. Časopis Društva doktora medicine Republike Srpske Vol. 42 • No 2 • October 2011. Medical Society of the Republic of Srpska EDITORIALS/UVODNICI Statins: Benefits and Risks in Treatment of Cardiovascular Disease R. IGIĆ How to Write a Scientific Paper: the Problems Facing Beginners SCRIPTA MEDICA ORIGINAL ARTICLES/ORIGINALNI ČLANCI An Outbreak of Infection Due to Metallo--Lactamase-Producing Proteus mirabilis in the Surgical Intensive Care Unit V. MIROVIĆ, B. CAREVIĆ, S. STEPANOVIĆ, Z. LEPŠANOVIĆ Uticaj metaboličkog sindroma na pojavu ishemijskog moždanog udara M. VUJNIĆ, N. RAŠETA, M. KULAUZOV, D. RAČIĆ, B. AZARIĆ, A. D. KOVAČEVIĆ REVIJSKI ČLANCI/REVIEW ARTICLES Statini – neželjena dejstva i interakcije T. KAŽIĆ Ex Vivo Expansion Of Hematopoietic Cells Today Z. IVANOVIĆ CLINICAL PROBLEM-SOLVING/RJEŠAVANJE KLINIČKOG PROBLEMA Synovial Osteochondromatosis Mimicking Septic Arthritis S. GUPTA, P. JAIN CASE REPORTS/PRIKAZI SLUČAJEVA Fifty-Four-Year-Old Man with Inguinal and Testicular Masses Y. TAKHALOV Anesthetic Management of a Patient With Obstructive Sleep Apnea and Narcolepsy L. STOJILJKOVIC, A. ZENDNER Surgical Treatment of Coronary Artery Aneurysm Ž. S. JONJEV, S. SRDIĆ LETTERS TO THE EDITOR/PISMA UREDNIKU Swollen and Tender Umbilical Nodule S. ZHANG Atorvastatin-Associated Myalgia Triggered by Grapefruit A. M. LAZAREVIĆ Statin-Induced Leg Pain at Night G. LJUBOJEVIĆ, N. TOMIĆ, N. STOJAKOVIĆ SPECIAL ARTICLE/SPECIJALAN ČLANAK Great Scientists From a Small Country in War and Peace R. IGIĆ, R. ŠKRBIĆ, S. STOISAVLJEVIĆ ŠATARA CONTINUING MEDICAL EDUCATION/KONTINUIRANA MEDICINSKA EDUKACIJA Questions and Answers R. GAJANIN, B. ALEXANDER, S. STOISAVLJEVIĆ ŠATARA, A. STASZKIEWICZ, M. JERINIC ISTORIJSKA PERSPEKTIVA /HISTORIC PERSPECTIVE www.scriptamedica.com Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Scripta Medica (Banja Luka) Časopis Društva doktora medicine Republike Srpske UREĐIVAČKI ODBOR EDITORIAL BOARD MEĐUNARODNI UREĐIVAČKI ODBOR INTERNATIONAL A DVISORY BOARD Glavni urednik Editor-in-Chief Pavle Anđus, Belgrade, Serbia Shigetoshi Chiba, Matsumoto, Japan Nada Đokanović, Toronto, Canada Ervin G. Erdös, Chicago, USA Igor Francetić, Zagreb, Croatia Faruk Hadžiselimović, Basel, Switzerland Zoran Ivanović, Bordeaux, France Vladimir Kanjuh, Belgrade, Serbia Tomislav Kažić, Belgrade, Serbia Nebojša Lalić, Belgrade, Serbia Kafait U. Malik, Memphis, USA Momir Mikov, Novi Sad, Serbia Goran Milašinović, Belgrade, Serbia Satoshi Nakatani, Osaka, Japan Dragoslav Nenezić, Podgorica, Montenegro Aleksandar Nešković, Belgrade, Serbia Momir Ninković, Munich, Germany Miodrag Č. Ostojić, Belgrade, Serbia Miralem Pašić, Berlin, Germany Mirjana Pavlović, Boca Raton, USA Shmuel Penchas, Tel Aviv, Israel Božina Radević, Belgrade, Serbia Marin Sekosan, Chicago, USA Goran Stanković, Belgrade, Serbia Ljuba Stojiljković, Chicago, USA Ksenija Vitale, Zagreb, Croatia Vladan Vukčević, Belgrade, Serbia Nathan D. Wong, Irvine, USA Slavica Žižić-Borjanović, Belgrade, Serbia Rajko Igić Urednici Senior Editors Aleksandar Lazarević Slobodan Milovanović Miloš P. Stojiljković Članovi Members Dejan Bokonjić Marija Burgić-Radmanović Radoslav Gajanin Ljerka Ostojić Nenad Ponorac Jelica Predojević-Samardžić Aida Ramić Nela Rašeta Duško Vulić Enver Zerem Milan Jokanović IZDAVAČKI SAVJET/PUBLISHING COUNCIL Web site Editor: Zdravko Grubač Prof. Dr. Duško Vasić, predsjednik Prof. Dr. Ranko Škrbić Dr. Bakir Ajanović Akademik Drenka Šećerov-Zečević Doc. Dr. Momčilo Biuković Prof. Dr. Zdenka Krivokuća Prof. Dr. Veljko Marić Prof. Dr. Mirko Stanetić Prof. Dr. Gordana Tešanović Tehnički sekretar: Biljana Radišić Lektor za srpski jezik: Biljana Kuruzović Lektor za engleski jezik: Dalibor Kesić Prelom teksta/Layout: Medici.com, Banja Luka Dizajn/Design: CGM Design, Banja Luka Izdavač/Publisher: Društvo doktora medicine RS Štampa/Printed by: Atlantic bb, Banja Luka Copyright © Društvo doktora medicine Republike Srpske ISSN 0350-8218 Tiraž: 1.000 primjeraka 71 72 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Sadržaj 107 LETTERS TO THE EDITOR/PISMA UREDNIKU Swollen and Tender Umbilical Nodule S. ZHANG Atorvastatin-Associated Myalgia Triggered by Grapefruit A. M. LAZAREVIĆ Statin-Induced Leg Pain at Night G. LJUBOJEVIĆ, Contents N. TOMIĆ, N. STOJAKOVIĆ 110 73 EDITORIALS/UVODNICI Great Scientists From a Small Country in War and Peace R. IGIĆ, R. ŠKRBIĆ, S. STOISAVLJEVIĆ ŠATARA Veliki naučnici iz male zemlje u ratu i miru Statins: Benefits and Risks in Treatment of Cardiovascular Disease R. IGIĆ How to Write a Scientific Paper: the Problems Facing Beginners SCRIPTA MEDICA 118 75 127 S. STEPANOVIĆ, Z. LEPŠANOVIĆ, Epidemija infekcije u hirurškoj jedinici intenzivne nege izazvane bakterijom Proteus mirabilis koja stvara metalo-beta-laktamazu Uticaj metaboličkog sindroma na pojavu ishemijskog moždanog udara M. VUJNIĆ, N. RAŠETA, M. KULAUZOV, S. DOBRIĆ 130 REVIJSKI ČLANCI/REVIEW ARTICLES 132 Statini – neželjena dejstva i interakcije T. KAŽIĆ Statins – Side Effects and Drug Interactions Ex Vivo Expansion Of Hematopoietic Cells Today 134 RADOVI PUBLIKOVANI U STRANIM ČASOPISOMA/PUBLISHED IN FOREIGN JOURNALS 140 UPUTSTVO AUTORIMA/INSTRUCTIONS FOR CONTRIBUTORS Ex vivo ekspanzija hematopoetskih ćelija CLINICAL PROBLEM-SOLVING/RJEŠAVANJE KLINIČKOG PROBLEMA Synovial Osteochondromatosis Mimicking Septic Arthritis S. GUPTA, P. JAIN Sinovijalna osreohondromatoza koja liči na septički artritis CASE REPORTS/PRIKAZI SLUČAJEVA Fifty-Four-Year-Old Man with Inguinal and Testicular Masses Y. TAKHALOV Anesthetic Management of a Patient With Obstructive Sleep Apnea and Narcolepsy, L. STOJILJKOVIC, A. ZENDNER Surgical Treatment of Coronary Artery Aneurysm Ž. S. JONJEV, S. SRDIĆ IN MEMORIAM/OBITUARY Prof. dr Tomislav Kažić (1937-2011) SCRIPTA MEDICA Z. IVANOVIĆ 100 ISTORIJSKA PERSPEKTIVA/HISTORIC PERSPECTIVE S. Bošković - Život i delo D. ŠEĆEROV ZEČEVIĆ Metabolic syndrome affects stroke 97 PRESENTATION OF MEDICAL JOURNALS The New England Journal of Medicine SCRIPTA MEDICA Vojnosanitetski pregled (Military Medical Review) D. RAČIĆ, B. AZARIĆ, A. D. KOVAČEVIĆ 84 CONTINUING MEDICAL EDUCATION Questions and Answers R. GAJANIN, B. ALEXANDER, S. STOISAVLJEVIĆ ŠATARA, A. STASZKIEWICZ, M. JERINIC ORIGINAL ARTICLES/ORIGINALNI ČLANCI An Outbreak of Infection Due to Metallo-Lactamase-Producing Proteus mirabilis in the Surgical Intensive Care Unit V. MIROVIĆ, B. CAREVIĆ, SPECIAL ARTICLE/SPECIJALAN ČLANAK Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com EDITORIAL Statins: Benefits and Risks in Treatment of Cardiovascular Disease Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide.1 Improved prevention in people without existing disease (primary prevention) is an important strategy for managing the overall problem of CVD. Other means of reducing the risk of CVD include control of smoking, hypertension and hyperlipidemia. In addition, avoidance of a high intake of dietary salt, obesity and sedentary life style are necessary, as is adequate management of glucose levels in people with diabetes. According to the Cochrane Review,2 effectiveness of statins for the primary prevention of CVD was studied in more than a dozen randomized controlled trials, but a number of questions remain. First, only limited evidence suggests that primary prevention with these drugs is cost-effective. Adverse reactions to statins are generally underreported, and were not reported at all in eight of fourteen trials. Only one trial was publicly funded, while nine others were sponsored either fully or partially by pharmaceutical companies.3 The NICE guidance4 suggests, with good reason, that use of statins for primary prevention of CVD is recommended as part of the management strategy and should be limited to adults with a 20% or greater 10-year risk of developing CVD; preference is given to interventions aimed at reducing risk factors. The decision to initiate statin therapy should be made only after an informed discussion between the responsible clinician and the patient about the risks and benefits of statin treatment; this decision should take into account additional factors, such as co-morbidities and life expectancy. As Professor Tomislav Kažić concludes in his excellent review,5 statins are effective drugs for secondary prevention in patients at high risk for CVD. Nevertheless, vigilance during statin therapy must be maintained. Although statins are safe medications for the majority of patients, intolerance to these drugs is frequently seen in clinical practice6,7. Muscular pain (myalgia with or without increase of plasma creatinin kinase) and/or elevation of hepatic aminotrasferases constitute approximately two-thirds of reported adverse events during statin therapy. Because these side effects are likely to reduce patient acceptance and adherence to a therapeutic regimen and consequently the cardiovascular benefits, clinicians should be aware of them and explore alternative ways to manage patients with statin intolerance. Rajko Igić References 1. 2. 3. 4. 5. 6. 7. Finally, it seems obvious that if statins were used for primary CVD prevention in developing countries, scarce healthcare resources would be wasted, and patients would be subjected unnecessarily to adverse effects. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997;349(9061):1269-76. Taylor F, Ward K, Moore THM, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD004816. DOI: 10.1002/14651858.CD004816.pub3. Heneghan C. Considerable uncertainty remains in the evidence for primary prevention of cardiovascular disease [editorial]. The Cochrane Library 2011 (19 Jan). www.thecochranelibrary.com/ details/editorial/983199/ Considerable-uncertainty-remains-inthe-evidence-for-primary-prevention-of-cardi.html (accessed August 24, 2011). National Institute for Health and Clinical Excellence. Statins for the prevention of cardiovascular events. NICE Technology Appraisal TA94. London: NICE 2006. http://www.nice.org.uk/ TA094 (accessed August 24, 2011). Kažić T. Statini—neželjena dejstva i interakcije. [Statins—side effects and drug interactions.] Scr Med 2011;42:84-91. Lazarević A. Atorvastatin-associated myalgia triggered by grapefruit. Scr Med 2011;42:108. Ljubojević G, Tomić N, Stojaković N. Statin-induced leg pain at night. Scr Med 2011;42:109. 73 74 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com EDITORIAL How to Write a Scientific Paper: the Problems Facing Beginners There are many excellent books to help the novice author write a scientific paper, including several written in Serbian and Croatian languages.1-4 However, these writing books fail to address all the various problems facing beginners. Consequently, medical societies, universities, large hospitals, and even some medical journals use to organize writing workshops for young researchers. A need for such a workshop in the Republic of Srpska became clear when several young researchers requested individual tutoring by the editors of Scripta Medica (SM) in scientific writing and data presentation. One significant problem was that English is their second language. Accordingly, the editors of the SM conducted two-day workshops in Banja Luka (Paprikovac and Institute “M. Zotović”) to provide training in planning scientific research and writing scientific articles. The courses were designed to teach participants how to prepare an informative title, how to write a case report, book review, an original clinical or scientific report, review article, abstract, and a letter to the editor. Title - Because the title of a piece is a vital part of each publication, and it is the first thing seen by a reader or an editor, special attention was devoted to constructing concise and descriptive titles. The participants selected several different titles for each piece, which helped them realize how much time and effort are needed to create this part of the manuscript. Case report - For many medical doctors, a case report is a useful exercise in learning to write, and it becomes their first publication. SM publishes such contributions. Abstract for a scientific meeting also require good writing. They summarize work clearly and concisely, and an abstract accepted for presentation will be converted into either an oral presentation format or a well-designed poster. In addition to the title, the abstract of a paper (unstructured or structured) is likely to be the basis on which the work is judged by uncritical readers. The workshop participants were taught how to prepare the four basic parts of an abstract or any good scientific paper include:5 • Introduction or overview or Why the study was done, • Methods of research or What was done, • Results or What was found, • Discussion and Conclusion of the research performed. Review article is frequently written in response to an invitation from a journal, but the process of writing a review article is often an integral part of medical training and mentorship. For that reason, the workshop participants need to understand the benefits and limitations of those papers (systematic reviews and meta-analysis) that summarize other publications.6 Letter to the editor and response of the authors7,8 were analyzed in order to inform and stimulate discussion among the workshop participants. The dual role of a manuscript assessor (reviewer) was explained, and suitable examples were given to show how the reviewer provides both an assessment of the manuscript for the editor and a constructive critique for the authors. After the participants had read the recommended papers, discussion included the following topics: • What is the best way to display data? • Why is the design of a study more important than the analysis? • How can a non-statistician evaluate statistics presented in a paper? • How can a statistician help to determine the optimum number of patients for a study? • Finally, how does one write a Ph.D. dissertation proposal?9 Our workshops had 35 and 50 participants in attendance, suggesting that medical professionals are highly interested in courses on writing and planning scientific research. The absence of a fee might contribute to the high attendance in our area, but demand for similar courses conducted by a local journal in neighboring Croatia for the past several years was also high, despite a fee of 130 €. These observations indicate that medical journal editors have an important role in the scientific education of local researchers in developing countries; their participation in writing workshops should be favored and stimulated. Our journal, helps yong researchers by publishing short texts on this subject in the “Questions & Answers” section devoted to continuing medical education. In addition, brief contributions to this section provide a means for our readers to improve their English. Scripta Medica References 1. 2. 3. 4. 5. 6. 7. 8. 9. Igić R. Kako se pišu saopštenja o medicinskim istraživanjima. Sarajevo, Veselin Masleša, 1980. (Serbo-Croatian language) Silobrčić V. Kako sastaviti, objaviti i ocijeniti znanstveno djelo, treće izdanje. Zagreb, Medicinska naklada, 2003. (Croatian language) Brkić S, Vučković-Dekić Lj. Publikovanje u biomediciniNaučnoistraživački rad i prezentovanje rezultata istraživanja. Novi Sad, Primaprint, 2004. (Serbian language) Delibegović S. Kako pisati medicinski znanstveni članak. Sarajevo, Interliber, 2008. (Bosnian or Bosniak language) Hall GM. How to write a paper. London, BMJ, 1994. Greenhalgh T. How to read a paper. The basics of evidencebased medicine, Third edition. London, BMJ, 2006. Marušić M. Comment on Ethical issues concerning research in complementary and alternative medicine. JAMA;291:599-604. JAMA 2004;291:2193 Miller FG, Emanuel EJ, Rosenstein DL, Straus SE. The authors reply. JAMA 2004;291:2194. Igić R. Kako napisti projekat doktorske disertacije. Pedijatrija Danas 2009;5:185-90. 75 ORIGINAL ARTICLE An Outbreak of Infection Due to Metallo--Lactamase-Producing Proteus mirabilis in the Surgical Intensive Care Unit ABSTRACT Background. We described an emerging outbreak of infection caused by metallo-lactamase (MBL)-producing Proteus mirabilis that occurred in the surgical ICU of a Serbian university hospital, and assessed this outbreak in a retrospective observational study. Methods. Records from patients in this ICU who had MBL-producing P. mirabilis isolates were reviewed retrospectively. All enterobacterial isolates from clinical specimens (one per patient) were tested for MBL production. We used a multiplex PCR assay to detect and differentiate each of the MBL gene families: IPM, VIM, SPM, GIM and SIM. In July and in November 2008, we conducted a point prevalence survey of rectal colonization with MBL-producing P. mirabilis. Results. From June through November, 2008, nine patients in the surgical ICU were infected by MBL-producing P. mirabilis. These isolates exhibited multi-drug resistance. The outbreak was discovered in June and expanded rapidly; ten of twelve (83%) patients in ICU were colonized with outbreak strains in July. Seven cases of bacteremia, including 3 intravascular catheter related, one surgical site infection, and one urinary tract infection were identified. Six of nine MBL-positive P. mirabilis strains belonged to the IPM family, and three others belonged to the VIM family. Actual mortality was 56%, but we could not determine mortality indirectly attributable to the infection. Conclusion. The rapid emergence of MBL-producing P. mirabilis within a Serbian hospital created a challenge for clinicians, microbiologists, and epidemiologists. This resistant infection added further to the established cases of antimicrobial resistance within the hospital. KEY WORDS Proteus mirabilis, outbreak of infection, surgical ICU, antimicrobial resistance, mortality Veljko Mirović1 Biljana Carević1 Srđan Stepanović2 Zorica Lepšanović3 Clinical Center of Serbia, Belgrade, Serbia, 2School of Medicine, Belgrade, Serbia, 3Military Medical Academy, Belgrade, Serbia 1 Correspondence Veljko Mirović, MD, PhD Address: Vinogradski venac 16/14 11030 Beograd, Serbia Phone +381113514018 E-mail: [email protected] Submitted: September 18, 2011 Accepted: September 30, 2011 (Scr Med 2011;42:75-9) Because of their rapid spread, increasing diversity, and broad hydrolytic spectrum, the acquired metallo-βlactamases (MBLs) are an emerging threat (1). Carbapenems are used to treat severe hospital infections caused by multi-drug resistant organisms, but carbapenem-resistant bacteria present an increasing therapeutic challenge (1, 2). Five types of acquired MBLs have been identified: VIM, IPM, SPM, and SIM-type enzymes (1,2,3). The recently described New Delhi metallo-beta-lactamase 1 (NDM-1) is a growing problem worldwide (4). Two dominant groups of acquired MBLs are recognized: the IPM and VIM types (5). Moreover, since the MBL genes are linked to other resistance determinants, MBL-producing organisms are commonly multidrug resistant. MBLs have been spread throughout the world, with an overall trend moving from Pseudomonas aeruginosa into Enterobacteriaceae (5). Several recent reports described the emergence of VIMproducing Klebsiella pneumoniae, mainly in Southern Europe (5). MBL-positive isolates among other members of the family Enterobacteriaceae such as P. mirabilis have occurred sporadically ( 6) Setting and study design. We made a retrospective, observational study of the outbreak of infections caused by 76 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com P. mirabilis-producing MBL. The study involved patients hospitalized in a 12-bed surgical intensive care unit (ICU) of the University Clinical Center of Serbia, Belgrade. Our study was conducted during the period of June–November, 2008. An independent physician reviewed the medical records of all infected patients. Data collected included the age, sex, and underlying disease for each individual, as well as the source and date of MBL producing P. mirabilis isolates. The patients were followed until they were either discharged from the hospital or died. Rectal colonization with MBL-producing P. mirabilis isolates was determined twice, in July and again in November from cultures of rectal swabs. Microbiologic studies. All enterobacterial isolates were tested for MBL production by a disk-diffusion test based on the synergy between imipenem and EDTA, an MBL inhibitor (7,8). Only isolates from clinical specimens (one per patient) were studied. Species identification of isolated bacteria was done with API 20E strips (bioMerieux, France). Antimicrobial susceptibilities were determined by disc diffusion, in accordance with recommendations of Clinical and Laboratory Standards Institute. Minimal inhibitory concentrations (MICs) of imipenem and meropenem were evaluated with Etest (AB Biodisk). All isolates were screened for extended-spectrum beta-lactamases (ESBLs) activity; this involved the double-disc synergy test, which is based on synergy between clavulanate and ceftriaxone, ceftazidime and cefepime. The addition of EDTA to the clavulanate disc enabled us to show the production of ESBL in previously ESBL negative strains as a result of the synergy between EDTA-clavulanate and cefotaxime and/or cefepime disk (9). Disk diffusion based on synergy between imipenem and the MBL inhibitor EDTA was then used to detect MBL production (9). We used a multiplex PCR assay to detect and differentiate each of five families of MBL genes: IPM, VIM, SPM, GIM and SIM (10). In July and in November, 2008, we recorded the point prevalence of rectal colonization by MBL-producing P. mirabilis in our ICU. Samples were obtained by rubbing pre-moistened swabs over the rectal area. Swab samples were then plated on MacConkey agar plates. Procedures of identification and phenotypic and susceptibility testing were as described above. Results We identified MBL-producing isolates of P. mirabilis that were not susceptible to carbapenems in patients in a surgical ICU. During the five month study period, nine patients were infected with a P. mirabilis strains that produced MBL (Tables 1 and 2). Early in the study, we found that 10 out of 12 patients (83%) had rectal colonization with MBL-producing P. mirabilis strains. In the last month of the study (November) none had the MBL-producing bacteria. Six of nine MBL-positive P. mirabilis strains belonged to the IPM family, and three other strains belonged to the VIM fam- ily (Table 1). All VIM postive isolates were collected in the third month (September). The last IPM-positive isolate was collected in late July. These strains were multiresitant in antibiotic disk diffusion tests; the three VIM isolates were susceptible to amikacin and ciprofloxacin (Table 1). Two of the nine isolates with molecular markers for MBL were negative in the imipenem-EDTA synergy test (Table 1). All of the isolates produced ESBL. We found no MBL-producing P. mirabilis strains in patients out of the ICU. All patients who had MBLproducing P. mirabilis isolates were hospitalized in the same surgical ICU. Table 2 shows the clinical characteristics and outcomes of 9 patients who were diagnosed with the infection. The mean age was 48.5 years (range 38-73 years): six patients were male. The mean length of stay in hospital before infection was 21 days (range 6-43 days). Bacteremia was diagnosed in 7 patients with 3 intravascular catheterrelated cases, a surgical site infection was diagnosed in one, and a urinary tract infection was diagnosed in one patient. All infected patients were treated previously with carbapenems (6 to 20 days), and all had central venous and urinary catheters in place. Overall mortality among the cohort of infected patients was 56%. Discussion We described an outbreak of MBL-producing P. mirabilis infection. The infection occurred after prolonged hospitalization (mean duration 21 days). At the beginning of the outbreak, rectal colonization was identified in almost all patients in the ICU. Like in Greek hospitals, bacteremia was the most common result of infection. (5,11) A study from a Greek hospital reported that mortality with MBL-producing enterobacteria was 68.8% (11). We were unable to establish mortality attributable indirectly to the infection, otherwise our mortality figures might have been higher. According to the Greek authors, patients infected with an organism, for which the MIC-s of both imipenem and meropenem were >4 μg/mL, were more likely to die than those infected with VIM-positive carbapenem-susceptible or VIM-negative organisms (11). Their molecular epidemiology studies confirmed that the outbreak of MBLproducing Klebsiella pneumoniae infection was polyclonal. In the outbreak that we studied, there were at least two clones of P. mirabilis resistant to carbapenems (VIM and IMP), suggesting the possibility of two separate outbreaks caused by IPM and VIM strains (Table 1 and 2). We were unable to do epidemiological typing, which could have confirmed this possibility. Furthermore, the observational design of our study did not allow for any conclusions as to the potential risk for acquiring MBL- producing P. mirabilis infection in our ICU. Infection control measures were intensified throughout the ICU, beginning in June, to contain the outbreak. Dedi- Mirović et al. cated infection control personnel ensured compliance with all hygiene and contact isolations measures and with adherence of personnel to meticulous environmental cleaning. This stringent regime was successful, because by the end of the year, we found no infected or colonized patients in this ICU. by disk diffusion. We noted that the imipenem-EDTA synergy test does not include all MBL positive isolates (Table 1). The multiplex PCR assay is rapid and simple, making it suitable for monitoring MBL-producing enterobacteria, but many laboratories do not have access to this technology. The susceptibility profile of our P. mirabilis isolates (Table 1) underscores the limited therapeutic choices available for the treatment of infected patients. The isolated strains also accumulated other beta-lactam resistance mechanisms, e.g, all strain produced ESBL. Tygecyclin and colistin are possible options for the treatment of these infections (5,11). Our observations provide some insight into the epidemiology and the clinical importance of this new threat, MBLproducing P. mirabilis. As MBL-producing P. mirabilis emerges as a life-threatening pathogen, it is critical to ensure timely and effective treatment of infections caused by this agent. More importantly, there is an urgent need to implement guidelines for the detection of MBL-producing bacteria and enhanced infection control measures to contain their dissemination. In contrast to our findings, the Greek authors reported that P. mirabilis clinical isolates carrying VIM-1 MBL had MICs for imipenem of 32 to >128 mg/L, and MICs for meropenem ranged from 1 to 8 mg/L (12). Possibly the strains that we isolated had acquired additional mechanisms of resistance (ESBL). No potential conflict of interest relevant to this article was reported. MBL detection by clinical laboratories is hindered by the fact that the presence of the MBL gene does not always confer resistance (1). Our isolates expressed high level of resistance to carbapenems, making it easy to detect them Table 1. Microbiological characteristics of 9 Proteus mirabilis isolates exhibiting in vitro carbapenem resistance Case/isolate Imipenem MIC, μg/mL Meropenem MIC, μg/mL Antimicrobial susceptibility phenotype* EDTA synergy test Double disc synergy test for ESBL detection MBL family 1 >32 >32 - - + IPM 2 >32 >32 - - + IPM 3 >32 >32 - + + IPM 4 >32 >32 - + + IPM 5 >32 >32 - + + IPM 6 >32 >32 - + + IPM 7 >32 >32 AMK, CIP + + VIM 8 >32 >16 AMK, CIP + + VIM 9 >32 >32 AMK, CIP + + VIM *, Phenotype was determined by disc diffusion test. All isolates were resistant to ampicillin, amoxicillin/clavulanate, piperacillin/tazobactam, ceftriaxone, ceftazidime, cefotaxime, cefepime, gentamicin, and trimethoprim-sulfamethoxasole; all but three were resistant to amikacin and ciprofloxacin. 77 78 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Table 2. Clinical characteristics of 9 patients infected by metallo-beta-lactamase- producing Proteus mirabilis* Gender/age Underlying disease Source of infection Previous carbapenem therapy (duration, days) CVK Urinary catheter Outcome 9 June m/38 Acute pancreatitis CVK 14 + + Death 2 16 June m/40 Acute pancreatitis Blood 19 + + Death 3 17 June m/72 Ileus Wound 20 + + Death 4 29 July m/60 Multiple trauma Urine 13 + + Death 5 10 July m/19 Multiple trauma CVK 6 + + Discharge 6 23 June f/73 Acute cholecystitis Blood 12 + + Discharge 7 19 September f/34 Multiple trauma Blood 11 + + Death 8 23 September m/51 Ileus Blood 6 + + Discharge 9 30 September f/50 Multiple trauma CVK 10 + + Discharge Case Date of sampling in 2008 1 * The order of cases corresponds to the order on the table 1. References 1. 2. 3. 4. 5. 6. 7. Walsh TR, Toleman MA, Piorel L, Nordmann P. Metallo-βlactamases: the Quiet before the Storm? Clin Microb Rev 2005; 18: 306-25. Paterson DL, Bonomo RA. Extended β-Lactamases: a clinical update. Clin Microbiol Rev 2005; 18; 657-86. Jones RN, Biedanbach DJ, Sader HS, Fritche TR, Toleman MA, Walsh TR. Emerging epidemic of metallo-β-lactamasemediated resistences.Diag Microbiol Infect 2005; 51: 77-84. Struelens MJ, Monnet DL, Magiorakos AP, Santos O Conor F, Giesecke J. New Delhi metallo-beta-lactamase 1-producing Enterobacteriaceae: emergence and response in Europe. Euro Surveill. 2010; 15(46):pii=19716. Available at: http://www.eurosurveillance.org/ViewArticle.aspx?Articleld=19716. Accessed August 19, 2011. Daikos GL, Petrikkos P, Psichogiou M, Kosmidis C, Vryonis E, Skoutelis A, at al. Prospective Observational Study of the Impact of VIM-1 Metallo-β-lactamase on the Outcome of Patients with Klebsiella pneumoniae Bloodstream Infections. Antimicrob Agent Chemother 2009; 53: 1868-73. Miriagou V, Papagiannitsis CC, Tzelepi E. Detecting VIM-1 production in Proteus mirabilis by Imipenem-Dipicolinic Acid Double Disk Synergy Test. J Clin Microbiol 2010; 48:667-8. Queenan AM, Bush K.Carbapenemases: the Versatile β-lactamases. Clin Microbiol Rev 2007; 20: 440-58. 8. Giakkoupi P, Tzouvelekis LS, Daikos GL, Miriagou V, Petrikkos G, Legakis NJ, Vatopoulos AV. Discrepancies and Interpretation Problems in Susceptibility Testing of VIM-1-Producing Klebsiella pneumoniae isolates, J Clin Microbiol 2005; 43: 494-6. 9. Drieux L, F Brosser F, Sougakoff W, Jarlier V. Phenotypic detection of extended-spectrum β-lactamases production in Enterobacteriaceae: review and bench guide. Clin Microbiol Infect 2008; 14 suppl. 1: 90-103. 10. Ellington MJ, Kistler J, Livermore DM, Woodford N. Multiplex PCR for rapid detection of genes ancoding aquired metallo-βlctamases. J Antimicrob Chemother 2007; 59:321-2. 11. Souli M, Kontopidou FV, Papadomickelakis E, Galani I, Armaganidis A, Giamarellou H. Clinical expirience og serious infections caused by Enterobacteriaceae producing VIM-1 metallo-βlactanase in a Greek university hospital. Clin Infect Dis 2008; 46:847-54. 12. Tsakris A, Ikonomidis TA, Poulou A, Spanakis N, Pornaras S, Markou F. Transmission in the community of clonal Proteus mirabilis carrying VIM-1 metallo-beta-lactamase. J Antimicrob Chemother 2007; 60:136-9. Mirović et al. Epidemija infekcije u hirurškoj jedinici intenzivne nege izazvane bakterijom Proteus mirabilis koja stvara metalo-beta-laktamazu Veljko Mirović, Biljana Carević, Srđan Stepanović, Zorica Lepšanović APSTRAKT Uvod. U radu je opisana epidemija infekcije u hirurškoj jedinici intenzivne nege (JIN) izazvane izolatima P. mirabilis koji stvaraju metalo-beta-laktamaze (MBL). Metode. Ovo je opservaciona retrospektivna studija. Podaci o bolesnicima, od kojih su poticali izolati P. mirabilis koji stvaraju MBL, prikupljeni su i analizirani retrospektivno. Svi izolati enterobakterija u posmatranom periodu su ispitani na stvaranje MBL. Izolati iz kliničkih uzoraka koji stvaraju MBL (samo jedan izolat od jednog bolesnika) ispitani su primenom multiplex lančane reakcije polimeraze kojom su detektovane i diferencirane familije gena za stvaranje MBL: IPM, VIM, SPM, GIM i SIM. Jula i novembra 2008. godine u ovoj jedinici intenzivne nege, uzeti su brisevi rektuma od svih bolesnika i ispitani na prisustvo izolata P. mirabilis koji stvaraju MBL. Rezultati. U periodu juni - novembar 2008. godine, ukupno devet pacijenata je bilo inficirano sa P. mirabilis koji stvara MBL. Epidemijski izolati prvi put su otkriveni u junu te godine i brzo su se proširili na odeljenju pa je sledećeg meseca, u studiji preseka, kod 10 od ukupno 12 pacijenata (83,3%) nađena kolonizacija rektuma sa P. mirabilis koji stvara MBL. Sa druge strane, posle primene epidemioloških mera kontrole i nadzora, novembra 2008. godine, u posmatranoj jedinici intenzivne nege nije bilo bolesnika s kolonizacijom rektuma ili infekcijom bakterijama P. mirabilis koje stvaraju MBL. Utvrđeno je sedam slučajeva bakterijemije uključujući tri slučaja povezana sa primenom intravenskog katetera, jedna infekcija rane hirurškog mesta i jedna infekcija urinarnog trakta. Šest od devet MBL pozitivnih izolata P. mirabilis pripadalo je IPM familiji, dok su ostala tri pripadala VIM familiji. Stopa smrtnosti inficiranih pacijenata iznosila je 56%, ali se nije mogla utvrditi smtrnost koja bi se mogla pripisati samoj infekciji. Zaključak. Pojava P. mirabilis koji stvara MBL u našoj bolnici predstavlja važan izazov za kliničke lekare, mikrobiologe i bolničke epidemiologe jer uz postojeću visoku učestalost rezistencije ograničava se mogućnost efikasne antibiotske terapije. Epidemiološke mere kontrole i nadzora nad ovom epidemijom bile su uspešne. KLJUČNE REČI karbapenemi, rezistencija na antibiotike, bolničke infekcije, enterobakterije 79 80 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com ORIGINAL ARTICLE Uticaj metaboličkog sindroma na pojavu ishemijskog moždanog udara APSTRAKT Uvod. Metabolički sindrom predstavlja skup metaboličkih i hemodinamskih poremećaja koji se pojavljuju udruženo kod pojedinih osoba i višestruko povećavaju rizik obolijevanja od aterosklerotskih kardiovaskularnih oboljenja i dijabetes melitusa tipa 2. Cilj rada je bio ispitati učestalost metaboličkog sindroma kod pacijenata sa ishemijskim moždanim udarom, analizirati zastupljenost pojedinih komponenti metaboličkog sindroma, te utvrditi rizik za pojavu ishemijskog moždanog udara u odnosu na broj pojedinačnih komponenti metaboličkog sindroma. Metode. Ispitivanje je obavljeno u Zavodu “Dr Miroslav Zotović“. Eksperimentalnu grupu je sačinjavalo 53 ispitanika koji su imali ishemijski moždani udar, a kontrolnu grupu 40 ispitanika sa degenerativnim oboljenjem lumbo-sakralne kičme. Svim ispitanicima je određen obim struka, visina krvnog pritiska, nivo glikemije, triglicerida i HDL holesterola. Dijagnoza metaboličkog sindroma je postavlena na osnovu novih, usaglašenih kriterijuma više međunarodnih organizacija iz 2009. godine. Rezultati. Učestalost metaboličkog sindroma kod ispitanika sa ishemijskim moždanim udarom je iznosila 89%, a kod kontrolne grupe 70% (p<0.05). Najzastupljenija pojedinačna komponenta metaboličkog sindroma kod eksperimentalne grupe je bila arterijska hipertenzija (100%), a najmanje zastupljena je bila poremećena glikoregulacijom (51%). Od svih ispitanika sa tri pojedinačne komponente metaboličkog sindroma 33% je imalo ishemijski moždani udar, dok je taj procenat za ispitanike sa svih pet pojedinačnih komponenti bio 77% (p<0.05). Zaključak. Značajno je veća učestalost metaboličkog sindroma kod ispitanika sa ishemijskim moždanim udarom nego kod kontrolne grupe. Najzastupljenija pojedinačna komponenta metaboličkog sindroma kod eksperimentalne grupe je bila arterijska hipertenzija. Prisustvo većeg broja pojedinačnih komponenti metaboličkog sindroma značajno povećava rizik oboljevanja od ishemijskog moždanog udara. Milorad Vujnić1, Nela Rašeta1, Milenko Kulauzov1, Duško Račić2, Bosa Azarić3, Aleksandra Dominović-Kovačević2 Katedra za patološku fi ziologiju, Medicinski fakultet, Banja Luka 2 Klinika za neurologiju, Banja Luka 3 Zavod za kliničku biohemiju, Banja Luka 1 Correspondence Milorad Vujnić, MD, MSc Katedra za patološku fi ziologiju, Medicinski fakultet Save Mrkalja 14, Banja Luka Tel: ++387 65 200-029 E mail: [email protected] KLJUČNE RIJEČI Ishemijski moždani udar, metabolički sindrom, inzulinska rezistencija, visceralna gojaznost (Scr Med 2011;42:80-3) Metabolički sindrom predstavlja skup metaboličkih i hemodinamskih poremećaja koji se pojavljuju udruženo kod pojedinih osoba i višestruko povećavaju rizik za aterosklerotska kardiovaskularna oboljenja i dijabetes melitusa tip 21. Pacijenti koji boluju od metaboličkog sindroma tri puta češće obolijevaju i dva puta češće umiru od srčanog udara ili ishemijskog moždanog udara u poređenju sa osobama koje ne boluju od metaboličkog sindroma. Takođe, osobe sa metaboličkim sindromom pet puta češće obolijevaju od dijabetes melitusa tipa 22. Patofiziološka osnova metaboličkog sindroma još uvijek je nedovoljno poznata. Smatra se da su glavni uzročnici meta- Submitted: September 20, 2011 Accepted: October 3, 2011 boličkog sindroma visceralna gojaznost i inzulinska rezistencija. Najčešće navođene komponente metaboličkog sindroma su visceralna gojaznost, poremećaj glikoregulacije, povišen arterijski krvni pritisak, povišen nivo triglicerida i snižen nivo HDL holesterola. Međutim, postoje dokazi o povezanosti metaboličkog sindroma sa brojnim drugima oboljenjima, uključujući sindrom policističnih jajnika, nealkoholno masno oboljenje jetre, poremećaj disanja i spavanja, Alzheimer-ova bolest, karcinom pluća, prostate i gušterače3. Različiti kriterijumi za dijagnozu metaboličkog sindroma su bili predloženi od strane više stručnih organizacija. Prvu definiciju i kriterijume za postavljanje dijagnoze dala je Svjetska Vujnić et al. zdravstvena organizacija 1998. godine. Nakon toga definicije su dali Evropska grupa za studije inzulinske rezistencije, Nacionalni program edukacije o holesterolu-treći panel za odrasle (NCEP-ATPIII), Međunarodna federacija za dijabetes (IDF)4. Postojanje većeg broja definicija metaboličkog sindroma i kriterijuma za njegovo utvrđivanje otežavalo je poređenje podataka brojnih studija koje su se bavile istim, a takođe i njegovo etabliranje kao posebnog kliničkog entiteta u ljekarskoj praksi. Tokom 2009. godine održan je sastanak nekoliko međunarodnih organizacija koje se bave metaboličkim sindromom, u pokušaju da se usaglase dijagnostički kriterijumi. Kao rezultat toga utvrđeni su novi, jedinstveni kriterijumi za dijagnozu metaboličkog sindroma5. Cilj ovog rada je da se ispita učestalost metaboličkog sindroma kod pacijenata sa ishemijskim moždanim udarom, analizira zastupljenost pojedinih komponenti metaboličkog sindroma, te utvrdi rizik za pojavu ishemijskog moždanog udara u odnosu na broj pojedinačnih komponenti metaboličkog sindroma. Materijal i metode Istraživanje je provedeno kao prospektivna studija u Zavodu „Dr Miroslav Zotović“ u Banjaluci. Eksperimentalnu grupu su sačinjavala 53 ispitanika koja su preboljela akutni ishemijski moždani udar, a nalazili su se na rehabilitaciji u navedenoj zdravstvenoj ustanovi. Kod svih ispitanika ove grupe dijagnoza moždanog udara bila je potvrđena „imaging“ metodom (kompjuterizovana tomografija ili magnetna rezonancija endokranijuma). Kontrolnu grupu je sačinjavalo 40 ispitanika, oboljelih od degenerativnih oboljenja lumbosakralnog dijela kičmenog stuba (lumbago, lumbalna polidiskopatija ili lumboišijalgija). Ispitanici ove grupe su odabrani uvidom u dostupnu medicinsku dokumentaciju, a kod njih je isključeno postojanje ranijeg vaskularnog oboljenja (infarkt mozga, infarkt srca, angina pektoris, aterosklerotska oboljenja perifernih arterija). Eksperimentalna grupa je bila prosječne starosti 63±5.9 godina, a kontrolna 58±5.4 godina. Svim ispitanicima u cilju postavljanja dijagnoze metaboličkog sindroma izvršeno je mjerenje obima struka u stojećem stavu sa petama razmaknutim oko 30 cm na sredini rastojanja između donje ivice poslednjeg rebra i grebena karlične kosti, određivanje krvnog pritiska živinim manometrom u sjedećem položaju i stanju relaksacije dva puta u razmaku od 5 minuta (za analizu je korištena srednja vrijednost navedenih mjerenja), određivanje nivoa triglicerida, HDL holesterola i glukoze u serumu, a uzorak venske krvi za biohemijske analize je uziman na tašte, najmanje 12 časova nakon posljednjeg obroka (serumske koncentracije HDL holesterola, triglicerida i glukoze su određivane standardnim biohemijskim metodama pomoću aparata Roche Cobas C111). Za postavljanje dijagnoze metaboličkog sindroma korišteni su novi, usaglašeni kriterijumi iz 2009. godine. Prema njima osoba boluje od metaboličkog sindroma, ako ima najmanje tri od sledećih pet poremećaja: povećan obim struka (≥94 cm za muškarce, ≥80 cm za žene), povišeni trigliceridi u krvi (≥1,7 mmol/L ili uzimanje lijekova za snižavanje triglicerida), snižen HDL holesterol u krvi (<1,0 mmol/L za muškarce, <1,3 mmol/L za žene), povišen arterijski krvni pritisak (sistolni ≥130 mmHg i/ili dijastolni ≥85 mmHg) ili ranije dijagnostikovana arterijska hipertenzija, poremećaj glikoregulacije (povišena glikemija na tašte ≥5,6 mmol/L ili ranije dijagnostikovan dijabetes melitus tipa 2)5. U statističkoj analizi je korišten 2 test. Statistički značajne razlike smatrane su vrijednosti ako je p<0.05. Rezultati U grupi bez moždanog udara 70% ispitanika je imalo metabolički sindrom, dok je procenat u grupi ispitanika sa moždanim udarom iznosio je 88,6%. Razlika u učestalosti metaboličkog sindroma između posmatranih grupa je statistički značajna (p<0.05). Svi ispitanici eksperimentalne grupe imali su povišen arterijski krvni pritisak, oko 80% ispitanika ove grupe je imalo snižen HDL holesterol u krvi, a sličan je bio i procenat ispitanika sa povećanim obimom struka. Povišeni trigliceridi u krvi nađeni su u 73,6% ispitanih sa moždanim udarom, poremećaj glikoregulacije u krvi je nađen kod 50,9% ispitanih, a 26,4% ispitanih sa moždanim udarom je bolovalo od dijabetes melitusa tipa 2. (Slika 1). Slika 1. Zastupljenost komponenti metaboličkog sindroma za ispitanike sa moždanim udarom Na tabeli 1 prikazano je da povećanje broja pojedinačnih komponenti metaboličkog sindroma uvećava rizik od ishemijskog moždanog udara. Od svih ispitanika sa manje od tri komponente metaboličkog sindroma 33% je imalo moždani udar. Sa povećanjem broja komponenti metaboličkog sindroma, procenat ispitanika sa moždanim udarom raste i dostiže vrijednost od 77% za ispitanike sa svih pet komponenti metaboličkog sindroma. Ove razlike su statistički značajne (p<0.05). Diskusija U ovom istraživanju je utvrđena izuzetno visoka učestalost metaboličkog sindroma kod ispitanika sa ishemijskim 81 82 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Tabela 1. Učestalost i zastupljenost ispitanika sa moždanim udarom u odnosu na broj pojedinačnih komponenti metaboličkog sindroma Metabolički sindrom (broj komponenti) Sa MU Bez MU Svega Učestalost % Učestalost % 6 33.33 12 66.67 18 3 11 45.83 13 54.17 24 4 19 65.52 10 34.48 29 5 17 77.27 5 22.73 22 0-2 moždanim udarom, ali je učestalost ovog sindroma takođe povećana i kod kontrolne grupe. Razlika u učestalosti metaboličkog sindroma između te dve grupe bila je značajna. Rizik za pojavu ishemijskog moždanog udara se povećavao sa povećanjem broja pojedinačnih komponenti metaboličkog sindroma. Osobe sa četiri ili pet komponenti metaboličkog sindroma su značajno češće oboljevale od ishemijskog moždanog udara u odnosu na osobe kod kojih su bile prisutne tri ili manji broj komponenti metaboličkog sindroma. Analizirajući zastupljenost i značaj pojedinačnih komponenti metaboličkog sindroma kod ispitanika eksperimentalne grupe, ustanovljeno je da je najzastupljenija bila arterijska hipertenzija, tako da su svi ispitanici imali povišen krvni pritisak prilikom mjerenja ili su od ranije bolovali od arterijske hipertenzije. Četiri od pet ispitanika su imali snižen nivo HDL holesterola u krvi i povećan obim struka, a nešto manji broj je imao povišen nivo triglicerida u krvi. Oko polovine ispitanika sa ishemijskim moždanim udarom je imalo poremećaj glikoregulacije (povišena glikemija na tašte ili dijabetes melitus tipa 2) i to je bila najmanje zastupljena pojedinačna komponenta metaboličkog sindroma kod ovih ispitanika. Od dijabetes melitusa tipa 2 je bolovala četvrtina ispitanika sa ishemijskim moždanim udarom. U ovom istraživanju nije praćen poremećaj tolerancije glukoze, što bi moglo imati uticaja na pojavu kardiovaskularnih incidenata6. Olijhoek i saradnici7 su ispitivali učestalost metaboličkog sindroma, definisanog prema ATP III kriterijumima, kod pacijenata sa već postojećim, različitim aterosklerotskim oboljenjima. Pacijenti oboljeli od moždanog udara su imali učestalost metaboličkog sindroma od 43%. Oni su pokazali da metabolički sindrom uzrokuje dodatno oštećenja krvnih sudova kod pacijenata sa navedenim oboljenjima. Da Silva i saradnici8 su ustanovili veću učestalost metaboličkog sindroma kod ispitanika Južno Azijskog u odnosu na ispitanike Kineskog porijekla (61%: 47%), što naglašava uticaj etničke pripadnosti na pojavu metaboličkog sindroma. U Saudijskoj Arabiji je nedavno nađeno da učestalost metaboličkog sindroma, definisanog prema ATP III kriterijumima, iznosi 57% za sve tipove moždanog udara, a 64% za ishemijski moždani udar9. Milinois je sa saradnicima10 ispitivao vezu između metaboličkog sindroma, definisanog različitim definicijama, i rizika od prvog, neembolijskog ishemijskog moždanog udara kod starije populacije. Prema NCEP ATP III kriterijuma OR za ishemijski moždani udar je bio 2,59, a prema kriterijumima Američke asocijacije za srce 3,18. Metabolički sindrom definisan prema IDF definiciji nije bio značajno povezan sa ishemijskim moždanim udarom. Hoorn studija je pokazala da metabolički sindrom, bez obzira na korištene kriterijume za postavljanje dijagnoze, povećava za oko dva puta ukupni mortalitet i morbiditet od kardiovaskularnih oboljenja kod Evropske populacije11. Chen12 i Malik13 su ustanovili da osobe sa jednom i dvije komponente metaboličkog sindroma imaju manji HR za pojavu ishemijskog moždanog udara i koronarnog oboljenja srca u odnosu na osobe sa tri i više komponenti metaboličkog sindroma. U studiji Doi-a14 i saradnika u populaciji Japana rizik za kardiovaskularna oboljenja se povećavao sa povećanjem broja komponenti metaboličkog sindroma jedino ako je bila prisutna centralna gojaznost. Veći broj istraživanja je pokazao da je arterijska hipertenzija najzastupljenija pojedinačna komponenta metaboličkog sindroma7,8,15. Na osnovu našeg istraživanja možemo zaključiti da postoji značajno veća učestalost metaboličkog sindroma kod ispitanika oboljelih od ishemijskog moždanog udara u odnosu na kontrolnu grupu, ali je evidentna visoka učestalost metaboličkog sindroma i kod kontrolne grupe. Najzastupljenija pojedinačna komponenta metaboličkog sindroma kod ispitanika sa moždanim udarom je arterijska hipertenzija, a povećanje broja pojedinačnih komponenti metaboličkog sindroma povećava rizik oboljevanja od ishemijskog moždanog udara. Ovi podaci su u skladu sa većinom podataka iz literature. Ti podaci ukazuju na potrebu smanjenja učestalosti faktora rizika u opštoj populaciji edukacijom stanovništva i sprovođenjem mjera primarne prevencije. Pored toga, važna je kontrola faktora rizika i metaboličkog sindroma kod pacijenata sa već postojećim aterosklerotskim oboljenjima, uključujući ishemijski moždani udar, radi prevencije dodatnih vaskularnih oštećenja i nastanka rekurentnog moždanog udara. M. V. je dobitnik finansijske pomoći Ministarstva za nauku i tehnologiju Vlade RS za izradu ovog istraživanja. Ostali autori nisu deklarisali konflikt interesa vezan za ovo istraživanje. Vujnić et al. Literatura 1. 2. 3. 4. 5. 6. 7. 8. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA et al. Diagnosis and management of the metabolic syndrome. AHA/NHLB scientific statement. Circulation 2005; 112: 2735-52. The IDF consensus worldwide definition of the metabolic syndrome. International diabetes federation, 2005. Handelsman Y. Metabolic syndrome pathophysiology and clinical presentation. Toxicol Pathol 2009; 37: 18-20. Huang PL. A comprehensive definition for metabolic syndrome. Dis Models Mech. 2009; 2: 231-7. Alberti KGMM, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA et al. Harmonizing the metabolic syndrome. A joint interim statement of the International diabetes federation task force on epidemiology and prevention; National heart, lung, and blood institute; American heart association; World heart federation; International atherosclerosis society; and International association for the study of obesity. Circulation 2009; 120:1640-5. DeFronzo RA, Abdul-Ghani M. Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose. Am J Cardiol 2011; 108(3 Suppl): 3B-24B. Olijhoek JK, Van der Graaf Y, Banga JD, Algra A, Rabelink TJ, Visseren FLJ. The metabolic syndrome is associated with advanced vascular damage in patients with coronary heart disease, stroke, peripherial arterial disease or abdominal aortic aneurysm. Eur Heart J. 2004; 25. 342-8. Da Silva DA, Woon FP, Xie XY, Chen CLH, Chang HM and Wong MC. Metabolic syndrome among ethnic South Asian patients with ischemic stroke and comparison with ethnic Chinese patients: The 9. 10. 11. 12. 13. 14. 15. Singapore general hospital experience. J Stroke Cerebrovasc Dis 2007; 16: 119-21. Reffat S, Sheikh B, Fath-El-Bab M, GabalAM, Ibrahim M, Hassan A and Sandgji H. Metabolic syndrome in acute stroke patients in Al-Madinah Al-Munawarah Kingdom of Saudi Arabia. Journal of Medicine and Biomedical Sciences 2010; 1: 2078-83. Milionis HJ, Kostapanos MS, Liberopoulos EN, Goudevenos J, Athyros VG, Mikhailidis DP, Elisaf MS. Different definitions of the metabolic syndrome and risk of first ever acute ischaemic non-embolic stroke in elderly subjects. Int J Clin Pract 2007, 61: 545-51. Dekker JM, Girman C, Rhodes T, Nijpels G, Stehouwer CDA, Bouter LM and Heine RJ. Metabolic syndrome and 10-year cardiovascular disease risk in the Hoorn study. Circulation 2005; 112: 666-73. Chen HJ, Bai CH, Yeh WT, Chiu HC, Pan WH. Influence of metabolic syndrome and general obesity on the risk of ischaemic stroke. Stroke 2006; 37: 1060-4. Malik S, Wong ND, Franklin SS, Kamath TV, L′Italien GJ, Pio JR et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease and all causes in United States adults. Circulation 2004; 110: 1245-50. Doi Y, Ninomiya T, Hata J, Yonemoto K, Arima H, Kubo M, Tanizaki Y, Iwase M, Iida M and Kiyohara Y. Proposed criteria for metabolic syndrome in Japanese based on prospective evidence: The Hisayama study. Stroke 2009; 40: 1187-94. Morag NK, Goldbourt U, Tanne D. Relation between the metabolic syndrome and ischaemic stroke or transient ischaemic attack: A prospective cohort study in patients with atherosclerotic cardiovascular disease. Stroke 2005; 36: 1366-71. Metabolic syndrome affects stroke Milorad Vujnić, Nela Rašeta, Milenko Kulauzov, Duško Račić, Bosa Azarić, Aleksandra Dominović-Kovačević ABSTRACT Introduction. Metabolic syndrome is a set of metabolic and hemodynamic disorders that appear associated with certain persons and multiply the risk of atherosclerotic cardiovascular diseases and diabetes mellitus type 2. The aim of this study was to examine the prevalence of metabolic syndrome in patients with ischemic stroke, to analyze the representation of individual components of metabolic syndrome, and to determine the risk of ischemic stroke in relation to the number of individual metabolic syndrome components. Methods. The study was conducted at the Institute “Dr Miroslav Zotović”. The experimental group included 53 examinees who had ischemic stroke and control group included 40 examinees with degenerative lumbo-sacral spine diseases.Data on waist circumferences, blood pressure, blood glucose, triglycerides and HDL holesterol levels were recorded for all examinees. Diagnosis of metabolic syndrome was set based on new criteria, which were agreed by a number of international organizations in 2009. year. Results. The prevalence of metabolic syndrome in examinees with ischemic stroke amounted 89% and 70% of the control group (p<0.05). The most common single component of the metabolic syndrome in the group with stroke was hypertension (100%) and least common one was impaired glycoregulation (51%). Out of all examinees who had three individual components of metabolic syndrome 33% had ischemic stroke, while the percentage of those who had all five individual components was 77% (p<0.05). Conclusion. There is significantly higher prevalence of metabolic syndrome in examinees with ischemic stroke than in the control group. The most common single component of the metabolic syndrome in the experimental group was hypertension. The presence of a large number of individual components of metabolic syndrome increases the risk for developing ischemic stroke. KEY WORDS Ischemic stroke, metabolic syndrome, insulin resistance, obesity 83 84 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Tomislav Kažić REVIJSKI ČLANAK/REVIEW ARTICLE Beograd Statini – neželjena dejstva i interakcije APSTRAKT „Statini se načelno dobro podnose, teška neželjena dejstva su retka, i znatno su manje važna od koristi zbog smanjenja mortaliteta i morbiditeta“ – je fraza koja se ponavlja kao opšte mesto u tekstovima o statinima, ili plašt koji pokriva veliki deo populacije bolesnika među kojima se nalaze značajne grupe: stari, mršavi, žene, osobe sa bolestima bubrega, jetre, tireoideje i alkoholičari – koji su bili izbegavani ili u malom broju uključivani u randomizirane kontrolisane studije, na osnovu kojih se formira profil neželjenih dejstava pojedinih statina. Međutim, ovi bolesnici se ne ostavljaju bez statina, te se može očekivati mnogo veća incidenca neželjenih dejstava od deklarisanih. To je glavni naučni oslonac za tvrdnju da su neželjena dejstva statina nepotpuno procenjena. U medicinskoj praksi zasnovanoj na kliničkim studijama trajanja od 2 do 5 godina, i kod bolesnika sa visokim KV rizikom tj. u studijama sekundarne prevencije, najveća pažnja se posvećuje efikasnosti tj. smanjenju morbiditeta i mortaliteta, a u oblasti neželjenih dejstava simptomatskim tegobama usled oštećenja mišića: mijalgija, miozitis, miopatija, rabdomioliza (koje prate povišene vrednosti CK), i asimptomatskim povišenjima nivoa jetrinih enzima transaminaza ALT i AST, koje su nagoveštaj hepatotoksičnosti. Ovi tipovi neželjenih dejstava su zajednički za statine kao grupu, zavise od doze – a doze se povećavaju zbog snižavanja ciljnih vrednosti LDL-H – i pouzdano su reverzibilne posle prekida terapije. Očekuje se da bolesnici uzimaju statine barem 20-30 godina, za koje vreme nema pouzdanih podataka ni o efektivnosti niti o neželjenim dejstvima. Upotreba statina u primarnoj prevenciji KV rizika u razvijenom svetu je već uzela neslućene razmere. Na nastalu euforiju slabo deluju izolovana upozorenja Preporuka ili sistematskih revija da propisivanju statina bolesnicima sa malim KV rizikom treba pristupati oprezno. Kod proučavanja neželjenih dejstava upotrebe statina u primarnoj prevenciji nailazi se na veliki nesklad između rezultata pojedinačnih studija i meta-analiza. Pojedine studije argumentovano ukazuju da statini mogu izazvati anksioznost, depresiju, samoubistva, slabljenje memorije, dijabetes i deluju kancerogeno, a neznatno smanjuju KV rizik – iako znatno snižavaju nivoe LDL-H. Nasuprot tome, meta-analize tvrde da statini i u primarnoj prevenciji smanjuju mortalitet i KV rizik (mada u manjem procentu) bez povećanja incidence neželjenih dejstava. U našim krajevima upotreba statina još nije velika kao u nekim bogatim delovima sveta. KLJUČNE RIJEČI Statini, prevencija KV rizika, neželjena dejstva, miopatija, hepatotoksičnost, interakcije (Scr Med 2011;42:84-91) U toku protekle decenije traje velika ekspanzija upotrebe statina, primarno kao lekova za bolesnike velikog KV rizika – u tzv. sekundarnoj prevenciji – posle preležanog infarkta miokarda, sa potvrđenom ishemijskom bolesti srca, i posle ishemijskog šloga ili sa bolestima perifernih arterija. U ovim populacijama, mnoge randomizirane kliničke studije i meta-analize su pokazale da statini smanjuju KV mortalitet i morbiditet srazmerno sniženju nivoa LDL-holesterola (LDL-H), tako da se može generalizovati stav da sniženje LDL-H za 1 mmol/l (40 mg%) smanjuje KV mortalitet i morbiditet za 22-25%. Submitted: August 5, 2011 Accepted: August 15, 2011 U ovim studijama, neželjena dejstva jesu bila praćena, ali sa mnogo manje entuzijazma (s obzirom da su sponzori studija uglavnom firme proizvođači), ali se ipak saopštava da su ona raznovrsna (Tabela 1), da su dozno-zavisna, da je incidenca mala, a intenzitet uglavnom blag, te da je šteta po zdravlje neznatna u odnosu na korist od smanjenja KV rizika. Ipak, 5.2% bolesnika u kontrolisanim kliničkim studijama je prekinulo lečenje zbog neželjenih dejstava atorvastatina, a 4% u placebo grupama. Kažić Tabela 1 Neželjena dejstva statina – prema dokumentaciji proizvođača (SPC) Lokalizacija Česta (1/100 - 1/10) Infekcije i infestacije Nazofaringitis Nisu česta (1/1,000 1/100) Krv i limfni sistem Imuni sistem Alergijske reakcije Psihijatrijski poremećaji Neurološki poremećaji Glavobolja Anafilaksa Hipoglikemija, dobijanje težine, anoreksija Nesanica, košmarni snovi Vrtoglavica, parestezije, Periferna neuropatija hipoestezije, disgeuzija Oko Nejasan vid Uho i labirint Tinitus Respiratorni trakt i toraks Bol u guši i grlu, epistaksa Gastrointestinalni trakt Nauzeja, dispepsija, dijareja, opstipacija Hepatobilijarni sistem Koža i potkožno tkivo Depresija Poremećaji vida Gubitak sluha Povraćanje, bolovi u abdomenu, podrigivanje, pankreatitis Hepatitis Holestaza Urtikarija, ospa, svrab, alopecija Angioedem, dermatitis, eritema multiforme, Stevens-Johnson sindrom, toksična nekroliza epiderma Mijalgija, artralgija, bol u eks-tremitetiBol u vratu, zamor ma, spazmi mišića, mišića otok zglobova, bolovi u kičmi Reproduktivni sistem i dojke Hepatička insuficijencija Miopatija, rabdomioliza, miozitis, tendinopatija do rupture Ginekomastija Slabost, bol u grudima, periferni edemi, zamor, povišena temperatura Opšte stanje Laboratorijski nalazi Vrlo retka (< 1/10,000) Trombocitopenija Metabolizam i ishrana Hiperglikemija Mišići, kosti i vezivno tkivo Retka (1/10,000 1/1,000) Poremećaj testova jetre: transaminaze 0.8%. CPK 0.4% Leukociti u mokraći Tipovi i učestalost neželjenih dejstava su zajednički za sve statine, mada se na tom planu vodi velika i ne uvek poštena konkurentska bitka u kojoj se jedni hvale većom jačinom i brzinom dostizanja ciljnih nivoa LDL-H, a rivali ih otpužuju za veću incidencu opasnih neželjenih dejstava. U tim okršajima prvi je stradao cerivastatin, koji je bio oko 100 puta jači od ostalih statina, a napušten je 2001., posle samo godinu dana primene zbog 52 smrtna slučaja usled rabdomiolize posle interakcije sa gemfibrozilom. Sada, 2011. na udar je došao simvastatin, zapravo visoke doze simvastatina, takođe zbog veće incidence miopatije. Kako se grupa statina povećava uvođenjem rosuvastatina i pitavastatina, ona počinje gubiti monolitnost, ukazuje se potreba za diferenijaciju na slabe i jake, na dobre i još bolje, i ne treba se iznenaditi ako se pitavastatin uskoro promoviše kao statin koji ne izaziva miopatiju. 85 86 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Najčešće jesu nespecifične gastrointestinalne tegobe i alergijske reakcije: nadutost stomaka, opstipacija, dijareja i ospe, hepatotoksičnost i miopatija, i o vim poslednjim se jedino opširno razmatra ne samo u preglednim člancima posle prve decenije, već i u najnovijim Preporukama iz 2011.1 Na talasima marketinške euforije statini se proglašavaju čudotvornim lekovima “koji spasavaju hiljade života”, progresivno se povećava propisivanje statina toliko da oni postaju ne samo najviše korišćena grupa lekova za terapiju dislipidemija, već i najviše propisivana grupa lekova uopšte, i svakako grupa lekova koja najviše puni kase firmi proizvođača i najviše prazni fondove socijalnog osiguranja. Nekontrolisana upotreba statina zahvatila je i inače racionalne Britance; nastaje stanje u kojem: 7 miliona ljudi uzima neki statin ili jedna od tri osobe starije od 40 godina, svake godine se za 30% povećava broj recepata za statine jer se stimuliše propisivanje statina svakom muškarcu starijem od 50 i ženi starijom od 60 godina bez obzira na KV rizik, a male doze simvastatina se mogu kupiti i bez recepta.2 U SAD je situacija još dramatičnija, jer oko 40 miliona Amerikanaca svakodnevno uzima statine, sa trendom stalnog porasta. Prema izveštaju Centra za kontrolu bolesti za 2010, u periodu 1988-2008. upotreba statina se povećala 10 puta, tako da sada jedna od četiri osobe uzima statine odnosno svaki drugi muškarac stariji od 45 godina, i jedna od tri žene u godinama od 65 do 74.3 Međutim, SAD su poseban slučaj, nepogodan za poređenje, jer su iz te države svi proizvođači statina, i dozvoljeno je slobodno reklamiranje lekova koji se propisuju na recept uključujući statine, tako da su svi mediji puni hvale za ove čudotvorne lekove, mada ima i osporavanja. U Evropi se nalazi u prometu pet statina: lovastatin, simvastatin, atorvastatin, fluvastatin i rosuvastatin, a u SAD još i pitavastatin. Međutim, daleko najviše se koriste simvastatin i atorvastatin, i uz male varijacije čine oko 90% ukupne potrošnje. Procene o efikasnosti i podnošljivosti se uglavnom donose analizom rezultata kliničkih studija ova dva leka. Upotreba statina u svetu nije uravnotežena, jer postoje velike regionalne razlike. U Norveškoj su statini najviše propisivani lekovi sa preko 100 DDD/1000 stanovnika/ dan, a u Italiji 3-5 puta manje, zavisno od godine iz koje su podaci. Između njih su ostale države EU. Prema proceni Euro-Med-Stat grupe iz 2005. 4, upotreba statina raste za oko 35% godišnje, delom zbog medicinskih, ali većim delom zbog nemedicinskih razloga koji uključuju i ekonomske, tj. nedostupnost zbog visokih cena. Pri tome se konstatuju dva nepovoljna trenda: nedovoljna je upotreba statina u sekundarnoj prevenciji – koja je dokazano korisna, a povećava se upotreba u primarnoj prevenciji – koja je dokazano štetna i nema dokaza da je korisna. U Srbiji statini su 2009. bili tek na šestom mestu po prodaji; propisivalo se ukupno 26 DDD/1000 stanovnika/dan (13 simvastatin, 11 atorvastatin). U Republici Srpskoj statini se propisuju još ređe. U primarnoj prevenciji, efektivnost statina se dokazuje vrlo teško ili nikako, jer vrlo veliki broj inače zdravih osoba sa malim KV rizikom treba da uzima statine da bi samo jedna od njih bila pošteđena nekog KV događaja (NNT = 250-500) (NNT = number needed to treat). Nasuprot tome, milioni ljudi se nepotrebno izlažu riziku od pojave nekog neželjenog dejstva. Zato se otvaraju ozbiljne sumnje u efektivnost statina i izražavaju strahovi od niza neželjenih dejstava o kojima se nije vodilo mnogo računa u studijama sekundarne prevencije KV rizika. Raspravlja se o tome da li statini prouzrokuju depresiju, slabljenje mentalnih funkcija, perifernu neuropatiju, dijabetes, kancer i povećanje mortaliteta. Ove teme zaslužuju veću pažnju posle saznanja da se statini koriste već oko 30 godina, a da su profili neželjenih dejstava formirani na osnovu studija koje su trajale 2-5 godina. Uostalom, ako je u studijama sekundarne prevencije primarni cilj dokazivati efikasnost i smanjivati mortalitet i morbiditet po principu Primum optime curare, u primarnoj prevenciji treba da bude primarna bezbednost upotrebe lekova po starom terapijskom principu: Primum non nocere. Otuda sazreva svest da je upotreba statina dosad najveći eksperiment na ljudima koji impresionira smanjenjem KV rizika kod jedne grupe bolesnika i enormnim profitima, ali ostavlja bez odgovora mnoga pitanja. Miopatija i rabdomioliza Miopatija se standardno definiše kao povišenje nivoa kreatin kinaze (CK) u serumu za deset puta u odnosu na gornje granice normale (GGN ili engl. upper limits of normal = ULN), uz neobjašnjivu slabost mišića ili bol. U novije vreme, uključujući Preporuke Evropskih udruženja za kardiologiju i aterosklerozu prihvataju kao podnošljivo povišenje za pet puta u odnosu GGN/ULN. Rabdomioliza se definiše kao teški oblik miopatije koji prate neobjašnjiv bol ili slabost mišića uz povišenje nivoa CK u serumu za više od četrdeset puta u odnosu na GGN/ULN. Povišenje CK se prihvata kao primarni marker za oštećenje ćelija mišića koje je u toku i smrt ćelije, a oslobođeni mioglobin direktno oštećuje bubrege.1 Uprkos nesporne i značajne KV efektivnosti, statini prouzrokuju miopatiju različitog intenziteta, od asimptomatskog povišenja serumske CK do bolova ili slabosti u mišićima sve do fatalne rabdomiolize. Generalno, miopatija nastaje kod bolesnika sa kompleksnim zdravstvenim problemima i/ili koji uzimaju veći broj lekova – naročito ako ometaju transport ili katabolizam statina, kod starih osoba (starijih od 80 godina), kod disfunkcije jetre i bubrega, dijabetesa, nelečenog hipotireoidizma, nežne telesne građe i češće kod žena. Kažić Mijalgija – bez povišenja CK – sreće se kod 5-19% bolesnika u kliničkoj praksi; njih treba upozoriti da se odmah jave lekaru, ali se terapija može nastaviti ako su tegobe blage i lako podnose. Jaki statini kao atorvastatin i rosuvastatin bi se mogli davati svaki drugi dan da se smanje tegobe. Nedavno je došlo u žižu interesovanja nesrazmerno povećanje incidence miopatije izazvano visokim dozama simvastatina. Ostavljajući za ovu priliku po strani kliničku efektivnost, ovde se ističe da je u velikoj studiji SEARCH (12.064 bolesnika koji su preživeli akutni infarkt miokarda), miopatiju imalo 52 bolesnika koji su dobijali 80 mg simvastatina, a samo 1 koji je dobijao dozu od 20 mg. U skladu sa time, rabdomioliza je bila registrovana kod 22 bolesnika iz grupe 80 mg, a ni kod jednog iz grupe lečenih sa 20 mg simvastatina.5 Generalno, rabdomioliza može se završiti fatalno kod 1 od milion recepata.6 Analiza ostalih velikih studija u kojima su davane visoke doze statina, incidenca miopatije jeste bila vrlo mala za sve statine, ali je ipak bila tri puta češća kod bolesnika koji su dobijali 80 mg simvastatina nego kod upotrebe statina koji su čak i više snižavali LDL-H kao atorvastatin i rosuvastatin. U skladu sa time je nalaz da je prijava fatalne rabdomiolize bila češća kod bolesnika koji su dobijali 80 mg simvastatina nego kod onih koji su dobijali po 80 mg atorvastatina ili 20-40 mg rosuvastatina. Uzroci ove pojave se ne traže u posebnostima strukture molekula simvastatina, već u činjenici da se on ekstenzivno metaboliše u sistemu enzima CYP3A4, zbog čega ulazi u interakcije sa lekovima koji se istovremeno primenjuju kao amiodaron, diltiazem i amlodipin – koje povećavaju rizik od miopatije. Zato se pretpostavlja da bi studiozna istovremena upotreba ostalih lekova sa nižim dozama simvastatina mogla smanjiti rizik od miopatije. Bitno je da se zna da je rizik od simvastatinom izazvane miopatije i rabdomiolize najveći u prvoj godini terapije. Incidenca miopatije se smanjuje sa 5 na 1 1000 bolesnik-go- dina, a rabdomiolize sa 2 na 0.4 bolesnik-godina posle 12 meseci terapije. Ovo smanjenje ukazuje da se u ranoj fazi terapije otkriva subpopulacija bolesnika sklonih razvoju miopatije i rabdomiolize, i da su to osobe sa varijacijama gena SLCO1B1, koji u hepatocitima kodira transporter za statine.7 Polazeći od činjenice da maksimalne doze simvastatina nose veći rizik od miopatije nego ostali lekovi, FDA nedavno predlaže sledeće nove modifikacije doziranja da bi se taj rizik smanjio: 6 dozu od 80 mg simvastatina mogu da nastave uzimati samo oni koji je već uzimaju duže vreme (npr. 12 meseci ili duže) bez znakova ili simptoma oštećenje mišića; bolesnicima koji uzimaju po 80 mg simvastatina dnevno bez neželjenih dejstava, ali treba da im se uključi u terapiju neki od lekova koji izazivaju interakcije i koji su kontraindikovani u kombinaciji sa simvastatinom (Tabela 2), treba zameniti simastatin nekim drugim statinom sa manjim potencijalom za interakcije; bolesnicima kod kojih se ciljni nivo LDL-H ne može postići sa 40 mg simvastatina treba dati neki od jačih statina sa manjim rizikom od miopatije, npr. atorvastatin ili rosuvastatin. Hepatotoksičnost Statini prouzrokuju česta, prolazna, asimptomatska i reverzibilna oštećenja hepatocita, koja se otkriju na promenjenim laboratorijskim nalazima funkcije jetre, kao povišeni nivoi transaminaza. U prvoj deceniji upotrebe statina u sekundarnoj prevenciji uz primenu doza od 10 do 40 mg statina, transaminaze su bile povišene kod 1-3% bolesnika, u odnosu na 1.1 % u placebo grupama.6 Mada je teška hepatotoksičnost retka pojava, ipak je bio registrovano 30 slučajeva ili 1 na milion bolesnik-godina. S obzirom da je realna incidenca mnogo veća od broja prijavljenih slučajeva, savetuje se kontrola transaminaza (ALT) neposredno pre uvođenja statina i kasnije prema kliničkoj potrebi. Međutim, ako se bolesnici leče maksimalnim dozama statina – npr. 80 mg atorvastatina i simvastatina ili 40 mg rosuvastatina – onda su potrebne kontrole svaka 3 meseca. Kad vrednosti dođu u granice normale, Tabela 2 Interakcije simvastatina povezane sa povećanim rizikom za miopatiju i Preporuke FDA8 Lekovi koji izazivaju interakciju Preporuke za propisivanje simvastatina Azoli: Itrakonazol, Ketokonazol, Posakonazol Kontraindikovani sa simvastatinom Makrolidi: Eritromicin, Klaritromicin, Telitromicin Kontraindikovani sa simvastatinom Inhibitori HIV proteaze: Fosamprenavir, Lopinavir, Sakvinavir i drugi Kontraindikovani sa simvastatinom Ostali lekovi: Ciklosporin, Nefazodon, Gemfibrozil Kontraindikovani sa simvastatinom KV lekovi: Amiodaron, Diltiazem, Verapamil Najviše 10 mg simvastatina dnevno KV lekovi : Amlodipin, Ranolazin Najviše 20 mg simvastatina dnevno Sok od grejpfruta do 240 ml dnevno Bez ograničenja u doziranju 87 88 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com određivanja ALT ne treba ponavljati, osim kada to zahteva klinička situacija.9 Nove preporuke ESC/EAS iz 2011.1 navode malo niže procente incidence povišenja transaminaza od 0.5 do 2% i naglašavaju njihovu zavisnost od doze, i potrebu da povišene vrednosti budu nađene u dva uzastopna merenja u kratkom periodu. Grupa autora Preporuka sumnja da su povišenja transaminaza odraz istinske hepatotoksičnosti, jer je izuzetno retka progresija do insuficijencije jetre. Smanjenje doze dovodi često do normalizacije nivoa transaminaza. Zato bolesnika sa povišenim vrednostima ALT i AST treba pratiti čestim određivanjem transaminaza do normalizacije. Ako bi se vrednosti preko 3 puta veće od GGN održavale, terapiju statinima treba prekinuti. Postupaka za poboljšanje podnošljivosti statina i eliminaciju miopatije ima nekoliko: • prelaz na drugi statin (po mogućnosti sa različitim putem metabolizma), • doziranje svaki drugi dan ili jednom nedeljno statina dugog dejstva (npr. rosuvastatin), • kombinivana terapija sa ezetimibom uz proređeno doziranje statina, • zamena statina nestatinskim hipolipemikom: ezetimib, fibrat, holestiramin, nikotinska kiselina, • pomena dijete i dijetski suplementi. Nedostatak ovih izmena lekova i doza je što nema dokaza da smanjuju KV rizik, iako mnoge od njih poboljšavaju podnošenje terapije.10 Depresija i drugi poremećaji psihe Poremećaji psihe se javljaju u toku terapije statinima sa malom incidencom ali su prilično raznovrsni, od nesanice i košmara, do anksioznosti, depresije, sklonosti samoubistvu, poremećaja memorije i mišljenja. Smatra se da su oni posledica smanjenja sinteze holesterola u mozgu, i da nedostatak holesterola remeti ove funkcije usled oštećenja membrana neurona, strukture serotoninskih receptora i inhibicije oslobađanja neurotransmitera u sinapsi. Koncept o nivoima holesterola “Što niže to bolje” (engl. the lower the better) koji se forsira kod bolesti srca, može biti štetan za funkcije mozga.2,11,12 Dijabetes Terapija statinima povećava rizik za pojavu novih slučajeva dijabetesa tip 2 na dozno-zavisan način, pokazala je nedavna meta-analiza pet studija u kojima je bilo 32.000 bolesnika.13 Rizik povećavaju i umerene doze statina, ali ga visoke doze – tzv. intenzivna terapija – povećava za još 2 nova slučaja na 1000 bolesnik-godina. Korist od lečenja visokim dozama statina je bila znatno veća od rizika, jer je NNT bio 155 za godinu, a NNH 498 za godinu. U primarnoj prevenciji, kod osoba sa malim KV rizikom, kakvi su bili ispitanici u čuvenoj JUPITER studiji sa ro- suvastatinom bilo je prijavljeno povećanje incidence novih slučajeva dijabetesa u odnosu na placebo za 25% (270 prema 216), te je verovatno zbog toga studija koja je trebalo da traje pet godina bila prekinuta posle samo 1.9 godina. Doduše, autori i sponzori tvrde da je razlog za prekid bila velika efikasnost rosuvastatina jer je KV rizik bio smanjen za 55%; međutim to je bilo smanjenje relativnog rizika, dok je apsolutni rizik bio smanjen samo za 0.2% ili 2 od 1000. Statistički to jeste bilo signifikantno, ali klinički irelevantno, što je izuzetno retko za studije sa statinima. NNT = 500, a cena za prevenciju 1 infarkta 683.000 US dolara.14 Evropske preporuke iz 2011., posvećuju samo četiri reda i jednu referencu riziku od novih slučajeva dijabetesa kod bolesnika koji uzimaju statine, ističući da je incidenca (nedefinisano) mala, i da je kod bolesnika sa visokim rizikom korist zbog smanjenja KV rizika preteže nad potencijalno malim rizikom vrlo malog povećanja incidence dijabetesa. Autori se pozivaju na veliku meta-analizu iz 2010., koja je obuhvatila preko 90.000 bolesnika iz 13 studija od kojih je u svakoj bilo više od 1.000 bolesnika, i u kojoj je terapija statinima povećavala rizik od dijabetesa za 9% uz minimalne varijacije između studija. Trebalo je lečiti 255 bolesnika prosečno 4 godine da se pojavi 1 novi slučaj dijabetesa; NNH = 1.020 (NNH = number needed to harm). Incidenca jeste mala, i autori ove meta-analize zaključuju da za bolesnike sa umerenim i visokim rizikom ili sa aktuelnom KV bolesti ne treba menjati terapiju statinima zbog rizika od dijabetesa.15 Za kritiku je, ili bar neobjašnjivo, da ni autori ove britanske meta-analize iz 2010. godine niti autori Preporuka ESC/ EAS iz 2011.1 bez komentara prelaze preko pomame za statinima (koja dominira u godinama pisanja ovih tekstova) u kojoj su nesumnjivo najbrojnije osobe sa malim KV rizikom, iz koje populacije se – prema statističkom paradoksu – regrutuje najveći broj stradalnika svake vrste. Dakle, ipak treba postaviti pitanje da li je kod osoba sa malim KV rizikom povećanje incidence dijabetesa za 9% toliko neznatno da ne zaslužuje komentar? Statini i rizik od karcinoma Kontraverze oko teze da duga upotreba statina povećava ili ne povećava rizik od pojave karcinoma traju više od 10 godina kako u rezultatima pojedinačnih studija tako i metaanaliza. Iznenađujući nalazi 2002. da pravastatin u studiji PROSPER povećava kod starih osoba incidencu karcinoma za 25% nije se mogla prenebregnuti, ali se utopila u generalnu bazu podataka o pravastatinu, te se značajnost toga nalaza izgubila.16 Kasnije, u SEAS studiji sa simvastatinom i ezetimibom 2008., pokazalo se da intenzivno sniženje LDL-H kombinacijom ovih lekova povećava visoko signifikantno incidencu karcinoma čak i kada se ne ostvaruje sniženje KV događaja.17 To je zabrinulo promotere preparata VYTORIN (simvastatin + ezetimib), koji su obećali da će u većoj studiji IMPROVE-IT do 2011. razjasniti taj neprijatni nalaz. Međutim, 2011. se odlaže publikovanje rezultata ove Kažić studije za 2013., jer je negde nešto zapelo, a na tržištu SAD je VYTORIN jedan od najbolje prodavanih preparata statina. Mnogo je rezigniranih komentara, a po sažetosti se izdvaja jedan koji objavljuje: “Ova studija je toliko puta modifikovana, da kakvi god bili rezultati, u njih se neće moći verovati.” Prve meta-analize iz 2001. su bile umirujuće i relativizujuće, tvrdeći da u periodima terapije do 5 godina nema dokaza za povećanje incidence karcinoma, ali da treba sačekati rezultate praćenja u dužem periodu, s obzirom da se očekuje da bolesnici uzimaju statine nekoliko decenija.18 Kasnije je bilo nekoliko meta-analiza koje su ukazivale da sniženje LDL-H statinima sistematski povećava rizik od karcinoma, ali se otvara nova dilema: da li je to posledica delovanja same molekule statina, ili niskih nivoa LDL-H koje oni prouzrokuju. Autori jedne od meta-analiza su ustanovili zakonomernost tj. doznu zavisnost rizika od karcinoma od sniženja LDL-H: za svakih 10 mg% sniženja LDL-H, rizik se povećava za 2.2 slučaja karcinoma na 1000 bolesnik-godina.19 Od mnogih komentara jedan je posebno zanimljiv jer tvrdi: “Niski LDL je posledica, a ne uzrok kancera”.20 Lucidnost ove opaske smanjuje podatak da je njen autor zagovornik maksimalnih sniženja LDL-H do 50 mg%. Tako se formira klupko koje je teško rasplesti. Pri tome, neki drugi eksperti oslobađaju odgovornosti statine i oslanjaju se na epidemiološke podatke WHO/SZO iz 164 države da je kod osoba sa vrlo niskim nivoima ukupnog holesterola visoka prevalenca karcinoma, te da je ukupni mortalitet najmanji ako je raspon 200-240 mg%.21 Najnovija Cochrane revija iz 2011. ukazuje da kod osoba sa malim KV rizikom: ispod 1% za smrtni ishod za godinu ili ispod 2% za KV događaj za godinu – nema dokaza za opravdanost upotrebe statina. Trebalo bi lečiti 1000 bolesnika godinu dana da jedan od njih ne umre; prekid pušenja i korekcija životnih navika je poželjnija i efektivnija.2 Rasprava o temi Statini i rizik od kancera se nastavlja i ne može joj se sagledati kraj jer su učesnici opterećeni predubeđenjima i/ili interesima, a pojedinačne studije i meta-analize donose kontradiktorne rezultate. Ipak, u ovom grmu je suviše dima, da ne bi bilo i vatre. Da situacija bude još manje jasna, ima podataka da upotreba statina smanjuje incidencu nekih vrsta kancera, npr. karcinoma prostate i jetre. Interakcije Statini su lekovi sa malim potencijalom za interakcije, i jedina prava briga jeste kako izbeći kombinacije lekova Tabela 3 Farmakokinetičke interakcije lekova sa statinima (atorvastatin) Atorvastatin Lekovi koji se primenjuju istovremeno Doza (mg) Promena AUC Klinička preporuka Ciklosporin 5.2 mg/kg/dan stabilna doza 10 mg jednom dnevno 8.7 puta Ne davati više od 10 mg atorvastatina Klaritromicin 500 mg 2 puta dnevno, 9 dana 80 mg jedno dnevno 4.4 puta Ne davati više od 10 mg atorvastatina, a ako se daje 20 mg dnevno, pojačati kontrolu Itrakonazol 200 mg jednom dnevno, 4 dana 40 mg jedna doza 3.3 puta Ne davati više od 10 mg atorvastatina, a ako se daje 20 mg dnevno, pojačati kontrolu Eritromicin 500 mg 4 puta dnevno, 7 dana 10 mg jednom dnevno Smanjiti maksimalnu dozu i pojačati kontrolu Rifampicin 600 mg jednom dnevno 40 mg jedna doza 30% Uvesti kliničku kontrolu Amlodipin 10 mg jednom dnevno 80 mg jedna doza 18% Nema posebnih preporuka Diltiazem 240 mg jednom dnevno, 28 dana 40 mg jedna doza 51% Uvesti kliničku kontrolu bolesnika Fenofibrat 160 mg jednom dnevno dnevno 40 mg jedna doza 3% Smanjiti početnu dozu i uvesti kliničku kontrolu Gemfibrozil 600 mg dva puta dnevno 40 mg jedna doza 35% Smanjiti početnu dozu i uvesti kliničku kontrolu 33% Sok od grejpfruta 240 ml jednom dnevno 40 mg jedna doza 37% Ne preporučuju se veće količike soka 89 90 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com koji povećavaju rizik od miopatije zbog inhibicije CYP3A4. Miopatija jeste retka pojava sa incidencom od 1 do 3%, ali se na nju ukazuje jer može biti potencijalno fatalna (Tabele 2 i 3). Na nju treba misliti kod svakog bolesnika koji dobije difuznu mijalgiju, bolnu osetljivost i slabostu mišića i/ili veliko povišenje vrednosti CK. Kad se ustanove visoke vrednosti CK, statine treba obustaviti. Vrlo su retki slučaji rabdomiolize sa akutnom renalnom insuficijencijom i fatalnim ishodom. Zaključak Statini su efektivni lekovi u sekundarnoj prevenciji – za bolesnike sa visokim KV rizikom. U toj populaciji je korist od sniženja KV rizika mnogo veća od potencijalne štete usled neželjenih dejstava. S obzirom da se daju visoke doze statina velikom broju bolesnika, neophodna je klinička i laboratorijska kontrola bolesnika, jer je rabdomioliza potencijalno fatalna. U primarnoj prevenciji upotreba statina ima mnogo nedostataka, jer se sniženje LDL-H ne prenosi u smanjivanje KV rizika, oni ne deluju kod žena i ne poboljšavaju kvalitet života (već ga smanjuju neizbežnim neželjenim dejstvima: dijabetes, depresija, slabljenje memorije). Moguće je da statini povećavaju rizik od karcinoma. 7. 8. 9. 10. 11. 12. 13. 14. 15. Neželjena dejstva statina jesu manje česta i većinom manje opasna, ali se njima nepotrebno izlažu milioni ljudi. Tako je kod šteta od davanja statina zdravim osobama koje imaju nizak KV rizik izvesnija od koristi. Zato takve osobe dravi ljudi i osobe ne bi trebalo da uzimaju statine, već da vode zdrav život bez cigareta, da se hrane uravnoteženo i da imaju redovne fizičke aktivnosti. Autor ovog članka nije deklarisao konflikt interesa u vezi s ovim istraživanjem. 16. 17. 18. 19. Reference 1. 2. 3. 4. 5. 6. ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J 2011;32:1769-818. Taylor F, Ward K, Moore THM et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2011;1(CD004816). Nainggolan L. Statin use skyrockets in US, CV health mixed in CDC report. Heartwire 2011, Feb 17. WWW.theheart.org/article/1186565.do (accessed August 15, 2011) Walley T Folino-Gallo P, Stephens P et al for the EuroMedStat group. Trends in prescribing and utilization of statins and other lipid lowering drugs across Europe 1997–2003. Br J Clin Pharmacol 2005;60: 543–51. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 2010; 376:1658-69 Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischemic heart dis- 20. 21. ease and stroke. Systematic review and meta-analysis. BMJ 2003;326:1423-1430. The SEARCH Collaborative Group. SLCO1B1variants and statin/ induced myopathy – a genomewide study. NEJM 2008;359:78999. Egan A, Colman E. Weighing the benefits of high-dose simvastatin against the risk of myopathy, NEJM 2011; 365:285-7. Mahley RW, Bersot TP. Drug therapy for hypercholesterolemia and dyslipidemia. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th edition, Brunton LL, Lazo JS, Parker KL (editors), McGraw Hill 2005:933-66. Arca M, Pigna G. Treating statin intolerant patients. Diabetes, Metabolic Syndrome and Obesity: Targ Ther 2011;4:155-66. Yeon-Kyun Shin. Cholesterol-reducing drugs (statins) may lessen brain function Biochem Biophys Molec Biol 2009;515: 2948-530. Shrivistava S, Pucudyl TJ, Paila DP et al. Cholesterol depletion using statins impairs the function and dynamics of human serotonin 1A receptors. Biochemistry 2010;49:5426. Preiss D, Seshasai SR, Welsh P et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:2556-64. Ridker PM et al. on behalf of the JUPITER study group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. NEJM 2008;359:2195-207. Sattar N, Preiss D, Murray HM et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735-42. Shepherd J, Blauw GJ, Murphy MB et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet 2002;360:1623-30. Rossebø AB, Pedersen TR, Boman K et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. NEJM 2008;359:1343-56. Bjerre LM, LeLorier J. Do statins cause cancer? A meta-analysis of large randomized clinical trials. Am J Med 2001;110:716-23. Alsheikh-Ali AA, Trikalinos TA, Kent DM, et al. Statins, low-density lipoprotein cholesterol and risk of cancer. JACC 2008;52:1141-7. Steinberg D. Statin treatment does not cause cancer. JACC 2008;52:1148-9. www. heartstats.org/documents Kažić Statins – Side Effects and Drug Interactions Tomislav Kažić, Beograd ABSTRACT “Statins are generally well tolerated, their serious side effects are infrequent, and much less important than the reduction of mortality and morbidity”. This sentence is commonly used to describe the importance of efficacy over tolerability, particularly in clinical studies in secondary prevention of CV risk. This assumption belies the fact that many patients are not regularly included in, or were excluded from, randomized clinical trials (RCT) designed to provide relevant committees with side effect profiles for drugs under investigation. In the real life, however, patients such as the elderly, individuals with small body size, women, those with kidney and liver failure, hypothyroidism, multisystem disease and alcoholics are not left untreated where a statin may be indicated. As a result, one would expect a higher incidence of side effects than declared in the requisite SPCs (summaries of product charactetristics). This is the main scientific standpoint for those who claim that the side effects are underestimated; the manipulations of marketing also serve to downgrade the side effects of statins. RCTs that address secondary prevention include high-risk patients. Their aim is to demonstrate the efficacy in reduction of hard clinical endpoints, morbidity and mortality, whereas any undesirable effects are of secondary importance. However, special attention is paid to symptomatic complaints due to muscle damage: myalgia, myositis, myopathy and rhabdomyolysis (when serum CK levels are elevated), and to asymptomatic elevation of hepatic enzymes ALT and AST levels, indicative of hepatotoxicity. A significant proportion of space in SPCs is devoted to Special warnings and precautions for use and to measures for the prevention of side effects. As with other effective drugs, side effects of statins should be taken seriously, even though some side effects are not regarded serious enough to restrict the use of these drugs. Many clinicians disregard the fact that patients may be expected to continue treatment with statins for 20-30 years, and that data for long-term tolerability are lacking. In primary prevention studies, there is a significant discrepancy between single clinical trials and meta-analyses regarding side effects. Some large and important clinical trials indicate that statins induce anxiety, depression, memory loss, suicidal behavior, diabetes and cancer – without significant reduction of CV risk – despite significant reductions of LDL-C levels. In contrast, meta-analyses are almost unanimous in claiming that statins significantly reduce both LDL-C levels and CV risk without toxicity. In some meta-analyses, the authors mention that side effects were not reported regularly, or they may indicate flaws in the inclusion criteria to justify indicating caution before prescribing a statin for primary prevention in low risk patients. The use of statins is not as high in Serbia and Republic of Srpska as in the some wealthier parts of the world. Before excessive use of these drugs prevail, a review of medical problems resulting from their uncontrolled use might help doctors to make an informed decision whether to include new patients into this large human medical experiment. A little foresight may thus prevent many undesirable effects, particularly in low risk patients. KEY WORDS Statins, CV risk prevention, side effects, myopathy, hepatotoxicity, drug interactions 91 92 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Zoran Ivanović REVIEW ARTICLE Ex Vivo Expansion Of Hematopoietic Cells Today ABSTRACT Ex vivo expansion (amplification) of hematopoietic stem and progenitors cells is a concept aimed to resolve the problem of insufficient number of cells for engraftment and/or to accelerate hematopoietic reconstitution after transplantation. After a long period, during which this approach failed to demonstrate its clinical utility, the first successful clinical trials were achieved. Here, we are explaining this breakthrough, mainly resulting from recent understanding of some fundamental properties of stem cell related to its anaerobic metabolic character. KEY WORDS Hematopoietic stem cells, committed progenitors, ex vivo cell expansion, CD34+, stem cell transplantation Aquitaine-Limousin Branch of French Blood Institute & UMR 5164 CNRS/Ségalen University Bordeaux, France Correspondence Professor Zoran Ivanović Etablissement français du Sang Aquitaine-Limousin et UMR 5164 CNRS/Université Ségalen, Bordeaux, France E-mail: [email protected] Submitted: August 15, 2011 Accepted: September 8, 2011 (Scr Med 2011;42:92-6) The concept of ex vivo expansion of hematopoietic cells for transplantation directly derives from the fundamental knowledge of Experimental Hematology. It enabled us to realize that a critical quantity of different sub-populations of stem and progenitor cells is necessary to get a rapid and sustained hematopoietic reconstitution. These principles, transposed to human cells (originating from bone marrow, peripheral blood, cord blood) inevitably required some fundamentally significant technological innovations (conception of the specific media, recombinant technology of cytokine production, etc.), in order to achieve the first efficient clinical trials (at the moment for cells mobilized in peripheral blood)1,2. This goal still remains to be reached for cord blood cells. Although frequently named “stem cells”3, the human CD34+ cell population is extremely heterogeneous from a functional point of view. Within an acceptable approximation4,5, it is considered to be composed of i) committed progenitors (or “Colony Forming Cells – CFC”), representing a relative majority; ii) a low number of short term-repopulating stem cells (usually revealed by the functional in vitro and in vivo assays as Long-Term Culture Initiating Cells – LTC-IC or cells generating the committed progenitors in the secondary liquid cultures: - pre-CFC); iii) the primitive stem cells exhibiting the capacity of in vivo engraftment. Their evidence could be established by transplantation to NOD/SCID (or another immunodeficient strain) mice (Scid-Repopulating Cells - SRC); iv), the most primitive and rare population of stem cells that could be demonstrated by their capacity to maintain the human stem cell potential after being transplanted to the first generation of recipient mice (i.e. on the basis of their capacity to engraft the secondary recipient mice). Any culture system aimed to expand the CD34+ cells results in the production of precursors and mature cells and, in most cases, in the simultaneous amplification of committed progenitors. The first result relies upon the fact that the differentiation of committed progenitors is enhanced in ex vivo cultures, and the second is based upon two simultaneous events: the amplification of committed progenitors by their own divisions and by their production from the stem cells differentiating rapidly in culture and, hence, exhausting themselves. Most probably, these facts could explain the positive effect of transplanted expanded cells on the shortening of posttransplantation neutropenia. This is the reason why the precursors and committed progenitors should be amplified to the highest possible level. There is however, another opposite demand to an ex vivo expansion procedure: to maintain the long-term engraftment capacity, the activity of very primitive stem cells in the expansion product should be preserved or, even better, amplified. In order to reach this goal, enabling the expansion of the whole CD34+ content from one CB unit for transplantation without taking its substantial part as “unmanipulated CB fraction”, many research groups studied the different culture conditions (reviewed in: 6) . Ivanović The First Clinical Trials The first clinical trials based on ex vivo expanded hematopoietic cells did not demonstrate an acceleration of posttransplantation hematopoietic reconstitution7-11. If only the trials based on hematopoietic stem and progenitor cells mobilized into peripheral blood with nowadays knowledge were considered, at least one, but even more reasons could be found for the inefficiency of ex vivo expanded grafts. (Reviewed in the reference #6). In most cases, the cytokine combination employed enhances differentiation of stem cells, leading to their exhaustion during expansion culture12. In other trials, the fold of expansion was low i.e. the absolute number of cells (whatever functional category considered) obtained after expansion was insufficient. The first clinical trial demonstrating almost complete abrogation of post transplant agranulocytosis was that of Bordeaux group1. In this trial, hematopoietic cells, expanded from CD34+ fraction mobilized in peripheral blood of myeloma patients were auto-transplanted The average period of post transplant agranulocytosis, which is about 10 days with non manipulated grafts was completely abrogated or reduced (median of 1.5 days). In the first 14 patients, the amplification of 36, 15, 2.7 fold for total cells chronogenic progenitors, and CD34+ cells respectively, was achieved in a 10 day liquid culture stimulated by SCF, G-CSF, PEGMGDF. In this first trial, the ex vivo amplified cells were transplanted together with a non manipulated fraction of graft. A similar approach was also used for autologous transplantation in the context of breast cancer (11 patients transplanted). This trial also demonstrated a positive effect which, however, was not as spectacular as the first one. Several other trials showed similar yields and results. Transplant ex vivo Expanded Cells, Only These trials provided a solid basis for the analysis related to distinct cell population and quantity to achieve an accelerated blood reconstitution. Given the fact that there were autologous transplantations, the issue of the persistence of primitive stem cells after expansion and their influence on long term hematopoietic reconstitution of the receiver could not be considered. After the analysis of these first trials, a new clinical trial was set up, considering transplantation of only expanded cells. The results concerning acceleration of hematopoietic reconstitution were similar to those of previous studies where both expanded and non manipulated cells were transplanted2,13. The analysis of these results showed that the extent of shortening of posttransplant neutropenia was well correlated to the number of nucleated cells and to the dose of clonogenic progenitors transplanted per kg of patient. On the contrary, this correlation was less obvious, and even inexistent, for CD34+ cells. Given that the expansion fold for clonogenic progenitors was more than 13 times higher than the one of CD34+ cells, the final result gave two fold more progenitors than CD34+ cells in term of absolute cell number. That means that expansion culture produced a huge quantity of CD34progenitors. This trial was interrupted because both clini- cal grade MGDF and culture medium (Irwin) were not available. In order to restart this trial, we tested several media and thrombopoietin (Tpo) preparations. These trials highlighted Macopharma HP01 medium and Peprotec Tpo molecule. We carried out pre-clinical testing based on these conditions and finally restarted this clinical trial which was successfully achieved, yielding the results very similar to those where the expanded and non-expanded cells were transplanted together13. Expansion of Hematopoietic Cells From Cord (placental) Blood Cord (placental) blood represents a source of stem and progenitor cells for engraftment. These cells are, in general, more primitive with respect to those mobilized into peripheral blood. For example, the CD34+ population of cord blood cells is for 1 to 2 log richer in stem cells capable to engraft the immunodeficient mice (Scid Repopulating CellsSRC). The cells of cord blood did not respond the same way to the cytokines, and their amplification kinetic ex vivo is different from that of the peripheral blood cells. The transplantation of cord blood cells is limited by a low number of cells in one cord blood unit. In addition, given that these cells are more primitive, the time for mature cells production is rather long. This emphasizes an important consequence: a very slow blood reconstitution after transplantation (agranulocytosis period is about one month). Due to this inconvenience, the transplantation of cord blood cells was limited to children and adults of low body weight. This problem is reduced by the practice of simultaneous transplantation of 2 cord blood units. However, even with this approach, the time of post transplant neutropenia is rarely below 2 weeks. So there is an evident interest for ex vivo expansion of cord blood cells in order to: 1. Amplify the number of total cells 2. Differentiate several sub-populations of stem cells and progenitors and amplify these populations in order to get a shortage or even abrogation of post-transplant agranulocytosis period. At the same time the absolute imperative is to: 3. Maintain or even amplify the primitive stem cells in order not to jeopardize the capacity of long term maintenance of hematopoiesis. This third point would allow to consider the ex vivo amplification and consecutive transplantation of the whole cord blood unit without saving a non manipulated part. At the moment, the expansion of hematopoietic cells from cord blood is aimed to the allogenic transplantation, although its use in autologous settings cannot be excluded. The allogenic hematopoietic transplantation exhibits another dimension with respect to autologous transplanta- 93 94 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com tion: the immune-compatibility aspect. With that respect, the effects of the modification of immunogenesis during ex vivo expansion could only be properly evaluated in a clinical trial (transplantation procedure). The CD34+ cells selection, conditio sine qua non for successful ex vivo expansion, eliminates the immunocompetent cells from the graft. Since the “graft vs. tumor” effect is considered as an important part of therapy mechanism for cord blood transplantation, we considered that it would be of significant relevance to be injected together with ex vivo amplified cells, the CD34- fraction cells issued from the same cord blood unit. The analysis of 4 clinical trials15-17 concerning transplantation of the ex vivo expanded cord blood CD34+ cells however, did not reveal a shortening of the post transplant agranulocytosis period. In our opinion, it is still insufficient, since despite its expansion ex vivo, the total number of progenitors and CD34+ cells transplanted per kilo of donor weight, was low. Indeed, a more accurate analysis of these trials revealed at least five reasons that could be responsible for the absence of effects: low extent of expansion; an exhaustion of cell populations capable to induce a rapid short term hematopoietic reconstitution; a time-lag of 8 to 12 days for the injection of expanded cells with respect to non manipulated fraction; only a fraction of cord blood unit was ex vivo expanded. The combination of points 1, 2 and 4 gave as a result, an insufficient number of cells belonging to the populations critical for hematopoietic reconstitution. After several years of experimentation at basic and preclinical level of our and other groups18,19, and taking into consideration the results from our above mentioned clinical trials (autologous transplantation)1,2,14, we developed a very efficient protocol for ex vivo expansion of hematopoietic cells starting from CD34+ cells of cord blood. This could have been achieved today, since the advancements in the media quality and the cytokines selections allowed it. As a matter of fact, these major advancements are related to the compensation of the negative effects of a culture hyperoxygenation (atmospheric 20% O2) i.e. to the cultures that better represent the physiologic conditions of hematopoiesis20-22. The same principle, considered through the evolutionary prism (as explained by “Oxygen Stem Cell Paradigm”) is targeting the regulation of ancestral genes involved in the basic cellular functions (simple proliferation and survival of cells), considered to be the factors of “stemness” or of “self renewal”13. Most of these genes are proved either to be activated by a low O2 concentration or to have a sequence called “Hypoxia Responsing Elements” (HRE). In that context, it should be noted that the latest approaches in ex vivo expansion research try to exploit these features24-27. Our ex vivo expansion procedures are based on the principles that the association of a medium with a powerful system of antioxidants with MGDF (Tpo) (stabilizing HIF1a transcripts28 mimics the physiological low O2 environment of hematopoiesis, whereas the other cytokines (SCF, GCSF, Flt3 ligand) in relatively high doses provoke a “regenerating bone marrow-like” effect (Reviewed in: 6). As an example, here is presented the development of a clinical-grade procedure for the ex vivo expansion of cord blood CD34+ cells isolated from previously frozen cord blood units with or without volume reduction, allowing the amplification of total cells by factor ~350 and of committed progenitors by factor ~130 (mean values) without significantly impairing the activity of primitive stem cells. The last point was explored using NOG/SCID model both in usual transplantation model as well as in a model of serial transplantation (i.e. the only way to detect the activity of primitive stem cells today)29. That was important since we aimed to amplify ex vivo the CD34+ cells from a whole cord blood unit without saving its substantial fraction as a non manipulated background. This issue was also critical to obtain an agreement from the State Sanitary Authority enabling us to avoid a split in 2 parts of one cord blood unit in the clinical expansion set up. Our two-steps clinical grade serum-free culture system [SCF, FLT3-L, MGDF, (100 ng/m each), G-CSF (10 ng/ml)], initially upgraded30 on the basis of the experimental data of Douay’s group31 in onestep cultures with the medium IRWIN (no longer commercialized)30, was subsequently improved with serum-free medium Macopharma HP01 an Tpo instead of MGDF32. In the design of clinical protocol, the intention was to ensure an immunologic power of the graft. Since it was not possible, with the amplified fraction only, the protocol proposed to inject – together with the expansion product – a CD34-negative fraction that was refrozen after selection of CD34+ cells and thawed before transplantation. It was necessary to demonstrate that this procedure does not impair the immunocompetent cells (T and B cells), although it does destroy an important fraction of granulocytes (cells out of our interest). Epilogue Based on these data with some minor modifications a clinical grade procedure was set up. This ongoing clinical trial led by Professor Noel Milpied started in 2010. Seven patients were transplanted so far, with very promising results. For example, the first patient transplanted more than one year ago exhibited peripheral blood reconstitution only one week after transplantation and still has a hundred percent donor chimerism. No potential conflict of interest relevant to this article was reported. Ivanović References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Reiffers J, Cailliot C, Dazey B, Attal M, Caraux J, Boiron JM. Abrogation of post-myeloablative chemotherapy neutropenia by ex-vivo expanded autologous CD34-positive cells. Lancet 1999;354:1092-3. Boiron JM, Dazey B, Cailliot C, Launay B, Attal M, Mazurier F, McNiece IK, Ivanovic Z, Caraux J, Marit G, Reiffers J. Largescale expansion and transplantation of CD34(+) hematopoietic cells: in vitro and in vivo confirmation of neutropenia abrogation related to the expansion process without impairment of the long-term engraftment capacity. Transfusion 2006;46:1934-2 Koestenbauer, S, Zisch, A, Dohr, G, Zech, NH. Protocols for hematopoietic stem cell expansion from umbilical cord blood. Cell Transplant 2009;18:1059-69. Guenechea, G; Gan O. I, Dorell C, Dick JE. Distinct classes of human stem cells that differ in proliferative and self-renewal potential. Nat Immunol 2000;2:75-82. Ivanovic Z. Hematopoietic stem cells in research and clinical applications: the “CD34 issue”. World J Stem Cells 2010;2:18-23. Ivanovic Z, Boiron JM. Ex vivo expansion of hematopoietic stem cells: concept and clinical benefit. Transfus Clin Biol 2009;16:489-500. Bachier CR, Gokmen E, Teale J, Lanzkron S, Childs C, Franklin W, Shpall E, Douville J, Weber S, Muller T, Armstrong D, LeMaistre CF. Ex-vivo expansion of bone marrow progenitor cells for hematopoietic reconstitution following high-dose chemotherapy for breast cancer. Exp Hematol 1999;27:615-23. Stiff P, Chen B, Franklin W, Oldenberg D, Hsi E, Bayer R, Shpall E, Douville J, Mandalam R, Malhotra D, Muller T, Armstrong RD, Smith A. Autologous transplantation of ex vivo expanded bone marrow cells grown from small aliquots after high-dose chemotherapy for breast cancer. Blood 2000;95: 2169-74. Engelhardt M, Douville J, Behringer D, Jähne A, Smith A, Henschler R, Lange W. Hematopoietic recovery of ex vivo perfusion culture expanded bone marrow and unexpanded peripheral blood progenitors after myeloablative chemotherapy. Bone Marrow Transplant 2001;27:249-59. Pecora AL, Stiff P, LeMaistre CF, Bayer R, Bachier C, Goldberg SL, Parthasarathy M, Jennis AA, Smith AK, Douville J, Chen B, Armstrong RD, Mandalam RK, Preti R. A phase II trial evaluating the safety and effectiveness of the AastromReplicell system for augmentation of low-dose blood stem cell transplantation. Bone Marrow Transplant 2001;28: 295-303. Brugger W, Heimfeld S, Berenson RJ, Mertelsmann R, Kanz L.Reconstitution of hematopoiesis after high-dose chemotherapy by autologous progenitor cells generated ex vivo. N Engl J Med 1995;333:283-7. Holyoake TL, Alcorn MJ, Richmond L, Farrell E, Pearson C, Green R, Dunlop DJ, FitzsimonsE, Pragnell IB, Franklin IM. CD34 positive PBPC expanded ex vivo may not provide durable engraftment following myeloablative chemoradiotherapy regimens. Bone Marrow Transplant 1997;19:1095-101. Milpied JN, Marit Gerald, Dazey B, et al. Ex vivo Expanded peripheral Blood stem Cells (EVEC) Compared with Un Manipulated Peripheral Blood Stem Cells (PBSC). Autologous Transplantation for Multiple Myeloma: a pair match analysis. ASH Annual Meeting Abstracts, volume 114, issue 22, p 207. 51th ASH annual Meeting. New Orleans. December 2009. 14. Pecora AL, Stiff P, Jennis A, Goldberg S, Rosenbluth R, Price P, Goltry KL, Douville J, Armstrong RD, Smith AK, Preti RA. Prompt and durable engraftment in two older adult patients with high risk chronic myelogenous leukemia (CML) using ex vivo expanded and unmanipulated unrelated umbilical cord blood. Bone Marrow Transplant 2000;25:797-9. 15. Shpall EJ, Quinones R, Giller R, Zeng C, Baron AE, Jones RB, Bearman SI, Nieto Y, Freed B, Madinger N, Hogan CJ, SlatVasquez V, Russell P, Blunk B, Schissel D, Hild E, Malcolm J, Ward W, McNiece IK. Transplantation of ex vivo expanded cord blood. Biol Blood Marrow Transplant 2002;8: 368-76. 16. Jaroscak J, Goltry K, Smith A, Waters-Pick B, Martin PL, Driscoll TA, Howrey R, Chao N, Douville J, Burhop S, Fu P, Kurtzberg J. Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase 1 trial using the AastromReplicell System. Blood 2003;101: 5061-7. 17. de Lima M, McMannis J, Gee A, Komanduri K, Couriel D, Andersson BS, Hosing C, Khouri I, Jones R, Champlin R, Karandish S, Sadeghi T, Peled T, Grynspan F, Daniely Y, Nagler A, Shpall EJ. Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial. Bone Marrow Transplant 2008;41:771-8. 18. Ivanovic Z, Hermitte F, Brunet de la Grange P, Dazey B, Belloc F, Lacombe F, Vezon G, Praloran V. Simultaneous maintenance of human cord blood SCID-repopulating cells and expansion of committed progenitors at low O2 concentration (3%). Stem Cells 2004; 22: 716-24. 19. Hermitte F, Brunet de la Grange P, Belloc F, Praloran V, Ivanovic Z. Very low O2 concentration (0.1%) favors G0 return of dividing CD34+ cells. Stem Cells 2005;24: 65-7. 20. Fan J, Cai H, Yang S, Yan L, Tan W.Comparison between the effects of normoxia and hypoxia on antioxidant enzymes and glutathione redox state in ex vivo culture of CD34(+) cells. Comp Biochem Physiol B Biochem Mol Biol 2008;151:153-8. 21. Ivanovic, Z, Duchez P, Dazey B, Hermitte F, Lamrissi-Garcia I,Mazurier F, Praloran V, Reiffers J, Vezon G, Boiron J M. A clinical-scale expansion of mobilized CD 34+ haematopoietic stem and progenitor cells by use of a new serum-free medium. Transfusion 2006;46:126-31. 22. Prus E, Fibach E. The effect of the copper chelator tetraethylenepentamine on reactive oxygen species generation by human hematopoietic progenitor cells. Stem Cells Dev 2007;16:1053-6. 23. Ivanovic Z. Hypoxia or in situ normoxia: The stem cell paradigm. J Cell Physiol 2009;219:271-5. Review. 24. Campbell C, Risueno RM, Salati S, Guezguez B, Bhatia M. Signal control of hematopoietic stem cell fate: Wnt, Notch, and Hedgehog as the usual suspects. Curr Opin Hematol 2008;15:319-25. 25. Tanaka H, Matsumura I, Itoh K, Hatsuyama A, Shikamura M, Satoh Y, Heike T, Nakahata T, Kanakura Y.HOX decoy peptide enhances the ex vivo expansion of human umbilical cord blood CD34+ hematopoietic stem cells/hematopoietic progenitor cells. Stem Cells 2006;24:2592-602. 26. Dickson GJ, Kwasniewska A, Mills KI, Lappin TR, Thompson A. Hoxa6 potentiates short-term hemopoietic cell proliferation and extended self-renewal. Exp Hematol 2009;37:322-33. 95 96 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com 27. Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger R L, Bernstein I D. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med 2010;16:232-6. 28. Yoshida K, Kirito K, Yongzhen H,et al. Thrombopoietin (TPO) regulates HIF-1alpha levels through generation of mitochondrial reactive oxygen species. Int J Hematol 2008;88:43-5. 29. Ivanovic Z, Duchez P, Chevaleyre J, Vlaski M, Lafarge X, Dazey B, Robert-Richard E, Mazurier F, Boiron JM. Clinical-scale cultures of cord blood CD34+ cells to amplify committed progenitors and maintain stem cell activity. Cell Transplant in press, 2011 30. Duchez P, Dazey B, Douay L, Vezon G, Ivanovic Z. An efficient large-scale thawing procedure for cord blood cells destined for selection and ex vivo expansion of CD34+ cells. J Hematother. Stem Cell Res 2003;12:587-9. 31. Kobari L, Pflumio F, Giarratana M, Li X, Titeux M, Izac B, Leteurtre F, Coulombel L, Douay L. In vitro and in vivo evidence for the long-term multilineage (myeloid, B, NK, and T) reconstitution capacity of ex vivo expanded human CD34 (+) cord blood cells. Exp Hematol 2000;28:1470-80. 32. Duchez P, Chevaleyre J, Vlaski M, Dazey B, Bijou F, Lafarge X, Milpied N, Boiron JM, Ivanovic Z. Thrombopoietin to replace megakaryocyte-derived growth factor: impact on stem and progenitor cells during ex vivo expansion of CD34+ cells mobilized in peripheral blood. Transfusion 2011;51:313-8. Ex vivo ekspanzija hematopoetskih ćelija Zoran Ivanović APSTRAKT Ekspanzija (umnožavanje) hematopoetskih matičnih ćelija i progenitora ex vivo je koncipirana da bi se rešio problem nedovoljnog broja ćelija za transplantaciju i ubrzala posttransplantacijska hematopoetska rekonstitucija. Posle dugog perioda, tokom koga ovaj pristup nije davao zadovoljavajuće rezultate, pojavili su se prve uspešne kliničke studije. Članak opisuje u čemu se sastoji ovaj kvalitativni pomak koji je većim delom zasnovan na razumevanju nekih elementarnih svojstava matične ćelije kao što je njen anaerobni metabolički karakter. KLJUČNE RIJEČI Matične ćelije hematopoeze, opredeljeni progenitori, umnožavanje ćelija ex vivo, transplantacija matičnih ćelija 97 CLINICAL PROBLEM-SOLVING Shweta Gupta, Prantesh Jain Synovial Osteochondromatosis Mimicking Septic Arthritis Department of Medicine John H Stroger Jr Hospital of Cook County 1900 W Polk St, 15th Floor Chicago, IL 60612 USA ABSTRACT Synovial osteochondromatosis is an uncommon benign condition with rare malignant potential. We describe an unusual case of synovial osteochondromatosis in a very elderly lady, who presented with an acute painful swollen knee, mimicking septic arthritis. This required knee replacement for long-term symptom control. Correspondence KEY WORDS Synovial osteochondromatosis, painful swollen knee, knee replacement Shweta Gupta, MD Div of Hematology-Oncology John H Stroger Jr Hospital of Cook County 1900 W Polk St, 7 th Floor Chicago, IL 60612, USA Phone: +1-312-864-7250 Fax: +1-312-864-9002 Email: [email protected] (Scr Med 2011;42:97-9) Submitted: September 3, 2011 Accepted: September 20, 2011 Synovial osteochondromatosis is an uncommon benign condition with rare malignant potential, where there is formation of cartilaginous or osteocartilaginous loose bodies within and around the joint space of a joint. It could be asymptomatic or present with joint symptoms similar to osteoarthritis. There are cases described in literature involving large and small joints, with the youngest reported age of seventeen to oldest in the sixties. We describe an unusual case of synovial osteochondromatosis in a very elderly lady, who presented with an acute painful swollen knee, mimicking septic arthritis and required knee replacement for long-term symptom control. Case Presentation We present a case of a 75 years old lady with a history of osteoarthritis of the knees bilaterally who was admitted to the hospital with complaints of worsening pain in the right knee since one day. She was taking off and on pain medications and was able to walk without support. She woke up in the morning the day of admission and heard a cracking sound from the right knee after which the pain started. Over the course of the day the pain worsened and movements of the right knee joint became more painful, so much so that she was walking with a limp by evening. The knee also got swollen and painful to touch. Her left knee was at baseline with mild pain, no new changes and no swelling or tenderness. She denied any fever or preceding trauma to the joint. She also denied any previous history of similar complaints. She was taking off and on pain medications, namely Tylenol and ibuprofen, and was able to walk without support before this presentation. Physical exam showed a healthy elderly woman in some distress due to pain. Her vital signs were normal. Systemic exam showed clear lung fields to auscultation, normal heart sounds with no murmurs, normal abdominal exam. She had no apparent focal neurological deficits. Examination of the right knee joint showed that it was swollen and erythematous anteriorly. On palpation the knee was tender and range of motion was restricted due to pain and swelling to 30 degrees flexion and unable to be fully extended. There was a moderate effusion in the right knee joint as well. In the emergency room she was given pain medications, an X-ray of the knee was ordered and arthrocentesis of the right knee was performed to rule out a septic joint. Her complete blood count was normal with no increase in white cells and no left shift. The electrolytes, renal function and liver function tests were normal as well. The imaging showed popcorn calcifications in and around the right knee joint as shown in Figure 1-3. There was no fracture. The synovial fluid analysis showed 90,000 red blood cells with total white cell count of 550 cells with 10% polymorphs, 10% lymphocytes and 80% monocytes. There were no crystals seen and the gram stain was negative with final cultures reported negative as well. The above was consistent with a diagnosis of synovial osteochondromatosis, which likely caused one of the calcifications to break loose in the joint space, causing locking and a cracking sound with internal trauma and some bleeding as seen in the synovial fluid analysis. She was managed conservatively with pain medications and hot fomentation and her knee improved. The orthopedic service 98 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com 1 3 2 knee replacement and she agreed. Post surgery imaging is shown in Figure 4. At this time with more than 30 months after replacement, she continues to do well and is being followed in the general medicine clinic. Discussion Synovial osteochondromatosis is an entity, which has been described in literature as early as the early 20th century1. Dr Mussey, in 1949 described osteochondromatosis as a condition in which cartilaginous and osteocartilaginous bodies are formed within and by the synovial membranes of joints and, occasionally, of bursae and tendon sheaths1. It was shown in 1927 that microscopically formation of these bodies follow the same stages that occur in the embryonic formation of the cartilage3. Since then, there have been case reports of osteochondromatosis with two case series. In 1977 Milgram proposed a classification of the disease entity into 3 phases: (1) active intra synovial disease only, with no loose body; (2) transitional lesions, with both active intra synovial proliferation and free loose bodies; and (3) multiple free osteochondral bodies with no demonstrable intra synovial disease4. Fig 1, 2 and 3. Popcorn calcifications in and around right knee joint AP and lat views was consulted for opinion and they agreed with conservative management at the time. She was discharged in stable condition with follow-ups with medicine and orthopedics. However her symptoms persisted intermittently and interfered with daily activities. Hence two months later, due to presence of long standing baseline osteoarthritis and added osteochondromatosis, it was decided to offer her total Synovial chondromatosis is characteristically a monoarticular condition, which has been described to affect large joints most commonly knee and elbow1,5, however over the past decade there have been reports of involvement of temporo-mandibular joint, lumbar spine6,7, hip, and finger2. The age at presentation has been described as low as 17 years to as high as 642,6,7. The disease has a predilection for men; however, the TMJ cases are more common in women6. Gupta, Jain transformation in 5% of cases2. Recurrence rates despite treatment of up to 15% have been described2. 4 Our case is unique where synovial osteochondromatosis occurred in a very elderly 75 years old lady with majority of the calcification being outside the joint spaces in the soft tissues. Also, the joint space loose bodies caused acute atraumatic locking with hemorrhagic joint effusion within the joint space, and the constellation of knee findings seemed clinically like a septic joint. The symptoms were severe enough to warrant a total knee replacement, a measure not reported for this disease, after which there was complete resolution of symptoms. No potential conflict of interest relevant to this article was reported. References 1. 2. Fig 4. Right knee post replacement 3. Clinical presentation could be non-specific, with most commonly reported symptoms being pain, stiffness, swelling and history of limitation of movement of the affected joint with occasional reports of locking of the joint8. Symptoms may occur with no history of preceding trauma. Exam can reveal joint tenderness with decreased range of motion. Imaging may show multiple radio opaque loose bodies in many but not all cases (depending on the phase of disease)8. 4. 5. 6. 7. 8. Treatment traditionally includes removal of loose bodies with or without synovectomy. It is generally regarded as a benign condition with rare progression to chondrosarcoma, with one case series of 53 cases showing malignant Robert D Mussey Jr, Melvin S. osteochondromatosis. J Bone Joint Surg Am 1949; 31:619-27. Davis RI, Hamilton A, Biggart JD. Primary Synovial Chondromatosis: A Clinicopathologic Review and Assessment of Malignant Potential. Human Pathology 1998;29:683-8. Jones HT. Loose body formation in synovial osteochondromatosis with special references to the etiology and pathology. J Bone Joint Surg 1927;6:407-58. Milgram JW. Synovial osteochondromatosis: a histopathological study of thirty cases. J Bone Joint Surg Am 1977;59:792–801. Crotty JM, Monu JU, Pope TL Jr. Synovial osteochondromatosis. Radiol Clin North Am 1996;34:327–34. Boffano P, Viterbo S, Bosco GF. Diagnosis and surgical management of synovial chondromatosis of the temporo-mandibular joint. J Craniofac Surg 2010;21:157-9. Kim SW, Choi JH. Synovial chondromatosis presenting with lumbar radiculopathy. Spine 2009;34:E414-7. Iyengar J, Luke A, Ma CB. An unusual presentation of synovial chondromatosis of the knee: A case report. Clin J Sport Med 2007;17:157-9. Sinovijalna osreohondromatoza koja liči na septički artritis Shweta Gupta, Prantesh Jain APSTRAKT Sinovijalna osteohondromatoza je retko benigno oboljenje koje ima mali maligni potencijal. Mi opisujemo neobičan slučaj sinovijalne osteohondromatoze kod starije žene (75 godina) koja nam se javila s akutnim bolom i otečenim kolenom, stanjem koje je ličilo na septički artritis. Simptomi su bili tako teški da je bilo neophodno ugraditi veštačko koleno kako bi se postiglo dugotrajno otklananje tih simptoma. KLJUČNE RIJEČI Sinovijalna osteohondromatoza, bolni otok kolena, veštačko koleno 99 100 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Yury Takhalov CASE REPORT Fifty-Four-Year-Old Man with Inguinal and Testicular Masses (Scr Med 2011;42:100-1) Department of Pathology University of Illinois at Chicago and Stroger Hospital of Cook County Chicago, IL 60612, USA Correspondence Yury Takhalov, MD Department of Pathology, University of Illinois at Chicago Chicago, IL 60612, USA Submitted: July 13, 2011 Accepted: August 15, 2011 An extensive lipomatous growth was discovered in the inguinal region of a 54-year-old male during hernia repair surgery. The differential diagnoses included lipoma, angio-myolipoma, well differentiated liposarcoma and myxoid liposarcoma. After further work up, the diagnosis of well-differentiated liposarcoma seemed most credible, and total resection of the tumor was recommended. Resection of the left inguinal canal and left orchiectomy was performed, and the gross specimen is shown in Figure 2. A well-circumscribed mass of 6.5 cm (A) within the tunica vaginalis displaced, but did not invade, the testicle (C) and extended into the spermatic cord. The mass traveled up the spermatic cord for 5.5 cm, connecting to a second mass of 4.5 cm (B) within the inguinal region. A CT scan was done to establish the extent of the tumor. Figure 1. shows the CT scan of the patient with a mass on the left side in the inguinal region. There was no evidence of invasion. Tissue sections viewed under low power microscopy showed dense fibrotic zones alternating with mature adipocytes of varying size (Figure 3). Examination under higher power showed atypical pleomorphic stromal cells within the dense fibrotic zones (Figure 4). Our final diagnosis was well-differentiated liposarcoma, sclerosing type. Well-differentiated liposarcomas of any type have no potential for metastasis unless they undergo dedifferentia- Figure 1. CT scan of the patient with a mass on the left side in the inguinal region. Figure 2. Gross specimen, after resection of the left inguinal canal and left orchiectomy, is presented. Takhalov Figure 3. Tissue sections viewed under low power microscopy showed dense fibrotic zones alternating with mature adipocytes of varying size.the inguinal region. Figure 4. Examination under higher power showed atypical pleomorphic stromal cells within the dense fibrotic zones. tion.1 They are generally found in adults between the ages of 40-60. The most common location for this tumor is within the lower limbs, retroperitoneum, paratesticular and mediastinal regions. They can be circumscribed or infiltrative; on gross examination appear as bulging, large, yellow white tumors, coarsely lobulated with pale, firm areas. Microscopically, they exhibit mature, variably sized adiposities and fibromyxoid stroma that contains spindle cells with large, dark staining nuclei along with marked nuclear enlargement and pleomorphism. The cellularity is usually low, and mitotic figures are rare. Lipoblasts may be obvious, but these cells are not essential to confirm the diagnosis of liposarcoma. Reference 1. Laurino L, Furlanetto A, Orvieto E, Dei Tos AP. Well-differentiated liposarcoma (atypical lipomatous tumors). Semin Diagn Pathol 2001;18:258-62. 101 102 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com CASE REPORT Ljuba Stojiljkovic, Amber Zendner Anesthetic Management of a Patient With Obstructive Sleep Apnea and Narcolepsy Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago IL Correspondence Ljuba Stojiljkovic, M.D., Ph.D. Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago IL, USA Email: [email protected] Submitted: September 21, 2011 Accepted: September 26, 2011 (Scr Med 2011;42:102-3) A 59-year-old male (height 157 cm, weight 93 kg, BMI 37.6) with history of obstructive sleep apnea (OSA) and narcolepsy was scheduled for laparoscopic sigmoid colon resection and left lighted ureteral stent placement for recurrent diverticulitis. The patient was taking both methylphenidate and modafinil for the treatment of narcolepsy, and was on home continuous positive airway pressure (CPAP) machine for OSA. Other medical history was unremarkable. In the pre-operative area the patient consented for a combined general-epidural anesthesia. He received midazolam 1mg intravenously (IV) and fentanyl 50mcg IV prior to placement of thoracic (T9-10) epidural catheter. The patient was taken to the operating room and general anesthesia was induced with propofol 150mg IV and rocuronium 50mg IV. A combined general-epidural anesthesia was maintained with desflurane and 0.25% bupivacaine infusion at 4-5 mL/hr via the epidural catheter. At the conclusion of the procedure, the patient was successfully awakened, extubated and transferred to the postanesthesia care unit (PACU). Of note the patient did not receive any opiates during the procedure. During the two hour PACU stay, he was started on a patient controlled epidural analgesia (PCEA) with background continuous infusion of 4 mL/hr of mixture of 0.1% bupivacaine and 5 mcg/ mL fentanyl, and patient controlled boluses of 4 mL of the same bupivacaine/fentanyl mixture with 15 min lockout interval. During PACU stay patient did not complain of any pain, and oxygen saturation was maintained above 95% on room air. Subsequently he was discharged to continuous oxygen saturation-monitored bed, and his home settings of CPAP were used overnight. During first two postoperative days (POD) pain was well controlled with the PCEA and 30 mg of ketorolac every 6 hours IV. On POD#2 patient returned his bowel function (BF) and his home medications for narcolepsy (modafinil and methylphenidate) were re- started. The epidural catheter was removed and oral acetaminophen-hydrocodone (325mg/10mg) and ibuprofen were given for pain control. He was discharged home on POD#4 without any complications. Obstructive sleep apnea (OSA) and narcolepsy are sleep related disorders1. OSA is a disorder characterized by cessation of breathing due to obstruction of the upper airway during sleep2. Narcolepsy is characterized by recurrent, uncontrollable episodes of sleep, that may be accompanied in more severe cases by cataplexy (loss of muscle tone without loss of consciousness) and sleep paralysis1. Underlying pathophysiological mechanism of narcolepsy is loss of orexinergic neurons in the lateral hypothalamus3. Orexin (also known as hypocretin) neuronal pathways are important regulators of sleep/wake cycles, as well as energy homeostasis3. Orexigenic neurons produce two neuropeptides, orexin A and orexin B from the same precursor, prepro-orexin3. Approximately 90% of patients with narcolepsy have decreased level of orexin A in cerebrospinal fluid (CSF), and a low level of CSF orexin A is now recognized as one of the diagnostic criteria for narcolepsy3. Recently, studies have shown that patients with OSA also have lower levels of orexin A as compared to subjects without OSA 4. In addition, there is strong evidence that orexinergic neuronal activation plays an essential role in emerging from general anesthesia5. An estimated 23 million Americans are affected by obstructive sleep apnea and 1 in 2000 Americans have symptoms consistent with narcolepsy. The incidence of patients with both narcolepsy and OSA is unknown and our knowledge on anesthetic management for these patients is limited. In addition, both conditions are associated with increased body mass index and obesity which further complicates anesthetic management. Stojiljković , Zendner Patients with combined OSA and narcolepsy represent unique anesthetic challenge due to their increased sensitivity to anesthetic agents, and risks of prolonged emergence due to opioid-induced respiratory depression and stimulant withdrawal hypersomnia. Our patient was receiving two central nervous system (CNS) stimulants (modafinil and methylphenidate) which had to be withheld in the perioperative period (until return of BF). Methylphenidate is a CNS stimulant which is approved for treatment of attention deficit hyperactivity disorder, as well as narcolepsy. Mechanism of action involves inhibition of monoamine uptake (dopamine and norepinephrine). Modafinil is a relatively new drug that is approved for treatment of narcoplepsy, and is used as a wake-promoting agent in patients with OSA. Mechanism of action has not been completely understood, however, histaminergic system activation via the orexinergic neurons is recently proposed6. Our major concern in this case was that withdrawal of two potent CNS stimulants may prolong emergence from general anesthesia and cause withdrawal hypersomnia and sleep paralysis. Therefore, we used low-soluble volatile anesthetic desflurane, which allowed rapid titration of general anesthesia and did not result in significant accumulation of the anesthetic. In addition, combination of continuous infusion of local anesthetic bupivacaine, through epidural catheter, decreased the use of the volatile anesthetic and systemic opiates via its powerful anesthetic and analgesic effect. It is widely accepted that OSA patients are very sensitive to respiratory-depressant effects of narcotics, especially during perioperative period. Therefore, our goal was to minimize the use of systemic opiates, while providing effective postoperative pain relief. Combining general and epidural anesthesia was an effective method to decrease the risk of serious postoperative complications related to OSA and narcolepsy such as apnea, hypersomnia, cataplexy and sleep paralysis. References 1. 2. 3. 4. 5. 6. Sansa G, Iranzo A, Santamaria J: Obstructive sleep apnea in narcolepsy. Sleep Medicine 2010; 11: 93-95 Strollo PJ, Jr., Rogers RM: Obstructive sleep apnea. N Engl J Med 1996; 334: 99-104 Sakurai T, Mieda M: Connectomics of orexin-producing neurons: interface of systems of emotion, energy homeostasis and arousal. Trends Pharmacol Sci; 2011; 32: 451-62 Busquets X, Barbe F, Barcelo A, de la Pena M, Sigritz N, Mayoralas LR, Ladaria A, Agusti A: Decreased plasma levels of orexin-A in sleep apnea. Respiration 2004; 71: 575-9 Kelz MB, Sun Y, Chen J, Cheng Meng Q, Moore JT, Veasey SC, Dixon S, Thornton M, Funato H, Yanagisawa M: An essential role for orexins in emergence from general anesthesia. Proc Natl Acad Sci U S A 2008; 105: 1309-14 Ishizuka T, Murotani T, Yamatodani A: Modanifil activates the histaminergic system through the orexinergic neurons. Neurosci Lett 2010; 483: 193-6 103 104 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com CASE REPORT Živojin S. Jonjev1, Svetozar Srdić2 Surgical Treatment of Coronary Artery Aneurysm University of Novi Sad, Institute for Cardiovascular Diseases of Vojvodina, Clinic of Cardiovascular Surgery, Sremska Kamenica, Serbia 2 Clinical Center Banja Luka, Clinic for Cardiovascular Diseases, Banja Luka, Bosnia & Herzegovina 1 Correspondence Živojin S. Jonjev, MD, PhD Clinic of Cardiovascular Surgery Institutski put 4 21204 Sremska Kamenica, Serbia E-mail: [email protected] (Scr Med 2011;42:104-5) A 59-years-old man was transferred from an outside hospital with recurrent postero-inferior myocardial infarction. On admission both physical exam and chest roentgenogram indicated ischemic cardiomyopathy (NYHA III/IV). An electrocardiogram confirmed normal sinus rhythm (F=86/min) as well as an old myocardial infarction of the posterior wall of the left ventricle. Cardiac catheterization showed large coronary aneurysms on both the proximal right coronary artery (RCA) and the left anterior descending artery (LAD) along with RCA occlusion and significant LAD stenosis (>90%), just below the aneurismal sac. The circumf lex artery (RCx) had multiple stenoses, resulting in poor visualization of the distal RCx (Figure 1a and b). Trans-thoracic echocardiography revealed decreased left ventricle function (EF=29%), and mild mitral and tricuspid regurgitation (I/II degree). Despite the significantly increased perioperative mortality risk (EuroSCORE [E-log]=24.12%), the patient underwent elective heart surgery. Upon exposure of the heart, two large, firm and partially calcified coronary aneurysms were found: one on the RCA (Ø ≈ 3cm) and one on the proximal LAD (Ø ≈ 1.5cm). Myocardial revascularization was successfully achieved with double coronary bypass using the left internal mammary artery to graft the LAD site and a saphenous venous graft for the distal RCA site (Figure 2). The patient’s postoperative course was uneventful. He was discharged from the hospital on postoperative day #7 and remained stable three months after surgery. Submitted: September 21, 2011 Accepted: September 26, 2011 Coronary artery aneurysm (CAA) is a very rare finding. It is usually described as a focal dilatation of the adjacent coronary artery that exceeds the diameter of the native coronary artery by 1.5 times or more. CAA could be highly symptomatic, or it might be diagnosed postmortem at autopsy. Registry studies indicate that the incidence of CAA is less than 5%. However, improved imaging techniques suggest that the true incidence may be underestimated. Therapeutic modalities for CAA are still controversial and consist of medical therapy alone, coronary stenting or surgical reconstructive techniques. Our patient’s disease was Figure 1a: Radiography of the RCA. Findings show occlusions of both the CAA and RCA just below the aneurysmal sac. RCA-right coronary artery; CAA-coronary artery aneurysm. Jonjev, Srdić Figure 1b: Radiography of the left coronary artery. It shows poor visualization of the distal RCx, a large coronary artery aneurysm in the proximal LAD and significant coronary stenosis (>90%) just below the aneurismal sac. LAD - left anterior descending artery; RCx - circumflex artery; CAA – coronary artery aneurysm. Figure 2: Intraoperative view. It shows a CAA of the right coronary artery repaired distally with a saphenous venous graft and the LAD repaired with a LIMA graft. CAA – coronary artery aneurysm; SVG – saphenous venous graft; LIMA - left internal mammary artery. caused by atherosclerosis; medical treatment alone in such individuals has only limited efficacy. Occlusion of the aneurysmatic nonstenotic coronary artery usually causes myocardial infarction,1 as it did in this particular case. Accordingly, surgical intervention should occur as soon as possible to reduce the risk of thromboembolic events, even in a setting of antiplatelet therapy. cardiography and magnetic resonance imaging can be used not only for diagnosis but for follow-up as well. We recommend surgery as soon as possible to prevent thromboembolic complications, especially in cases with severe coronary stenosis and persistent angina despite optimal medical therapy. References Several surgical techniques have been described.2 Our choice is short and simple CABG surgery. This approach improves antegrade coronary flow distally to CAA, which prevents potential thromboemboli arising from the aneurismal sac and lowers the risk of myocardial ischemia. Good angiographic visualization, trans-esophageal echo- 1. 2. Brecker SJ, Gray HH, Oldershaw PJ. Coronary artery aneurysms and myocardial infarction: adult squeals of Kawasaki disease? Brit Heart J 1988; 59:509-12. Ercan E, Tengiz I, Yakut N et al. Large atherosclerotic left main coronary aneurysm: a case report and review of literature. Int J Cardiol 2003; 88:95-8. 105 106 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Correspondence 107 LETTER TO THE EDITOR Swollen and Tender Umbilical Nodule To the Editor: With regard to the recent case report, “A young woman with a swollen and tender umbilical nodule” by August A. Natalie and Anjeli K. Isaac.1 I would like to express my doubt as to the diagnosis of umbilical endosalpingiosis. The patient reported intermittent pain in the biopsy area since age nine, and her menarche began at age ten. She recalled monthly episodes of umbilical swelling and bleeding, followed by regression. The histology of the punch biopsy from the umbilical nodule showed two small ciliated glands, and the stroma around these two glands appeared edematous with some loosely arranged spindle cells. The combination of this clinical presentation and the observed histology are more suggestive of umbilical endometriosis than of endosalpingiosis. Admittedly, cutaneous umbilical endosalpingiosis is a rare disease, but all reported cases show similar histology.2-4 The features described include a large cystic lumen, papillary projection, and ciliated columnar lining epithelium, unlike the findings in the current case. An immunohistochemical stain for CD10 on endometrial stromal cells might help to differentiate umbilical endometriosis from endosalpingiosis. In my opinion, the author should stain sections for CD10 before rendering a diagnosis of cutaneous umbilical endosalpingiosis. Songlin Zhang, MD, PhD Assistant Professor Department of Pathology LSUHSC Shreveport, LA 71115, USA E-mail: [email protected] References 1. Natalie AA, Isaac AK. A young woman with a swollen and tender umbilical nodule. Scr Med 2011:42:28-9. 2. Redondo P, Idoate M, Corella C. Cutaneous umbilical endosalpingiosis with severe abdominal pain. J Eur Acad Dermatol Venereol 2001;15:179-80. 3. Perera GK, Watson KM, Salisbury J, et al. Two cases of cutaneous umbilical endosalpingiosis. Br J Dermatol 2004;151:924-5. 4. Papavramidis TS, Sapalidis K, Michalopoulos N, et al. Umbilical endosalpingiosis: a case report. J Med Case Reports 2010;4:287. The authors reply: Zhang rightfully claims that CD10 is an important marker for normal endometrial stroma. In one small study, the sensitivity of CD10 for marking known ectopic endometrial stroma was 88%1, with 48% staining strongly. The more important clinical question at hand is the specificity of CD10 for ectopic endometrial stoma. This is currently unknown, but information from other studies suggests that it is likely to be low. For example, CD10 stains various normal tissues of the vulva, vagina, cervix, ovaries, and fallopian tubes.2 More importantly, normal cervical stroma1 (which would be important in endocervicosis) and the stroma adjacent to endosalpingiosis3 have been shown to stain positively for CD10. At this time, we find insufficient evidence to support using CD10 to differentiate cutaneous endometriosis from cutaneous endosalpingiosis. Histologically, the lack of hemosiderin pigment deposition, intracystic blood and debris, and dense fibrosis between glandular foci coupled with the presence of both ciliated and nonciliated columnar cells, as well as small papillary projections into the lumen, all favor a diagnosis of cutaneous endosalpingiosis rather than cutaneous endometriosis. Although cyclical umbilical bleeding is a well documented symptom of umbilical endometriosis, presentation of cyclical symptoms (such as pain and pruritus) has been reported with endosalpingiosis. We believe the presence of bleeding in our case adds support to the metaplastic pathogenesis theory. August A. Natalie, MD Anjeli K. Isaac, MD John H. Stroger Jr. Hospital of Cook County Chicago, IL 60612, USA E-mail: [email protected] References 1. Sumathi VP, McCluggage WG. CD10 is useful in demonstrating endometrial stroma at ectopic sites and in confirming a diagnosis of endometriosis. J Clin Pathol 2002;55:391-2. 2. Ordi J, Romagosa C, Tavassoli FA, et al. CD10 expression in epithelial tissues and tumors of the gynecologic tract: a useful marker in the diagnosis of mesonephric, trophoblastic, and clear cell tumors. Am J Surg Pathol 2003;27:178-86. 3. Fukunaga M, Mistuda A, Shibuya K, et al. Retroperitoneal lymphangioleiomyomatosis associated with endosalpingiosis. APMIS 2007;115:1460-5. 108 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com LETTER TO THE EDITOR Atorvastatin-Associated Myalgia Triggered by Grapefruit To the Editor: An obese 57-year-old female, a former smoker, presented with a complaint of frequent chest pain at rest. She was treated previously for hypertension, stable angina pectoris after left ventricular anterior myocardial infarction, hyperlipoproteinaemia and left ventricular dysfunction (ejection fraction 20%). The patient was afebrile with an arterial pressure of 140/90 mm Hg. Her neck veins were not distended. The action of the heart was rhythmic, but the heart tones were muffled, and a systolic murmur was detected at the apex. The lungs were clear on auscultation. The abdominal wall was soft, and both surface and deep palpations were painless. There was no limb edema. An electrocardiogram showed sinus rhythm, PQ 0.20” and a left bundle branch block. The patient was treated with carvedilol (2 x12.5 mg), enalapril (2 x 5 mg), aspirin (100 mg), furosemid (20 mg), spironolactone (25 mg), atorvastatin (20 mg). The patient was advised to increase the dosage of carvedilol to 2 x 25 mg, to introduce fraxiparine (5000 IU bid, s.c.) and to take 40 mg of atorvastatin a day. Several days after therapy, the chest pain disappeared, but the patient complained of pain in her muscles of legs and arms. When asked whether she had eaten any grapefruit, she confirmed that she had eaten almost one kilogram of grapefruit. The laboratory measurement of CK was 415 U/l; LDH was 536 mmol/l. After a pause in the medication, Atorvastatin was reintroduced. This time the patient had no further pain in her muscles. Most of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) except pravastatin are metabolized by cytochrome P450 (CYP) enzymes1,2. Interactions involving CYP are thus possible. Myopathy and an asymptomatic increase in hepatic transaminases are side effect of statins, but these occur rarely. Several classes of drugs may increase bioavailability of statins with subsequent production of myositis. As occurred in this patient, consumption of grapefruit can inhibit CYP, increasing plasma concentrations of atorvastatin as much as three fold. To prevent such pharmacokinetic drug-interactions, physicians and pharmacists should regularly warn patients who take statins to avoid grapefruit and pomegranates. Some pharmacists mark statin medications with a visible warning: “Do not take grapefruit nor drink grapefruit juice while you are taking this drug.” Because one study indicates that consumption of grapefruit juice has only a minimal effect on pitavastatin acid, this drug might be preferable for some patients who need a statin. In any case, the goal should be to prevent pharmacokinetic drug-interactions.3 Aleksandar M. Lazarević, MD, Ph.D. Internal Medicine Outpatient Clinic „Cardio“ Pave Radana 17 78000 Banja Luka Republic of Srpska Bosnia and Herzegovina E-mail: [email protected] References 1. 2. 3. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther. 1999; 66:118-27. Williams D, Feely J. Pharmacokinetic–pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet 2002; 41: 343–70. Ando H, Tsuruoka S, Yanagihara H, et al. Effects of grapefruit juice on the pharmacokinetics of pitavastatin and atorvastatin. Br J Clin Pharmacol 2005; 60: 494-7. 109 LETTER TO THE EDITOR Statin-Induced Leg Pain at Night To the Editor: A 74-year-old man complained of severe leg pain at night that disrupted his sleep. He stated that after getting up and standing or walking for a few minutes, the pain would stop. His leg pains occurred once, rarely twice, during the night with episodes usually two or three times a week. Similar symptoms sometimes occurred after 10 to 15 minutes of fast walking. This disorder first appeared about five years ago; initially, the attacks of pain were less frequent. This patient has had arterial hypertension and disordered glycoregulation (glucose intolerance) for twenty years. In the last 10 months, his HbA1c ranged from 6.2 to 7.6% (RV = 4.0 to 6.2%). Eye fundus examination, lipid status, liver and kidney laboratory tests, which are monitored each year, were within the optimal ranges. The patient maintained good glycemic control by diet alone. His blood pressure has been well regulated with daily doses of atenolol (25 mg) and lisinopril (10 mg) Because of a myocardial infarction 17 years ago, the patient takes daily doses of simvastatin (40 mg) and aspirin (81 mg). All inhibitors of HMG Co-A reductase (statins) can cause side effects involving the muscles (myopathy, rhabdomyolysis), but there are some differences between these drugs. Myopathy is defined as muscle pain followed by an increase in CK values as much as 10 times or more, or, there could be only an asymptomatic increase in CK values. Lovastatin has the lowest risk of these adverse reactions1, and a change of statins generally results in the disappearance of symptoms2. The incidence of adverse reactions to statins increases with the drug dosage, polypharmacy, aging and diabetes3. Considering that our patient is an elderly person with a longterm glycemic disorder along with probable generalized atherosclerotic changes, he has a predisposition for painful leg cramps. We can conclude that the statins likely emphasized an existing tendency to night leg pain. This combination of effects eventually led to the situation that brought him into the clinic. Gordana Ljubojević, Clinical Pharmacist Nataša Tomić, MD, MSc, Nataša Stojaković, MD, MSc Medical Faculty, 78000 Banja Luka Republika Srpska, Bosna i Hercegovina Corespondence e-mail: [email protected] Tel:+387 51 234 130 References After the patient suspected that simvastatin could be causing the pain in his legs, he stopped taking the drug of his own accord. A few days later, the night leg pain completely disappeared. Twenty days later, the patient started to use simvastatin again in the same dose of 40 mg. Shortly afterwards, the symptoms returned, although this time they were less pronounced and less frequent. At his last check up, leg electromyoneurography (EMNG) was suggested, as well as a measurement of CK and potassium. The EMNG fi nding was normal, the concentration of potassium was within normal limits (4.4 mmol/ L, RV=3.5 to 5.5 mmol/L), but CK was slightly increased (238 U/L , RV=up to 170/L). 1. 2. 3. Wortmann RL, Tipping RW, Levine JG, Melin JM. Frequency of myopathy in patients recieving lovastatin. Am J Cardiol 2005;95:983-5. Sochman J, Podzimkova M. Not all statins are alike: induced rhabdmyolysis on changing from one statin to another one. Int J Cardiol 2005;99:145-6. Sewright KA, Clarkson PM, Thompson PD. Statin-myopathy: incidence, risk factors, and pathophysiology. Curr Atheroscler Rep 2007;9:389-96. 110 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com SPECIAL ARTICLE Great Scientists From a Small Country in War and Peace ABSTRAKT Great scientific discoveries rarely originate from small and poor countries. The Balkan region, an area with frequent wars and numerous invasions, is not considered an appropriate base for scientific research. Despite such opinions, a number of well educated, curious, wise, and brave minds from Serbia and the former Yugoslavia have been able to make significant scientific contributions. As an example, we briefly outline the lives and achievements of two scientists: Milutin Milankovic (1879-1958) and Ivan Djaja (1884-1957). Nikola Tesla (1856-1943), and two Nobel laureates of Yugoslav origin, Leopold Ružička (1887-1976) and Vladimir Prelog (1906-1998), are not included here because their scientific contributions were mainly conducted in the USA or Switzerland. Milankovic and Djaja overcame many obstacles, including wars, to contribute significantly to science. Unfortunately, each generation in Serbia and in the former Yugoslavia has been severely disturbed by at least one war. However, some researchers, despite wars and limited resources were able to complete their great scientific projects. Notably, such scientists stayed in the country or returned home as soon as peace returned. However, following the recent civil war that split Yugoslavia, many capable scientists did not return to their prewar homes. Rajko Igić1,2, Ranko Škrbić2, Svjetlana Stoisavljević-Šatara2 John Stroger Hospital of Cook County, Chicago, IL 60612, USA, 2 Medical School, University of Banja Luka, 78000 Banja Luka, Republic of Srpska, Bosnia and Herzegovina 1 Correspondence Rajko Igić, M.D., Ph.D. Anesthesiology Research, Room 531 Hektoen, 657 S. Wood Street, Chicago, IL 60612, USA Phone: (312) 864-4632 E-mail: [email protected] KEY WORDS Yugoslavia, Serbia, great scientists, Milankovich Cycles, Djaja, Gjaja, US von Euler, thermoregulation (Scr Med 2011;42:110-5) Great scientific discoveries rarely originate from small and poor countries, especially if they are frequently engulfed in wars, like it was the case with Serbia, and other parts of the former Yugoslavia. Despite the odds, quite a few well educated, curious, wise, and brave minds have made significant contributions under such circumstances. For example, the achievements of Laza K. Lazarević (18511891), Milutin Milankovic (1879-1958), Ivan Djaja (18841957), Pavao Stern (1913-1976), and several other Yugoslav researchers clearly show that some scientists are able to make great discoveries under limited resources. 1 Nikola Tesla (1856-1943), and two Nobel laureates of Yugoslav origin, Leopold Ruzicka (1887-1976) and Vladimir Prelog (1906-1998), are only mentioned here because their major scientific contributions had been mostly conducted in the USA and Switzerland. Presented here a brief history depicting the life and achievements of M. Milankovic and I. Djaja with commentary on the influence of recent war and NATO military interventions during the disintegration of the former Yugo- Submitted: May 30, 2011 Accepted: August 15, 2011 slavia and on scientific output as measured by changes in numbers of articles published in peer-reviewed journals. Milutin Milanković Milutin Milanković (also known as Milutin Milankovitch or Milankovich) was a geophysicist, who became well known for his discoveries related to climate change. His theory on climate change is based on the variations of three orbital parameters. The climate changes on very long timescales are known as ‘Milankovich Cycles’. These cycles are primarily responsible for the global climate changes for at least 1.6 million years. Milutin was born in Dalj in 1879 (Austria-Hungary, now Croatia) to Serbian parents. He died in Belgrade in 1958. He graduated in 1901 from the Technische Hochschule in Vienna (Civil Engineering) and two years later earned a doctorate in technical sciences. For five years after graduation, he was a practicing civil engineer in Vienna. In 1909, he accepted the position of chair of applied mathematics in Belgrade. Igić et al Scientific Activity. Milankovic’s position at the University of Belgrade was a great challenge for his basic scientific research, and he became deeply involved in the problems of solar climates and temperatures on the planet but unfortunately the wars soon disturbed his work. However, while he was an intern in Budapest, he was allowed to visit a library where he continued to work on his mathematical theory of thermal phenomena caused by solar radiation. Soon after the war, in 1920, these findings were published. Later on, he completed his theory of solar radiation.2 Like other planets, the Earth travels in an orbit around the Sun. One revolution lasts a little over 365 days (a period of one year). At the same time, the Earth spins around from west to east, and the Sun seems to travel across the sky in the opposite direction, from east to west. The value of the solar constant - total amount of radiation incident on the earth in one year is not perfectly constant. It is variable for less then 1% of the average value. Milankovic advanced the theory that the periodic changes of climate between glacial and interglacial periods are related to the orbital changes of the Earth. Long-term variations of three Milankovic orbital parameters are eccentricity (the shape of the orbit around the sun), precession (changes in the average distance Earth-Sun), and tilt of the Earth. Figure 1. Title page of Milankovic’s major book, Kanon der Erdbestrahlung, that was published in 1941. When Milankovic was fully aware that his theory of solar radiation had been completed, he prepared a manuscript for a book to be published in Belgrade, just before Germany occupied Yugoslavia. The Germans heavily bombed Belgrade on the Easter Sunday in 1941, just a few days after the book was printed, but not bound. The printer’s building was totally destroyed. Fortunately, after the wreckage was cleaned, majority of intact pages were found in the cellar storage. The rest of pages were printed after the war and the book was mailed to the libraries all over the world. The authors of this paper have borrowed a copy of the Kanon from the Math Library, University of Illinois at Urbana Champaign, Illinois, USA. One can see that the color of paper of the additionally printed pages is slightly different. The book was translated in English and published in 1969 by the U.S. Department of Commerce and the National Science Foundation under the title Canon of insolation of the Ice Ages problem. The eccentricity varies regularly during a cycle that averages about 100.000 years, and it is associated with change in solar constant of about 0,1%. When eccentricity is relatively high, the Earth receives more radiation causing warmer summers and colder winters. Thus, the seasons on one Hemisphere are strengthened, while weakened on the other. Another orbital parameter that influences seasonal and latitudinal changes presents the angle of tilt of the Earth’s axis of rotation (varies from 22o to 24,5o with a periodicity of about 40.000 years). Also, a large tilt causes extreme seasons in each Hemisphere, and the duration of the winter-darkness near a pole is determined by the tilt only. Precession presents the change of direction in space of the Earth’s rotational axis that occurs with a periodicity of about 22.000 years. The precession affects the seasonality in each Hemisphere; the variations of these three orbital parameters are important for climate changes on very long-term scale, and the periods of these orbital motions are known as Milankovich Cycles. Two short Balkan wars and World War (WW) I interrupted Milankovic’s work. At the beginning of WWI, during his visit to his home in Dalj, Austro-Hungarian soldiers captured him and he was imprisoned in Hungary. Due to his friendship with some influential people, he spent most of his prison years in Budapest. When Milankovic was in his early sixties, another great obstacle for his and other Yugoslav scientists’ work appeared: WWII and the German occupation. Citations of Milankovic’s publications. Milankovic’s publications, according to the Science Citation Index and Web of Science were quoted 780 times in the period from 1945 to 20053. His mayor work that deals with the origin of Ice Age, Kanon der Erdbestrahlung und seine Anwendung auf das Eiszeitenproblem [Canon of insolation of the Earth and its application to the problem of the Ice Age] (Figure 1), published in 1941, was most often cited during this period. As a rule, the number of citations for most publications de- 111 112 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com creases over time, but citation distribution of Milankovic’s works shows the opposite pattern. In the period from 1945 to 1960, the number of citations of his papers was modest (2,6 per year on average), but later on it steadily increased 4. For about 50 years, Milankovic’s theory was largely unnoticed, until a study of Hayes et al5 on examination of deepsee sediment showed that Milankovic’s theory did correspond to periods of climate change. Since this study, the scientists have embraced the Milankovitch Cycle model, and contemporary scientists became interested in his publications from 1920 to 1941 (Figure 2). Thus, his publications belong to a rare category that is known as “Sleeping Beauty”.6 have an impact on the climate changes, as well. Regardless of this finding, Milankovic’s theory has explained to climatologists the single factor that is primarily responsible for the global climate changes for at least 1.6 million years. Additional interests and recognition. In addition to scientific papers, Milankovic also published a textbook on the history of astronomy, two books for laypersons (Through space and centuries and Through the realm of science), and three volumes of autobiography (Recollections, Experiences, and Vision). In May 1923, he participated at the Congress of Orthodox churches (Constantinople) to present some corrections of the Julian calendar. This calendar was introduced by Julius Caesar in 45 BC upon the advice of the Greek astronomer Sosigens. Although the Julian calendar is considered inferior to the Gregorian calendar, the former calendar is used by many Orthodox Churches (including Serbia and Russia). Milankovic was a member of the Serbian Academy of Sciences and Arts (Belgrade), the Yugoslav Academy of Sciences and Arts (Zagreb), the German Academy of Naturalists “Leopoldina” (Halle), and a member of many other scientific societies and organizations in Yugoslavia and abroad. Thus, he significantly influenced scientific and cultural development in many countries. The following cosmic objects were named after him: Milankovic—a lunar crater on the far side of the Moon (77,2o N, 168,8 o E); Milankovic—a 118 km crater on Mars (at 54,4 o N, 213,3 o E); and 1605 Milankovich—a miniature planet. Figure 2. Citations of Milankovic’s publications according to the Science Citation Index and Web of Science (from 1928 to March 2011). Milankovic’s publications belong to a rare category of “Sleeping Beauty.” Famous example of this type is the Mendel’s work on plant hybridization. Mendel’s findings were for long distrusted because “mathematics has not legitimate application to biological science.” Also, not many of the Milankovic’s contemporaries believed in possibility that the calculus may explain climate changes. Bulletin “Kontakt” recorded appreciation of his work. The “Kontakt”, an official journal of the Yugoslav Society of Biomedical Journals and Bulletins, has published the article Ledena doba i teorija Milutina Milankovica [The Ice Ages and the Theory of Milutin Milankovic] in 1994. 7 In addition to a brief introduction, several segments from the paper entitled “The Ice Ages” 8 were printed and distributed locally in order to spread the awareness of chemical record found in the ocean sediments in 1984, which supported Milankovic’s theory. The paper also presents the Devil’s Hole findings suggesting that the changes of the Ice Ages are not always cyclical, indicating that the other factors Ivan Djaja Ivan Djaja (also known as Jean Giaja) had a remarkable scientific career in Belgrade. He was a physiologist internationally known for his research on thermoregulation and deep hypothermia. Djaja was born in 1884 in France to a Serbian father and French mother. He declared himself as a Serb of Catholic religion. When he was six, his family moved to Belgrade where Djaja attended school. In 1909, he got his doctoral degree in Physiology at Sorbonne University, Paris. He was invited in Belgrade, in 1910, by the Kingdom of Serbia. Djaja was a chairman and founder of the department of physiology at the University of Belgrade. He lived in Belgrade up to his death in 1957. His research work was interrupted by two short Balkan wars, and by the WWI and WWII. The worst period for him was the period of German occupation, 1941-1945 as he suffered like many Serbian intellectuals and was even imprisoned for some time in the Banjica Concentration Camp. Djaja published about 200 papers in various biomedical journals in French, Serbian, German, English, and Italian. His two books “L’Homeothermie” and “La Thermoregulation” (Figure 3) 9 are well known among physiologists. He also published several fiction books, and three philosophical books, including L’ homme et la vie inventive”.10 Igić et al were unsuccessful and it was concluded by the German physiologists that below 15 oC, the rat couldn’t be successfully revived. The closed vessel method of cooling animals, in which hypoxia and hypercapnia are combined, initiated an anecdotal publication on this method.11 Enthusiasm for experimental work is a characteristic feature of all Claude Bernard pupils and their followers. Thus, Djaja proclaimed a motto Nulla dies sine experimento - a paraphrase of Nulla dies sine linea by Leonardo Da Vinci. Such enthusiastic research that lasted until his death resulted in his acceptance to the French academy of Science, where he was elected on May 23, 1956 as a replacement for Sir Alexander Fleming (Figure 5). Djaja died in Belgrade in 1957 during second day of the ‘International Symposium on Hibernation’ that was organized in his honor. Thus, he lived and worked in Belgrade for 47 years where he established a great school of physiology. Figure 3. Two books published by Ivan Gjaja in 1938. Major discoveries. Djaja’s main scientific contributions are in the field of thermoregulation and thermal adaptation, and his department soon became internationally known as the “Belgrade School of Physiology.” Djaja’s Ph.D. student, Radoslav K. Andjus (1926-2003), was the first to reanimate a rat that was in deep hypothermia.11 Previous attempts to re-warm deeply cooled rats Epilogue The Balkan region, so frequently devastated by wars, is generally not considered a fertile ground for scientific research. However, there have been researchers and intellectuals, such as Lazarevic, Milankovic, Djaja, Andric, Stern, who despite wars and limited resources in Yugoslavia, were able to realize their projects. Thus, in each generation some brilliant men enriched certain areas of science and arts. Of note, these individuals stayed in the country or returned home, as soon as freedom came. However, after the recent civil war that split the former Yugoslavia, many capable scientists were not allowed to return to their homes, especially if they belonged to a different nationality. Consequently, this war in Yugoslavia has been most damaging to scientific endeavors in Serbia, and B & H.12 (Figure 5). When Lazarevic, Milankovic, Djaja and other young scientists who were trained in developed countries returned home, they received appropriate support and were given freedom to initiate independent research programs. Such an approach appeared to stimulate their creativity and adherence to their universities. There is a consensus that when young scientists are given such freedom, despite often losing time seeking adequate methods and deciding what they really want to study, acquire an independent and critical way of thinking earlier than researchers who work in a research group with a fi xed research program and methods. However, poor countries, cannot afford to finance many scientists, and the selection of the most promising, well trained, researchers is the main challenge for those who make the decisions regarding scientific research. Figure 4. In 1956, Djaja was eleced in the French Academy of Science as substitute to Sir Alexander Fleming. Another aspect for facilitating science in a small country is international cooperation and this process should be bidirectional. Scientists from small country should be able to 113 114 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com visit international laboratories in prestigious institutions. However, it is also important to invite established foreign scientists to a small country to visit, so as to stimulate local researchers. This is a way to create cooperative international scientific projects that may facilitate scientific research worldwide. First International Symposium on Substance P organized by professor Pavel Stern in Sarajevo (1968)13 is an example of such cooperation, as many of the participants continued collaborating with the scientists in Yugoslavia long after the symposium had ended. One of these participants, U.S. von Euler, assisted the Yugoslav pharmacologists in various ways, and he visited Yugoslavia again in 1976 (University of Belgrade) in and in 1982 (University of Tuzla). ‘brain-drain’. The return of these scientists with valuable experience gained in other more prominent countries, will significantly help the educational, scientific and cultural recovery in these war torn countries. In addition, international scientific, technical, and cultural cooperation should involve local interstate collaboration, so these states that recently were fighting for independence or territorial gains could improve their relationships. Acknowledgments The authors thank to Dr. Eugene Garfield (Philadelphia, Pennsylvania, USA) and Mrs. Adrienne Einarson (Toronto, Canada) for suggestions on the manuscript. References 1. 2. 3. 4. 5. 6. 7. Figure 5. Publications from six former Yugoslav republics. The papers published from 1988 to 2000 in the journals covered with Science Citation Index from Bosnia & Herzegovina, Croatia, Macedonia, Montenegro, Slovenia, and Serbia are presented. 8. 9. 10. During the recent war in Yugoslavia and NATO bombings of B&H and Serbia many well educated people have left these states, with a number of them having received training and research experience. It is now time for newly formed states to invite them to return home. The government needs to create a program to turn around this 11. 12. 13. Igic R. Can outstanding research be done under less than ideal conditions? Einstein J Biol Med 2003; 20: 23-7. Milankovitch M. Kanon der Erdbestrahlungen und seine Anwendung auf das Eiszeitenproblem. [Canon of the Earth’s insolation and ist application to the Ice Age problem.], Beograd, Koniglich Serbishe Akademie, 1941; Editions speciales, 133, Section des Sciences Mathematiques et Naturales 33: 1-633. www.unilib.bg.ac.yu/eng/about_us/exhibitions/milankovic_ virtual/radovi. Dimitrijevic MS. Milutin Milankovic in Science Citation Index 1946–1996. Bull Astron (Belgrade) 1997; 156: 205-41. Hays JD, Imbrie J, Shackleton NJ. Variations in the earth’s orbit: Pacemaker of the ice ages. Science 1976; 194: 1121-32. VanRaan, AFJ. Sleeping beauties in science. Scientometrics 2004;59:467-72. Anonimous. Ledeno doba i teorija M. Milankovica. [The ace ages and Milankovic’s Theory.] Kontakt (Novi Sad) 1994; 2 (2): 3-4. Yoon CK. The ice ages. Earth 1993; 2: 20-3. Giaja J. L’homeothermie et thermoregulation: (I) L’homeothermie, (II) La thermoregulation. Paris, Hermann, 1938. Đaja, I. (1955) L’Homme et la vie inventive, Paris: Pacomhy; «Čovek i inventivni život». Beograd, Biološki fakultet, 1999. Andjus PR. Ivan Đaja (edicija “Život i delo srpskih naučnika”). Beograd, SANU, 2010. Igic R. The influence of the civil war in Yugoslavia on publishing in peer-reviewed journals. Scientometrics 2002; 53: 447-52. Von Euler, US. Historical notes. In: Substance P. Von Euler, U.S. and Pernow, B. (eds.), New York, Raven Press, 1977. Igić et al Veliki naučnici iz male zemlje u ratu i miru Rajko Igić, Ranko Škrbić, Svjetlana Stoisavljevic-Šatara APSTRAKT Značajna naučna otkrića retko potiču iz malih i siromašnih zemalja. Međutim, dostignuća nekolicine jugoslovenskih naučnika pokazuju da su oni prevazilazili niz teškoća, uključujući ratove i teške posleratne periode i značajno doprineli nauci. Nažalost, svaka generacija u Jugoslaviji bila je ometena barem jednim ratom i takvi uslovi značajno štete naučnu produkciju. Zato nema mnogo stvaralaca poput Milutina Milankovića (1879-1958) i Ivana Đaje (1884- 1957) i još nekolicine drugih naučnika, koji su unatoč ratova i ograničenih sredstava prevazilazili teške uslove da bi završili svoje naučne projekte. Uočljivo je da su ti naučnici vreme rata provodili u svojoj zemlji ili su se vraćali kući, odmah posle rata. Ovde samo pominjemo u svetu poznatog inovatora i istarživače jugoslovenskog porekla, Nikolu Teslu (1856-1943) i dva Nobelovca, Leopolda Ružičku (1887-1976) i Vladimira Preloga (1906-1998) koji su većinu svojih dela stvorili u Americi, odnosno u Švajcarskoj. Kao primer uspešnih stvaralaca u našim uslovima, u ovom članku su dati podaci o životu i radu M. Milankovića i I. Đaje. U komentaru se navodi da su nakon nedavnog rata, koji je pocepao Jugoslaviju, mnogi stučnjaci otišli u inostranstvo i da ih se većina nije vratila u svoju zemlju. 115 Continuing Medical Education Questions and Answers 118 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Questions and Answers Ova rubrika (Q & A) sadrži neznatno izmenjene segmente iz navedene literature ili za ovu priliku napisan tekst. Cilj nam je da ovi prilozi posluže čitaocu kao vežba za unapređenje stručnog engleskog jezika. [This section presents short segments of texts from the Literature or original texts. The main purpose is to provide questions and answers that readers can use to improve their English.] Scripta Medica (Scr Med 2011;42:118-26) Questions 1. Following statements are either true or false: a. Drug-eluting stents are associated with less periprocedural risks but a higher incidence of postprocedural myocardial infarction, repeat revascularization, and 12-month major adverse cardiac and cerebrovascular events compared with coronary artery bypass grafting. b. Cryotherapy is not recommended for treating skin cancers on the face. c. Fluorouracil cream is an effective treatment for basal cell carcinomas. d. Paracetamol does not cross the placenta. e. NSAIDs should be avoided during the third semester. f. Dehydration is a risk factor for delirium in older people. g. Benzodiazepines are recommended for the treatment of delirium tremens. 2. Which famous medical doctor came from Sombor to Belgrade at the end of the 19th century? Radoslav Gajanin1 Bozana Alexander2 Svjetlana StoisavljevićŠatara1 Andrzej Staszkiewicz2 Miroslav Jerinic1 1 Medical School University of Banja Luka 78000 Banja Luka Republic of Srpska Bosnia and Herzegovina 2 Departement of Anesthesiology & Pain Management, Stroger Hospital, Chicago, IL 60612, USA Correspondence Dr. Radoslav Gajanin Medical School University of Banja Luka 78000 Banja Luka Republic of Srpska Bosnia and Herzegovina a. Sputum culture is the definitive investigation for diagnosing latent tuberculosis. b. A negative tuberculin skin test rules out the possibility of active tuberculosis. 7. What are the noninvasive methods for the evaluation of a patient with peripheral artery disease? 8. Which serum enzyme activity should be adjunctively used to diagnose sarcoid, and to determine the effectiveness of corticosteroid therapy? 9. What are the main signs of Niemann—Pick disease? 10. What medications may interact with sildenafil (eg. Viagra) and cause severe and potentially fatal hypotension? 11. Why the use of verb tense can help ensure smooth expression? 12. How we can increase economy of expression? 3. How the American Association for the History of Medicine commemorated Sir William Osler? 4. What are effective topical therapies for intraocular neovascularization and retinal edema? 13. How to write a letter to a journal? 14. When the authors should check the reference list? 5. What are clinical features of cutaneous tuberculosis? 15. How should you answer questions at the oral presentation when you are not fluent in English? 6. The following statements are either true or false 16. A newborn boy delivered at 38 weeks is small for gesta- Gajanin et al. tional age. Physical examination shows microcephaly, frontal bossing, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebral fissures, thin elongated philtrum, vermilion border of the upper lip, dental malocclusion, saddle nose, tooth enamel hypoplasia, and uvular hypoplasia. Ocular problems include microphthalmia, corneal clouding, coloboma, nystagmus, strabismus, and ptosis. A systolic murmur is heard on auscultation, and echocardiography shows a membranous ventricular septal defect. Which of the following conditions is most likely to produce these findings? 19. What is interventional pain management? Answers 1a: True Numerous studies have compared the outcomes of two competing interventions for multivessel coronary artery disease: coronary-artery bypass grafting (CABG) and coronary stenting. In 2003, drug-eluting stents were introduced for the purpose of reducing restenosis, which has continued to be a problem associated with the use of baremetal stents. a. Congenital rubella b. Placenta previa c. Maternal diabetes mellitus d. Trisomy 21 e. Fetal alcohol syndrome 17. A 50-year-old man has developed truncal obesity, back pain, and skin that bruises easily over the past 5 months. On physical examination, he is afebrile, and his blood pressure is 160/95 mm Hg. A chest radiograph shows an ill-defined, 4-cm mass involving the left hilum of the lung. Cytologic examination of bronchial washings from bronchoscopy shows round cells that have the appearance of lymphocytes but are larger. The patient is told that, although his disease is apparently localized to one side of the chest cavity, surgical treatment is unlikely to be curative. He also is advised to stop smoking. Which of the following neoplasms is most likely to be present in this patient? a. Adenocarcinoma b. Bronchial carcinoid c. Bronchioloalveolar carcinoma d. Large-cell carcinoma e. Metastatic renal cell carcinoma f. Non-Hodgkin lymphoma g. Small-cell carcinoma h. Squamous cell carcinoma 18. A study of patients recently diagnosed with type 2 diabetes mellitus follows them for 20 years to determine the prevalence and severity of complications of the disease. The records of these patients are analyzed to identify the laboratory methods used to monitor patients’ ability to maintain disease control and reduce the potential for complications. Which of the following laboratory studies is most likely to afford the best method of monitoring disease control in these patients? a. Random plasma glucose b. Fasting plasma glucose c. Glycosylated hemoglobin d. Glycosylated serum albumin D (E) Serum fructosamine f. Microalbuminuria Systematic review and meta-analysis of randomized and nonrandomized comparative studies done in 2010 in an attempt to compare the safety and efficacy of drug-eluting stents with coronary artery bypass grafting for patients with coronary artery disease. In these 25 studies 34 278 patients were compared, of whom 18 538 received drugeluting stents and 15 740 underwent coronary artery bypass grafting. It was concluded that drug-eluting stents are associated with less periprocedural risks but a higher incidence of postprocedural myocardial infarction, repeat revascularization, and 12-month major adverse cardiac cerebrovascular events compared with coronary artery bypass grafting. Subgroup analysis of patients with multivessel coronary artery disease showed similar results. 1b: True Skin cancers have traditionally been treated with surgical excision. This is the most effective treatment option. However, over the last few decades non-surgical treatments, such as cryotherapy and topical fluorouracil, have become available. Non-surgical treatments should not be used when the diagnosis is unclear or if follow-up is not assured. Liquid nitrogen cryotherapy is most suited for low-risk primary tumors of basal cell carcinoma or Bowen’s disease (squamous cell carcinoma in situ) on the trunk and limbs. It has lower cure rates on the face so it is not recommended for treating facial skin cancers. 1c: False Fluorouracil cream should not be used as a treatment for basal cell carcinomas as there is little evidence of its efficacy. Excisional surgery is considered to be effective in treating basal cell carcinoma. Fluorouracil is used as 5% cream twice a day for three weeks as a treatment for multiple solar keratoses, particularly on the head and scalp areas. There are also a small number of case reports indicating that 5% fluorouracil cream can be used quite effectively to treat Bowen’s disease. This is usually used twice a day for 4-6 weeks. The cream usually produces significant inflammation that will take 1-2 weeks to settle. Cold compresses and medium potency steroid creams can ease the 119 120 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com symptoms. 1d: False Paracetamol readily crosses the placenta in its unconjugated form. However, in therapeutic doses it does not appear to increase the risk of birth defects or other adverse pregnancy outcomes. Despite paracetamol’s widespread use there are no prospective controlled studies about its use in pregnancy. A registry- based study from Denmark of 26424 children who were exposed to paracetamol in utero during the first trimester found no increase in either the specific or the overall rate of birth defects compared with unexposed controls. 1e: True NSAIDs including ibuprofen, naproxen, indomethacin and diclofenac have not been shown to increase the risk of structural birth defects or preterm delivery. However, a case-control and population-based observational cohort study from Scandinavia demonstrated an increased risk of spontaneous abortion with the first trimester use of NSAIDs. A Californian study also showed an 80% increase in the risk of miscarriage associated with first trimester use of both aspirin and NSAIDs. This association was not seen with paracetamol. A suggested mechanism to explain the increased risk of miscarriage is interference with implantation as a results on the prostaglandin pathway; NASIDs are inhibitors of cyclo-oxygenase. 1f: True Delirium is an acute syndrome characterized by altering levels of consciousness, attention and cognitive function. The symptoms of delirium usually fluctuate throughout the day and night, with disturbance of the sleep-wake cycle resulting in agitation at night and drowsiness during the day. It has many causes and frequently leads to, or occurs during, hospitalization. Delirium requires urgent medical assessment. It is a common emergency with high mortality rates, affecting older patients. Unfortunately, the diagnosis is often missed. Risk factors for delirium include dementia, older age, multiple co-morbidities, psychoactive medication, sleep deprivation, dehydration, immobility, pain, sensory impairment and hospitalization. The pathophysiology of delirium is poorly understood. Susceptibility to this condition reflects a balance between the severity of the insult and the frailty of the central nervous system, so anyone can get delirium, including young people especially those who are using recreational drugs. If drugs are needed, antipsychotics are accepted as firstline, except in delirium tremens. However, phenothiazine antipsychotic drugs such as chlorpromazine, which have prominent anticholinergic propreties, should be avoided in old patients. Well known aphorism of geriatric pharmacology, ‘start low and go slow’, should be always remembered. Thus, suggested initial doses for older patients are halpperidol 0.5 mg, risperidon 0.5 mg or olanzapine 2.5 mg. Depending on the response additional doeses can be given after 2-4 hours, otherwise daily. The patient should be closely monitored for over-sedation. 1g: True Benzodiazepines are the treatment of choice for delirium tremens and delirium associated with benzodiazepine withdrawal. They can also be used in patients with neuroleptic malignant syndrome, Parkinson’s disease or Lewy body dementia. 2. On February 17, 1749, Sombor received the status of a Free Royal Town. Since then, this town has been developing both culturally and economically. In 1778, Teachers College (now Pedagoški Fakultet) was founded in there, and it is the oldest college in Serbia and the Balkan region. In 1880, Sombor got new building that was designed for a hospital. Dr. Đorđe Maksimović (1838-1881) was the founder and the first director of this hospital. Dr. Milan Jovanović-Batut came to Sombor soon after he got an MD degree at the University of Wien in 1878. Dr. Jovanovic worked there for three years. In addition to medical practice, he founded there a journal “Zdravlje.” That was the first popular journal for public health printed in a language of the South Slavs. However, when King Nicola the First invited him to Montenegro, he left Sombor and publishing this journal was ended. In 1887, Dr. Jovanovic came to Belgrade where he became one of the founders of the Medical School at the University of Belgrade that was opened in 1919. He was the first professor of forensic medicine and hygiene, and the first dean of the School. Dr. Jovanovic was extraordinary educator of medical students and citizens of Serbia. Also, he significantly contributed to development of the public health in Croatia, and other parts of Yugoslavia. He published numerous books related to public health and hygiene, and notable medical essays. Czechoslovakian medical community paid a special tribute to his work and accomplishments. 3. From 1942, the American Association for History of Medicine (AAHM), awards the medal that commemorates Sir William Osler, who stimulated an interest in the humanities among medical students and physicians. Osler Gajanin et al. Medal Essay Contest is awarded annually for the best unpublished essay on a medical historical topic written by a student enrolled in a school of medicine or osteopathy in the United States or Canada. The writer of the winning essay is invited to attend to the AAHM meeting where the medal is conferred. Travel expenses are provided and a two-year complimentary membership in the AAHM is provided. If the Committee also selects an essay for honorable mention, its author receives a certificate and two-year complimentary membership to the Association. [Sir William Osler (1849 – 1919) was a Canadian physician. He was one of the “Big Four” founding professors at Johns Hopkins Hospital as the first Professor of Medicine and founder of the Medical Service there. Osler created the first residency program for specialty training of physicians, and he was the first to bring medical students out of the lecture hall for bedside clinical training. He has been called the “Father of modern medicine. Osler was a pathologist, physician, educator, bibliophile, historian, and author.] Physiological and biochemical societies in some of the former Yugoslav republics, from time to time, award students or young researchers to commemorate our great scientists and physicians. Perhaps, we should have awards that each year commemorates one of our great men, such as, Laza LazarevicćIvan Djaja, Kosta Todorović, Milan JovanovićBatut, Pavel Štern, and Vladimir Prelog. If we decide to create the medal that commemorates Vladimir Prelog, a Nobel Laureate who was born in Sarajevo and made his discoveries in Switzerland, it could be awarded to a student from Bosnia & Herzegovina or Switzerland. 4. Laser photocoagulation remain the cornerstone treatment for intraocular neovascularization and retinal edema. Experimental treatments include topical application of antiangiogenic agents (VEGF inhibitors or multitargeted kinase inhibitor). Barring death, blindness is one of the most feared complications of human disease. The vast majority of visual loss results from pathologic neovascularization of the choroid and retina or retinal edema. These pathologic ocular changes are caused by age-related macular degeneration, diabetic retinopathy, retinal-vein occlusion, rethinopathy of prematurity, and numerous inflammatory and neoplastic conditions. Until recently, laser photocoagulation was the only primary therapeutic option. In addition to destroying areas of otherwise functional retina to preserve central vision, the procedure is not universally effective and is associated with unavoidable side effects. Therapeutic use of VEGF inhibitors (ranibizumab and pegaptanib) that are injected into the eye has revolution- ized the treatment of age-related macular degeneration. It allows recovery of lost vision. Thus, intraocular injection of VEGF inhibitors has supplanted laser and other therapies. However, these drugs are expensive, the treatment regimen is associated with discomfort in patients, and it is critically dependant on the availability of an ophthalmologist to apply medication intarvitreally each month. An intravitreal injection incurs the rare but visually devastating risk of retinal detachment and endophthalmitis. Proliferative diabetic retinopathy and neovascular glaucoma are sensitive totreatment with VEGF inhibitors. In contrast, thepatients with retinal edema have only partial response to VEGF inhibitors. This implies that pathways other than that of VEGF are involved. VEGF-independent mechanisms in diabetic retinal disease may include erythropoietin, and the carbonic anhydrase-kallikrein system. The inhibition of multiple targets simultaneously tends to result in a robust therapeutic effect. This suggests that targeting of more than one patway supporting angiogenesis may increase the clinical benefit in the eye. The ability to provide effective topical therapies for intraocular neovascularization and retinal edema could revolutionize the current care of many diseases that lead to the most severe sight-threatening conditions of our time. 5. Cutaneous tuberculosis occurs rarely, despite a high and increasing prevalence of tuberculosis worldwide. It forms a small proportion of all cases of extrapulmonary tuberculosis, which in turn constitutes only a small fraction of all tubercular infections. Recently, an increasing incidence of cutaneous tuberculosis has reemerged in areas with a high prevalence of human immunodeficiency virus (HIV) infection. Cutaneous tuberculosis can be acquired exogenously or endogenously and present as a multitude of differing clinical morphologies. Direct infection of the skin or mucous membranes from an outside source of mycobacteria results in an initial lesion called the tuberculous chancre. Such primary infection develops in a previously uninfected, nonsensitized host. The chancres are firm shallow ulcers with a granular base. They appear about 2-4 weeks after mycobacteria enter through broken skin. The immune response of the patient and the virulence of the mycobacteria determine the type and severity of cutaneous tubeculosis. Primary infection in a previously uninfected, nonsesitized host, may also be expressed as acute disseminated miliary tuberculosis (also termed tuberculosis cutis disseminata and tuberculosis cutis acuta generalisata). Alternatively, the host may be presensitized to mycobacterial antigens, through either previous infection or immunization with bacille Calmette-Guerin (BCG). In such individuals, secondary infection with another strain of M. tuberculosis may result in “reinfection tuberculosis,” 121 122 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com with lupus vulgaris (variants: plaque form, hypertrohic form, ulcerative form, vegetative form) and tuberculosis verucosa cutis as its distinct manifestations. Reactivation of the dormant “persister” mycobacteria is responsible for “reactivation” secondary tuberculosis, which manifests as either scrofuloderma or tuberculosis cutis orificialis. Mycobacterium tuberculosis, Mycobacterrium bovis, and the Bacille Calmette-Guérin vaccine can cause tuberculosis involving the skin. Microbiological confirmation is poor, despite scientific advances, such as the more frequent use of polymerase chain reaction. In addition, these lesions resemble many other dermatological conditions that are often primarily considered. The diagnosis of cutaneous tuberculosis is often difficult because these lesions resemble many other dermatological conditions that are often primarily considered. The diagnosis is partially based on following relative criteria: morphologic features, characteristic history of evolution, Mantoux test, microscopic examination of the tissue section that depicts a tuberculoid and tuberculous granuloma. However, absolute criteria include demonstration of acidfast bacilli, recovery of M. tuberculosis in culture, recovery of M. tuberculosis on inoculation of material from lesions into guinea pigs, and the polymerase chain reaction. 6a: False fection, other immunosuppressive illnesses, residence in geographical areas where exposure to TB is common, etc. In 2010, WHO endorsed a new and novel rapid test for tuberculosis, especially relevant in countries most affected by this disease. The test could revolutionize TB care and control by providing an accurate diagnosis for many patients in about 100 minutes, compared to current tests that can take up to three months to have result. WHO’s endorsement of the rapid test, which is a fully automated NAAT (nucleic acid amplification test) follows 18 months of rigorous assessment of its field effectiveness in the early diagnosis of TB, as well as multidrug-resistant TB (MDRTB) and TB complicated by HIV infection, which are more difficult to diagnose. Evidence to date indicates that implementation of this test could result in a three-fold increase in the diagnosis of patients with drug-resistant TB and a doubling in the number of HIV-associated TB cases diagnosed in areas with high rates of TB and HIV. Many countries still rely principally on sputum smear microscopy, a diagnostic method that was developed over a century ago. But this new ‘while you wait’ test incorporates modern DNA technology that can be used outside of conventional laboratories. It also benefits from being fully automated and therefore easy and safe to use. 6b: False Comment for Q 6a and 6b: The approach to testing for tuberculosis (TB) depends on whether the aim is to diagnose active disease or latent infection. If active disease is suspected, it is important to identify the site of disease. Analysis of sputum specimens for mycobacteria remains the definitive means for diagnosis of active tuberculosis. Colelction of specimens should include three morning sputa whatever the suspected site of disease, unless chest X-ray is normal and there are no respiratory symptoms in a person with localized extrapulmonary disease. An infection should never be diagnosed as latent until active disease has been excluded. Tuberculin skin testing is recommended for diagnosing latent infection, but interferon gamma release assays (Quantiferon Gold) may be useful in some circumstances when high specificity is desired. Tuberculin test measures a patient’s immune response to M. tuberculosis antigens (tuberculin). A small amount of tuberculin is injected intradermally and skin reaction is measured two or three days later (Mantoux method). Only the diameter of induration should be read, not the diameter of erythema. Criteria for defining a tuberculin skin testing reaction as positive are based on the size of the induration produced by an intradermal injection of 5 units of purified protein derivative (PPD) are given by local guidelines. The diameter of induration used to define a positive reaction of >5 mm, >10 mm or >15 mm depends on recent (within 2 years) or old exposure, BCG vaccinated status, HIV in- WHO is now calling for the fully automated NAAT to be rolled out under clearly defined conditions and as part of national plans for TB and MDR-TB care and control. Policy and operational guidance are also being issued based on findings from a series of expert reviews and a global consultation held in Geneva. Nucleic acid amplification tests have moderate sensitivity and high specificity for TB in a predominantly HIVseropositive population with negative sputum smears. Although newer, more sensitive nucleic acid assays may enhance detection of Mycobacterium tuberculosis in sputum, even currently available tests can provide substantial clinical impact in smear-negative populations. 7. Main noninvasive tests to diagnose peripheral artery disease are: Physical exam (a weak or absent pulse below a narrowed area of artery, bruits over arteries, evidence of poor wound healing in the area where blood flow is restricted, and decreased blood pressure in the affected limb), ankle-brachial index (ABI compares the blood pressure in the arm and ankle; in addition to a regular pressure cuff, the examiner needs a special ultrasound device to evaluate blood pressure and flow; an ABI of 0.97 or less almost always represents some form of arterial occlusive disease), and ultrasound imaging (Doppler ultrasound can help us to evaluate blood flow through blood vessels and identify blocked or narrowed arteries). Gajanin et al. Invasive methods include angiography and catheter angiography. Angiography is based on injecting a contrast material into the vessel and tracing the flow of the contrast media using imaging techniques such as X-ray imaging or magnetic resonance angiography (MRA), or computerized tomography angiography (CTA). Catheter angiography is more invasive procedure that involves guiding a catheter through an artery to the affected area and injecting the dye that way. This type of angiography allows for simultaneous diagnosis and treatment— finding the narrowed area of a blood vessel and then widening it with an angioplasty procedure or administering medication to improve blood flow. 8. Elevated serum angiotensin I converting enzyme (ACE) levels was found in patients with active sarcoidosis, and with resolution of the disease or with control of the disease by systemic steroids, the ACE activity became normal. Sarcoidosis is a multisystem granulomatous disease of unknown etiology, which most often involves the lungs and lymphatic system. Cutaneous involvement is found in approximately 25% of cases of sarcoid. Approximately 30% of patients seen in a dermatology clinic with cutaneous sarcoidal granulomas will have disease apparently limited to the skin. In order to increase the diagnostic specificity of sarcoid, it has been shown that the ACE activity leads to a more accurate diagnosis. Elevated serum ACE activity is found in some other conditions leading to false-positive results. Although not specific for sarcoidosis, serum ACE activity can be used adjunctively to diagnose this disease, and to determine the effectiveness of corticosteroid therapy. 9. Niemann—Pick disease is an autosomal recesive sphingolipidosis with different clinical forms, characterized by a protruding abdomen due to hepatosplenomegaly, neurological complications of variable severity, cherry-red spot of the retina, thin extremites and growth deficiency. Main signs of this disease are presented as: Type A (acute form with neurological complications), Type B (chronic form without neurological complications), Type C (chronic form with neurological complications), Type D (Nova Scotia variant; similar to type C, progressive psychomotor deterioration between the second and fifth years, hepatosplenomegaly, impaired co-ordination), Type E (adult form without neurological complications), Type F (‘sea-blue histocytosis’ is ophtalmoplegic neurolipidosis). Frequency: Over 100 patients known; of these , 85% type A in Ashkenazy Jews. Type D endemic in Nova Scotia. The ophtalmological neurolipidosis has been documented in 39 patients to date. Course, prognosis: Type A: death before the fourth year of life from pleumonia. Type B: endangered by pneumonias. Type C and D: death between the fifth and 15th years. Type E: unknown. Type F: death from pneumonia in 12 patients between the fifth and 29th years. Treatment: No specific therapy. Splenectomy for mechanical indications or in case of hypersplenism. Genetic counseling. Prenatal diagnosis for types A and B only. 10. Concurrent use of protease inhibitors, such as ritonavir (Norvir), saquinavir (Invirase), fosamprenavir (Lexiva), indianavir (Crixivan), and nelfinavir (Viracept), and sildenafil may result in severe and potentially fatal hypotension. Mechanism: inhibition of sildenafil metabolism. Onset of such interaction is rapid. Death was reported in a 47-year-old man following concurrent use of ritonavir, saquinavir, and sildenafil. In healthy volunteers not infected with HIV, administration of ritonavir 500 mg twice daily at steady-state, with a single sildenafil 100 mg dose, increased peak sildenafil plasma levels 4-fold.At 24 hours, sildenafil plasma levels were still approximately 200 ng/ ml, compared with approximately 5 ng/ml when sildenafil was given alone. Pharmacologic effects of sildenafil may be prolonged, resulting in prolonged erections, in patients receiving opioid analgesics (rapid onset), or cimetidine (delayed onset). These interactions increase risk of sildenafil’s side effects. Grapefruit juice may increase sildenafil plasma concentrations. However, severity of this interaction is minor. 11. Scientific prose and creative writing serve different purposes. Devices that are often found in creative writing, such as, setting up ambiguity, inserting the unexpected, omitting expected, and suddenly shifting the topic, verb tense, or person, can confuse readers of scientific prose. Abruptness may result from sudden, unnecessary shift in verb tense within the same paragraph or in adjacent paragraphs. By being consistent in the use of verb tenses, you can help ensure smooth expression. Past tense (e.g., “Smith showed”) or present perfect tense (e.g., “researchers have shown”) is appropriate for the literature review and the description of the procedure. Stay within the chosen tense. Use past tense (e.g., “anxiety decreased significantly”) to describe the results. Use the present tense (e.g., “the results of Experiment 2 indicate”) to discuss the results and to present the conclusions. Verbs are vigorous, direct communicators. Use the active rather than the passive voice, and select tense and mood carefully. 123 124 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Poor: The experiment was designed by Simpson (2001). Better: Simpson (2001) designed the experiment. The passive voice is acceptable in expository writing and when you want to focus on the object or recipient of the action rather than on the actor. Use the past tense to express an action or a condition that occurred at a specific time in the past, as when discussing another researcher’s work and when reporting your results. Examples: - Sanches (2000) presented the same results. - In Experiment 2, response varied. (Result section.) - As demonstrated in Experiment 2, response varies. (Discussion section.) Use the present perfect tense to express a past action or condition that did not occur at a specific, definite time or to describe an action beginning in the past and continuing to the present. Example: Since that time, investigators from several studies have used this method. 12. Economy of expression can be increased when we say only what needs to be said. We can tighten long papers by eliminating redundancy, wordiness, jargon, evasiveness, overuse of passive voice, circumlocution, and clumsy prose. In addition, we should weed out overly detailed descriptions of apparatus, participants, or procedures (particularly if methods were published elsewhere, in which case we should simply cite the original study); elaborations of the obvious, and irrelevant observations or asides. Short words and short sentences are easier to comprehend there are long ones. However, a long technical term may be more precise than several short words, and technical terms are inseparable from scientific reporting. Writing only in short, simple sentences produces choppy and boring prose, and writing exclusively in long, involved sentences creates difficult, sometimes incomprehensible material. Varied sentence helps readers maintain interest and comprehension. Direct, declarative sentences with simple, common words are usually best. Similar cautions apply to paragraph length. Single-sentence paragraphs are abrupt, and some medical journals do not accept manuscripts with single-sentence paragraph. Paragraphs that are too long are likely to lose the reader’s attention. New paragraphs provide a pause for the reader— a chance to assimilate one step in the conceptual development before beginning another. A writer should look for a logical place to break a long paragraph. Unity, cohesiveness, and continuity should characterize all paragraphs. 13. When you think of submitting a letter to a journal, first consider the following basic questions: - What is the purpose of your letter? - Is a letter format appropriate for this particular journal? - Does what you want to say justify a communication? The purpose of a letter varies between journals. Most letters are comments in response to a previous publication, although brief communications that do not justify an extended or concise report are sometimes appropriate as letters. With respect to length, always be brief. 14. Before you submit your manuscript, look over your reference list, especially if you have used a bibliography program or your notebook. You do not want the reviewers and editors to think that you are a careless scientist. If you did not use a bibliography program, verify each citation against the original article for the spelling of the authors’ names, the exact title of the article, and the year, volume, and page numbers. Finally, make sure that the references are cited in the correct order, as they appear in the text. References have many purposes. Fore example, they demonstrate your familiarity with existing knowledge in the field, direct readers to other literature of interest, provide other investigators with the sources for your methods, and furnish editors with a list of potential reviewers. A few basic rules apply to all references: statements of fact—except those from your present study and the facts that are so obvious that referencing them may seem silly—must be referenced; do not use a reference that you have not read; pay attention to the order of references within a sentence so that readers can easily identify which studies support which point; the results section should almost never have any reference citations, and always redo your literature search and references each time you submit, or resubmit, a manuscript. There are several bibliography programs for the personal computer that can simplify the process of preparing a reference list. You can easily add references to your citation database manually, or by downloading the references from the literature search. The latter process reduces but does not eliminate typographical errors. Always check for them. Most electronic references include extraneous material, such as “see comments”. Delete these phrases as you download the reference. Follow the journal’s rule about how citations should appear in the text. Most journals follow a standard reference format known as the Vancouver style because it originated at a meeting of medical journal editors in Vancouver, Canada, in 1978. Guidance on this reference format is provided in the Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Some journals make minor modifications to the Vancouver style. Other journals have their own reference styles, and you will need to provide your references in the appropriate format. Remember that the more your article looks like it Gajanin et al. belongs in the targeted journal, the more likely it is t be accepted. Every little bit helps. 15. Even investigators who read English well, and can write well enough to make their point, often have difficulty with spoken English. It is essential to be well prepared. Write out your talk in advance, and have a native English speaker review the talk and correct errors in grammar and meaning. Then practice reading the corrected talk aloud, several times. It is easier to do your talk, than to answer the subsequent questions. The audience may overestimate your facility with English, if you are well rehearsed. If this applies to you, end your talk by saying: “Thank you for your attention. I will be happy to try to answer your questions, but English is not my first language. Please speak slowly and simply.” If you have difficulty understanding a question, say “I’m sorry, but I don’t understand your question. Perhaps we can discuss it after the session.” 16. True (E). Alcohol is one of the most common environmental teratogens affecting fetuses, although the effects can be subtle. There is no threshold amount of alcohol consumption by the mother to produce fetal alcohol syndrome; no amount is safe. Children with fetal alcohol syndrome tend to be developmentally impaired throughout childhood, but the physical anomalies tend to become less apparent as the child ages. Vertebral abnormalities, including scoliosis, can be present. The liver can have fatty metamorphosis with hepatomegaly and elevated serum transaminases. The major effects of congenital rubella occur during organogenesis in the first trimester and result in more pronounced defects, including congenital heart disease. Placenta previa, a low-lying placenta at or near the cervical os, can cause significant hemorrhage at the time of delivery or uteroplacental insufficiency with growth retardation before delivery. Placental causes of intrauterine growth retardation result in asymmetric growth retardation with sparing of the brain. Maternal diabetes often results in a larger infant, and malformations may be present. The findings of trisomy 21 are subtle at birth, but typically include brachycephaly, not microcephaly. 17. True (G) This patient has features of Cushing syndrome, a paraneoplastic syndrome resulting from ectopic corticotropin production (most often from a pulmonary small-cell carcinoma), which drives the adrenal cortices to produce excess cortisol. Small-cell carcinomas are aggressive tumors that tend to metastasize early. Even when they appear to be small and localized, they are not or will not remain so. Surgery is not an option for these patients. They are treated as if they have systemic disease; some chemotherapy protocols afford benefit for 1 year or more, but cure is uncommon. Adenocarcinomas and large-cell carcinomas tend to be peripheral neoplasms in the lung, and they are less likely to produce a paraneoplastic syndrome. Bronchi- al carcinoids tend to be small and are not likely to produce paraneoplastic effects; rarely, they produce carcinoid syndrome. Renal cell carcinomas have been associated with Cushing syndrome, but the typical pattern of metastases is multiple nodules in both lungs. Non-Hodgkin lymphomas rarely occur in the lung, are not associated with smoking, and do not produce Cushing syndrome. Squamous cell carcinomas can be central and occur in smokers, but they are more likely to produce hypercalcemia. 18. True (C) Nonenzymatic glycosylation refers to the chemical process whereby glucose attaches to proteins without the aid of enzymes. The degree of glycosylation is proportionate to the level of blood glucose. Many proteins, including hemoglobin, undergo nonenzymatic glycosylation. Because red blood cells have a life span of about 120 days, the amount of glycosylated hemoglobin is a function of the blood glucose level over the previous 120-day period. The level of glycosylated hemoglobin is not appreciably affected by short-term changes in plasma glucose levels. Random glucose testing is an immediate way for monitoring short-term adjustments with diet and medications such as insulin and oral agents. Fasting glucose testing affords a better way to diagnose diabetes mellitus initially. Measurements of glycosylated albumin and fructosamine have no value in diabetes mellitus. Microalbuminuria may presage the development of diabetic renal disease. 19. Interventional pain management as a discipline involves invasive approaches to treat existing pain, whether acute, chronic or cancer pain, with the objective of reducing pain, restoring function, and eliminating or minimizing suffering. The protective role of pain may be reversed, and pain is the most frequent cause of disability that seriously impairs quality of life. Acute and chronic pain annually affect up to one third of the population in the industrialized nations, and in many instances it is not adequately controlled. Of the patients with chronic pain more than a half are either partially or totally disabled for weeks, months, or permanently. Chronic pain in particular is a serious economic problem. The development of multidisciplinary pain clinics has been attributed largely to an army anesthesiologist John Bonica. He started a multidisciplinary approach to pain management on veterans with traumas, frostbites, and phantom limb pain as well as the pain syndromes like causalgias. Bonica’s 1953 publication of the first comprehensive book on pain management entitled, “The Management of Pain,” led to his universally recognized role in history as the founder of modern pain management. The publication of the “gate control” theory by Melzack and Wall in 1965 offered better understanding of the pathways of pain, pain conduction and pain modulation. 125 126 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com In the foreword of the second edition of “Interventional Pain Management,” written by Steven Waldman and Alon P. Winnie (Saunders, 1996). Dr Waldman states: “When I presented the program to Alon for his comments, he asked ‘What in the world is Interventional Pain Management?’ I explained I had coined the term interventional pain management (which I had liberally borrowed from our radiology colleagues) in an effort to recognize and distinguish the increasing number of pain management physicians who devoted their efforts to help patients in pain by the use of interventional pain management techniques as opposed to limiting their efforts to pharmacological approach. Hence, the subspecialty of pain management was born.” In the past two decades, substantial advances in understanding and managing acute, chronic and cancer pain have emerged. Neural information in response to chronic pain can be modified. Changes can take place along the pain-conduction pathway, in the neurons, pain receptors, ion channels and signaling molecules. This may lead to a “pain memory” leaving a long lasting effect. The frequency of interventional procedures, including epidural, facet joint interventions, sacroiliac joint injections, nerve blocks and procedures involving implantables continue to increase. Management of pain is one of the most important issues of the scientific health community and society in general. When optimizing the quality of care one should integrate patient values, clinical expertise, and an algorithmic approach and guidelines. References (Kraći izvodi iz sledećih publikacija su korišćeni za pripremu ovog edukacionog materijala. Većinu tih tekstova smo modifikovali, a neke u celini sastavili. Svrha ovog poglavlja je da čitaoci usavrše svoj medicinski engleski.) 1. Aiello LP. Targeting intraocular neovascularization and edema— One drop at the time. N Engl J Med 2008; 967-9. 2. Anonymous. Publication manual of the American Psychological Association, fifth edition. Washington, DC, American Psychological Association, 2002. 3. Anonymous. WHO endorses new rapid tuberculosis test. A major milestone for global TB diagnosis and care http://www. who.int/topics/en/ 4. Berber S. Isorija somborskog zdravstva. Novi Sad, Matica srpska, 2004. 5. Browner WS. Publishing and presenting clinical research, second edition. Philadelphia, Lippincott Williams and Wilkins, 2006. 6. Collin B, Rajaratnam R, Lim R, et al. A retrospective analysis of 34 patients with cutaneous sarcoidosis assessed in a dermatology department. Clin Exp Dermatol 2010;35:131-4. 7. Davis JL, Huang L, Worodria W, et al. Nucleic acid amplification tests for diagnosis of smear-negative TB in a high HIVprevalence setting: a prospective cohort study. PLoS One. 2011;6:e16321. 8. Frankel A, Penrose C, Emer J. Cutaneous tuberculosis: a practical case report and review for the dermatologist. J Clin Aesthet Dermatol 2009;2:19-27. 9. Hannan EI, Wu C, Walford G, et al. Drug-eluting stents vs. coronary-artery bypass grafting in multivessel coronary disease. N Engl J Med 2008;358:311-41. 10. Igic R, Alexander B. Neurophysiologic approach to pruritus and pain in cancer patients. J BUON, 2006; 11:143-52. 11. Kennedy D. Analgesics and pain relief in pregnancy and breast feeding. Australian Prescriber 2011; 34:8-10. 12. Klatt EC, Kumar V. Robbins and Cotran Review of Pathology, third edition. Philadelphia, Saunders Elsevier, 2010. 13. Konstantinos A. Testing for tuberculosis. Australian Prescriber 2010;33:12-8. 14. Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran Pathologic basis of disease, eight edition. Philadelphia, Saunders Elsevier, 2010. 15. Mills SE. Sternberg’s Diagnostic surgical pathology, fifth edition. Philadelphia, Lippincott Williams and Wilkins, 2010. 16. Morris DB. An Invisible History of Pain: Early 19th-Century Britain and America Clin J Pain, 1998. 17. Sehgal VN. Cutaneous tuberculosis. Dermatol Clinic 1994; 12: 645-53. 18. Shumack SP. Non-surgical treatments for skin cancer. Australian Prescriber 2011;34:6-7. 19. Tatro DS. Drug interaction facts. The authority on drug interactions 2011. Philadelphia, Wolters Kluwer, 2011. 20. Vomela S. Profesor dr. Milan Jovanovič - Batut, patriarcha jugoslávské zdravotnické kultury. Zvl ot z Věstníku čsl lékařů, 1937, čís. 42 15 s. Vědecká knihovna Olomouc. 21. Weiss RA. Vascular studies of the legs for venous or arterial disease. Dermatologic Clinic 1994; 12:175-90. 22. Wiedemann H-R, Kunze J, Grosse F-R. Clinical syndromes, third edition. London, Mosby, 1997. 23. Yan TD, Padang R, Poh C, et al. Drug-eluting stents versus coronary artery bypass grafting for the treatment o coronary artery disease: A meta-analysis of randomized and nonrandomized studies. J Thorac Cardiovasc Surg. 2011;141:1134-44. Presentation of Medical Journals 128 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com The New England Journal of Medicine The New England Journal of Medicine (NEJM) is dedicated to bringing physicians the best research and key information at the intersection of biomedical science and clinical practice, and to presenting the information in an understandable and clinically useful format. A career companion for physicians, NEJM keeps practicing physicians informed on developments that are important to their patients and keeps them connected to both clinical science and the values of being a good physician. NEJM employs a highly rigorous peer-review and editing process to evaluate manuscripts for scientific accuracy, novelty, and importance. The editors have set policies to ensure that authors disclose all relevant financial associations and that those financial associations do not influence published content. These factors contribute to NEJM’s reputation as the “gold standard” for quality biomedical research and for the best practices in clinical medicine. NEJM is the most widely read, cited, and influential general medical periodical in the world. As it evolves to meet the changing needs of its readers in the 21st century, it is committed to maintaining that reputation and integrity, while using innovative formats and technologies for new features and faster delivery and access. History The New England Journal of Medicine is the oldest continuously published medical periodical, close to completing its second century of service to the medical community. In 1811, John Collins Warren, a Boston physician and scholar, collaborated with his colleague, James Jackson, to establish the first medical journal in New England. The first quarterly edition of the New England Journal of Medicine and Surgery and the Collateral Branches of Medical Science was published in Boston in January 1812. Sixteen years later, after merging with the Boston Medical Intelligencer, it became the Boston Medical and Surgical Journal, and weekly publication began. The Massachusetts Medical Society purchased it in 1921 for $1. In 1928, it was renamed the New England Journal of Medicine. NEJM has published reports from the frontiers of medical science and practice since its early days. NEJM documented the first public demonstration of ether anesthesia in 1846, the first full description of a spinal-disk rupture in 1934, and the first successes in the treatment of early childhood leukemia in 1948. More recent articles include some of the earliest descriptions of AIDS and then of its treatment, of aspirin and cholesterol-lowering agents in the prevention of heart disease, and of new molecular advances in the treatment of chronic leukemia and lung cancer. Nejm Today NEJM’s influence has grown to an international scale. More than 600,000 people in 177 countries read it each week. More than half of the research reports submitted to NEJM originate from outside the U.S. NEJM is cited more often in scientific literature than any other medical journal, and in 1978, became the only American medical journal ever to receive the Polk Award for journalistic merit. Free online access is available in more than 100 low-income countries, and full text of research articles is free to all six months after publication. NEJM.org was created in 1996, and now more people see NEJM articles online than in print. NEJM redefined the medical journal with the launch of its new website along with the full NEJM Archive in 2010. The new website gives users a deeper, broader, and more engaging experience through enhanced search and navigation, specialty pages, interactive elements, and a number of integrated multimedia features. Through the NEJM Archive, every article published in NEJM since 1812 — a rich history of modern medicine — is available and completely searchable online. Scripta Medica www.nejm.org Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Vojnosanitetski pregled (Military Medical Review) The Vojnosanitetski pregled is the official journal of physicians, pharmacists and dentists of the Serbian Army. It has been published since 1944 and continued tradition of the Vojnosanitetski glasnik (Military Medical Courier, in English) which was published from 1930 to 1941. The Vojnosanitetski pregled is published monthly and presently it is the only monthly medical journal in Serbia that indicates the high influx of articles not only from military but, also, civilian medical and academic instututions. From its inception to now a cover page ,of the Journal has been changed several times with constant improvement of its contents quality (since 2006 the Journal has got a cover page with images related to the contents of a particular issue). The contents of the Journal is divided in several sections: original articles, short communications, editorials, reviews/meta-analyses, current topics, case reports, personal views, practical advices for physicians, invited comments, letters to the editor, articles on medical history (general and military), reports from scientific meetings, book reviews, and an In memoriam column. The Journal used to publish articles in Serbian or English with abstracts in both langueges. Due to better “visibility” of the Journal in the international scientific community since January 2011 only manuscripts written in English have been received and accepted for publication. The Editorial Board of the Journal is composed of 30 domestic and 15 foreign well-known experts for various medical fields. Along with them, more than 100 reviewers, also known authorities in their specific medical fields provide that only high quality articles are published in the Journal. Bacause of that the Journal has been indexed from the very beginning by a few well-known indexed journals and their electronic databases, e.g. Index Medicus (MEDLINE and PubMed), Excerpta Medica (EMBASE), Chemical Abstracts, International Pharmaceutical Abstracts, and six other secundary publications. It is also included in the EBSCO Publishing Base Academic Search Premier, and exchanged with 40 foreign and 36 domestic medical and pharmaceutical journals. Since 2008 the Journal has been selected for coverage in the famous Thomson Reuters products: Science Citation Index Expanded (SCIE) and Journal Citation Reports/Science Edition. In June 2011, it received the first impact factor of 0.199. According to the impact factor value it is ranked at 133th position among 151 journals in the field Medicine, General & Internal. Contents of the Vojnosanitetski pregled is available online, free off charge at the Internet site: www.vma.mod.gov. rs/vsp, and also through CrossRef (via DOI Serbia). Silva Dobrić Editor-in-Chief Military Medical Academy Institute for Scientific Publication Crnotravska 17, 11000 Belgrade, Serbia Tel./fax. +381 11 26 69 689 e-mail: [email protected] 129 130 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com ISTORIJSKA PERSPEKTIVA Sreten Bošković - Život i delo Sreten Bošković je rođen u Slavonskom Brodu 1931. godine. Osnovnu školu i gimnaziju pohađao je u Doboju i Herceg Novom. Studije medicine je upisao 1949. u Sarajevu i diplomirao 1955. godine. Nakon završenog obaveznog lekarskog staža i položenog stručnog ispita specijalizirao je opštu hirurgiju na Hirurškoj klinici Medicinskog fakulteta u Sarajevu. Specijalistički ispit iz opšte hirurgije položio je 1961. godine. Za vreme obavljanja specijalističkog staža, 1958. godine, postavljen je za šefa Stanice za transfuziju krvi Kliničke bolnice u Sarajevu. Još u početku svoje lekarske karijere dr Bošković je pokazao veliko interesovanje za probleme u vezi s transfuzijom krvi, zbog čega se i opredelio za supspecijalizaciju iz transfuziologije. Supspecijalizaciju je obavio na Vojnomedicinskoj akademiji u Beogradu i 1963. godine položio ispit, te tako postao prvi supspecijalista iz te oblasti u BiH. Zahvaljujući upornosti, znanju i višegodišnjem angažovanju Sretena Boškovića, Stanica za transfuziju krvi prerasta u Zavod za transfuziju krvi. U sklopu Zavoda za transfuziju krvi Sreten Bošković 1965. osniva Odsjek za eksperimentalnu hirurgiju gde je intenzivno radio na problemima vaskularne i transplantacione hirurgije. Izgradnjom nove komforne zgrade Zavod postaje Institut za transfuziologiju i hematologiju koji se vremenom, zahvaljujući izvanrednim rezultatima koje postiže tim lekara sa dr Boškovićem na čelu, svrstava među vodeće ustanove toga tipa u SFRJ. Sreten Bošković doktorsku disertaciju Mehanički uticaj na rezistenciju eritrocita u konzervisanoj krvi odbranio je 1964. godine na Medicinskom fakultetu u Sarajevu. Na istom fakultetu habilitirao je 1967. godine, nakon čega je izabran za docenta za predmet hirurgija. Univerzitetsku karijeru Sreten Bošković počinje 1964. godine, učestvujući kontinuirano u nastavi na Medicinskom i Stomatоloškom fakultetu u svim zvanjima − od asistenta, docenta, vanrednog i redovnog profesora. Početkom građanskog rata u Bosni i Hercegovini 1992. godine profesor Bošković odlazi u Beograd, gde se zapošljava u Kliničkom centru Srbije kao koordinator za transplantaciju organa. Nakon revitalizacije Medicinskog i Stomatološkog fakulteta u Foči, Univerziteta Republike Srpske u Sarajevu, Sreten Bošković se stavlja na raspolaganje Hirurškoj katedri, a postaje i konsultant Centra za transplantaciju bubrega Kliničkog centra u Banjaluci. Sreten Bošković je bio čovek široke kulture, veliki erudi- ta, vrstan poznavalac svoje struke, velike radne energije i upornosti u borbi za medicinsku istinu i integritet medicinske tehnologije, nepoštedan u borbi protiv svih pojava improvizacije i neodgovornosti u medicinskom ponašanju. Među studentima i lekarima uživao je ugled izuzetnog predavača, velikog pedagoga, s naglašenom željom da mladima prenese najnovija dostignuća iz struke s kojima se i sam upoznavao boraveći na stručno-naučnim usavršavanjima u raznim centrima Evrope i SAD. Pored nastave na dodiplomskim studijama, redovno je održavao kurseve za lekare i tehničare iz oblasti transfuziologije i reanimacije. Po pozivu, održavao je iste kurseve u okviru poslediplomske nastave na Medicinskom fakultetu u Zagrebu i fakultetima u Beogradu, Skoplju, Titogradu i Nišu. Profesor Bošković bio je mentor u izradi nekoliko doktorskih disertacija na Medicinskom fakultetu u Sarajevu, Novom Sadu i Skoplju. Bio je nosilac ili koordinator više naučnoistraživačkih projekata Republičkog fonda za naučni rad SR BiH. Ovakva blistava univerzitetska karijera Sretena Boškovića rezultat je zavidnih rezultata postignutih u stručnom i naučnom radu kojima se bavio kao lekar kliničar. Prvih 20 godina svog kliničkog rada Sreten Bošković je posvetio formiranju i razvoju službe za transfuziju krvi u SR BiH. Pored formiranja Republičkog zavoda za transfuziju krvi, osnovao je i 15 bolničkih stanica za transfuziju krvi u Bosni i Hercegovini. Uveo je niz metoda u konzervaciji krvi, u kliničkoj primeni transfuzije krvi i zamenika, metodologiji rada u ustanovama za transfuziju krvi, forenzičnoj imunologiji, a udario je i temelje analizi koagulacionih poremećaja u hirurškom lečenju. Sreten Bošković, zahvaljujući svom predanom radu, podigao je ovu granu medicine na klinički nivo. Publikovao je, sam ili sa saradnicima, niz naučno-stručnih publikacija iz ove oblasti kao i više knjiga, među kojima posebno mesto zauzima knjiga Transfuziologija (Sarajevo 1975, dopunjeno izdanje 1981). Živeći u izbeglištvu, boreći se sa svim nedaćama s kojima se susreće izbeglica u odmaklim godinama, on nije zaustavio stručnu i istraživačku aktivnost. I dalje predano radi na trećem izdanju knjige Transfuziologija, dopunjujući je najnovijim dostignućima iz te oblasti. Knjiga je štampana 1998. godine u Beogradu. Svojim mnogobrojnim knjigama i publikacijama iz ove oblasti Sreten Bošković je stekao afirmaciju vrsnog stručnjaka i naučnog radnika u domaćoj i međunarodnoj naučnoj javnosti. Prof. dr Sreten Bošković je osnovao Institut za transplantaciju organa i 1974. godine izveo je prvo presađivanje bubrega u BiH, da bi nakon toga ovu službu razvio do jugoslovenskih razmera i formirao najjači centar za ovu vrstu delatnosti u SFRJ. Presađivanje bubrega, Šećerov-Zečević zahvaljujući njemu, postaje rutinska metoda lečenja bolesnika od jedne od najtežih bolesti u humanoj medicini. U toku 16 godina rada na transplantacijama bubrega obavio je uspešno preko 450 zahvata na pacijentima iz svih krajeva Jugoslavije. Prof. dr Sreten Bošković prvi je u jugoslovenskoj medicinskoj praksi obavio transplantaciju bubrega od živih nesrodnih osoba (bračni supružnici) i kod krvno-grupno inkompatibilnih osoba (supružnička transplantacija). Zapaženi su njegovi radovi iz područja endemske nefropatije i njenoj interferenciji sa lečenjem transplantacijom bubrega, što predstavlja dragocen doprinos evropskoj nauci, što se vidi iz čestih citiranja njegovih rezultata u stranim publikacijama. Prvi je uspešno primenio transplantaciju bubrega u lečenju endemske nefropatije i time nedvosmisleno dokazao da se ne radi o sistemskom oboljenju, toksičnoj etiologiji, nego o genetskoj anomaliji koja zahvata samo bubrege. Na ovaj način prof. dr Bošković obogatio je ovu hiruršku disciplinu novim saznanjima i otvorio nove pravce naučnih istraživanja. Baveći se transplantacijom bubrega, dr Bošković je preuzimao na sebe rešavanje ličnih drama jer se radi o pacijentima kojima je transplantacija poslednja šansa za produžetak života. Odgovornost hirurga je velika s obzirom na to da u tom momentu neko najbliži bolesniku donosi odluku da daruje deo svoga tela kako bi omogućio život svom najdražem. Banalan propust u lečenju može da dovede do nepredvidivih komplikacija i kod davaoca i primaoca organa. Zato nije ništa iznenađujuće bila preterana strogost dr Sretena Boškovića, kako prema sebi, tako i prema svojim saradnicima. Ta strogost je bila permanentan strah za život pacijenta, što mnogi ljudi nisu razumeli. Institut za transplantaciju organa u Sarajevu svojom opremljenošću, disciplinom i rezultatima rada, zahvaljujući Sretenu Boškoviću, služio je kao uzor, ne samo u našoj zemlji, nego i šire, kako treba da izgleda i funkcioniše ustanova takvog tipa. Radi razmene iskustava Sreten Bošković uspostavio je razgranate stručne veze Instituta za transplantaciju organa u Sarajevu sa odgovarajućim centrima u Rimu, Lionu, Frajburgu, Bostonu, Ajovi, Helsinkiju, Moskvi i Pragu, afirmišući na taj način jugoslovensku medicinu. Sreten Bošković, vrhunski menadžer, sa vizionarski nadahnutim idejama u oblasti zdravstva, intenzivno je radio na uvođenju u rutinsku praksu klinike za transplantaciju jetre, a prvi je u Jugoslaviji i na Balkanu izveo uspešnu transplantaciju pankreasa na svom institutu. U toku svoga tridesetpetogodišnjeg rada publikovao je preko 150 stručnih i naučnih publikacija i devet knjiga. Učestvovao je s referatima na mnogobrojnim domaćim i međunarodnim kongresima, gde je prezentirao rezultate svoga rada iz područja transfuziologije, koagulacionih poremećaja, eksperimentalne i transplantacione hirurgije. Sve ovo obezbedilo mu je da je postao poznati i priznati stručnjak i naučni radnik u našoj zemlji i inostranstvu i kao takav biran je u mnogim domaćim i međunarodnim organizacijama i udruženjima. Bio je član Međunarodnog udruženja transfuziologa i hematologa, dopisni član Njujorške akademije nauka, član Upravnog odbora Udruženja transfuziologa i hematologa Jugoslavije. Bio je odgovorni urednik većeg broja časopisa u BiH. Rad Sretena Boškovića i uspesi klinike nisu ostali nezapaženi od društvene zajednice pa je zasluženo postao dobitnik Ordena rada sa srebrnim vencem; 27-julske nagrade SR BiH; Ordena zasluga za narod sa srebrnom zvezdom; Nagrade izdavačkog preduzeća “Svjetlost”, Sarajevo, za naučno delo; Šestoaprilske nagrade grada Sarajeva za dugogodišnji uspešan rad iz oblasti vaskularne i eksperimentalne hirurgije; Zlatne medalje za zasluge Jugoslovenskog crvenog krsta, te nizom pohvala medicinskih udruženja. Blistava karijera i rezultati u stručnom i naučnom radu bili su dovoljni da Sreten Bošković 1997. godine bude izabran za dopisnog člana Akademije nauka i umjetnosti Republike Srpske. Bio je prvi sekretar Odjeljenja medicinskih nauka Akademije nauka i umjetnosti Republike Srpske. Iznenadna smrt 5. marta 2002. prekinula je sva njegova htenja i planove, a medicinsku struku i nauku osiromašila za velikog stručnjaka i naučnika. Sreten Bošković nije više fizički među nama, ali su ostala njegova dela kao trajno svedočanstvo koje kazuje o njemu kao čoveku, humanisti, velikom stručnjaku, neumornom borcu za ljudsko zdravlje i medicinsku istinu. Njegovom smrću medicinska struka, osobito transfuziologija i transplantacija organa, izgubila je vrhunskog stručnjaka i naučnika, njegovi brojni učenici i saradnici velikog učitelja, porodica brižnog oca i supruga, a mnogi njegovi pacijenti lekara kojeg se sa zahvalnošću sećaju. Kredo života prof. dr Sretena Boškovića bio je: Alteri vivas oportet, vis tibi vivere, jer njegov životni put predstavlja svetao lik čoveka − humaniste u permanentnoj i uspešnoj borbi za ljudsko zdravlje i ličnu sreću bolesnika, u čemu je postigao zavidne rezultate, koji treba da posluže kao primer budućim generacijama lekara. Akademik Drenka Šećerov Zečević 131 132 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com IN MEMORIAM Prof. dr Tomislav Kažić (1937-2011) Umro je poznati farmakolog, toksikolog i klinički farmakolog, istraživač, član međunarodnog uređivačkog odbora našeg časopisa, učitelj studenata i lekara, humanista i retko viđen kritički um koji je sve naše stručnjake koji se bave lekovima i lečenjem podsticao da nađu pravi put u mnoštvu stranputica. Profesor Kažić nas je ostavio, ali su nam ostala njegova dela, naučne publikacije i brojne knjige iz kojih će studenti i stručnjaci u raznim biomedicinskim disciplinama još dugo crpsti znanje i kritički pristup bolestima i lečenju. Stvaralački opus ovog izuzetno vrednog i sposobnog stvaraoca uključuje preko 200 publikacija u medicinskim časopisima i tridesetak knjiga od kojih su mnoge doživele više izdanja, a jedna čak 13! Trideset pet naučnih radova ovog vrsnog istaživača su publikovani u vodećim međunarodnim časopisma, uključujući najprestižniji britanski i svetski farmakološki časopis, British Journal of Pharmacology, čuvene američke časopise Neuropharmacology i Brain Research i poznat evropski European Journal of Pharmacology. Istraživanja profesora Kažića su se odvijala u tri faze. Najpre je istarživao ulogu acetetilholina u crevnoj peristaltici. Zatim je ispitivao značaj kateholamina u hipertenziji i regulaciji glatko-mišćnog tonusa, a posle toga se skoncentrisao na definisanje uloge adenozin trifosfata u regulaciji crevne peristaltike i tonusa glatkih mišića. Vredi iz ove faze istraživanja istaći njegov rad iz 1980.-te (Kažić T, Milosavljević D. Interaction between adenosine triphosphate and noradrenaline in the isolated vas deferens of the guinea-pig. Br J Pharmacol 1980;71:93-8.). Supstance koje su najviše interesovale Profesora Kažića bili su antagonisti kalcijumskih kanala i o njima je objavio seriju publikacija. Kao profesor Medicinskog fakulteta i dugogodišnji šef Katedre farmakologije, toksikologije i kliničke farmakologije, Prof. Kažić je dao ogroman doprinos edukaciji studenata dodiplomske i posle diplomske nastave. On je podsticao magistrande i doktorande da izrade kvalitetne radove za sticanje akademskih zvanja i nastave s naučnim radom sve dok ne počnu samostalna istraživanja. Karijera univerzitetskog profesora nije vodila ovog vrsnog stručnaka izolovanosti od medicinske prakse. On je svo vreme pratio i imao kritički odnos prema primeni lekova kod raznih bolesti, nastojao je da utemelji tzv. racionalno lečenje. Da bi to ostvario, napisao je seriju udžbenika, knjiga i priručnika. Najuspešnija dela su mu doživela više izdanja, poput udžbenika Farmakologija i klinička farmakolo- gija (pet izdanja), priručnika Gotovi lekovi (trinaest izdanja) i njegove najbolje knjige Klinička kardiovaskularna farmakologija (pet izdanja). Profesor Kažić je bio vizionar kada je podsticao razvoj kliničke farmakologije, nove medicinske discipline u Jugoslaviji i Srbiji. Tako je značajno doprineo boljem i sigurnijem lečenju našeg naroda. On je osnivač Sekcije kliničke farmakologije Srpskog lekarskog društva i njen prvi predsednik. Kazić je, između ostalog, bio mentor ili komentor više kvalitetnih doktorskih disertacija i magistarskih radova, višegodišnji predsednik Savezne komisije za lekove u bivšoj Jugoslaviji, šef Instituta za farmakologiju, vrstan predavač na naučnim i stručnim skupovima i zapažen član Komisije za lipide. Pre više od petnaestak godina, dr Rajko Igić je ponudio profesoru Kažiću da bude ko-mentor za izradu doktorske disertacije doktoranda iz Banja Luke. On je bio spreman da se prihvati tog zadatka samo ako je kadidat publikovao svoja istraživanja u poznatim međunarodnim časopisima. Kada su mu predočene tri publikacije toga dokoranda, prihvatio se dužnosti i kasnije je bio predsednik komisije za odbranu tog doktorata na Medicinskom fakultetu u Beogradu. Taj primer pokazuje kakav je odnos Profesora Kažića prema izradi naučnih radova za sticanje najviše akademske titule, doktora medicinskih nauka. Kao član redakcionog odbora ovog časopisa, Scripta Medica, Tomislav Kažić je u tom časopisu prošle godine objavio članak u kome je razmatrao probleme vezane za “medikalizaciju društva”, a u ovom broju objavljen je njegov poslednji članak. Čitaoci tog časopisa imaju priliku da u revijskom članku “Statini—neželjena dejstva i interakcije” vide njegov pristup racionalnoj upotrebi lekova. Dr Kažić je davao značajan doprinos i uređivanju ovog časopisa, a proletos je na poziv Društva doktora Republike Srpske u Banja Luci, pred velikim auditorijem na promiciji našeg časopisa, održao nezaboravno stručno predavanje. Pored pomenutog članka, uskoro će u Beogradu biti objavljeno drugo izdanje njegove knjige “Leksikon—Bolesti i lekovi”. Profesor Kažić je ostavio dubok trag ne samo svojim stručnim i naučnim doprinosom, on je bio veliki čovek, dobar drug i prijatelj, voljen i omiljen nastavnik od strane studenata i postdiplomaca na Medicinskom fakultetu i Višoj medicinskoj školi u Beogradu. Kažić je bio skroman, uman i radan stručnjak koji je zadužio farmakologiju i toksikologiju, njegove kolege, njegove đake, lekare Srbije i bivše Jugoslavije, a indirektno i hiljade pacijenata na našim prostorima jer se odavno leče lekovima i savremenije i sigurnije. Profesor Tomislav Kažić je za sobom ostavio suprugu Vanju, sina Milutina, kćer Mirjanu i malu unuku Irenu. Scripta Medica Naslov teksta maksimalmo dva reda, po potrebi povecati sirinu tekst boksa da stane naslov, Etiam dapibus iaculis euismod Radovi publikovani u stranim časopisoma 133 134 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Surg Radiol Anat. 2011 May;33(4):313-8. Morphological variability of the subcallosal area of man Spasojević GD, Malobabić S, Suščević D, Stijak L, Nikolić V, Gojković I. Department of Anatomy, Faculty of Medicine, University of Banja Luka, Save Mrkalja 14, 78000 Banja Luka, Republic of Srpska, Bosnia and Herzegovina. Pneumologia. 2011 Jan-Mar;60(1):36-9. Changes in spirometry over time in uremic patients receiving long-term hemodialysis therapy Kovacević P, Stanetic M, Rajkovaca Z, Meyer FJ, Vukoja M. Pneumologia. 2011 Jan-Mar;60(1):36-9. Changes in spirometry over time in uremic patients receiving long-term hemodialysis therapy Kovacević P, Stanetic M, Rajkovaca Z, Meyer FJ, Vukoja M. Medical Intensive care unit, University Hospital Banja Luka, Republika Srpska, BiH. Med Pregl. 2011 May-Jun;64(5-6):323-6. Adenomyomatosis of the gallbladder-case report Lalović N, Cvijanović R, Vladicić ND, Marić R, Jokanović D, Skipina DB. Clinical Hospital Centre Foca, Second Surgery Clinic, Republika Srpska, Bosna i Hercegovina. Med Pregl. 2011 May-Jun;64(5-6):323-6. Adenomyomatosis of the gallbladder-case report Lalović N, Cvijanović R, Vladicić ND, Marić R, Jokanović D, Skipina DB. Clinical Hospital Centre Foca, Second Surgery Clinic, Republika Srpska, Bosna i Hercegovina. Med Pregl. 2011 May-Jun;64(5-6):323-6. Adenomyomatosis of the gallbladder-case report Lalović N, Cvijanović R, Vladicić ND, Marić R, Jokanović D, Skipina DB. Clinical Hospital Centre Foca, Second Surgery Clinic, Republika Srpska, Bosna i Hercegovina. J BUON. 2011 Jan-Mar;16(1):170-3. Pulse carboxyhemoglobin-oximetry and cigarette smoking. Sokolova-Djokić L, Milosević S, Skrbić R, Salabat R, Voronov G, Igić R. Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Psychiatr Danub. 2011 Mar;23(1):64-8. Eating attitudes in adolescent girls. Radmanović-Burgić M, Gavrić Z, Burgić S. Department of Psychiatry, Medical Faculty , University Banja Luka, Save Mrkalja 14, 78000 Banja Luka, Bosnia and Herzegovina. Pneumologia. 2011 Jan-Mar;60(1):36-9. Changes in spirometry over time in uremic patients receiving long-term hemodialysis therapy. Kovacević P, Stanetic M, Rajkovaca Z, Meyer FJ, Vukoja M. Environ Toxicol Pharmacol. 2010 May;29(3):195-201. Neurotoxic effects in patients poisoned with organophosphorus pesticides. Jokanović M, Kosanović M. Faculty of Medicine, University of Nish, Nish, Serbia; Academy of Sciences and Arts of Republic Srpska, Banja Luka, Bosnia and Herzegovina. Acta Clin Croat. 2010 Jun;49(2):151-7. Functional outcome after thrombolytic therapy. Miljković S, Prtina D, Rabi Zikić T, Vujković Z, Racić D, Dajić V, Jesić A, Arbutina M, Zikić M. University Department of Neurology, Banja Luka Clinical Center, Bosnia and Herzegovina. Am J Cardiovasc Drugs. 2010;10(2):109-14. Extent of control of cardiovascular risk factors and adherence to recommended therapies in US multiethnic adults with coronary heart disease: from a 2005-2006 national survey. Vulic D, Lee BT, Dede J, Lopez VA, Wong ND. Department of Internal Medicine, University of Banja-Luka, Banja-Luka, Bosnia and Herzegovina. Eur J Clin Pharmacol. 2010 Feb;66(2):177-86. Outpatient utilization of drugs acting on nervous system: a study from the Republic of Srpska, Bosnia & Herzegovina. Marković-Peković V, Stoisavljević-Satara S, Skrbić R. Health Insurance Fund, Republic of Srpska, Banja Luka, Bosnia and Herzegovina. 135 136 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Med Pregl. 2010 Jan-Feb;63(1-2):51-6. [Digital morphometric study of the extrasulcal surface of the cingulate gyrus in man]. Spasojević G, Malobabić S, Stojanović Z, Jandrić S, Dordević M. Zavod za anatomiju, Medicinski fakultet Banja Luka, Republika Srpska. Vojnosanit Pregl. 2010 Feb;67(2):123-7. [Asymmetry and sexual dimorphism of the medial frontal gyrus visible surface in humans]. Spasojević G, Stojanović Z, Susćević D, Malobabić S, Rafajlovski S, Tatiić V. Zavod za anatomiju, Banja Luka, Republika Srpska, Bosna i Hercegovina. Med Pregl. 2010 May-Jun;63(5-6):340-2. [Causes of blindness in the Republic of Srpska]. Kozomara R, Kozomara B. SpecijalistiCka oftamoloska ambulanta Kozomara, Banja Luka. J BUON. 2010 Jan-Mar;15(1):182-7. Statistical presentation of data in biomedical publications. Igić R, Stoisavljevic-Satara S. Psychiatr Danub. 2010 Jun;22(2):298-300. Comorbidity in children and adolescent psychiatry. Burgić-Radmanović M, Burgić S. Bosn J Basic Med Sci. 2010 Feb;10(1):65-7. Complications following autologous latissimus flap breast reconstruction. Burgic M, Bruant Rodier C, Wilk A, Bodin F, Rifatbegović A, Halilbasic E, Burgic M, Brkic E, Avdagic H. Bosn J Basic Med Sci. 2010 Nov;10(4):303-6. Detection of pulmonary calcification in haemodialised patients by whole-body scintigraphy and the impact of the calcification to parameters of spirometry. Rajkovača Z, Kovačević P, Jakovljević B, Erić Z. Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Basic Clin Pharmacol Toxicol. 2009 Mar;104(3):185-91. Epub 2008 Jan 31. Simvastatin and indomethacin have similar anti-inflammatory activity in a rat model of acute local inflammation. Nezić L, Skrbić R, Dobrić S, Stojiljković MP, Jaćević V, Satara SS, Milovanović ZA, Stojaković N. Department of Pharmacology, Toxicology and Clinical Pharmacology, Medical Faculty, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina. Gen Physiol Biophys. 2009;28 Spec No:119-26. Effect of simvastatin on proinflammatory cytokines production during lipopolysaccharide-induced inflammation in rats. Nezić L, Skrbić R, Dobrić S, Stojiljković MP, Satara SS, Milovanović ZA, Stojaković N. Department of Pharmacology, Toxicology and Clinical Pharmacology, Medical Faculty, Save Mrkalja 14, 78000 Banja Luka, Republic of Srpska, Bosnia and Herzegovina. Br J Pharmacol. 2009 Dec;158(8):1932-41. Hydrogen peroxide affects contractile activity and anti-oxidant enzymes in rat uterus. Appiah I, Milovanovic S, Radojicic R, Nikolic-Kokic A, Orescanin-Dusic Z, Slavic M, Trbojevic S, Skrbic R, Spasic MB, Blagojevic D. University of Belgrade, Institute for Biological Research Sinisa Stankovic, Department of Physiology, Belgrade, Serbia. Am J Phys Med Rehabil. 2009 Apr;88(4):328-35. Quality of life of men and women with osteoarthritis of the hip and arthroplasty: assessment by WOMAC questionnaire. Jandrić S, Manojlović S. Department of Physical Medicine, Rehabilitation and Rheumatology, Institute for Rehabilitation Dr Miroslav Zotovic, Banja Luka, Republika Srpska, Bosnia and Herzegovina. Med Pregl. 2009 May-Jun;62(5-6):236-40. [Effects of rehabilitation and arthroplasty on the hip isometric muscle strength in patients with osteoarthritis of the hip]. Jandrić SD. Zavod za rehabilitaciju “Dr Miroslav Zotović”, Banjaluka, Republika Srpska, Bosna i Hercegovina. 137 138 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Ther Apher Dial. 2009 Apr;13(2):113-20. Malnutrition-inflammation complex syndrome and hepatitis C in maintenance hemodialysis patients. Vlatkovic V, Trbojevic-Stankovic J, Stojimirovic B. International Dialysis Center, Banja Luka, Republic of Srpska, Bosnia and Herzegovina. Pharmacoepidemiol Drug Saf. 2009 Apr;18(4):320-6. Utilisation of cardiovascular medicines in Republic of Srpska, Bosnia and Herzegovina, 5 years study. Markovic-Pekovic V, Stoisavljevic-Satara S, Skrbic R. Health Insurance Fund, Republic of Srpska, Banja Luka, Bosnia and Herzegovina. Peptides. 2009 Oct;30(10):1945-50. Epub 2009 Jul 10. Seven decades of angiotensin (1939-2009). Skrbic R, Igic R. Department of Pharmacology, Toxicology, and Clinical Pharmacology, Medical Faculty, University of Banja Luka, 78000 Banja Luka, Republic of Srpska, Bosnia and Herzegovina. Br J Pharmacol. 2009 Dec;158(8):1932-41. Hydrogen peroxide affects contractile activity and anti-oxidant enzymes in rat uterus. Appiah I, Milovanovic S, Radojicic R, Nikolic-Kokic A, Orescanin-Dusic Z, Slavic M, Trbojevic S, Skrbic R, Spasic MB, Blagojevic D. Basic Clin Pharmacol Toxicol. 2009 Mar;104(3):185-91. Simvastatin and indomethacin have similar anti-inflammatory activity in a rat model of acute local inflammation. Nezić L, Skrbić R, Dobrić S, Stojiljković MP, Jaćević V, Satara SS, Milovanović ZA, Stojaković N. Gen Physiol Biophys. 2009;28 Spec No:119-26. Effect of simvastatin on proinflammatory cytokines production during lipopolysaccharide-induced inflammation in rats. Nezić L, Skrbić R, Dobrić S, Stojiljković MP, Satara SS, Milovanović ZA, Stojaković N. Vojnosanit Pregl. 2009 Aug;66(8):663-6. Review. Serbian. No abstract available. [Modem visualisation techniques in brain functions estimation]. Ristić S, Kozomara R, Medenica S, Rajkovaca Z. Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com J Oral Rehabil. 2008 Jun;35(6):424-32. TMD chronic pain and masseter silent period in psychiatric patients on antidepressive therapy. Ivkovic N, Mladenovic I, Petkoci S, Stojic D. Division of Prosthodontics, Faculty of Dentistry, University of East Sarajevo, Republic of Srpska, Bosnia and Herzogovinia. Med Pregl. 2008 Mar-Apr;61(3-4):164-8. [Correlation between C-reactive protein levels with leading risk factors for cardiovascular disease in men]. Mirjanić-Azarić B, Derić M, Vrhovac M, Males-Bilić L. Dom zdravlja “Banja Luka”, Banja Luka, Republika Srpska. 139 140 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Uputstvo autorima Scripta Medica je internacionalni časopis koji objavljuje originalne članke (klinička, laboratorijska i epidemiološka istraživanja), ali i članke koji imaju za cilj da edukuju i obavijeste ljekare i stručnjake srodnih disciplina. Na engleskom ili srpskom jeziku, časopis objavljuje radove o originalnim istraživanjima, pregledne članke, istorijske članke, uvodnike, rješavanje kliničkog problema, prikaze slučajeva i slike iz kliničke medicine (images in clinical medicine). Prednost imaju članci napisani na engleskom jeziku. Samo na srpskom jeziku se objavljuju specijalna saopštenja (edukativni članci i članci koji ukazuju na savremene trendove u medicini), prikazi knjiga, vijesti, izvještaji sa stručno-naučnih skupova i prevodi izvoda članaka domaćih autora koji su objavljeni u međunarodnim časopisima. Izuzetno, edukativni članci mogu biti pisani na engleskom jeziku. Uvodnici donose komentare objavljenih članaka u časopisu ili izražavaju stavove Uređivačkog odbora. Ove članke pišu urednici časopisa ili stručnjaci po narudžbi urednika. Ovo uputstvo je sastavljeno prema vodiču “Uniform Requirements for Manuscripts Submitted to Biomedical Journals” (www.icmje.org). Kako se šalje rukopis Rukopis se šalje elektronski na sljedeću e-adresu: [email protected] Rukopis i propratno pismo treba slati u .DOC formatu (Microsoft Word program), a slike u JPG ili TIFF formatu (300dpi i više rezolucije). Od autora se traži da u popratnom pismu predlože dva ili više potencijalnih recenzenata, stručnjaka koji posjeduju značajno iskustvo s predmetom predloženog rukopisa, ali taj prijedlog nije obavezan. Svaki rukopis mora imati autora s kojim se vrši dopisivanje (Corresponding Author), a on piše i popratno pismo uredniku u kome navodi da je materijal originalan, da nije publikovan i da nije poslat u neki drugi časopis. Izuzetak su skraćeni prevodi radova na srpski jezik koji su objavljeni u poznatim međunarodnim časopisima. Autor s kojim se vrši dopisivanje mora za originalno istraživanje, revijski članak, specijalni članak, prikaz slučaja i rešavanje kliničkog problema dati izjavu o potencijalnom konfliktu interesa za sebe i koautore rukopisa. Recenziranje rukopisa Rukopisi se prvo recenziraju od strane uređivačkog tima tako što ih pregledaju najmanje dva urednika. Potom se odabrani rukopisi šalju recenzentima. Kada se izvještaji recenzenata vrate uredništvu, urednik šalje pismo autoru s odgovarajućom odlukom i izvještajima recenzenata. Nastojimo da u roku od tri mjeseca od prijema rukopisa bude donijeta konačna odluka. Razlog za odbijanje rada može biti manjak originalnosti, veće greške načinjene tokom istraživačkog postupka, izostanak jasne poruke o značaju tog istraživanja ili procjena da članak nije interesantan za čitaoce časopisa. Priprema rukopisa Rukopisi se pišu s duplim proredom. Rukopis članka o vlastitom istraživanju izgleda ovako: Prve dvije strane su naslovna strana i apstrakt s ključnim riječima, slijede stranice na kojima se piše uvod, materijal i metode, rezultati i reference. Pored toga, rukopisu se odvojeno prilažu tabele, ilustracije i legende. Rukopis preglednog članka, pored naslovne strane i apstrakta, sadrži poglavlja koja značajno variraju u zavisnosti od predmeta koji obrađuje članak. Prikaz slučaja sadrži sljedeće dijelove: naslov (kratak i deskriptivan), uvod, opis slučaja (ili više njih), diskusiju, zaključak i reference (ne više od 6). Uvod treba da je veoma kratak. Prikaz slučaja može imati najviše pet autora. Specijalni članci uključuju istorijske teme, edukaciju, demografiju, savremene teme iz zdravstva, rješenje kompleksnog kliničkog problema i sl. Dodatne instrukcije za specijalne članke mogu biti dobijene od urednika. Naslovna strana rukopisa, pored naslova, sadrži imena i prezimena autora, nazive ustanova u kojima je obavljeno istraživanje, mjesto (državu) i adresu, telefone i e-mail autora zaduženog za korespodenciju. Naslov članka o vlastitom istraživanju treba da bude informativan, kratak (da sadrži manje od 17 riječi) i jasan. U njemu se ne pišu skraćenice i nepotrebne („prazne“) riječi. Naslov treba da je jasan kada stoji sam. Čitaoci treba da saznaju predmet saopštenja, a ne detalje sadržaja. Zato naslov samo ukazuje na ono o čemu je riječ, a ne kakvi su nalazi ili zaključci. Za članke na srpskom ili engleskom jeziku piše se strukturisani apstrakt informativnog tipa (do 250 riječi). Strukturisan apstrakt sadrži ove delove: uvod, metode, rezultati i zaključak. Na posebnoj strani se piše naslov rada i tekst sa sljedećim podnaslovima: uvod i cilj rada, metode (uključujući izbor ispitanika, laboratorijskih životinja, tkiva ili ćelijskih kultura), rezultati i zaključak. Ispod aspstrakta, autori treba da navedu 3-8 riječi ili kratkih fraza. Treba koristiti termine koje koristi Index Medicus za “Medical Subject Headings”. Za pregledni članak i specijalne članke koji se odnose na istorijske teme, apstrakt je nestrukturisan, indikativnog tipa, a piše se u jednom pasusu (do 150 riječi) na srpskom i engleskom. Za ostale tipove članaka apstrakt se ne piše. Rukopisi originalnih istraživanja treba da sadrže ova poglavlja: uvod, materijal i metode, rezultati, diskusija i reference. Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Uvod Glavni cilj uvoda je da se čitaocu saopšti zašto je vršeno to istraživanje - da se rasvijetli neka nejasnoća, razriješe konfliktna zapažanja ili da se na neki drugi način dopuni postojeće znanje. Zato se u uvodu uvijek postavlja istraživački problem tj. pitanje na koje se traži odgovor. Problem se ne mora postaviti baš u formi pitanja, već se svrha istraživanja može tako navesti da se iz nje jasno uočava pitanje. Na primjer: “Cilj ovog istraživanja je da se uporedi preživljavanje nakon godinu dana od početka liječenja metastaskog karcinoma prostate novom kombinacijom hemoterapijskih lijekova sa standardnom kombinacijom.” Cilj istraživanja se, takođe, može navesti kao testiranje hipoteze. U uvodnom dijelu članka treba citirati samo najvažnije reference kojima se opravdava to istraživanje. Najbolje je izabrati radove različitih istraživačkih grupa, pogotovo ako su iz različitih zemalja. Predlažemo autorima da pišu uvod ne više od tri pasusa. Materijal i metode Opis metoda treba da ima logički slijed koji kazuje kakav je dizajn studije, kako je izvedeno istraživanje (opisati ispitanike ili eksperimentalne životinje, randomizaciju, navesti podatke o korišćenim materijalima, dati tačne doze i način davanja lijekova, detaljno opisati neuobičajene aparate, navesti saglasnost lokalnog etičkog komiteta za ispitivanja na ljudima i životinjama), kako su dobijeni podaci, kako su oni prikazani i koji su testovi korišćeni za statističku analizu. Procedure i eksperimente treba tako opisati da ih drugi istraživači mogu ponoviti. Korišćene metode koje su ranije opisane treba skraćeno opisati, uz navođenje reference. Često primjenjivane kliničke i laboratorijske metode, kao i uobičajene statističke operacije se ne opisuju, a za složenije statističke metode treba navesti reference. Jedinice mjere za dužinu i težinu se izražavaju metričkim sistemom, a laboratorijski i klinički podaci se navode u jedinicama SI sistema, s tim da se uobičajene metričke jedinice mogu staviti u zagradu. Novije statističke metode treba opisati s dovoljno detalja da čitaoci mogu verifikovati saopštene rezultate. Detalje randomizacije treba navesti, dati broj opservacija, navesti statistički program, ako je takav korišćen, opisati metod određivanja veličine uzorka. Rezultati Dobijeni rezultati se prikazuju tekstualno, tabelama i ilustracijama. U tekstu se ukazuje na najznačajnije rezultate i njega obično prati tabelarni prikaz podataka. U tabelama se ne smije duplirati informacija koja je data u tekstu ili ilustracijama. Kod sumiranja podataka u poglavlju Rezultati, navesti metode statističke analize. Pošto su standardna devijacija (SD) i standardna greška srednje vrijednosti (SE) pozitivni brojevi, prihvatili smo uputstvo Komiteta naučnih urednika (Council of Science Editors: Scientific Style and Format, 2006) da } znak kod prikazivanja SD i SE bude eliminisan. Zato se ti podaci pišu u zagradi. Na primjer, vrijednosti za sistolni krvni pritisak kod 87 studenata piše se ovako: “Srednja vrijednost sistolnog krvnog pritiska bila je 129 mmHg (SD= 6, n = 87). Ilustracije se koriste samo ako se dobijeni rezultati nemogu jasno prikazati na drugi način. Fotografi je treba da budu najboljeg kvaliteta. Fotografi je u boji se objavljuju, a njihovo štampanje se ne naplaćuje. Mikrosopske slike se prilažu uz navođenje tehnike bojenja, a skala se mora nalaziti na samoj fotografiji. Slajdovi (u PowerPointu) nisu najpogodniji za kvalitetnu reprodukciju. Za korišćenje već objavljenih tabela i ilustracija, autor mora pribaviti pismenu saglasnost od nosioca zaštićenog prava (obično izdavač) i autora. Sve ilustracije nose naziv “Slika” i one se numerišu redoslijedom njihovog prvog citiranja u tekstu. Diskusija U diskusiji se razmatraju dobijeni rezultati. Ta razmatranja se odnose i na ranije publikacije. U originalnim člancima i kratkim saopštenjima, glavni cilj diskusije je da se odgovori na pitanje koje je postavljeno u uvodu članka. Zato se obično već u prvom pasusu ukratko sumira najvažniji rezultat te studije i navodi glavni odgovor koji iz tih podataka proizlazi. U ovom poglavlju se razmatraju i nedostaci studije (dizajn, broj ispitanika, odgovarajuća kontrola i sl.) koji bi mogli doprinijeti da dobijeni rezultati budu drugačiji od rezultata u ranijim istraživanjima. Tu se navodi i sve ostalo što bi moglo objasniti neujednačenost dobijenih rezultata s podacima iz literature. Zato se definitivni odgovor na pitanje postavljeno u uvodu članka daje tek nakon ovih razmatranja koja sadrže dodatne dokaze koji potkrepljuju prikazane rezultate. Ukoliko je nakon razmatranja činjenica s obje strane nemoguće riješiti konfliktnu situaciju, autori mogu predložiti kojim bi se dodatnim istraživanjima eventualno moglo doći do rješenja. Zahvalnost Zahvalnost se piše na kraju tekstualnog dijela rukopisa, prije poglavlja Reference. U tom veoma kratkom poglavlju se autori najčešće zahvaljuju instituciji koja je finansirala istraživanje i onim osobama koje su značajno doprinijele realizaciji istraživanja, a ne postoji opravdanje za njihovo uključivanje među autore. Pri uključivanju osobe u ovo poglavlje, neophodna je njena pismena saglasnost. Reference Literatura se u tekstu obilježava arapskim brojevima koji se ispisuju kao superscript. Reference dobijaju brojeve po redoslijedu pojavljivanja u tekstu, tabelama i legendama i tim redom one budu ispisane u poglavlju Reference. Ne treba stavljati tačku ili zarez iza brojeva već ispred. Sve reference za članke na engleskom se pišu na tom jeziku. Ako su radovi objavljeni na nekom drugom jeziku, naslov se ispisuje na engleskom, a na kraju reference u zagradi se navede naziv tog jezika. Reference radova koji su prihvaćeni 141 142 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com za štampu se navode uz dodatak “u štampi“, a rukopisi predati u štampu, koji nisu prihvaćeni, budu citirani u tekstu tako što se u zagradi navede “neobjavljeni podaci“. Ne prihvata se citiranje apstrakta s naučnih skupova, doktorskih disertacija i drugih nepublikovanih dokumenata. Reference se ispisuju prema preporuci datoj od strane tzv. Vankuverske grupe (www.nlm.nih.gov/bsd/ uniform_requirements.html). Standardne skraćenice časopisa mogu se naći na sajtu PubMed. Primjeri De Lacey G, Record C, Wade J. How accurate are quotations and references in medical journals. BMJ 1985; 291: 884-6. Dragojević-Simić V, Stojiljković MP, Stanulović M, Bosković B, Janković SM, Milovanović D. Clinical pharmacology in Serbia: the time for new challenges. Vojnosanit Pregl 2007; 64: 257-63. [In Serbian] International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. Croat Med J 2003; 44: 770-83. Huth EJ. How to write and publish papers in the medical sciences. Philadelphia: ISI Press, 1982. Davidović L, Marković. M, Colić. M, Ili. N, Končar I, Svetković S, Sinđelić R, Marković D. Treatment of traumatic rupture of the thoracic aorta. Srp Arh Celok Lek 2008; 136: 498-504. [in Serbian] Kažić. T, Ostojić M, editors. Clinical cardiovascular pharmacology, Fifth edition. Beograd: Integra, 2009. [in Serbian] Curtis MJ, Shattock MJ. The role of the manuscript assessor. In: Hall GM, editor. How to write a paper. London: BMJ Publishing Group; 1994, pp 89-95. Primeri citiranja elektronskih publikacija i upućivanje na Internet - veb lokacije (engl. „Web sites“): International Society of Scientometrics and Informatics Web site. Available at: http://www.issisociety. info/Accessibility Verifi ed September 20, 2010. Lock SP. Journalology: are the quotes needed? CBE Views. 1989:1257-9. Available at: http://garfi eld.libraryupenn. edu/essays/v13po19y1990.pdf. Accessed May 25, 2010. Wong DN, Vulic BD, Sobot M. Implementation of secondary prevention methodologies in ischemic heart disease. Scr Med 2010;41:29-35. Available at: http://www.scriptamedica. com. Accessed October 1, 2010. Članci o originalnim istraživanjima ne treba da budu duži od 3000 riječi, uz maksimalno 5 tabela ili ilustracija. Pregledne članke uredništvo prima samo ukoliko jedan od autora navođenjem više od 5 auto-citata u recenziranim časopisima pokaže da je kompetentan za tu oblast. Pregledni članak ne treba da ima više od 3500 riječi s maksimalno dvije tabele i ne više od 60 referenci. Specijalni članci se odnose na sve aspekte medicine i zdravstva, a pišu se na do 3000 riječi uz najviše 5 tabela ili ilustracija. Pismo uredniku ne treba da bude duže od 200 riječi s maksimalno 5 referenci, jednom tabelom ili jednom ilustracijom. Prednost imaju pisma koja sadrže primjedbe na članak objavljen u prethodnom broju časopisa. Po potrebi, pisma se recenziraju od strane spoljašnjih recenzenata. Sva pisma se šalju autorima na čiji se rad odnose, bez obzira na to hoće li biti objavljena ili ne. Tekstualni dio prikaza slučajeva, bez referenci i tabele, smije da sadrži do 700 riječi. Slike iz kliničke medicine (Images in Clinical Medicine) moraju biti odličnog kvaliteta, visoke rezolucije i popraćene tekstom do 250 riječi. U prikazu knjige treba da se procijeni njena vrijednost. Zato već u prvom pasusu slijedi odgovor na seriju pitanja. Da li je ta knjiga potrebna? U čemu se razlikuje i da li je bolja od postojećih? Kome je namijenjena i da li je napisana baš za tu kategoriju čitalaca? Zašto se ona svidjela autoru prikaza? U drugom, a eventualno i u dodatnim pasusima, iznosi se sve što se odnosi na kvalitet i namjenu knjige, a u posljednjem pasusu se iznosi zaključak s odgovarajućom ocjenom i preporukom. Ukupan broj riječi prikaza knjige treba da je manji od 300. Tabele Tabele se mogu korisiti za opis odlika grupa u poglavlju “Materijal i metode“, a najčešće budu korištene za prikaz rezultata. U tabelu ne treba unositi vertikalne linije. Horizontalne linije se koriste samo za odvajanje naslova i za razdvajanje pojedinih sekcija tabele. (Ukoliko program za obradu teksta automatski postavi nepotrebne linije, treba ih izbrisati.) Tabele se označavaju arapskim brojevima redoslijedom pojavljivanja (Tabela 1, Tabela 2, itd.) i svakoj se daje naslov. Dodatna objašnjenja se mogu napisati ispod naslova i taj tekst se ispisuje manjom veličinom slova, a ako se objašnjenja daju u fusnoti, onda se za njih koriste simboli: *,¶, €, £, \, §. Svaka tabela mora da se pomene na odgovarajućem mjestu u tekstu. Ako se u tabeli koriste tuđi podaci, obavezno se moraju citirati kao i svaki drugi podatak iz literature. Tabele se prilažu odvojeno od tekstualnog dijela rukopisa. Tabele treba pisati s dvostrukim proredom na posebnoj strani. Svaka tabela mora posjedovati kratak naslov. Objašnjenja treba staviti u fusnotu, a ne u zaglavlje tabele. Skraćenice treba navesti u fusnoti svake tabele. Svaku tabelu treba citirati u tekstu redoslijedom pojavljivanja. Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Ilustracije Svi oblici grafičkih priloga nose naziv slike. Ilustracije se šalju u posebnom fajlu (GIF ili TIF format, rezolucija 300 dpi). Sve oznake na slici treba da su tolike veličine da nakon umanjenja budu čitljive. Naslov i objašnjenje ilustracije (figure legend) treba da bude sastavni dio .DOC dokumenta (Microsoft Word) koji se šalje priložen uz fajl s ilustracijama. Slike se numerišu arapskim brojevima prema redoslijedu citiranja u tekstu. Njih treba profesionalno izraditi. Umjesto originalnih crteža, rendgen filmova i drugog materijala, mogu se izraditi fotografije. Simbole, strelice, brojeve ili slova kojima se označavaju dijelovi ilustracija treba objasniti u legendi. Internu skalu treba objasniti i navesti metod bojenja mikroskopskih uzoraka. Skraćenice i simboli Skraćenice ne treba koristiti u naslovu i apstraktu. Standardne skraćenice se mogu koristiti u tekstu, a sve ostale se načine tako što se iza punog naziva kod prvog pominjanja u zagradi daje skraćenica. Jezik i stil Tekst originalnih saopštenja, preglednih članaka, prikaza slučajeva i uvodnika piše se latinicom, a ostali članci ćirilicom ili latinicom na ekavskom ili ijekavskom narječju. Prošlo vrijeme se koristi kada se saopštavaju dobijeni rezultati, a sadašnje vrijeme za prikaz publikovanih radova. Otuda većina teksta u poglavljima apstrakt, metode i rezultati budu pisani u prošlom vremenu, a sadašnje vrijeme se koristi kada se pišu zaključci. Duge rečenice otežavaju čitanje, a ponekad i razumijevanje poruke. Scripta Medica ne prihvata pasuse koji sadrže samo jednu rečenicu. Glagole je najbolje upotrebljavati u aktivu. Pri sastavljanju rukopisa, autori treba da imaju na umu da pišu članak koji je namijenjen čitaocima s opštim medicinskim znanjem. Autorstvo, integritet istraživača, konflikt interesa i etički standardi Vankuverska grupa je ukazala da koautor članka može biti ona osoba koja je dala “značajan” doprinos istraživanju. Zato se od svakog koautora rukopisa koji se šalje u SM traži da je učestvovao u radu u mjeri koja ga obavezuje na odgovornost prema naučnoj i stručnoj javnosti za odgovarajući dio u izvođenju istraživanja i izrade rukopisa. To uključuje: (1) koncept i dizajn istraživanja ili prikupljanje podataka, te njihovu analizu i interpretaciju; (2) pisanje prve verzije ili vršenje revizije rukopisa; i (3) prihvatanje finalne verzije koja se šalje u SM. Saradnici ne treba da uredništvu prilažu opis svojih poslova, jer glavni autor (garant) uzima na sebe odgovornost za integritet članka i autorstva. Ostali saradnici koji su doprinijeli radu, a ne ispunjavaju uslove za autorstvo, mogu se pomenuti u ‘Zahvalnosti’ s tim da se naznači u čemu je bio njihov doprinos. Plagijatizam, falsifikovanje i izmišljanje podataka su naj- teži oblici kršenja integriteta istraživača. Takve pojave se ponekad dešavaju, ali se one veoma često otkrivaju prije ili poslije publikovanja članka. Autori su dužni da saopšte redakciji finansijsku vezu autora sa industrijom (na primjer, konsultacije, honorari, posjedovanje akcija i sl.). Uredništvo će procijeniti koliki je potencijalni uticaj takve veze i ukoliko postoji značajniji konflikt interesa, isti će biti objavljen na kraju članka. Na početku poglavlja “Materijal i metode” se za eksperimente na ljudima ili životinjama mora navesti da su odobreni od strane odgovarajućeg etičkog odbora ustanove (EOU), a za eksperimente na ljudima se mora naznačiti i da su učesnici dali pismenu saglasnost (informed consent). Urednik može od autora zatražiti kopiju odobrenog zahtjeva EOU. Pisanje materijala za sredstva javnog informisanja (“press release”) Informaciju namijenjenu široj javnosti pišu autori na 150 do 250 riječi kada to predloži uredništvo. Rečenice treba da budu kratke, a izrazi razumljivi širokoj publici. Tehničke termine treba pri prvom pominjanju objasniti. Na kraju teksta, navodi se ime autora koji je zadužen za kontakt s medijima, njegova adresa, telefon i e-adresa. Autorima je zabranjeno davati direktne informacije novinarima prije nego što se skine embargo, tj. iste se mogu dati tek nakon objavljivanja rada u časopisu. 143 144 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Instructions for Contributors Scripta Medica is a peer-reviewed international journal published under the auspices of the Medical Society of the Republic of Srpska. The journal will publish original biomedical studies, including ethical and social issues. Scripta Medica gives preferences to clinically oriented studies over those with experimental animals and will publish peerreviewed original research papers, case reports systematic reviews, medical history and educational essays, clinical mages, book reviews, letters to the editor and editorials. The journal’s full text is available, free of charge, online at www.scriptamedica.com. Each contributor should participate in one or more of the following aspects of an original article: (1) the concept and design of the study; (2) acquisition of data, its analysis and interpretation; (3) drafting and critical revision; (4) final approval of the version to be published. The senior-corresponding author is responsible for the integrity of the work as a whole. The corresponding author must provide a Cover letter indicating that all authors agree to the contents of the submitted paper. Conflict of interest must also be provided. These instructions are in accordance with the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals” (www.icmje.org). Manuscripts deemed suitable for publication by in-house assessment will be reviewed by two or more outside experts. Contributors are encouraged to provide names of two or more qualified reviewers with experience in the subject of the submitted manuscript, but this is not mandatory. Page proofs of accepted articles will be sent to the corresponding author, and the corrected proofs should be returned within three days. The entire process, from submission of the manuscript to the final review, including the sending and receiving of page proofs can be completed online. Technical Requirements The journal will review manuscripts submitted to: [email protected] For the text one should use .DOC format (Microsoft Word), and for the illustrations JPG or TIFF format (300 dpi or higher resolutions). Manuscripts of Original Research Manuscripts that describe clinical or laboratory investigations may be no longer than 3000 words, excluding abstract, tables, and references. Each manuscript should contain following sections: a) Title page. The title page contains the title of the article, the full name of each author, the name of the department(s) and institution(s) to which the work should be attributed, disclaimers (if any), name and address of the corresponding author, and a short running title of no more than 40 characters, including spaces. b) Abstract and Key Words. When required, provide an Abstract of no more than 250 words. It should contain four labeled paragraphs: Background, Methods, Results, and Conclusions. Conclusions should emphasize new and important aspects of the study or original observations. Below the abstract authors should provide 3-8 key words or short phrases. Use terms from the Medical Subject Headings from Index Medicus. Review articles and Special articles (only history) require a 150 words, single paragraph (not structured) abstract. Case reports need no Abstract. c) Introduction. This section includes the purpose of the study and summarizes the rationale for doing it, using only relevant references. d) Materials and Methods. Clearly describes selection of observational or experimental subjects (patients, laboratory animals, tissue samples or cell lines) and relevant controls. Indicate age, sex, and other important characteristics of the subjects. Manuscripts describing investigations using humans or animals must confirm approval of the study by an Institutional Review Board. Identify all methods, apparatus (manufacturer’s name and location in parentheses), and describe procedures in sufficient detail to allow others to reproduce them. Measurements of distance, length, and weight are to be expressed in metric units. Laboratory, hematological, and clinical data should be expressed in SI units, with conventional metric units indicated in parentheses. Reference all established methods, including statistical analyses. Identify all drugs and chemicals used, including generic names, doses, and routes of administration. Statistical methods should be described such that a reader with access to the original data could verify the reported results. Variability should be expressed in terms of means and standard deviations (SD), not the standard error of the mean (SEM). Because SD and SEM are positive numbers, the Council of Science Editors (Reston, 2006) recommends elimination of a +/- sign; instead, the SD is given in brackets. For example, “systolic blood pressure in group of healthy students was 129 mm Hg [SD=6, n=87].” Authors submitting review manuscripts should describe the methods used to locate, select, extract, and synthesi- Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com ze data. These methods should also be summarized in the abstract. e) Results. Results should be presented in logical sequence using the text, tables, and illustrations. Do not repeat data presented in tables or illustrations in the text. Emphasize or summarize only important observations. f) Discussion. Emphasize the new and important aspects of the study and the conclusions that follow from them. Discuss the implications of the findings and their limitations. Significant findings should be related to other relevant studies, and conclusions should be linked to the goals of the study. Do not repeat data or summarize material from the Introduction or the Results sections. g) Acknowledgments. List all contributors who helped, even if they did not meet the criteria for authorship as well as financial and material supporters. h) References. References should be numbered consecutively with Arabic numerals (superscripts) in the order in which they first mentioned in the text, tables, and legends. References cited only in tables or figure legends should be numbered in accordance with the sequence established by their first mention in the text or figure or table. Titles of journals are to be abbreviated according to the Index Medicus. All titles of should be in English with the original language in brackets. Examples given here conform to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals (www.icmje.org): De Lacey G, Record C, Wade J. How accurate are quotations and references in medical journals. BMJ 1985; 291: 884-6. DragojeviÉ-SimiÉ V, StojiljkoviÉ MP, StanuloviÉ M, Boskovic B, Jankovic SM, Milovanovic D. Clinical pharmacology in Serbia: the time for new challenges. Vojnosanit Pregl 2007; 64: 257-63. [In Serbian] International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. Croat Med J 2003; 44: 770-83. Huth EJ. How to write and publish papers in the medical sciences. Philadelphia: ISI Press, 1982. DavidoviÉ L, MarkoviÉ M, ColiÉ M, IliÉ N, KonÏar I, SvetkoviÉ S, SindjeliÉ R, MarkoviÉ D. Treatment of traumatic rupture of the thoracic aorta. Srp Arh Celok Lek 2008; 136: 498-504. [In Serbian] KaŀiÉ T, OstojiÉ M, editors. Clinical cardiovascular pharmacology, Fifth edition. Beograd: Integra, 2009. [In Serbian] Curtis MJ, Shattock MJ. The role of the manuscript assessor. In: Hall GM, editor. How to write a paper. London: BMJ Publishing Group; 1994, pp 89-95. Electronic publications: International Society of Scientometrics and Informatics Web site. Available at: http://www.issi-society.info/Accessibility Verified September 20, 2010. Lock SP. Journalology: are the quotes needed? CBE Views. 1989:1257-9. Available at: http://garfi eld.libraryupenn. edu/essays/v13po19y1990.pdf. Accessed May 25, 2010. Wong DN, VuliÉ BD, Sobot M. Implementation of secondary prevention methodologies in ischemic heart disease. Scr Med 2010;41:29-35. Available at: http://www.scriptamedica. com. Accessed October 1, 2010. Tables Tables (maximum 4) should be self-explanatory and numbered in Arabic numerals in order of their mention in the text. Type each table, double-spaced, on a separate sheet and supply a brief title. Place any explanatory text in footnotes, not in the heading. Defi ne abbreviations in footnotes. Illustrations (Figures) Figures should be professionally drawn and numbered with Arabic numerals in the order of their mention in the text (maximum 2). All lettering should be dark against a white background and of sufficient size to be legible when reduced for publication. Do not send original artwork, xray films, or ECG tracings but rather photographs of such material. Images need to be at least 300 DPI. Figure legends should be typed double-spaced on a separate page with Arabic numerals corresponding to the figure. All symbols, arrows, numbers, or letters should be explained in the legend. Photomicrographs should include an internal scale, and methods of staining should be described in the legend. Review Articles Review articles are written by individuals who have worked sufficiently in a particular area to be considered experts. Word count is limited to 3500 words or less, excluding tables (maximum 4), references and abstract. The manuscript may have as many as 50 references. Case Reports New, interesting, or rare cases can be reported in communications no longer than 700 words. They should include the following: Introduction, Case Presentation, Discussion, and up to six References. Up to three illustrations is permitted. Case reports could be authored by up to five authors. 145 146 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com Images in Clinical Medicine The editors will consider original, high quality images showing novel or “classic” findings for publication. All submissions should be accompanied by a cover letter as well as a concise description of no more than 250 words including the title page and references. Clinical Problem-Solving Solution for various clinical problems, including certain clinical studies, should include the following: Introduction, Methods or Case(s) Presentation, Discussion, and References. Four tables or illustrations. This communication should be no longer than 1400 words, including references and tables. Letter to the Editor If in reference to a recent journal article, letters are limited to 150 words, excluding references, or 200 words in all other cases. The letter should contain no more than five references, and may include one figure or table. Please include your full address, phone number, fax number, and an e-mail address. Editorials Editorials are solicited by the Editorial Board to provide editorial perspective on articles published in the journal and/or express the general policies or opinions of the Editorial Board. Special Articles Articles that do not readily fall into the above categories may be published as Special Articles (e.g., history, education, demography, contemporary issues, etc). Word count is limited to 3000 words for history articles or educational articles with up to 6 tables or illustrations. Other Special articles may have up to 1000 words. Only history articles need Abstract (unstructured). Conflict of Interest Authors of research articles should disclose at the time of submission any financial arrangement they may have with a company whose product figures prominently in the submitted manuscript. Such information will be held in confidence while the paper is under review; if it is accepted for publication, the editors will discuss with the author how such information will be communicated to the reader. Review Procedure At least two members of the editorial board initially evaluate all submissions for originality, relevance, statistical methods, significance, adequacy of documentation, reader interest, and composition. Articles that do not conform to the journal instructions will be returned to the authors. Manuscripts suitable for peer review will be sent to two outside reviewers, who then have up to a month to provide their reviews. The ultimate authority to accept or reject an article rests with the Editor. Revised manuscripts may be accepted depending upon the adequacy of responses to suggestions and criticisms during the initial review. A letter to the principal author will communicate acceptance of the manuscript. Naslov teksta maksimalmo dva reda, po potrebi povecati sirinu tekst boksa da stane naslov, Etiam dapibus iaculis euismod 147 148 Scripta Medica Vol. 42 • No 2 • October 2011. www.scriptamedica.com
