Number 3 July/September 2014
Transcription
Number 3 July/September 2014
Number 3 July/September 2014 Volume 20, Number 3, pp 141-212 July/September 2014 141 120 anniversary of the National Hospital in Sarajevo 120 godina Zemaljske bolnice u Sarajevu 142 New ICU - Central Medical Building - Clinical Center University of Sarajevo Nova Intenzivna njega - Klinički Centar Univerziteta u Sarajevu 143 New Central Medical Building - Clinical Center University of Sarajevo Novi Centralni Medicinski Blok - Klinički Centar Univerziteta u Sarajevu Medical Journal www.kcus.ba www.kcus.ba Medical Journal PUBLISHER Institute for Research and Development Clinical Center University of Sarajevo 71000 Sarajevo, Bolnička 25 Bosnia and Herzegovina For publisher: Damir Aganović, MD, PhD General Manager CCUS AIMS AND SCOPE The Medical Journal is the official quarterly journal of the Institute for Research and Development of the Clinical Center University of Sarajevo and has been published regularly since 1994. It is published in the languages of the people of Bosnia and Herzegovina i.e. Bosnian, Croatian and Serbian as well as in English. The Medical Journal aims to publish the highest quality materials, both clinical and scientific, on all aspects of clinical medicine. It offers the reader a collection of contemporary, original, peer-reviewed papers, professional articles, review articles, editorials, along with special articles and case reports. Copyright: the full text of the articles published in the Medical Journal can be used for educational and personal aims i.e. references cited upon the authors’ permission. If the basic aim is commercial no parts of the published materials may be used or reproduced without the permission of the publisher. Special permission is available for educational and non-profit educational classroom use. Electronic storage or usage: except as outlined above, no parts of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means without prior written permission from the Publisher. All rights reserved©2014. Institute for Research and Development CCUS. Notice: The authors, editor and publisher do not accept responsibility for any loss or damage arising from actions or decisions based on information contained in this publication; ultimate responsibility for the treatment of patients and interpretation of published materials lies with the medical practitioner. The opinions expressed are those of the authors and the inclusion in this publication of materials relating to a specific product, method or technique does not amount to an endorsement of its value or quality, or of the claims made by its manufacturer. EDITORIAL OFFICE Address: Medical Journal, Institute for Research and Development, Clinical Center University of Sarajevo, 71000 Sarajevo, Bolnička 25, Bosnia and Herzegovina, Phone: +387 33 668 415; +387 33 297 264. Email: [email protected] Web. www.kcus.ba Technical secretariat: [email protected] Editor-in-Chief: [email protected] SUBSCRIPTION Annual subscription rates: Bosnia and Herzegovina € 50; Europe € 80; and other € 100. Editor-in-Chief Mirza Dilić Editorial Board Zoran Hadžiahmetović, President, Damir Aganović, Ismet Gavrankapetanović, Mehmed Gribajčević, Safet Guska, Almira Hadžović-Džuvo, Mustafa Hiroš, Bećir Heljić, Sebija Izetbegović, Adnan Kapidžić, Abdulah Kučukalić, Bakir Mehić, Rusmir Mesihović, Senka Mesihović-Dinarević, Nermina Obralić, Łilijana Oruč, Sead Redžepagić, Svjetlana Radović, Senija Rašić, Sandra Vegar-Zubović, Hasan Žutić, Secretary International Advisory Board Kenan Arnautović (USA), Raffaele Bugiardini (Italy), Erol Ćetin (Turkey), Maria Dorobantu (Romania), Oktay Ergene (Turkey), Zlatko Fras (Slovenia), Dan Gaita (Romania), Mario Ivanuša (Croatia), Steen Dalby Kristensen (Denmark), Mimoza Lezhe (Albania), Mario Marzilli (Italy), Milica MedićStojanovska (Serbia), Davor Miličić (Croatia), Fausto Pinto (Portugal), Mihailo Popovici (Moldova), Marcella Rietschel (Germany), Nadan Rustemović (Croatia), Georges Saade (Lebanon), Petar Seferović (Serbia), Dragan Stanisavljević (Slovenia), Bojan Tršinar (Slovenia), Panos Vardas (Greece), Gordan Vujanić (UK), Jose Zamorano (Spain) English language revision Svjetlana Baroševčić Medical Journal is Indexed in EBSCO publishing USA www.ebscohost.com SUPPLEMENTS, REPRINTS AND CORPORATE SALES For requests from industry and companies regarding supplements, bulk articles reprints, sponsored subscriptions, translation opportunities for previously published material, and corporate online opportunities, please contact; Email: [email protected] PRINT Eurografika Zvornik Printed on acid-free paper. TECHNICAL EDITOR Eurografika CIRCULATION 500 copies Member of National Journals Networks of the European Society of Cardiology Content Medical Journal (2014) Vol. 20, No. 3 Original article Morphological characteristics of atherosclerotic lesions of coronary arteries in diabetic patients .................. 147 Aida Hasanović, Edin Omerbašić, Aida Sarač-Hadžihalilović The importance of intraperitoneal interleukin-6 in peritoneal solute transport rate in continuous ambulatory peritoneal dialysis patients.................................................................................................................................. 151 Snežana Unčanin Lymph node metastasis predictors for prostate cancer in patients with serum PSA values ranging 2-10ng/Ml ........................................................................................................................................................................... 156 Benjamin Kulovac, Damir Aganović, Alden Prcić, Osman Hadžiosmanović, Nermina Obralić, Dženana Eminagić Hormonal variations in correlation to the outcome of medicamentous abortion in the second trimester of pathological pregnancy ................................................................................................................................................................... 159 Naima Imširija, Lejla Imširija, Zulfo Godinjak, Edin Idrizbegović, Fatima Gavrankapetanović, Mohammad Abou El–Ardat, Rama Admir The effect of smoking on the results of rehabilitation in patients after cerebrovascular accident .................... 163 Senad Selimović, Edina Tanović, Haris Tanović, Ksenija Miladinović Frequency of chromosomal aberrations among healthy population of Bosnia and Herzegovina . ...................... 167 Izeta Aganović-Mušinović, Mirela Mačkić-Đurović, Orhan Lepara Morphometric analysis of arterial Willis ring in patients with varying degrees of occlusion of the internal carotid artery ................................................................................................................................................................ 171 Alma Voljevica, Elvira Talović Evaluation of clinical and laboratory characteristics of childhood lymphoma ................................................... 175 Edo Hasanbegović, Nermana Čengić, Meliha Sakić, Adela Tunić, Senada Mehadžić Importance of noninvasive markers in the assessment of portal hypertension as a liver cirrhosis complication . . . 1 8 0 Nenad Vanis, Sanjin Glavaš, Amila Mehmedović, Rusmir Mesihović, Nađa Zubčević, Srđan Gornjaković, Azra Husić-Selimović, Aida Saray, Nerma Zahiragić Professional article Antimicrobial susceptibility of common isolated microorganisms in hip surgical wound .................................... 185 Tarik Muharemović, Mersiha Bašić-Muharemović, Šukrija Zvizdić, Sadeta Hamzić Five-year work of the birthing unit of the Clinic for Gynecology and Obstetrics; perinatal report.................... 191 Mohamad Abou El-Ardat Review article Oral precanceroses: clinical histopathological correlation. ............................................................................................... 194 Dedić A, Hodžić M, Avdić M, Hadžić S, Pašić E, Gojkov-Vukelić M., Kantardžić A Case report Staged surgical treatment of combined osteoarticular and vascular injury of the shoulder...................................... 197 Amel Hadžimehmedagić, Ismet Gavrankapetanović, Haris Vranić, Mehmed Jamakosmanović Perivascular epithelioid cells tumor; case report of uncommon clear cell neoplasm ligamentum teres uteri...... 200 Faika Mujanović-Glamočanin, Spahić Amir Blunt chest trauma and pericardial tamponade ................................................................................................................ 203 Dragan Milošević, Duško Golić, Dragan Rakanović, Vojislav Vujanović, Dušan Janičić A heart murmur which saved a life ...................................................................................................................................... 205 Amir Omerbašić, Mirsad Đugum, Mirela Tuce, Aida Kriještorac, Edin Omerbašić, Mirza Halimić Clinical picture of autoimmune hepatitis and cholangitis in a pregnant woman during pregnancy and after delivery ......................................................................................................................................................................... 208 Lejla Imširija, Naima Imširija, Sanjin Deković, Fatima Gavrankapetanović, Edin Idrizbegović Instructions to authors ................................................................................................................................................................ 210 Uputstva autorima ........................................................................................................................................................................ 212 Original article Medical Journal (2014) Vol. 20, No. 3, 147 - 150 Morphological characteristics of atherosclerotic lesions of coronary arteries in diabetic patients Morfološke karakteristike aterosklerotičnih lezija koronarnih arterija kod pacijenata sa dijabetesom Aida Hasanović1*, Edin Omerbašić2, Aida Sarač-Hadžihalilović1 Department of Anatomy, Faculty of Medicine, University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina; 2Heart Center, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina 1 * Corresponding author ABSTRACT SAŽETAK The aim of the study was to establish the morphological characteristics of atherosclerotic lesions of coronary arteries in patients with diabetes mellitus using coronary angiography. Diabetes is an important risk factor for the development of coronary artery disease. In the study which included 180 patients with suspected coronary artery disease (60 females, 120 males), we performed coronary angiography and tested the differences between diabetic (90) and non-diabetic (90) patients in ischemia detection by this method. All patients underwent coronary angiography in Heart Centre of the Clinical Center University of Sarajevo in period from June 2011 to June 2014. Coronary angiography was performed in the right and left anterior oblique position. Diabetic patients were found to have a significantly higher prevalence of stenotic atherosclerotic lesions of the coronary arteries. In 17 (19%) of our 90 diabetic patients stenosis of the right coronary artery (RCA) was found, in 10 patients (11%) stenosis of the circumflex branch (Cx) of the left coronary artery, and in 63 patients (70%) stenosis of the left anterior descending artery (LAD). Stenosis of the RCA was found in 22 (24%) of our 90 non-diabetic patients. Stenosis of the CX branch of the left coronary artery was found in 14 (16%) and stenosis of the LAD in 54 (60%) of non diabetic patients. Stenotic atherosclerotic lesions of the large coronary arteries were significantly more common in the left than in the right coronary artery, but the difference between the diabetic and the non-diabetic group did not reach statistical significance. Changes in the proximal segment of the left anterior descending artery were the most common finding in diabetic patients. The most frequently atherosclerotic lesion of the RCA was seen in the middle segment, rarely in the proximal and distal part. The diabetic patients had a higher prevalence of hypertension, higher BMI and triglyceride and cholesterol levels. Diffuse coronary artery narrowing develops not only in patients with diabetes but also in those with non-diabetes. These findings may prove clinically useful in the follow-up of diabetic patients, the choice of diagnostic procedures as well as in active treatment either by aterectomy or by percutaneous angioplasty and stenting. Cilj istraživanja je bio angiografski utvrditi morfološke karakteristike aterosklerotičnih lezija koronarnih arterija kod pacijenata sa dijabetes melitusom. Dijabetes melitus je važan riziko faktor razvoja koronarne bolesti. U ovoj studiji 180 pacijenata suspektnih na koronarnu bolest (60 žena, 120 muškaraca) podvrgnuto je koronarnoj angiografiji i testirane su razlike u ishemičnim promjenama između dijabetičara (90 pacijenata) i pacijenata bez dijabetesa (90 pacijenata). Svi pacijenti su podvgnuti koronarnoj angiografiji u Centru za srce Kliničkog centra Univerziteta u Sarajevu u periodu od juna 2011 do juna 2014. godine. Snimanje je vršeno u dvije projekcije: desnoj i lijevoj prednjoj kosoj projekciji. Angiografska analiza je pokazala signifikantno veću učestalost stenotičnih aterosklerotičnih lezija koronarnih arterija kod dijabetičara u odnosu na grupu pacijenata bez dijabetesa. Stenoza desne koronarne arterije uočena je kod 17 (19%) od ukupno 90 pacijenata sa dijabetes melitusom, kod 10 pacijenata (11%) stenoza r. circumflexus lijeve koronarne arterije i kod 63 pacijenta (70%) stenoza r. interventricularis anterior. Stenoza desne koronarne arterije nađena je kod 22 (24%) pacijenata od ukupno 90 bez dijabetesa. Stenoza r. circumflexus lijeve koronarne arterije uočena je kod 14 (16%), a stenoza r. interventricularis anterior kod 54 (60%) pacijenata bez dijabetesa. Stenotične aterosklerotične lezije velikih koronarnih arterija bile su učestalije na lijevoj nego na desnoj koronarnoj arteriji, ali razlike između dijabetičara i grupe bez dijabetesa nisu bile značajno statistički signifikantne. Promjene proksimalnog dijela r. interventrikularis anterior (LAD) lijeve koronarne arterije bile su najučestaliji nalaz na koronarogramima dijabetičara. Najčešće aterosklerotične lezije desne koronarne arterije uočene su u srednjem, rijeđe u proksimalnom i distalnom dijelu. Pacijenti sa dijabetesom su imali veću učestalost hipertenzije, veći indeks tjelesne mase, veći nivo triglicerida i holesterola. Difuzna suženja koronarnih arterija razvijaju se ne samo kod pacijenata sa dijabetesom nego i kod onih bez dijabetesa. Ovi nalazi dokazuju klinički značaj praćenja pacijenata sa dijabetesom, te izbor dijagnostičkih procedura u aktivnom tretmanu ili aterektomijom ili perkutanom angioplastikom ili stentom. Key words: coronary arteries, diabetes mellitus, atherosclerotic lesions, coronary angiography Ključne riječi: koronarne arterije, dijabetes melitus, aterosklerotične lezije, koronarna angiografija 148 INTRODUCTION Coronary angiographic studies of both symptomatic and asymptomatic patients with diabetes mellitus have documented a more diffuse narrowing of the coronary arteries than non-diabetics. Furthermore, earlier onset and accelerated progression of coronary artery disease has been suggested by other studies (1,2). Since the development of angiographically significant coronary artery stenosis is a late finding in the process of coronary atherosclerosis, the factors that contribute to this process have not yet been defined (3). Atherosclerosis is a diffuse disease with segmental lesions frequently involving particular vessels or their segments. In diabetic patients, these lesions are more extensively, diffusely and unevenly distributed than in non-diabetics. Diabetes mellitus (DM) as a risk factor for atherosclerosis further increases the effect of other risk factors, contributes to the more pronounced macroangiopathic changes, and increases the incidence of arterial wall calcification (1,4,5). The ischemic heart disease in patients with diabetes shows some specificities, such as being frequently of an asymptomatic course and showing nonspecific ECG changes, while coronary atherosclerotic changes in patients with diabetes mellitus regularly take up a greater number of branches and spread onto longer segments that in percutaneous interventions require the implantation of a greater number of stents (6,7). The incidence of myocardial infarction in patients with diabetes is two times greater in men and three times greater in women than in healthy individuals. Many aspects of the mechanism of coronary artery sclerosis in patients with diabetes are unclear (8,9,10,11). The purpose of the present study was to compare the extent and localization of stenosing lesions of the coronary arteries between diabetic and non-diabetic patients with a history of coronary artery disease and to elucidate which risk factors influence the progression of coronary artery sclerosis in patients with diabetes. MATERIALS AND METHODS In the study which included 180 patients with suspected coronary artery disease (60 females, 120 males), we performed coronary angiography and tested the differences between diabetic (90) and non-diabetic (90) patients in ischemia detection by this method. All patients underwent coronary angiography in Heart Centre of the Clinical Center University of Sarajevo (CCUS) in period from June 2011 to June 2014. All the patients underwent angiographic and laboratory analyses including total cholesterol and triglyceride. In addition, patients were assessed for the prevalence of coronary risk factors, i.e., hypertension, hyperlipidemia, smoking habits, and family history, and for the presence of diabetes complications, i.e., nephropathy, a history of myocardial and cerebral infarction, and the presence of arteriosclerotic obliterance. BMI was calculated as the weight in kilograms divided by the square of height in meters (4). Coronary angiography was performed by the percutaneous transfemoral approach using the Judkins technique. Selective coronary angiography was performed in multiple projections. The aim of the coronary angiography was to establish the coronary anatomy A. Hasanović et al. and the degree of the obstruction of coronary artery. The information obtained in this manner includes identifying localisation, the presence and severity of coronary luminal obstruction, as well as an estimate of the blood flow quality. The following parameters were used for the assessment of morphological characteristics in global coronary trees. The analysis included each major coronary artery: the right coronary artery (RCA); the left anterior descending artery (LAD); and the left circumflex artery (CX). Each of the arteries analyzed was longitudinally divided into equal thirds (proximal, medial and distal) for more precise stenosis localization. We defined significant coronary stenosis (stenosis > 70%.). Statistical analysis The statistical analysis of the results was performed using Kolmogorow-Smirnow test and the differences in the angiographic changes of all coronary arteries obtained in diabetic and non-diabetic patients were considered significant on the level p<0,05. RESULTS Out of 180 patients with suspected coronary artery disease treated in the Heart Center of CCUS the diabetic patients (90) had a higher prevalence of hypertension, higher BMI and triglyceride, and cholesterol levels in comparison to non diabetic patients (Table 1). Table 1 Demographic data and risk factors in diabetic and non diabetic patients. PATIENTS Gender M Non-diabetic 58 (n=90) Diabetic (n=90) 62 F Age (mean years) M F Hypertension Hyperlipidemia n % n % Cigarette smoking n % 32 67 63 52 57.7 41 45.5 55 61.1 28 66 61 60 66.6 62 68.8 39 43.3 In 17 (19%) of our 90 diabetic patients stenosis of the right coronary artery (RCA) was found, in 10 patients (11%) stenosis of the circumflex branch (Cx) of the left coronary artery, and in 63 patients (70%) stenosis of the left anterior descending artery (LAD). Stenosis of the RCA was found in 22 (24%) of our 90 non-diabetic patients. Stenosis of the CX branch of the left coronary artery was found in 14 (16%) and stenosis of the LAD in 54 (60%) of non diabetic patients (Table 2). Table 2 Type of vessel with coronary stenosis in diabetic and non-diabetic group. Coronary artery Diabetic patients (n=90) Hyperlipidemia N % N % RCA 17 (19) 22 24 CX 10 (11) 14 16 LAD 63 (70) 54 60 In the present study the morphological changes of small vessel diameter and diffuse vessel narrowing developed not only in the diabetes groups but also in the non-diabetic group. Morphological characteristics of atherosclerotic lesions of coronary arteries in diabetic patients Statistical analysis determinated that diabetic patients had a significantly higher prevalence of stenotic atherosclerotic lesions of the coronary arteries (p<0,001). However, some postoperative complications were significantly more prevalent among diabetics, mainly renal failure, neurological accidents and infection. Stenotic lesions of the large coronary arteries were significantly more common in the left than in the right coronary artery but the difference between the diabetic and the non-diabetic group did not reach statistical significance. Coronary angiograms of diabetic group showed the morphological changes caused by significant stenosis of coronary arteries (> 70%). Changes in the proximal segment of the left anterior descending artery (LAD) were the most common finding in diabetic patients. As well as stenosis of the CX branch was found in diabetic and non-diabetic group. The most frequently atherosclerotic lesion of the RCA was seen in the middle segment, rarely in the proximal and distal part (Figure 1). A Figure 1 B Figure 2 Coronary angiogram of the left coronary artery (left anterior oblique projection) (A) showing stenosis of the left main coronary artery (50%) and occlusion of the CX; (B) right anterior oblique projection showing subocclusion of CX and LAD. 149 DISCUSSION Diabetes mellitus is frequently associated to more severe coronary artery disease, with involvement of a larger number of vessels and more lesions. This metabolic disorder facilitates the development of coronary atherosclerosis, the frequency and severity of which usually increases with the severity of diabetes mellitus. Due to this relation, coronary accidents are the main cause of death in dia-betic patients and more serious clinical manifestations of ischemic heart disease, like acute coronary syndrome and acute myocardial infarction, are up to three times more frequent in diabetics than in non-diabetics. In addition, the diabetic patient usually has a more depressed ventricular function (5,6). The prevalence, localization and morphological features of atherosclerotic plaques have been thoroughly investigated in coronary angiograms of diabetic patients involved (1,2,3,4,8,11). Results of the present study showed that diabetic patients had a significantly higher prevalence of stenotic atherosclerotic lesions of the coronary arteries. In 17 (19%) of our 90 diabetic patients stenosis of the right coronary artery (RCA) was found, in 10 patients (11%) stenosis of the circumflex branch (Cx) of the left coronary artery, and in 63 patients (70%) stenosis of the left anterior descending artery (LAD). Our results are similar to results of the study by Vidljak et al. Atherosclerotic lesions of the large coronary arteries were significantly more common in the left than in the right coronary artery, but the difference between the diabetic and the non-diabetic group did not reach statistical significance. Changes in the proximal segment of the left anterior descending artery (LAD) were the most common finding in diabetic patients. The present study also revealed that stenoses affected proximal segments of the left anterior descending artery more frequently in diabetic patients. The most frequently atherosclerotic lesion of the RCA was seen in the middle segment, rarely in the proximal and distal part. Vidljak V et al (1) determined that hemodynamic conditions were found to be more important than diabetes for the occurrence of atherosclerotic lesions in these arteries. The diabetic patients had a higher prevalence of hypertension, higher BMI and triglyceride and cholesterol levels. Jakljević T et al. (7) in the study of 286 patients with suspected coronary artery disease and recent exercise single photon emission computed tomography (SPECT) test, performed coronary angiography with coronary fractional flow reserve (FFR) measurement, tested the differences between diabetic (103) and non-diabetic (183) patients in ischemia detection by this two methods and found that the diabetic patients had a higher prevalence of hypertension, higher BMI and cholesterol levels, as well as longer duration of hospitalization than non-diabetic patients. Wendler et. al (10) found that patients with diabetes mellitus who underwent surgical revascularization had a significantly higher prevalence of three-vessel disease, and a mean ejection fraction 5 points lower than that of non-diabetic patients. In our population, similar differences were appreciated. The diabetics had a significantly greater number of significant coronary stenoses, and a significantly lower ejection fraction than non-diabetics. Schofer et al. (9) also found that the mean caliber of the coronary arteries of insulin-dependent patients was smaller than in non-diabetics. In addition, the distal beds of these patients often show diffuse disease and have 150 more extensive zones of calcification. These circumstances, although difficult to quantify and record, can make conventional surgery difficult or impossible, and compromise the intermediate and long-term patency of coronary grafts. These unfavorable anatomic abnormalities are more important in older patients,when diabetes is prolonged and other vascular complications are associated. The present study showed that he diabetic patients had a higher prevalence of diabetes complications, i.e. nephropathy, a history of myocardial and cerebral infarction, and the presence of arteriosclerotic obliterance. These findings may prove clinically useful in the follow-up of diabetic patients, the choice of diagnostic procedures as well as in active treatment either by aterectomy or by percutaneous angioplasty and stenting. CONCLUSIONS In the present study the morphological changes of small vessel diameter and diffuse vessel narrowing developed not only in the diabetes groups but also in the non diabetic group. Diabetic patients were found to have a significantly higher prevalence of stenotic atherosclerotic lesions of the coronary arteries. Stenotic atherosclerotic lesions of the large coronary arteries were significantly more common in the left than in the right coronary artery but the difference between the diabetic and the non diabetic group did not reach statistical significance. Changes in the proximal segment of the left anterior descending artery (LAD) were the most common finding in diabetic patients. The most frequently atherosclerotic lesion of the RCA was seen in the middle segment, rarely in the proximal and distal part. The diabetic patients had a higher prevalence of hypertension, higher BMI and triglyceride and cholesterol levels. These findings may prove clinically useful in the follow-up of diabetic patients, in the choice of diagnostic procedures as well as in active treatment by either aterectomy or percutaneous angioplasty, and stenting. Conflict of interest: none declared. REFERENCES 1. Vidjak V, Hebrang A, Brkljačić B, Brajša M, Novačić K, Barada A, et al. Atherosclerotic lesions of supra-aortic arteries in diabetic patients. Coll. Antropol. 2007;31(3):723–32. A.Hasanović et al. 2. Hasanović A, Haxhibeqiri-Karabdić I, Sarač-Hadžihalilović A, Spužić M. Anatomic characteristics of arterial supply of the conductive system of the heart in patients with coronary disease and diabetes mellitus. Medicinski žurnal. 2013;19(4):270275. 3. Vavuranakis M, Stefanadis C, Toutouzas K, Pitsavos C, Spanos V, Toutouzas P. Impaired compensatory coronary artery enlargement in atherosclerosis contributes to the development of coronary artery stenosis in diabetic patients. An in vivo intravascular ultrasound study. Eur Heart J. 1997;18(7):1090-4. 4. Kataoka Yu, Yasuda S, Morii I, Otsuka Y, Kawamura A, Miyazaki S. Quantitative coronary angiographic studies of patients with angina pectoris and impaired glucose tolerance. Diabetes Care. 2005;28(9):2217–22. 5. González Santos JM, Castaño Ruiz M. Coronary artery surgery in diabetic patients. Rev Esp Cardiol. 2002;55(12):1311-22. 6. Scognamiglio R, Negut C, Ramondo A, Tiengo A, Avogaro A. Detection of coronary artery disease in asymptomatic patients with type 2 diabetes mellitus. J Am Coll Cardiol. 2006;47(1):65-71. 7. Jakljević T, Ružić A, Baždarić K, Zaputović L, Mavrić Ž, Champagne S, Teiger E. Detection of myocardial ischemia in diabetic patients: The limitations of myocardial perfusion imaging. Coll. Antropol. 2012;36(3):821–6. 8. Nishiyama A, Shikata C, Kimura N, Imanishi A, Hirai N, Ohta M, et al. Risk factors for coronary artery sclerosis in patients with diabetes. Exp Clin Cardiol. 2005;10(2):108-10. 9. Schofer J, Schluter M, Rau T. Influence of treatment modality on angiographic outcome after coronary stenting in diabetic patients: a controlled study. J Am Coll Cardiol. 2000;35(6):1554-9. 10.Wendler O, Hennen B, Markwirth T, Nikoloudakis N, Graeter T, Schäfers HJ. Complete arterial revascularization in the diabetic patient-early postoperative results. Thorac Cardiovasc Surg. 2001;49(1):5-9. 11.Hasanović A, Junuzović A, Spužić M, Kudumović A. Angiographic evaluation of myocardial bridges in relation to myocardial ischemia. HealthMED. 2010;4(2):398403. Reprint requests and correspondence: Aida Hasanović, MD, PhD Department of Anatomy Faculty of Medicine University of Sarajevo Čekaluša 90 71000 Sarajevo Bosnia and Herzegovina Phone: +387 33 665 949 Email: [email protected] Original article Medical Journal (2014) Vol. 20, No. 3, 151 - 155 The importance of intraperitoneal interleukin-6 in peritoneal solute transport rate in continuous ambulatory peritoneal dialysis patients Značaj intraperitonealnog interleukina-6 u brzini transporta kroz peritonealnu membranu u pacijenata na kontinuiranoj ambulantnoj peritonealnoj dijalizi Snežana Unčanin* Clinic of Nephrology, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT Inflammatory changes are often seen in the peritoneum, even in the absence of peritonitis, indicating that the peritoneum of a peritoneal dialysis (PD) patient may be chronically inflamed. Cytokines orchestrate the inflammatory response, and Interleukin-6 (IL-6) is central regulator of the inflammatory process. Effluent IL-6 may be an excellent marker for peritoneal inflammatory status and mesothelial cell activation in PD patients. Peritoneal solute transport rates (PSTR) for small solutes increased in parallel with the duration of PD. Purposes of this study was to evaluate possible relationships between dialysate IL-6 levels and PSTR of small solutes evaluated using the dialysate-to-plasma ratio (D/P) of creatinine, and to establish how they change during one year of follow-up. Methods: Sixty CAPD patients (52%F vs. 48% M), aged 56,63 ±15,06 years were divided into a short-term and a long-term PD group, where short-term were defined as patients with a PD duration between 1 and 12 months, and long-term patients with a PD duration of > 12 months. For the analysis of peritoneal solute transport rate (PSTR) of small solute the peritoneal functional test (PFT) (Fresenius Medical Care) was used. Samples for the determination of dialysate interleukin 6 (IL-6) were obtained from overnight dialysate effluent. Dialysate IL-6 was determined by use of an automated immune-chemiluminiscence method. Values are presented as mean ± standard deviation or as median (interquartile range). Paired Student’s t-test or Wilcoxon signed rank test was used to compare differences between baseline and 1-year evaluations, and Spearman rank correlation test was used for skewed variables. Differences between groups were evaluated by use of the Mann-Whitney test. Results: IL-6 of short-term patients (≤ 12 months) ranged from 14,95 pg/mL to 16,05 pg/mL, and Dialysate–to plasma ratio (D/P) of creatinine from 0,64 to 0,67. Long term patients (>12 months) had a IL-6 of 27,90 pg/mL - 26,0 pg/mL, and (D/P) creatinine of 0,65 - 0,70. There were a strong positive correlations between dialysate IL-6 and D/P creatinine in patients on peritoneal dialysis (≤ 12 months), at baseline (rho= 0,373; p<0,05) and after 1 year (rho =0,442; p<0,05), but not in patients treated by CAPD for a longer time (>12 months). Conclusions: our findings indicated that intraperitoneal inflammation, which was evaluated by measuring IL-6 in dialysate increased over the time on peritoneal dialysis. Peritoneal solute transport rate (PSTR) of small solute was also increased over the time. PSTR of small solute was related to interleukin-6 (IL-6 ) only in the early phase of PD treatment, but in the follow up evaluation no associations were observed, indicating that inflammation may not be directly linked to the high PSTR that develops following the long term peritoneal dialysis. Inflammation may, at least partly, be linked to development of high PSTR, which may contribute to the high transport PD patients. Key words: inflammation, interleukin-6, dialysate, peritoneal solute transport rates SAŽETAK Upalne promjene mogu se često vidjeti na peritoneumu, u odsustvu peritonitisa, što ukazuje da potrbušnica pacijenata na peritonealnoj dijalizi može biti hronično upaljena. Citokini upravljaju upalnim odgovorom, a interleukin-6 (IL-6) je središnji regulator akutnog upalnog procesa. IL-6 u efluentu može biti izvanredan pokazatelj upalnog stanja peritoneuma i mezotelijalne ćelijske aktivacije kod pacijenata na peritonealnoj dijalizi. Apsolutna brzina transporta kroz peritoneum (PSTR), za rastvorene supstance male molekulske težine povećava se sa dužinom liječenja pritonealnom dijalizom. Svrha ovog istraživanja bila je da se procijeni moguća veza između IL-6 u dijalizatu i (PSTR) koji se procjenjuje pomoću omjera koncentracije kreatinina u dijalizatu i plazmi, i kako se oni mijenjaju tokom jedne godine praćenja. Metode: šezdeset pacijenata na kontinuiranoj ambulatornoj peritonealnoj dijalizi (CAPD) (52% žena, 48% muškaraca), starosti 56,63 ±15,06 godina, bilo je podijeljeno u grupu sa kratkoročnim liječenjem peritonealnom dijalizom koja se definira sa trajanjem peritonealne dijalize između 1. i 12. mjeseci i dugoročnim peritonealnim bolesnicima sa trajanjem liječenja peritonealnom dijalizom >12 mjeseci. Za analizu brzine transporta kroz peritoneum, rastvorenih supstanci male molekulske težine korišten je peritonealni funkcionalni test (PFT) od firme Fresenius Medical Care. Uzorci za određivanje interleukina-6 u dijalizatu dobiveni su iz noćne 152 porcije dijaliznog efluenta. Dijalizat IL-6 određivan je korištenjem automatizirane imunohemiluminiscentne metode. Vrijednosti su prikazane kao srednja vrijednost ± standardno odstupanje ili kao medijana (interkvartilni rang). Upareni Student’s t-test je korišten za nezavisne uzorke u cilju procjene postojanja razlika između grupa ili Wilcoxon test rangova primjenjen je za uporedbu dobijenih rezultata na ponovljenim mjerenjima između osnovne i 1-godišnje procjene. U analizama korelacija (između rezultata laboratorijskih analiza i ishoda) primjenjen je Spirmanov (Spearman) koeficijent rank korelacije ρ (rho). Za uporedbu razlika između grupa korišten je Man-Vitnijev U (Mann Whitney U). Rezultati: IL-6 u dijalizatu kod bolesnika liječenih kraće (≤ 12 mjeseci) kretao se od 14,95 pg/ mL do 16,05 pg/mL, a omjer kreatinina u dijalizatu i plazmi D/P od 0,64 do 0,67. Bolesnici sa dužim dijaliznim liječenjem ( >12 mjeseci) imali su dijalizni IL-6 27,90 pg/mL - 26,0 pg/mL, a D/P kreatinina 0,65 - 0,70. Bila je izražena jako pozitivna korelacija između dijaliznog IL-6 i D/P kreatinina u pacijenata na peritonealnoj dijalizi ≤ 12 mjeseci na početku (rho= 0,373; p<0,05) i nakon godinu dana (rho =0,442; p<0,05), ali ne i kod pacijenata liječenih CAPD-om dužeg INTRODUCTION Peritoneal dialysis (PD) has been a successful form of renal replacement therapy for more than 20 years (1,2). Although peritoneal dialysis has proven its utility in renal replacement therapy (RRT) there are still several unsolved problems which reduce the greater acceptance of PD (3). However, peritonitis remains the major cause of acute drop-out from PD, resulting in considerable morbidity and transfer for haemodialysis. Severe or recurrent episodes of peritonitis and bioincompatible factors of the dialysis solutions may lead to long-term changes in peritoneal function, leading to loss of ultrafiltration and inadequate solute clearance. The traditional solutions used for PD are effective for dialysis, but all are acidic and lactate buffered, and all contain glucose as the osmotic agent, leading to hyperosmolality and to the presence of reactive glucose degradation products. Functional studies have shown that solute transport and peritoneal surface area appear to increase in parallel with the duration of PD (4,5,6). The increased diffusive transport of small solutes leads to rapid glucose absorption and loss of the osmotic driving force, resulting in decreased net ultrafiltration. High peritoneal permeability has been regarded as a risk factor predicting both technical failure and high mortality rate (7). The transport of fluid and solutes varies between different patients and also within an individual with time. Inflammatory changes are often seen in the peritoneum, even in the absence of peritonitis, indicating that the peritoneum of a PD patient may be chronically inflamed (5). Cytokines orchestrate the inflammatory response, and available data suggest that Interleukin-6 (IL-6) is a central regulator of the inflammatory process (8). Interleukin-6 (IL-6) is a multifunctional protein produced by wide array of cells such as lymphoid and non-lymphoid cells and by normal and transformed cells, including T cells, monocyte/ macrophages, fibroblasts, mesothelial cells and vascular endothelial cells (9). Smooth muscle cells in the tunica media of many blood vessels also produce IL-6 as a pro-inflammatory cytokine. IL-6 is one of the most important mediators in the acutephase response, which makes it an interesting protein in the early diagnosis of inflammation. Effluent IL-6 may be an excellent marker S. Unčanin trajanja (>12 mjeseci). Zaključci: naši rezultati su pokazali da se intraperitonealna upala, koja je procijenjena mjerenjem IL-6 u dijalizatu povećala sa dužinom liječenja peritonealnom dijalizom. Brzina transporta kroz peritoneum (PSTR), za rastvorene supstance male molekulske težine, takođe je porasla tokom vremena provedenog na peritonealnoj dijalizi. PSTR za rastvorene supstance male molekulske težine je povezana sa dijaliznim IL-6, samo u ranoj fazi liječenja PD-om, dok u toku perioda praćenja nije dokazana povezanost kod pacijena koji se dugoročno liječe PD-om, što ukazuje da upala ne mora direktno biti povezana sa visokim transportnim karakterstikama peritoneuma, koje se razvijaju nakon dugogodišnjeg liječenja peritonealnom dijalizom. Upala može bar djelimično biti povezana sa povećanjem brzine transporta kroz peritonealnu membranu za rastvorene supstancije male molekulske težine, a to opet može doprinijeti pojavi pacijenata sa visokim transportnim karakteristikama pritonelne membrane. Ključne riječi: upala, interleukin-6, dijalizat, brzina peritonealnog transporta for peritoneal inflammatory status and mesothelial cell activation in PD patients. Especially, because an increase is present in effluent IL-6 concentrations shortly before the onset of and during peritonitis, suggesting its local production and reflecting an intraperitoneal inflammatory state (10). Finally, inflammatory changes of the peritoneum are observed even before the initiation of PD treatment (11), suggesting that systemic factors related to uremia may, at least in part, be responsible for histological and functional changes of the uremic peritoneum. It has been speculated that increased levels of intraperitoneal pro-inflammatory cytokines such as interleukin -6, may contribute to high peritoneal small-solute transport rate (PSTR) in continuous ambulatory peritoneal dialysis (CAPD) patients. Purposes of this study was to evaluate possible relationships between dialysate IL-6 levels and PSTR of small solutes using the dialysate-to-plasma ratio (D/P) of creatinine, and to establish how they change during one year of follow-up. MATERIALS AND METHODS Sixty CAPD patients (52%F vs. 48% M), aged 56,63 ±15,06 years were divided into a short-term and a long-term PD group, where short-term related to patients with a PD duration between and 12 months, and a long-term patients to those with a PD duration of > 12 months. The clinical characteristics were retrieved from patients’ files. Exclusion criteria were the presence of systemic inflammatory disease (e.g. vasculitis, disseminated neoplasia) or peritonitis in 4 weeks prior to, or after the evaluation. All patients were treated with conventional glucose-based PD fluids, with an early evaluation peritoneal solute transport rate (PSTR) of small solute (within 1 month after start of PD), and a follow-up evaluation after about 1 year. For the analysis of peritoneal solute transport rate (PSTR) of small solute the peritoneal functional test (PFT) (Fresenius Medical Care) was used. This computer program was used to provide data on renal function, total Kt/V urea, creatinine clearance, water balance and transport parameters, as well as on nutritional state (12). During the PFT all patients were on CAPD and The importance of intraperitoneal interleukin-6 in peritoneal solute transport rate in continuous ambulatory peritoneal dialysis patients RESULTS No significant differences between the two groups of patients were noted in any of the measured parameters except according to duration of active treatment. Table 1 shows the patient demographics and clinical parameters as taken at the entry into the clinical study. Table 1 Baseline demographics of the patients. CAPD ≤ 12 months (n=30) Sex (male vs. female) (n) Age (years) PD duration (months) CAPD > 12 months P 0,3014 (n=30) 17/13 12/18 53.63 ± 14.44 59.63 ± 15.32 0,1239 5.43 ± 3.08 40.67 ± 19.04 <0,0001 Body mass index (kg/m2) 24.50 ± 3.46 25.91 ± 4.01 0,1516 Primary renal disease CAPD ≤ 12 months CAPD > 12 months P Diabetic nephropathy 17 14 0.6054 Hypertensive nephropathy 4 5 1.0000 Glomerulonephritis 0 2 0.4915 Obstructive nepropathy 0 1 1.0000 Polycystic kidney disease 1 2 1.0000 Other 8 6 0.1804 There were significant differences in dialysate IL-6 levels in patients treated by CAPD longer than 12 months [27,90 pg/mL (range 22,20 - 77,80 pg/mL) ], compeered with new peritoneal dialysis patients [14,95 pg/mL (range 10,28 - 21,80 pg/mL), p<0,001], at baseline and 1 year later [26,0 pg/mL (range 14,60 - 67,80 pg/mL) vs. 16,05 pg/mL (range 11,10 - 21,50 pg/mL), p<0,05], dispite significantly decreasing dialysate IL-6 levels, in the group of patients treated by CAPD longer than 12 months, at the end of the study. Figure 1 shows the results of the effluent concentration of IL-6 during the one year follow-up. All values mean ±SEM Interleukin-6 in dialysate showed no direct correlation with PD duration and number of previous episodes of peritonitis, but dialysate IL-6 was highly correlated with comorbidity (p<0,001), and inversely correlated with serum albumin (p<0,05 ) in the total study population. 400 350 . CAPD ≤ 12 months 300 . CAPD >12 months 250 200 P1<0.0001 P2=0.0545 150 100 50 0 DI IL-6 bbdijaliGbasa12 dijaliz 1 G13 DI IL-6 dijaliz 2 G25 b Baseline 1Year Figure 1 Interleukin-6 (IL-6) concentration in dialysate during the one year follow-up. In patients treated with CAPD less than 12 months, IL-6 in dialysate was correlated positively with age (r=0,680, p<0,001), at baseline and 1 year later, BMI (r=0,47, p<0,01) at baseline, but not in patients treated by CAPD longer than 12 months. Dialysate IL- 6 levels were significantly and inversely correlated with residual renal function (RRF) (r= - 0,543, p<0,001) at the beginning, in long term patients during the one –year follow-up (r= -0,363, p<0,05). Table 2 shows correlation of patient characteristics by dialysate interleukin-6. IL -6 in dialysate (pg/ml) used five exchanges of 1,5-2 L glucose-containing dialysis solution at standardized intervals. The glucose concentrations varied according to the standard program of the individual patents. Samples for determination of dialysate interleukin 6 (IL-6) were obtained from overnight dialysate effluent. Dialysate IL-6 was determined using an automated immune-chemiluminescence method. Values are presented as mean ± standard deviation or as median (interquartile range), unless otherwise specified. Paired Student’s t-test or Wilcoxon signed ranked test were used to compare the differences between baseline and 1- year evaluations, and Spearman rank correlation test was used for skewed variables. Differences between the groups were evaluated by using the Mann-Whitney test. Statistical analyses were performed by using the Statistical Package Med Calc for the Windows (version 12.6.1.0; MedCalc Software, Mariakerke, Belgium). 153 Table 2 Correlation of patient characteristics by dialysate interleukin-6 (IL-6). Baseline 1Year I group II group I group II group variables (CAPD≤12 months) (CAPD>12 months) IL-6 dialysate IL-6 dialysate Age 0,246 0,458** 0,285 0,680** 0,212 0,330 -0,089 Body mass index 0,477** 0,092 0,060 0,277 -0,089 PD duration Diabetic nephropathy 0,240 0,408* -0,124 0,218 0,758** 0,525** 0,564** 0,594** Comorbidity 0,031 0,076 0,233 0,249 Peritonitis Albumin -0,420* -0,423* -0,369* -0,391* -0,363* -0,328 -0,543** -0,058 RRF *p<0,05; **p<0,001; RRF-residual renal function The associations between dialysate-to-plama ratio (D/P) creatinine, and intraperitoneal Il-6 are presented in Figure 2 and 3. There were a strong positive correlations between dialysate IL-6 and D/P creatinine in patients on peritoneal dialysis for less than 12 months, at baseline (r= 0,373; p<0,05) and after 1 year (r =0,442; p<0,05), but not in patients treated by CAPD longer than 12 months. 154 S. Unčanin 140 = 0,373 p = 0,0033 Table 3 Dialysis adquacy and caracteristics of the peritoneal membrane during the one year follow-up. Baseline 120 IL -6 in dialysate (pg/ml) I group 100 (CAPD≤12 months) II group (CAPD>12 months) 1Year p I group II group 80 D/P crea 0,641±0,130 0,654±0,141 0,673 0,674±0,141** 0,705±0,13†† 60 Total urea Kt/V (/week) 2,04±0,598 1,74±0,363 0,041 40 PD crea clearance (L/1,73m2 weekly) 41,36±15,88 40,66±8,319 0,807 20 0 0.4 0.5 0.6 0.7 0.8 0.9 D/P Figure 2 Relationship between interleukin-6 (IL-6) and dialysate-to-plasma ratio (D/P) of creatinine in short –term patients at baseline. 1,96±0,398 1,75±0,22 p 0,318 0,007 41,73±12,14* 44,29±7,25†† 0,790 Total crea clearance 85,18±34,30 62,77±36,102 0,0018 75,36±23,16** 62,91±28,59 (L/1,73m2 weekly) 0,008 nPCR (gr/24h) 0,70±0,264 0,67±0,150 0,9823 0,74±0,234* 0,74±0,17† 0,544 D/P=dialysate-to-plasma ratio creatinine; Kt/V = total weekly clearance urea (peritoeal+residual renal); Crea= creatinine; nPCR-normalise catabolic rate *p<0,05- statistically significant to compare values in the first group at beginning and the end of study, **p<0,001- statistically significant to compare values in the first group at beginning and the end of study, † p<0,05- statistically significant to compare values in the second group at beginning and the end of study, †† p<0,001- statistically significant to compare values in the second group at beginning and the end of study. All values mean ±SEM DISCUSSION 140 = 0,442 p = 0,0144 IL -6 in dialysate (pg/ml) 120 100 80 60 40 20 0 0.4 0.5 0.6 0.7 D/P 0.8 0.9 1.0 Figure 3 Relationship between interleukin-6 (IL-6) and Dialysate-to-plasma ratio (D/P) of creatinine in short –term patients after 1 year. There were no significant changes in membrane characteristics evulated using dialysate–to plasma ratio (D/P) of creatinine in patients on peritoneal dialysis for less than 12 months compared to patients treated by CAPD longer than 12 months at baseline and after 1 year. Dialysate–to plasma ratio (D/P) of creatinine increased over the time, in both groups of patients, in the first group (0,641±0,130 vs. 0,674±0,141, p<0,001) and in the second group (0,654±0,141 vs. 0,705±0,13, p<0,001). At the same time, there was a significant decrease in the parameters of dialysis adequacy (total weekly Kt/V urea and total weekly creatinine clearance) between the first and the second group in CAPD patients at the beginning and at the end of the study. In both groups, nPCR increased significantly during the follow-up, but it did not show any significant differences compared to each other. The measurements of dialysis adequacy, PSTR of small solute and nutritional status are shown in Table 3. Despite the improvement in solution delivery systems and dialysis solutions, the long-term use of PD is often limited due to reduction of the ultra filtration and solute clearance capacity of the peritoneal membrane. Previous studies have shown that solute transfer increases and ultra filtration declines along with time on peritoneal dialysis (13,14). In our one-year follow–up study significant changes in dialysis-related parameters were found. The peritoneal solute transport, which was evaluated by using the dialysate-to-plasma ratio (D/P) of creatinine, increased over the time in all included patients. Dialysate IL-6 levels were significantly higher in long-term patients compared to short term patients despite significantly decreasing dialysate IL-6 levels in the group of patients treated by CAPD longer than 12 months during the evaluation. There were a strong positive correlations between peritoneal solute transport rate (PSTR) of small solute and dialysate interleukin-6 (IL-6 ) in short term patients. The results of this evaluation indicated that intraperitoneal inflammation increased in patients treated with conventional glucose-based PD solutions during the first year of PD, and that intraperitoneal inflammation could be interrelated with PSTR of small solute. In our study, the association between dialysate IL-6 and PSTR in patients treated by CAPD longer than 12 months, as opposed to the early asociation between dialysae IL-6 and PSTR, hypothetically suggests that transition in cytokine effluent production may reflect two distinct phases in the intraperitoneal inflammatory response, specifically an early (neutrophil mediated) and late (mononuclear leukocyte mediated) phase, which may reflect a resolved inflammation process. However, to confirm this hypothesis, it will be necessary to perform cytokine measurements during active inflammation (i.e. during peritonitis) (15,16). PSTR of small solute was related to interleukin-6 (IL-6 ) only in the early phase of PD treatment, indicating that inflammation may not by directly linked to the high PSTR that develops after long term perioneal dialysis. The increased PSTR (based on small solute transport) may indicate different mechanisms of solute transport, depending on the moment it is evaluated. Our results support the hy- The importance of intraperitoneal interleukin-6 in peritoneal solute transport rate in continuous ambulatory peritoneal dialysis patients pothesis that there may exist two distinct types of high transporters, specifically the early inherent high transporter (associated with high comorbidity, inflammation and protein leakage) and late acquired high transporter (not associated with comorbidities, inflammation and protein leakage) (17). The fall in residual renal function was obvious, and inversely correlated with dialysae IL-6 levels. It could be compensated, by increasing the delivered PD dose, which included increasing the glucose concentrations of the conventional dialysis solutions to the treatment. Nutritional problems were common among PD patients (18). They could be caused by poor appetite, inadequate food intake, insufficient dialysis, and protein loss though the peritoneal membrane. The role of inflammation in connection with malnutrition and atherosclerosis has been recognized only in recent years (19). Low albumin is a strong predictive factor for mortality in CAPD (20). Thus, it seems unlikely that inadequate dialysis would have caused deterioration of the nutritional status. In the present study, dialysate IL-6 was highly inversely correlated with serum albumins in the total study population. Interleukin-6 in dialysate showed high positive correlation with comorbidity in all peritoneal dialysis patients. Thus, even if the soluble factors in the dialysate are mainly produced locally, dialyste IL-6 seems to reflect also systemic inflammation, which may play a role in the decline of albumin concentrations, as a marker of deteriorating nutritional status (18, 19, 20). In short term patients, IL-6 in dialysate was correlated positively with age and body mass index (BMI). Some recent reports assume that low grade inflammation was associated with obesity (21). CONCLUSION In summary our findings indicate that intraperitoneal inflammation, evaluated by measuring IL-6 in dialysate, increased over the time on peritoneal dialysis. Peritoneal solute transport rate (PSTR) of small solute also increased over the time. PSTR of small solute was related to interleukin- 6 (IL-6 ) only in the early phase of PD treatment, but in the follow up evaluation no associations were observed, indicating that inflammation may not by directly linked to the high PSTR that develops after long term perioneal dialysis. The increased PSTR (based on small solute transport) may indicate different mechanisms of solute transport, depending on the moment of evaluation. In conclusion, inflammation may, at least partly, be linked to development of high PSTR, and this may contribute to the high transport PD patients. Our observations need to be confirmed in prospective studies, performed on a large number of patients, before definitive conclusions can be drawn. Conflict of interest: none declared. REFERENCES 1. Tokgoz B. Clinical advantages of peritoneal dialysis. Perit Dial Int. 2009;29(2):59–61. 2. Choi JY, Park SH, Kim CD, Cho JH, Kim YL. Clinical outcomes by dialysis modality in patients with end stage renal disease. J Korean Med Assoc. 2013;56(7):569-575. 3. Krediet RT. 30 years of peritoneal dialysis development: the past and the future. Perit Dial Int. 2007; 27(2):35-41. 155 4. Kendrick J, Teitelbaum I. Strategies for Improving Long-Term Survival in Peritoneal Dialysis Patients. CJASN. 2010;5(6):1123-1131. 5. Struijk DG. Monitoring of the peritoneal membrane. Nephrol Dial Transplant. 2008;(4):29-35. 6. Johansson AC, Haraldsson B. Physiological properties of the peritoneum in an adult peritoneal in an adult peritoneal dialysis population over a three year period. Perit Dial Int. 2006;26:482-489. 7. Balasubramaniyam R, Nirmala VR, Yogesh V, Sethuraman R, Booma Devi S, Balakrishnan NM. Comparison of peritoneal transport characteristics at the second week and at six months of peritoneal dialysis commencement. Indian J Nephrol. 2013;23(5):346–350. 8. Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J.2001;15:43-58. 9. Devuyst O, Margetts PJ, Topley N. The patophysiology of the peritoneal membrane. J Am Soc Nephrol. 2010; 21(7):1077-1085. 10. Barreto LD, Krediet RT. Current status and practical use of effluent biomarkers in peritoneal dialysis patients. Am J Kidney Dis. 2013;62(4):823-833. 11. Williams JD, Craig KJ, Topley N, Von Ruhland C, Fallon M, Newman GR,et al. Morphologic changes in the peritoneal membrane of patients with rnal disease. J Am Soc Nephrol. 2002;13:470-479. 12. Gotch FA, Lipps BJ. PACK PD: a urea kinetic modeling computer program for peritoneal dialysis. Perit Dial Int. 1997;17(2):126-130. 13.Mujais S, Nolph K, Gokal R, Blake P, Burkart J, Coles G, et al. Evoluation and menagement of ultrafiltration problems in peritoneal dialysis. International Society for Peritoneal Dialysis Ad Hoc Committee on Ultrafiltration Menagment in Peritoneal Dialysis. Perit Dial Int. 2000;20(4):5-21. 14.Coffin F. Peritonal membrane structural and functional hanges during peritoneal dialysis. Semin Dial. 2008;21:258-265. 15.Oh KH, Jung JY, Mo Y, Song A, Lee H, Ro H, Hwang YH, Kim DK, Margetts P, Ahn C. Intraperitoneal interleukin-6 system is a potent determinant of the baseline peritoneal solute transport in incident pritoneal dialysis patients. Korean peritoneal dialysis patients. Nephrol Dial Transplant. 2010; 25:1639-1646. 16.Fortes PC, Versari PH, Stinghen AEM, Pecoits-Filho R. Controlling inflammation in peritoneal dialysis: the role of PD-related factors as potential intervention targets. Perit Dial Int. 2007;27(2):76-81. 17.Pecoits-Filho R, Stenvinkel P, Wang AY, Heimburger O, Lindholm B. Chronic inflammation in peritoneal dialysis: the search for the holy grail? Perit Dial Int. 2004;24:327-39. 18.Abdu A, Ladeira N, Naidoo S, Naicker S. The nutritional status of continuou ambulatory peritoneal dialysis patients at a Johannesburg hospital. SAJCN. 2011;24(3):150-153. 19. Rao P, Reddy GC, Kanagasabapathyb AS. Malnutrition-inflammation-atherosclerosis syndrome in Chronic Kidney disease. Indian J Clin Biochem. 2008;23(3):209–217. 20.Lambie M, Chess J, Donovan KL, Kim JL, Do JY, Lee HB, et al. Indipendet effects of sistemic and peritoneal inflammation on peritoneal dialysis survival. J Am Soc Nephrol. 2013;24:2071-2080 21.de Mutsert R, Grootendorst DC, Boeschoten EW, Dekker FW, Krediet RT. Is obesity associated with a survival advantage in patients starting peritoneal dialysis? Contrib Nephrol. 2009;163:124-131. Reprint requests and correspondence: Snežana Unčanin, MD, PhD Clinic of Nephrology Clinical Center University of Sarajevo Bolnička 25 71000 Sarajevo Bosnia and Herzegovina Phone: +387 61 245 604 Email:[email protected] Original article Medical Journal (2014) Vol. 20, No. 3, 156 - 158 Lymph node metastasis predictors for prostate cancer in patients with serum PSA values ranging 2-10ng/Ml Prediktori limfnih metastaza karcinoma prostate za vrijednosti PSA 2-10 Ng/Ml Benjamin Kulovac1*, Damir Aganović1, Alden Prcić1, Osman Hadžiosmanović1, Nermina Obralić2, Dženana Eminagić2 1 Clinic of Urology, Clinical Centar University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2 Clinic of Oncology, Clinical Centar University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT SAŽETAK The aim of this paper is to determine which clinical and biopsy parameters can predict prostate cancer lymph node metastasis for PSA values 2-10ng/ml, in the case of patients who underwent radical retropubic prostatectomy. Material and methods: 80 patients underwent retropubic radical prostatectomy with bilateral pelvic lymphadenectomy. By application of clinical biopsy and radiologic analysis all the patients were suspected to have organ confines disease. Each patient was subjected to transrectal ultrasound guided prostate biopsy, and number of biopsy cores was determined by using Wienna nomogram. Serum PSA, fpsa/tpsa, PSAD, number of positive biopsy cores, percent of positive biopsy cores, localization of positive biopsy cores, perineural invasion and biopsy Gleason score (GS) were evaluated. Results: out of 80 patients with PSA values 2-10ng/ml, 4 (5%) had lymph node metastasis. All patients with lymph node metastasis had biopsy Gleason score 7 and perineural invasion. Using multivariate regression analysis, as significant predictors of lymph node metastasis biopsy, GS and perineural invasion were determined. Conclusion: biopsy Gleason score and perineural invasion are statistically significant predictors of lymph node metastasis for PSA values 2-10ng/ml. Number, percent, and localization of positive biopsy cores are on the borderline of statistical significance. Cilj istraživanja je utvrditi koji klinički i biopsijski parametri mogu predvidjeti limfne metastaze karcinoma prostate za vrijednsoti PSA 2-10 ng/ml, kod pacijenta podvrgnutih radikalnoj retropubičnoj prostatektomiji. Materijal i metode: radikalnoj retropubičnoj prostatektomiji sa bilateralnom pelvičnom lifadenomektomijom je podvrgnuto 80 pacijenta za koje se kliničkim, biopsijskim, radiološkim analizima predvidjelo da se radi o organ-ograničenom tumoru. Biopsija prostate je uređena pod kontrolom transrektalnog ultrazvuka, broj biopsijskih uzoraka je određen pema Vienna nomogramu. Evaluirani su serumski PSA, fpsa/tpsa, PSAD, broj pozitivnih biopsija, procenat pozitivnih biopsija, lokalizacija pozitivnih biopsija, perineuralna invazija, biopsijski Gleason score (GS). Rezultati: od 80 pacijenta sa vrijednsosti PSA 2-10 ng/ml, 4 (5%) pacijenta su imala limfne metastate. Pacijenti sa limfnim metastazama su svi imali biopsijski GS 7 i perineuralnu invaziju. Multivarijatnom regresijskom analizom kao značajni prediktori limfnih metastaza su biopsijski GS i perineualna invazija. Zaključak: biopsijski GS i perineuralna invazija su statistički značajni preditkori limfnih metastaza za vrijednosti PSA 2-10 ng/ml. Broj pozitivnih biopsija, procenat pozitivnih biopsija, lokalizacija pozitivnih biopsija su na granici statističke signifikantnosti. Key words: prediction, lymph node metastasis, prostate cancer, radical prostatectomy, PSA Ključne riječi: predikcija limfnih metastaza, karcinom prostate, radikalna prostatektomija, PSA INTRODUCTION more than half of the patients have a locally advanced disease or metastasis at the time of the disease detection. Pathological treatment of surgically removed regional lymph nodes is the only method which can provide us with 100% accurate answer on the current condition regarding lymph node metastasis. Patient with lymph node metastasis are facing poor prognosis. Identification rate of prostate cancer lymph node metastasis has lower values after introducing serum PSA. Detection rate of lymph node metastasis in the 1970-1980 period was 20-60%, while in the current data lymph node metastasis rate is 1-9%, depending on PSA and biopsy GS values. Various author’s Prostate carcinoma is one of the most commonly diagnosed malignancies in men; in the US it is the second cause of death. Recently, we have had a dramatic increase in new tumor discovery. It could be related to introduction of new, more sensitive detection methods, but also to an increase of incidence. Aside from huge incidence, the disease is characterized by different biological activity, and often unpredictable development, which presents a dilemma for clinicians regarding which therapeutic modality should be used. The fact is that Lymph node metastasis predictors for prostate cancer in patients with serum PSA values ranging 2-10ng/Ml normograms are recommended and are being used to predict prostate cancer lymph node metastasis, which are based upon different parameters. Pavlin’s tables are most frequently used (1-5). MATERIALS AND METHODS In the period of 30 months, 80 patients with PSA values 2-10ng/ ml treated at the Clinic of Urology of the Clinical Center University of Sarajevo (CCUS) were submitted to radical retro-pubic prostatectomy with bilateral lymphadenectomy. Patients diagnosed with prostate cancer after a trans urethral prostate resection and the patients who received hormonal therapy, were not included in the study. Number of biopsy samples was determined according to Vienna normogram with arithmetical mean 11 (randomizing from 8-16 samples). Biopsy samples were taken under TRUS control from the peripheral prostate zone and singly numbered in biopsy containers. Localization of positive samples, length of the tumor in the sample, percentage of positive biopsies and number of positive biopsies, GS in each positive sample, and the presence of perineural invasion were analyzed. Sample of prostate and lymph nodes obtained after surgical procedure was histologically processed at a definitive stage (T stage) as well as the lymph node metastasis presence (N stage). Serum values of PSA, FPSA/TPSA and PSAD were analyzed. RESULTS Table 1 Clinical and pathological characteristics of pa- tients with lymph node metastasis. Parameters Patient 1 Patient 2 Patient 3 Patient 4 Serum PSA ng/ml 9.0 9.8 8.9 9.5 R FPSA/TPSA 0.014 0.012 0.019 0.007 PSAD 0.21 0.28 0.24 0.18 GS biopsy 7 (4+3) 7 (4+3) 7 (4+3) 7 (4+3) not verified verified verified Peri-neural invasion verified 3 b 2 b 2 b 4 b Localization of 1c 1c 1c 1c positive samples 1a 1a 1a 1a Number of positive 5 4 4 6 samples Percentage of 31% 37% 66% 37% positive biopsies Tumor length in 1/2 of sample 1/2 of sample 1/2 of sample 2/3 of sample samples DRP pos. pos. pos. pos. TRUS isoechoic. hypoechoic. isoechoic. hypoechoic. Prostate volume 75 40 35 55 Tumor clinical stage G2T2b,mo,no G2T2b,mo,no G2T2b,mo,no G2T2b,mo,no Tumor histological G2T2c,mo,n1 G2T2c,mo,n1 G2T2c,mo,n1 G2T2c,mo,n1 stage GS prostate sample 7 (4+3) 7 (4+3) 7 (4+3) 7 (4+3) Table 1 shows clinical-pathological characteristics of the patients with verified lymph node metastasis. It is important to highlight the fact that in biopsy sample perineural invasion was verified in the patients. Digitorectal examination was positive in all four patients and they all had positive samples basally, centrally and apically, and they all had GS 7 (4+3). Serum PSA was within the range from 9.0 to 9.8 ng/ml, FPSA/TPSA ratio within the range from 0.007 to 0.19, number of positive biopsies was within the range 4-6, percentage of positive biopsies within the range 31-66%, tumor length in the sample of three patients was one half of the sample length and in on patient two thirds of the sample length. By using TRUS (trans rectal 157 ultrasound) in two patients one hypo echoic and one isoechoic mass was found, and a hyperchoic mass was found in the two remaining patients. In three patients with verified lymph node metastasis, T2b clinical stage of the disease was determined, and one patient had G2T2c disease stage. Average prostate volume was in the range from 35 to 75 gr. Lymph node metastasis were verified in 4 (5%) patients. Table 2 Regression correlation analysis of independent variable of lymph node metastasis in relation to a set of dependent variable predictors. t Sig. Unstandardized Coefficients Standardized Coefficients B Std. Error Beta ,427 ,671 ,389 ,166 (Constant) Age ,128 1,075 0,29 ,006 ,005 ,125 ,987 0,33 ,013 ,013 PSA ,120 ,891 0,37 ,555 ,494 PSA/ratio Primary biopsy ,006 ,020 0,98 ,100 ,002 grade GS Secondary biopsy -,576 -1,551 0,12 -,172 ,111 grade GS Gleason score ,830 1,440 0,04 ,109 ,157 of positive Number ,201 ,633 ,530 ,059 ,037 biopsies Tumor length in -,037 -,301 ,76 ,047 -,014 samples Basal tumor -,216 -,986 0,33 ,054 -,054 localization Central tumor -,069 -,387 0,70 ,055 -,021 localization Apical tumor ,065 ,411 0,68 ,063 ,026 localization DRP -,078 -,545 0,58 ,088 -,048 TRUS ,094 ,832 0,40 ,032 ,026 ,324 2,449 0,02 ,069 Peri-neural invasion ,169 G stage biopsy -,174 -1,088 0,28 ,087 -,095 T stage biopsy ,232 1,529 0,13 ,044 ,067 ,140 1,028 0,30 ,002 ,002 Prostate volume G stage ,189 1,076 0,29 ,095 ,102 Histological Histological T stage ,091 ,559 ,57 ,044 ,025 PSAD ,067 ,529 ,59 ,357 ,189 of Percentage ,132 ,660 ,31 ,004 ,002 positive biopsies By using multivariate regression analysis of twenty predictors, biopsy GS (p<0.04) and peri-neural invasion (p<0.02) variables were confirmed to be statistically significant predictors. Peri-neural invasion with beta coefficient is 0.169, t-test 2.44, p<0.02. Gleason score with beta coefficient is 0.257, t-test 1.44, p<0.04, are variables with statistically significant correlation (p<0.05). In the statistical data processing Windows SPSS 12 program was used. Multivariate regression analysis method was used to determine significant predictors of lymph node metastasis, on the level of statistical significance. DISCUSSION Lymph node metastasis presence (N+) in patients with prostate cancer is a weak prognostic factor. Until 1980 incidence of lymph node metastasis was in the range between 20-60% and after introducing PSA this number decreased significantly (2.7-9%). Before the operational procedure, it is important to monitor all clinical and biopsy parameters in order to more accurately assess the condition of lymph node metastasis and undertake adequate therapeutic measures. Various authors regard patients with PSA<10 ng/ml and GS<6 as low risk patients for lymph node metastasis and question the need 158 for pelvic lymphadenectomy. But, a different approach prevails, which implies that pelvic lymphadenectomy is inseparable part of the radical prostatecomy surgical procedure and should be performed regardless of the PSA and biopsy Gleason score values. Pelvic lymphadenectomy is important in determining the stage, and has a huge influence on therapy selection as well. It is important to point out the fact that recent studies have shown that after performing an extensive pelvic lymphadenectomy, obturator region is not the first affected by prostate cancer lymph node metastasis. It is determined that 20% of patients did not have lymph node metastasis in lymph nodes removed by standard obturator region lymphadenctomy, but they were found after performing extensive pelvic lymphadenectomy. As it is important whether or not there are lymph node metastases, some authors also consider the number of affected lymph nodes to be important. Lengthy procedure and morbidity are reasons for not performing lymphadenctomy. Following Partin’s pioneer ideas of establishing a normogram which could predict spreading of prostate cancer, other authors developed normograms, by using different variables, to predict spreading of prostate cancer. In Partin’s tables the following parameters are used: serum PSA, biopsy GS values and clinical stage of the disease. Hamburg study indicates serum PSA and Gleason grade 4/5 as the most important predictors for lymph node metastasis McNeal et al. indicte to a close connection between tumor volume, Gleason grade 4/5 and the presence of metastasis. Houston study states the following statistically significant predictors for lymph node metastasis: clinical stage, Gleason score, positive basal biopsy samples, high percentage of tumor in positive biopsy sample and maximum tumor length in biopsy sample, while Gleason grade 4/5 was confirmed as a dominant independent predictor. Most of the existing normograms use preoperative serum PSA value, clinical stage and Gleason score as predictors of lymph node metastasis,. Cagiannos added lymph node invasion prevalence of value as the fourth statistically significant predictor of nodal metastasis. In this study 4 (5%) patients had lymph node metastasis, which was higher in comparison with American studies (2.7%), but much lower than in some other European studies (24%). It is important to mention that there has not been sufficient number of studies regarding the incidence of lymph node metastasis for PSA values from 2-10 ng/ml. In this study there were no metastases in patients with PSA 2-10 ng/ml for T1c stage. Out of the predictors used in this study lymph node metastasis with regression multivariate analysis, perineural invasion and biopsy GS were proved as significant lymph node metastasis predictors. Number of positive biopsies, percentage of positive biopsies, tumor length in positive samples and localization of positive samples are not statistically significant but still close to the border of statistical significance, and should be taken into consideration when predicting prostate cancer lymph node metastasis (6,7,8,9,10). CONCLUSION Biopsy GS and perineural invasion are statistically significant predictors of lymph node metastasis for PSA values 2-10 ng/ml. Number of positive biopsies, percentage of positive biopsies, and localization of positive biopsies are on the borderline of statistical significance. Benjamin Kulovac et al. Conflict of interest: none declared. REFERENCES 1. Smith JA Jr, Scardino PT, Resnick MI, Hernandez AD, Rose SC, Egger MJ. Transrectal ultrasound versus digital rectal examination for the staging of carcinoma of the prostate: results of a prospective multi-institutional trial. J Urol. 1999;157(3):902-06. 2. Vogt H, Wawroschek F, Wengenmair H, Wagner T, Kopp J, Dorn J, et al. Sentinel lymph node diagnostic in prostate carcinoma: I: Method and clinical evaluation. Nuklearmedizin. 2002;41(2):95-101. 3. Partin AW, Kattan MW, Subong EN, Walsh PC, Wojno KJ, Oesterling JE, et al. Combination of prostate-specific antigen, clinical stage and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA. 1997;277(18):1445-51. 4. Briganti A, Chun FK, Salonia A, Zanni G, Scattoni V, Valiquette L, et al. Validation of a nomogram predicting the probability of lymph node invasion among patient undergoing radical prostatectomy and an extended pelvic lymphadenectomy. Eur Urol. 2006;49(6):1019-26; discussion 1026-7. 5. Wickermann D, Wawroschek F, Harzmann R. Is there need for pelvic lymph node dissection in low risk prostate cancer patients prior to definitive local therapy? Eur Urol. 2005:47(1):45-50; discussion 50-1. 6. Cagiannos I, Karakiewicz P, Eastham JA, Ohori M, Rabbani F, Gerigk C, et al. A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. J Urol. 2003;17085):1798-803. 7. Poulakis V, Witzsch U, de Vries R, Emmerlich V, Meves M, Altmannsberger HM, et al. Preoperative neural network using of magnetic resonance imaging variable specific antigen, and gleason score prostate cancer recurrence after radical prostatectomy. Urology. 2004;46(6):1165-70. 8. Conrad S, Graefen M, Pichlmeier U, Henke RP, Hammerer PG, Huland H. Systematic sextant biopsies improve preoperative prediction of pelvic lymph node metastases in patients with clinically localized prostatic carcinoma. J Urol. 1998;159(6):2023-9. 9. Graefen M, Augustin H, Karakiewicz PI, Hammerer PG, Haese A, Palisaar J, et al. Can predictive models for prostate cancer patients derived in the United States of America be utilized in European patients? A validation study of the Partin tables. Eur Urol. 2003;43(1):6-11. 10. Walsh PC, Retik AB, Vaughan ED, James E, Cardino T. Campbell Urology. Philadelphia: W.B. Saunders Company, 2003:3003-223. Reprint requests and correspondence: Benjamin Kulovac, MD, PhD Clinic of Urology Clinical Center University of Sarajevo Bolnička 25 71000 Sarajevo Bosnia and Herzegovina Phone: + 387 33 298 146 Email: [email protected] Original article Medical Journal (2014) Vol. 20, No. 3, 159 - 162 Hormonal variations in correlation to the outcome of medicamentous abortion in the second trimester of pathological pregnancy Hormonske promjene u korelaciji sa ishodom medikamentoznog abortusa kod patoloških trudnoća u drugom trimestru Naima Imširija*, Lejla Imširija, Zulfo Godinjak, Edin Idrizbegović, Fatima Gavrankapetanović, Mohammad Abou El–Ardat, Rama Admir Clinic of Gynecology and Obstetrics, Clinical Center University of Sarajevo, Patriotske lige 81, 71000 Sarajevo, Bosnia and Herzegovina 1 *Corresponding author ABSTRACT SAŽETAK One of the daily problems in clinical practice is how to terminate pathologic pregnancy in the first and second trimester. It is necessary for a modern gynecologist to find the best, the safest and the most efficient way in accordance with the existing regulations. Surgical methods often lead to complications such as infections, part of embryo left inside the womb (incomplete abortion), and uterine perforation. The question is to what extent the new drugs (mifepristone, misoprostol) improve efficiency and safety of an abortion in the first and second trimester of pathological pregnancies in respect to current protocols, and to what extent they protect sexual health and reproductive ability of future mothers in later – healthy pregnancies. The study was conducted at the Clinic of Gynecology and Obstetrics of the Clinical Center University of Sarajevo. It included 90 patients with pathological pregnancies in the second trimester and was conducted over a two-year period. The aim of the study was to establish the efficiency of mifepristone and misoprostol in the patients in the second trimester of pathological pregnancy, and level of the hormones (βHCG, progesterone, prolactin, testosterone, E2, androstenedione, cortisol, FSH and LH) during and after the abortion. Results and conclusion: Success of medical abortion in combination with mifepristone and misoprostol in the second trimester was 100% (of which 76.7% related to complete and 23,3% to incomplete abortions), whereas frequency of the drug side effects and complications in the procedure itself was reduced to a minimum. A combination of 600 mg of mifepristone and 200 μg of vaginal misoprostol proved to be the most efficient, and the abortions in this group were the fastest with minimum side effects and complications. During the induced abortion the hormonal status of the patients was monitored (βHCG, progesterone, cortisol, prolactin, FSH, LH, E2, testosterone, androstenedione) and it was concluded that the highest hormone drop was registered in βHCG and progesterone, whereas selective drop was registered in other hormones except for pituitary gland hormones FSH and LH, which values remained unchanged during the induced abortion. The level of the hormone drop influenced the efficiency of the abortion. This study should result in introducing medical abortion in everyday practice of health institutions throughout Bosnia and Herzegovina. Jedan od svakodnevnih problema u kliničkoj praksi je kako prekinuti patološku trudnoću u prvom i drugom trimestru. Za savremenog ginekologa je neophodno da u skladu sa važećim propisima nađe najbolji, najsigurniji i najpoštedniji način. Hirurški metod nerijetko dovodi do komplikacija kao što su infekcije, zaostali dio embriona u uterusu (residua), pa i perforacija uterusa. Nameće se pitanje koliko novi lijekovi (mifepriston, mizoprostol) poboljšavaju efikasnost i bezbjednost abortusa u prvom i drugom trimestru kod patoloških trudnoća u odnosu na dosadašnje protokole, te u kojoj mjeri štite polno zdravlje i reproduktivnu sposobnost budućih majki u narednim – zdravim trudnoćama. Ispitivanje je provedeno u Kliničkom centru Univerziteta u Sarajevu na Ginekološko-akušerskoj klinici. U studiju je uključeno 90 pacijentica sa patološkim trudnoćama u drugom trimestru. Istraživanje je trajalo dvije godine. Cilj istraživanja je bio utvrditi efikasnost mifepristona i mizoprostola kod ispitanica sa patološkom trudnoćom u drugom trimestru trudnoće, te nivoe hormona (βHCG, progesteron, prolaktin, testosteron, E2, androstendion, kortizol, FSH i LH) u toku i nakon završenog abortusa. Rezultati i zaključak: uspješnost medikamentoznog abortusa u kombinaciji mifepristona i mizoprostola u drugom trimestru je iznosila 100% (od toga 76,7% kompletnih pobačaja, a 23,3% inkompletnih pobačaja), dok je učestalost nus pojava lijekova i komplikacija same procedure svedena na minimum. Kombinacija od 600 mg mifepristona i 200 μg vaginalnog mizoprostola se pokazala najučinkovitijom, te su abortusi u ovoj skupini bili najbrže završeni uz minimalne nus pojave i komplikacije. Tokom indukcije pobačaja praćen je hormonalni status ispitanica (βHCG, progesteron, kortizol, prolaktin, FSH, LH, E2, testosteron, androstendion) došlo se do zaključka da su najveći pad hormona imali βHCG i progesteron, dok su ostali hormoni selektivno padali, izuzev hormona hipofize FSH i LH čije se vrijednosti nisu mijenjale tokom indukcije pobačaja. Nivo pada hormona je uticao na efikasnost pobačaja. Ovakva studija bi trebala da uvede medikamentozni abortus u svakodnevnu praksu u bolničkim ustanovama širom Bosne i Hercegovine. Key words: misoprostol, mifepristone, hormonal status, abortion Ključne riječi: mizoprostol, mifepriston, hormonalni status, abortus 160 INTRODUCTION Pathological pregnancies constitute a serious problem in clinical practice. Abortions performed in the first and second trimester of pregnancy may jeopardize future mothers’ health and their reproductive ability. In the past thirty years modern gynecologists have intensified their efforts in finding the best, the most efficient and the safest way to end pathological pregnancies. Pregnancy termination in the second trimester is an even bigger problem for a modern gynecologist. Surgical methods have been rejected due to increased number of complications (hemorrhages, infections, part of embryo left inside the womb (incomplete abortion), uterine perforation and even death). Based on the USA data, the abortion mortality rate in the first trimester was 1,6 (per 100.000 abortions) (1-3). In the second trimester, with the application of surgical methods, it climbs to an unbelievable 14,9 % (per 100.000 abortions) (4). The introduction of prostaglandin made a revolution and surely contributed to safety and efficiency of an abortion in the second trimester for both the patient and the gynecologist. In 2004, the project related to use of misoprostol (synthetic analog of prostaglandin E1) was approved at our Clinic in combination with prepidil-gel (prosta-glandin E2) (5). In the parallel study conducted in 2007 it was proven that misoprostol was much more efficient, safer and more effective then prostin M-15 (prostaglandin F2α), which was routinely used by then. The study was conducted exclusively on pathological pregnancies. mifepristone is a 19-nor steroid with substitutions at position 11b by fenol group. Mifepristone is an antiprogestogen, antiglucocorticoid and a weak antiandrogen. Mifepristone’s relative binding affinity at the progesterone receptor is more than twice that of progesterone, its relative binding affinity at the glucocorticoid receptor is more than three times that of dexamethasone and more than ten times that of cortisol, and is a weak antiandrogen (6). In medical abortion it causes endometrial decidual degeneration, cervix softening and dilatation and release of endogenous prostaglandins and an increase in the sensitivity of the myometrium to the contractile effects of prostaglandins. Mifepristone induced decidual breakdown indirectly leads to trophoblast detachment, resulting in decreased syncytiotrophoblast production of hCG, which in turn causes decreased production of progesterone by the corpus luteum. The side effects are rather mild, described as nausea, vomiting, diarrhea and fever (7). Aim: the aim of this study is to show correlation in the hormone value during medical abortion in the second trimester of pathological pregnancies. MATERIALS AND METHODS The study was conducted at the Clinic of Gynecology and Obstetrics of the Clinical Center University of Sarajevo. It included 90 patients with pathologic pregnancies in the second trimester and it was conducted over a two-year period. 90 patients in the second trimester were divided in three groups of 30 patients. The first group of 30 patients in the second trimester diagnosed with fetus mortus in utero up to 24 weeks of gestation was given 600mg of mifepriston orally and we monitored if the miscarriage happened (complete or incomplete). If the patients did not miscarry within 48 hours, they were given 200 µg of misoprostol vaginally in intervals of 4 hours until the miscarriage, up to 5 doses. The second group of 30 N. Imširija et al. patients in the second trimester diagnosed with genetic anomalies of the fetus in the 20th week of pregnancy was given 600mg of mifepristone orally and we monitored if the miscarriage happened (complete or incomplete). If they did not miscarry within 48 hours they were given 200 µg misoprostol vaginally in 4 hour intervals until the miscarriage, up to a maximum of 5 doses. The third group of 30 patients was treated with prepidil-gel intracervically, and after 6 hours we started giving them 200 µg of misoprostol vaginally in 4 hour intervals until the miscarriage. This is a standard procedure applicable at our Clinic in the past eight years. If after the therapy the miscarriage in the study groups failed, we announced the induction to be unsuccessful. All the patients were hospitalized and subjected to clinical and laboratory tests (blood count, blood sugar, urine, urea, creatinine, APTT, INR, βHCG, progesterone, cortisol, testosterone, androstenedione, FSH, LH, E2 and prolactin). Following an explanation of the miscarriage the patients gave their consent and written approval. The above stated laboratory tests were done on three occasions: before the drug administration, 24 hours following the drug administration, and after the abortion. Determination of βHCG, progesterone, cortisol, testosterone, FSH, LH, E2 and prolactina was done in the Clinical Laboratory of the Clinical Center University of Sarajevo by chemiluminescent enzyme-immunological technique on the Vitroseciq Ortoclinic Diagnostic (Siemens) machine, and determination of androstenedione was done by the same technique on the Immulite (Siemens) machine. RESULTS Table 1 contains analyses of the average age of Group II patients and values are presented under sub-groups. The average age of this group was 29.67±5.47 years. The average age of Group I patients (patients in the second trimester diagnosed with foetus mortus in utero in 24th week of pregnancy) was 29.06±3.96 years, the average age of Group II sub-group patients (patients in the second trimester diagnosed with genetic fetus anomalies in the 20th week of pregnancy) was 28.43±4.91 years, and the average age of Group III sub-group patients (patients in the second trimester diagnosed with pathological pregnancy in the 20th week) was 31.53±6.81 years. Application of the ANOVA test proved that there was no statistically significant difference in the average age values between Group I sub-groups, F=2.796; p=0.066. Table 1 Average age of Group II patients. Groups N X SD SEM 95% CI Minimum Maximum Lower Upper 30 29,06 3,96 ,72 27,58 30,54 19,00 38,00 III 30 28,43 4,91 ,89 26,59 30,26 19,00 38,00 III 30 31,53 6,81 1,24 28,98 34,07 19,00 45,00 Total 90 29,67 5,47 ,57 28,53 30,82 19,00 45,00 The average gestation period during pregnancy termination was 17,21±2,88 weeks. The patients from Group III had the longest gestation period, 18,03±2,89 weeks, followed by patients from Group I, which was 17,76±3,21 weeks, whereas the patients from Group II had the smallest gestation, 15,83±2,40 weeks. The ANOVA test proved that there was a statistically significant difference in the length of gestation during pregnancy termination among the study groups, F=5.295; p=0.007 (Table 2). Hormonal variations in correlation to the outcome of medicamentous abortion in the second trimester of pathological pregnancy Table 2 Average gestation during pregnancy termination. X SD SEM 95% CI Minimum Maximum Groups N Lower Upper I 30 17,76 3,21 0,58 16,56 18,96 13,00 24,00 II 30 15,83 2,40 0,43 14,93 16,73 13,00 21,00 III 30 18,03 2,89 0,52 16,95 19,11 12,00 25,00 Total 90 17,21 2,99 0,31 16,58 17,83 12,00 25,00 Table 3 shows analysis of the hormonal status of the patients in the second trimester of pathological pregnancy before, during and after abortion. It appears that the values of βHCG, progesterone, prolactine, E2, testosterone and androstenodione statistically significantly dropped during the induction, whereas FSH and LH values remained unchanged during the induced abortion. Analysis of the mentioned hormones showed that Group I had a significant drop in hormones (patients in the second semester diagnosed with foetus mortus in utero in 24th week of pregnancy) in respect to Group II (patients in the second trimester diagnosed with genetic fetus anomalies in the 20th week of pregnancy). Table 3 Analysis of hormonal status during induced abortion. Hormone βHCG Cortisol Progesterone Prolactin Groups I II I II I II I II I Beginning 32174 31642 894,73 733,06 90,09 106,78 2338 1241 0,10 After 24 hours 24808 29027 866,96 655,13 67,28 89,86 2164 1039 0,10 End 7256 12629 451,76 448,96 16,40 73,78 2070 863 0,10 Result Drop Drop Drop Drop Drop Drop Drop Drop Unchanged FSH II 0,10 0,10 0,10 Unchanged LH I 0,10 0,10 0,10 Unchanged II 0,10 0,10 0,10 Unchanged E2 I 10,254 8,947 8,762 Drop II 9,914 9,355 8,454 Drop I 3,10 2,59 1,53 Drop Testosterone II 2,97 2,46 1,22 Drop Androstenodione I 13,92 13,15 9,77 Drop II 30,64 29,30 17,77 Drop Table 4 Relative risk of unsuccessful medical treatment of induced abortion (Group I and II). 2,2857 Relative risk 1,1016 to 4,7427 95% CI 2,220 z statistic P = 0,0264 Significance level NNT (Benefit) 3,333 95% CI 1,872 (Benefit) to 15,162 (Benefit) Analysis of the relative risk of unsuccessful medical treatment of induced abortion showed that the relative risk of abortion was 2.28 times higher in Group I (patients in the second semester diagnosed with genetic fetus anomalies in 20th week of pregnancy) with respect to Group II (patients in the second trimester diagnosed with foetus mortus in utero in 24th week of pregnancy). It was also established that the patients from Group I and II, who were treated by 161 a combination of mifepriston and misoprostol had more success in induced abortion and less side effects in respect to Group III patients induced with prostaglandins E2 and E1. DISCUSSION Modern methods of medication abortion are nowadays available to women in many countries in various types and protocols. Invention of synergistic effects of antiprogestins (mifepristone) and synthetic analogue prostaglandin E1 (misoprostole), on early pregnancy termination and on second trimester pregnancy termination influenced development of a new, highly effective and safe method of medicamentous abortion. Nowadays, there are established schemes of the drugs administration in various gestation periods provided by the World Health Organization, based on numerous studies conducted in this field. In France, medicamentous abortion is approved even up to seven weeks of gestation in home conditions. The Protocol related to medicamentous pregnancy termination in the period between weeks 9 and 12 of pregnancy is still under consideration, and for abortions in the second trimester there are several schemes in development. If an unwanted pregnancy occurs, it is necessary to provide women with the opportunity to choose this contemporary method of medicamentous abortion which has been the choice of approximately half of the women in the countries in which it is available (8-11). The success of this treatment has been described in world literature and it rates from 60-80 in respect to application of mifepristone alone and 96% in respect to application of mifepristone in combination with misoprostol (8). Misoprostol belongs to a group of drugs referred to as “prostaglandin analogs”. In fact, it is a synthetic drug similar to prostaglandin E1 (alprostadil). Misoprostol is a main ingredient of ciprostal which we used in our study. It causes uterus contractions and according to the world literature the pregnancy termination success is up to 96% (in our clinical study conducted in the period from 2004 to 2007 the success was 99%) (9). Similar to all other medicaments, in a small percentage misoprostol can cause side effects manifested in nausea, vomiting, diarrhea, dizziness, fever. In local application these symptoms are minimal and almost unnoticeable (10). During the induced abortion the patients were subjected to hormone level tests during, after and following the induced abortion. Analysis of the hormonal status proved that the highest drop was registered in hormone βHCG and progesterone, while other hormones registered selective drop 24 hours following the induced abortion and after completed abortion. Values of the pituitary gland hormones FSH and LH remained unchanged. Hormone values registered a statistically significant drop in the patients subjected to complete miscarriages. The success of medicamentous induced abortions in the second trimester was in direct correlation with the level drops of certain hormones; i.e. the higher the drop in hormone levels the shorter the induction. CONCLUSIONS Non surgical termination of pathological pregnancies in the first and second trimester has significant benefits in comparison to the surgical method. It contributes to reduction of complications (infections, bleeding, residua post abortum) and consequently to the reduction in cervix incompetence in future pregnancies, as well as to 162 N. Imširija et al. the reduction of side effects (bleeding, nausea, vomiting). Psychological aspects of fear in medicamentous abortion are considerably small. Hormonal status of the studied hormones (βHCG, progesterone, prolactin, testosterone, E2, androstenodion, cortisol) is in direct correlation with the efficiency of miscarriage, except for pituitary gland hormones FSH and LH, which values remained unchanged. Conflict of interest: none declared. REFERENCES 1. Agarwal M, Das V, Agarwal A, Pandey A, Srivastava D. Evaluation of mifepristone as a once a month contraceptive pill. Am J Obstet Gynecol. 2009;200(5). 2. Finer LB, Wei J. Effect of mifepristone on abortion access in the United States. Obstet Gynecol. 2009;114(3):623-30. 3. Koivisto-Korander R, Leminen A, Heikinheimo O. Mifepristone as treatment of recurrent progesterone receptor-positive uterine leiomyosarcoma. Obstet Gynecol. 2007;109(2 Pt2):512-4. 4. Winikoff B, Dzuba IG, Creinin MD, Crowden WA, Goldberg AB, Gonzales J, et al. Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial. Obstet Gynecol. 2008;112(6):1303-10. 5. Kapp N, Borgatta L, Stubblefield P, Vragovic O, Moreno N. Mifepristone in second trimester medical abortion: a randomized controlled trial. Obstet Gynecol. 2007;110(6):1304-10. 6. Erenbourg A, Piccoli M, Ronfani L, Tamburlini G. Mifepristone for the treatment of uterine leiomyomas: methodological issues and clinical implications.Obstet Gynecol. 2009; 113(3):741. 7. Imširija-Galijašević N. Obstetričke karakteristike pobačaja induciranih Misoprostolom: Magistarski rad. Sarajevo: Medicinski fakultet Univerziteta u Sarajevu, 2007. 8. El-Refaey H, Templeton A. Induction of abortion in the second trimestar by a combination of Misoprostol and Mifepristone, a randomized comparison between two Misoprostol regiments. Hum Reprod. 1995;10(2):475-8. 9. World health organization. Termination of pregnancy with reduced doses of Mifepristone. Br Med J. 1993;307:532-7. 10. Zhou W, Nielsen GL, Møller M, Olsen J. Short-team complications after surgically induced abortions: A register-based study of 56117 abortions. Acta Obstet Gynecol Scand. 2002;81(4):331-6. 11.Kapamadžija A, Vukelić J, Bjelica A, Kopitović V. Abortus lekovima - savremena metoda prekida trudnoće. Med Pregl. 2010;LXIII (1-2):63-67. Reprint requests and correspondence: Naima Imširija, MD, PhD Clinic of Gynecology and Obstetrics Clinical Center University of Sarajevo Patriotske lige 81 71000 Sarajevo Bosnia and Herzegovina Phone: + 387 33 250 250 Email: [email protected] Our contribution to the reduction of cardiovascular diseases in Bosnia and Herzegovina! Naš prilog redukciji kardiovaskularnih bolesti u Bosni i Hercegovini! Original article Medical Journal (2014) Vol. 20, No. 3, 163 - 166 The effect of smoking on the results of rehabilitation in patients after cerebrovascular accident Uticaj pušenja na rezultate rehabilitacije kod pacijenata nakon cerebrovaskularnog inzulta Senad Selimović1, Edina Tanović*2, Haris Tanović3, Ksenija Miladinović2 JZU Aquaterm Olovo, Bosnia and Herzegovina, 2Clinic of Physical Medicine and Rehabilitation, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 3Clinic of Abdominal Surgery, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina 1 *Corresponding author ABSTRACT SAŽETAK The research objectives are: to analyze the prevalence of smoking as risk factor in patients with cerebrovascular accident and to assess how this risk factor is affecting the outcome of rehabilitation. Propose measures and procedures that will result in better rehabilitation. Materials and methods: the study included a total of 116 patients diagnosed with cerebrovascular infarction admitted to the Department of Physical Medicine and Rehabilitation of the Clinical Center University of Sarajevo in a period of one year. We analyzed the gender and age distribution of patients, duration of rehabilitation, the prevalence of smoking risk factor and assessed the results of rehabilitation by Barthel Index at the beginning and at the end of rehabilitation in patients with and without this risk factor. Results: from the total number of patients, most patients were 31-40 years of age, the average age of the patients was 65.45 years, 49% of patients were male and 51% female. In 28% of patients rehabilitation lasted from 31 to 40 days, 22% had smoking as a risk factor. Patients who were smokers had worse results in the assessment of activities of daily living by Barthel Index at admission and at discharge as compared to those who did not have that risk factor (p<0.001). Conclusion: smoking as a risk factor in patients with cerebrovascular accident is very frequent and have direct impact on the poor outcome of rehabilitation. Therefore, in addition to other measures of secondary prevention, energetic struggle against the risk factors such as smoking is highly recommended. Ciljevi istraživanja su: analizirati zastupljenost pušenja kao riziko faktora kod pacijenata sa cerebrovaskularnim inzultom te procijeniti koliko ovaj riziko faktor utiče na rezultate rehabilitacije. Predložiti mjere i postupke koji će uticati na bolje rezultate rehabilitacije. Materijal i metode: istraživanje je obuhvatilo ukupno 116 pacijenata sa dijagnosticiranim cerebrovaskularnim inzultom primljenih na Kliniku za fizikalnu medicinu i rehabilitaciju Kliničkog centra Univerziteta u Sarajevu (KCUS) u periodu od jedne godine. Analizirali smo dob, spol, vrijeme provedeno na rehabilitaciji, učestalost rizikofaktora pušenja te procjenili rezultate rehabilitacije po Barthel indexu na početku i kraju rehabilitacije kod pacijenata sa i bez ovog rizikofaktora. Rezultati: od ukupnog broja pacijenata najviše oboljelih je bilo od 31-40 g. života, prosječna starost pacijenata je bila 65,45 godina, 49% oboljelih je muškog, a 51% ženskog spola. 28 % pacijenata je provelo od 31 do 40 dana na rehabilitaciji, 22 % je imalo pušenje kao rizikofaktor. U aktivnostima svakodnevnog života lošiji rezultati po Barthel indexu su bili i prijemu i na otpustu kod pacijenata koji su imali rizikofaktor pušenje u odnosu na one koji nisu imali taj rizikofaktor (p<0.001). Zaključak: rizikofaktor pušenje kod pacijenata sa cerebrovaskularnim inzultom je veoma učestao te direktno utiče na lošije rezultate rehabilitacije. Zbog toga se, uz ostale mjere sekundarne prevencije, preporučuje energična borba protiv ovog rizikofaktora odnosno loše navike kao što je pušenje. Key words: rehabilitation, cerebrovascular accident, Barthel Index Ključne riječi: rehabilitacija, cerebrovaskularni insult, Barthel index INTRODUCTION and that 20-30% of all stroke survivors are left dependent on others for everyday activities. Besides dramatically disrupting family life and environment of the patient, it is a big financial burden for the community. By the year 2020, it is expected that cerebrovascular accident, along with coronary heart disease will be the leading cause of “healthy life years” loss (6). Cerebrovascular accident is classified by etiology of focal brain damage, so we distinguish ischemic and hemorrhagic cerebrovascular accident (7). Knowledge of risk factors for cerebrovascular disease and their elimination or controlling is extremely important for reducing the incidence of stroke (8). There are two types of stroke related risk factors: risk factors that we cannot influence, and there are risk factors that we can influence (9). Risk factors that we cannot influence are: gender, age, race, ethnicity and heredity (3,10). Risk factors that can be modified are: Stroke is a neurological deficit that persists beyond 24 hours or is interrupted by death within 24 hours (1), the definition of the World Health Organization. Acute cerebrovascular accident (CVA) is the third cause of death and the leading cause of disability in the developed countries of the world: it is estimated that every 45 seconds one person suffers stroke, and every three minutes one person dies from the consequences of stroke (2,3,4). Cerebrovascular accident is a major cause of long term disability and has a huge emotional and socio-economic impact on patients, families and health care. Living expenses per patient with stroke are estimated at between $ 59,800 to $ 230,000 (5). It is estimated that approximately half of all stroke survivors returned to some kind of employment, 164 a) well documented risk factors: hypertension, diabetes, smoking, dyslipidemia, atrial fibrillation and other cardiac disorders; b) potential risk factors less documented: obesity, physical inactivity, diet, hyperhomocysteinemia, alcohol use and use of oral contraceptives (11,12,). Primary prevention of occurrence of stroke includes control and treatment of risk factors that can be modified. Secondary prevention is carried out after the occurrence of cerebrovascular stroke in order to prevent the re-occurrence of stroke. It includes more vigorous treatment of diseases and eliminating harmful habits such as smoking (13). The research objectives are: to analyze the prevalence of smoking as risk factor in patients with CVI and to assess how this risk factor is affecting the results of rehabilitation. Propose measures and procedures that will result in better rehabilitation. MATERIALS AND METHODS S. Selimović et al. The youngest patient on rehabilitation was 30 years old and the oldest was 86 years old. The average age of the patients was 65.45 years (stand. deviation 10.368). Analysis of gender distribution showed that cerebrovascular accident occurred in 49% of male and in 51% of female patients. Figure 2 Analysis of duration of rehabilitation. We conducted a retrospective study that included a total of 116 patients diagnosed with cerebrovascular infarction admitted to the Clinic of Physical Medicine and Rehabilitation of CCUS in the period of one year. The study was analytic-retrospective cohort study, based on retrospective analysis of data from the history of the disease. During data acquisition, processing and presentation of the tables, privacy of any patient was not compromised; first and last names were not cited anywhere, or initials of the target group. From the history of disease the following parameters were registered in the study: name, year of birth, time spent in rehabilitation, incidence of smoking as risk factor, Barthel index at admission and at discharge in patients with and without smoking risk factors. Assessment of activities of daily living by Barthel Index scores were grouped as follows: 0-4 (complete dependence), 5-8 (heavy degree of dependence), 9-12 (medium degree of dependence), 13-16 (light dependence) and 17-20 (independence). The majority of patien ts with cerebrovascular infarction 32 (28%) spent 31-40 days on rehabilitation at the Clinic for Physical Medicine and Rehabilitation. Statistical analysis Smoking is the third most frequent stroke risk factor besides diabetes mellitus and hypertension with a prevalence of 22% among patients included in this study. Results are displayed numerically, graphically and in tables with legends and text explanation of some of the obtained values of the variables. Statistical analysis was performed on the PC functions in SPSS v 21.0, MS Excel 2009th. Parametric data were analyzed showing the absolute value calculation to the percentage value, the arithmetic mean with obligatory calculation of the standard deviation, while non-parametric data was processed by chi-square test. Figure 3 Frequency of risk factor: smoking in patients with CVI. RESULTS Following the research the following results were obtained: Figure 1 Age distribution among patients. Figure 4 Analysis of ADL by Barthel Index at admission and risk factor of smoking. Table 4 shows the statistical analysis of the relationship Barthel index at admission and risk factor of smoking. Chi-Square df L evel of significance 37,552 1 P<0,001 The effect of smoking on the results of rehabilitation in patients after cerebrovascular accident Statistical analysis shows that there is a statistically significant difference between the Barthel index at admission and risk factor of smoking (Chi-Square: 37.552, P<0.001). Figure 5 Analysis of ADL by Barthel Index at discharge and risk factor of smoking. Table 5 Shows the statistical analysis of relationship be tween the Barthel index at discharge and risk factor of smoking. 37,552 Chi-Square df 1 L evel of significance P<0,001 Based on the tables and graphs of the data presented, as well as on the basis of the calculated chi-square test (37.552), where P<0.001, it is proven that there is a statistically significant correlation between the Barthel index at discharge and risk factors of smoking. DISCUSSION Stroke is a neurological disorder that suddenly occurs after which it can develop a variety of different clinical changes expressed in varying degrees. This disorder can end in death, but it can also leave a smaller or larger consequences. Depending on the level of damage, rehabilitation can be long and unpredictable (12,13). Treatment after stroke requires a multidisciplinary approach, engagement of a patient and family, and also large economic expenses. The study included 116 patients with stroke who were admitted on rehabilitation in a period of one year at the Department of Physical Medicine and Rehabilitation. We analyzed age distribution in patients as shown in Table 1. Youngest patient at admission was 30 years old and the oldest was 86 years old. The average age of the patients was 65.45 years (stand. deviation 10.368). This finding is consistent with data from the literature as well as with our previous research which states that persons over 65 years of age frequently suffer from stroke. Most patients were 31-40 years of age (35%), which is the active population. This population is the most productive both as part of the family and society. This data is not consistent with the data from the literature probably because the patients in this age group were more frequent rehabilitated in stationary conditions with the aim of faster and better rehabilitation and created the impression that most affected patients are of this age (14,15). 165 Analysis of gender distribution showed that 51% of patients who suffered from cerebrovascular accident were female, and there is no statistical difference in age distribution. This data differs from the research conducted 15 years ago stating that stroke was more frequent in male patients. For the majority of patients with cerebrovascular infarction, 32 (28%), rehabilitation lasted from 31 to 40 days. This period is longer than usual due to a more severe form of illness after a stroke which required longer rehabilitation. This data contradicts the data from the literature suggesting a shorter rehabilitation for patients in stationary conditions (16). Nowadays, shorter stationary treatment with continued rehabilitation at home and ambulatory program through CBR is recommended. In patients suffering from stroke, in our study, the risk factor of smoking was third most frequent after hypertension and diabetes mellitus. This risk factor was present in 22% of the patients. In our research conducted 15 years ago, this risk factor was the second most common, after hypertension, and was found in the range of 33-42% depending on the studied groups (12). Smoking is a risk factor that can be modified (17-22). Health promotion and primary prevention make this proportion lower, but still high because it includes almost one-fifth of respondents (23,24,25). Studies done in Iran have confirmed a similar representation of smoking as a risk factor (20%). It is believed that prevalence of smoking is affected by a number of factors such as tradition, education, environmental effects and family (26). Many studies have confirmed that this stroke risk factor associated with other risk factors leads to increased mortality, severe consequences upon the occurrence of stroke and longer rehabilitation with worse results (17,21). Figure 4 shows the activities of daily living at admission for both groups, those with risk factor of smoking and those without risk factor of smoking. Activities of daily living were assessed by Barthel Index. From this chart we can see that there are statistically significant differences between these two groups (p<000.1). Figure 5 shows the activities of daily living at discharge for both groups, those with risk factor of smoking and those without risk factor of smoking. The analysis showed that there was significantly statistical difference between these two groups (p<000.1) at discharge. When comparing the activities of daily living as shown in graphs 4 and 5, we see that there was a significantly higher index values between Barthel on admission and at discharge in patients who had no risk factor of smoking. Our previous studies have shown worse results of rehabilitation in patients with risk factor of smoking (13,17). In particular, we noticed the existence of risk factors in younger patients (27). It is believed that the primary and secondary prevention of risk factors needs to be improved especially when it comes to the factors that we can influence. Stop smoking programs are of great importance for primary care specialists. CONCLUSION Smoking as a risk factor in patients with CVA is very common (occurring in 22% of patients) and it directly affects the poor results of rehabilitation and the patient’s daily activities. Therefore, in addi- 166 tion to other measures of secondary prevention, energetic struggle against this risk factor is highly recommended. Conflict of interest: none declared. REFERENCES 1. World Health Organization. Cerebrovascular Disorders: a clinical and research classification (Offset Publications). [Online]. Available from: http://whqlibdoc. who.int/offset/WHO_OFFSET_43.pdf [Accessed 21th Decembar 2013] 2. Sarti C, Rastenyte D, Cepaitis Z, Tuomilehto J. International trends in mortality from stroke, 1968 to 1994. Stroke. 2000;31:1588-1601. 3. Murray CJL, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet.1997;349(9061):1269-76. 4. Zavod za javno zdravstvo FBiH. Zdravstveno stanje stanovništva i zdravstvena zaštita u Federaciji Bosne i Hercegovine 2012. godina. [Online]. Available from: http://www.zzjzfbih.ba/wp-content/uploads/2009/02/Zdravstveno-stanje-stanovnis%CC%8Ctva-i-zdravstvena-zas%CC%8Ctita-u-FBiH-2012.pdf [Accessed 20th Decembar 2013] 5. Stein J, Harvey R, Macko R, Winstein C, Zorowitz R. Stroke Recovery and Rehabilitation. New York: Demos medical publishing; 2009. 6.Kannel WB. Blood pressure as a cardiovascular risk factor. JAMA. 1996;275(20):1571-1576. 7. SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA. 1991;265(24):3255-64. 8. Dorndorf W, Marx P. Stroke Prevention. In: Louis R. Caplan (eds.) Caplan’s Stroke: A Clinical Approach. 4th ed. Philadelphia: Sounders Elsevier; 2009;581592. 9. Gorelick PB, Alter M. The Prevention of Stroke. Boca Raton, Fla: Parthenon Publishing Group, 2002. . In: Louis R. Caplan (eds.) Caplan’s Stroke: A Clinical Approach. 4th ed. Philadelphia: Sounders Elsevier; 2009;581-592. 10. Depres J-P, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. Rimonabant in Obesity-Lipids Study Group. N Engl J Med. 2005 ;353(20):2121-34. 11. Al-Eithan MD, Amin M, Robert AA. The efects of hemiplegia/hemiparesis, diabete mellitus and hypertension on hospital length of stay after stroke. Neurosciences (Riyadh). 2011;16(3):253-6. 12.Tanović E. Uticaj etioloških faktora na rehabilitaciju nakon cerebrovaskularnog inzulta. Treći kongres fizijatara i Prva ISPO konferencija BiH sa međunarodnim učešćem, 27-30. oktobra 2010, Tuzla , Zbornik radova 54. 13.Tanović E, Tanović H. Functional elektric stimulation on walking rehabilitation on patients with hemiplegia after stroke. Nerol Croat. 2007;56(1):188-194. 14.Ones K, Yalcukaya EY, Toklu BC, Caglar N. Effects of age, gender and cognitive functional and motor status on functional otucomes of stroke rehabilitation. Neuro Rehabilitation. 2009;25(4): 241-9. 15. Ripley DL, Seel RT, Macciocchi SN, Schara SL, Raziano K, Ericson JJ. The impact of diabetes mellitus on stroke acute rehabilitation outcome. Am J Phys Med Rehabil. 2007;86(9):754-61. S. Selimović et al. 16.Tanović E. Gait Training and Functional Elaktric Stimulation with Hemiplegic Patients. Med Arch. 2007; 61(2): 82-85. 17. Tanović E. Effects of Functional Electric Stimulation in Rehabilitation with Hemiparesis Patients. Bosnian Journal of Basic Medical Sciences. 2009;9(1):49-53. 18.Putman K, Horn S, Smonth R, Dejong G, Deutcher D, Tian W, Hsich CH. Racial disparities in stroke functional outcomes upon discharge from patients rehabilitation facilities. Disabil rehabil. 2010;32(19):1604-11. 19.Tanović E, Brbović E, Hodžić N, Meholjić A, Tanović H. Uticaj diabetes mellitusa kao rizikofaktora na hemiplegije. Kongres ljekara za fizikalnu medicinu i rehabilitaciju (sa međunarodnim ućešćem), 1. Knjiga sažetaka; Sarajevo: Udruženje ljekara za fizikalnu medicinu i rehabilitaciju BiH; 2000;55. 20.Gokkaya N, Aras M, caralmas D, kaya A. Stroke rehabilitation outcomes: the Turkish experiences. Int J Rehabili Res. 2006;29(2):105-11. 21.Tanović E, Tanović H. Valorization of the rehabilitation after cerebrovacular insult by ET-test. Europ J Physical and Rehabilitation medicine. 2010;46(2):165. 22.De Wit L, Putman K, Devos H, Brikmann N, Dajarger E, De Weerdt W. et all. Five-year mortality and related prognostic factors after inpatient stroke rehabilitation: a European multi-centre study. J Rehabil Med. 2012;44(7):547-52. 23.Edjoc RK, Reid RD, Sharma M. The effectiveness of smoking cessation interventions in smokers with cerebrovascular disease: a systematic review. BMJ Open. 2012;20:2(6). 24.Papadakis S, Aitkens D, Gocan S, Riley D, at al. A randomized controlled pilot study of standardized counseling and cost-free pharmacotherapy for smoking cessation among stroke and TIA patients. BMJ Open. 2011;28;1(2). 25.Sienkiewitsz-Jarosz H, Zatorski B, Witkowski G, Rogowskia-Scinska A, Ryglewiczd D. Predictors of smoking cessation after stroke. Neurol Neurochir Pol. 2010;44(2):181-7. 26.Delbari A, Salman Roghani R, Tabatabei SS, Lökk J. A stroke study of an urban of Iran risk factors, length of stay, case fatality and discharge destination. J Stroke Cerebrovasc Dis. 2010;19(2):104-9. 27. Fegard RH; Nillson PM. Smoking and diabetes-the double health hazard! Prim Care Diabetes. 2009;3(4):205-9. Reprint requests and correspondence: Edina Tanović, MD, PhD Clinic for Physical Medicine and Rehabilitation Clinic Center University of Sarajevo Bolnička 25 71000 Sarajevo Bosnia and Herzegovina Phone: +387 33 298 465 E-mail: [email protected] Original article Medical Journal (2014) Vol. 20, No. 3, 167 - 170 Frequency of chromosomal aberrations among healthy population of Bosnia and Herzegovina Učestalost pojave hromosomskih aberacija kod zdrave populacije u Bosni i Hercegovini Izeta Aganović-Mušinović1*, Mirela Mačkić-Đurović1, Orhan Lepara2 Center for Genetics, Faculty of Medicine University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina, Department of Human Physiology, Faculty of Medicine University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina 1 2 *Corresponding author ABSTRACT SAŽETAK Structural chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBLs) have been applied for over 30 years in occupational and environmental settings (including radiation dosimetry) as a biomarker of early effects of human health. They can be involving the same locus on both chromatides-chromatid aberrations (CSAs) while chromosome type aberrations (CTAs) affect one chromatide of a chromosome. They could be induced by different mutagens. The aim of this study is to form baseline for chromosome aberrations frequency among healthy population of Bosnia and Herzegovina. We have found significant effect modification by gender – female had increased number of CAs – chromatid type, and the age infulence of both gender. Smoking habits did not influence CAs frequency of any type. The age and smoking habits did correlate in CAs frequency for non-smokers but did not correlate for smokers. Frequency distribution of CTAs and CSAs among male and female showed predominance of CTAs over CSAs, independently of gender. Strukturne hromosomske aberacije (CAs) iz limfocita perifene krvi se koriste preko 30 godina u procjeni profesionalnog ili okolišnog okruženja (uključujući i dozimetriju zračenja) kao biomarker ranih uticaja na zdravlje čovjeka. One mogu uključivati iste lokuse na obje hromatide (hromatidne aberacije-CSAs) dok hromosomske aberacije-CTAs uključuju jednu hromatidu hromosoma. Hromosomske aberacije mogu biti uzrokovane različitim mutagenima. Mi smo uočili značajan uticaj spola na pojavu hromosomskih aberacija – žene su imale povećan broj CAs – hromatidnog tipa, kao i uticaj dobi kod oba spola. Pušački status nije uticao na pojavu učestalosti CAs bilo kojeg tipa. Dob i pušački status su korelirali sa učestalošću pojavljivanja CAs kod nepušača, dok nisu korelirali kod pušača. Ovo se može koristiti kao bazna linija učestalosti hromosomskih aberacija u zdravoj populaciji. Distribucija učestalosti CTAs i CSAs među spolovima pokazuje predominantnost CTAs nad CSAs, neovisno o spolu. Key words: structural chromosomal aberrations, chromatid aberrations, chromosome type aberrations, gender, tobacco smoking Ključne riječi: strukturne hromosomske aberacije, hromatidne aberacije, hromosomski tip aberacija, spol, pušački status INTRODUCTION Other types of initial lesions (e.g. base alterations, cross-links, pyrimidine dimers, or single-strand breaks, depending on the inducer) induced by S-phase-dependent agents, including most chemical clastogens and UV light, give rise to CTAs (1, 2, 3) . It is obvious that chromosomal aberrations - CA generation requires one or several DNA double-strand breaks, but their formation schedule is different for CSAs and CTAs. A double-strand break is the primary lesion for CSAs (4), and CSAs observed in cultured PBLs are expected to reflect double-strand breaks mostly generated in vivo in G0 stage. For lymphocyte CTAs, however, double-strand breaks are probably formed from the initial DNA lesions in vitro in S phase. CSAs and CTAs have different mechanisms of formation resulting from different kinds of DNA lesions induced by different types of clastogens (5). Therefore, information of CAs among healthy population gives us a baseline for any other research of CAs. Structural chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBLs) have been applied for over 30 years in occupational and environmental settings (including radiation dosimetry) as a biomarker of early effects of human health (1). CAs include chromosomal breaks and exchanges visible in arrested metaphase-stage cells and are usually divided into chromosome-type aberrations (CSAs) and chromatid-type aberrations (CTAs), which differ from each other morphologically. CSAs involve the same locus on both sister chromatids on one or multiple chromosomes, whereas CTAs affect one or several sister chromatids of a chromosome or several chromosomes. CSAs and CTAs are induced by different types of environmental mutagens. In PBLs, which are mostly in a resting G0 phase, agents that produce double-strand breaks, such as ionizing radiation and radiomimetic clastogenic chemicals, create CSAs. 168 I. Aganović-Mušinović et al. The aim of this study is to form a baseline for chromosome aberrations frequency among healthy population of Bosnia and Herzegovina. MATERIALS AND METHODS We collected whole heparinized blood from 200 persons from Bosnia and Herzegovina. Those people had no record of cancer illness, no previous therapy of any kind (in the last three months) and were divided in 5 age groups (20-30; 30-40; 40-50; 50-60; 60-70) with an equal number of males and females in each group. We collected data of their smoking habits dividing them to smokers and no-smokers. Conventional Moorhead method was used on short-term cultures for 48 hr, with all cells being in the first division (6). Slides from each culture were numbered and blindly scored. At least 200 well-spread metaphases with 46 ± 1 centromeres were examined. Total CAs were subclassified as CSAs (including chromosome-type breaks, ring chromosomes, marker chromosomes, and dicentrics) and chromatid-type aberrations (CTAs; including chromatid-type breaks). Gaps were not scored as aberrations. All variables were expressed as the medians and interquartile ranges for continuous data with or without a normal distribution, respectively. Nonparametric data was compared between groups using the independent samples Mann–Whitney U-test. Additionally, Spearman’s correlation was used as measure of association for continues variables. P-value <0.05 was considered statistically significant. All statistical analyses were performed using the computer software Statistical Package for the Social Sciences, version 20.0 (SPSS, Chicago, IL). Figure 2 Relation among age and number of aberrations at female groups. rho-Spaerman’s correlation coefficient, p- probability Figure 3 Relation among age and number of aberrations at male groups. rho-Spaerman’s correlation coefficient, p- probability As shown in Figure 1 more frequent CAs are observed to correlate with age at both genders, whereas at females the pick is around the age of 50 which can be in connection with hormonal status and adjusting for menopause, males had a pick at the age of 60 and all were statistically significant using Spearman’s correlation (p<0,01; rho=0,463; rho=0,470; rho= 0,455; respectively) (Figure 2 and 3). Significant positive correlation among the age and number of aberrations within all groups of healthy population (rho=0,462; p<0,01) is evident. Spearman’s correlation was used to define the number of CAs among nonsmokers and it showed significance (p<0,05; rho=0,192) - Figure 4, while it was not significant for smokers (rho=0,229; p=NS) – Figure 5. Although the number of aberrations in smoker group is higher 1,0 (0,0 – 2,0) when compared with non-smoker group 0,0 (0,0 – 2,0) the difference has no statistic significance (p=NS). Figure 1 Relation among age and number of aberrations at all groups. rho-Spaerman’s correlation coefficient, p- probability Figure 4 Relation among age and number of aberrations at nonsmokers. rho-Spaerman’s correlation coefficient, p- probability RESULTS Frequency of Chromosomal Aberrations among Healthy Population of B&H 169 DISCUSSION Figure 5 Relation among age and number of aberrations at smokers. rho-Spaerman’s correlation coefficient, p- probability Mann-Whitney U test was used to determine the significance of chromosome aberrations frequency among male and female group. Number of aberrations at female group was 1,0 (0,0-2,0), higher than a number of aberrations at male group 0,0 (0,0 – 2,0). The difference has statistic significance (p=0,046) (Figure 6). Figure 6 Relation among number of aberrations at female and male group. rho-Spaerman’s correlation coefficient, p- probability, NS- not-significant Figure 7 Frequency distribution of CTAs and CSAs among male (1) and female (0). CTAs are far more frequent than CSAs at both gender, independently of age (Figure 7). The results of our study were used to make a baseline on chromosomal aberrations frequency on healthy population of Bosnia and Herzegovina. We have found significant effect modification by gender – female had increased number of CAs – chromatid type, and the age of both gender. Smoking habits did not influence CAs frequency of any type. The age and smoking habits did correlate in CAs frequency for non-smokers but did not correlate for smokers. This could be used as a baseline for chromosome aberrations frequency among healthy population. Our results correlate with other investigation’s results recently conducted in other European countries, though we did not correlate CAs frequency and cancer risk given that the project lasted one year and we did not have a long-lasting follow up. Frequency distribution of CTAs and CSAs among male and female showed predominance of CTAs over CSAs, independently of gender. The results of the presented study based on Nordic and Italian cohorts (5) support the conclusion that CA frequency in PBLs, as a biomarker of cancer risk, will not be improved by separating CSAs from CTAs. This suggests that both DNA double-strand breaks and other DNA lesions responsible for CSAs and CTAs, respectively, are associated with cancer risk. Authors point that the strength of the cancer predictivity by CA frequency did not decrease in time since the test, which is circumstantial evidence in favor of individual susceptibility factors or long-standing exposure to dietary, environmental, or endogenous carcinogens explaining the association between CA frequency and cancer incidence. There is no significant effect modification by sex, age at test, or time since the test bservation. Although there was no significant evidence of effect modification by type of occupational exposure, a stronger association was suggested among subjects exposed to ionizing radiation and to reactive chemicals than among unexposed subject. Among workers exposed to ionizing radiation, an increased risk was present for both high chromosome-type and high chromatid-type aberrations, although it was statistically significant only for the former type of aberrations (5). A statistically significant increase in relative risk was seen in medium and high chromosomal aberration categories in smokers but not in nonsmokers; however, smoking did not have a significant modifying effect. The increased risk among smokers was present for elevated chromosome-type aberrations but not for elevated chromatid-type aberrations. Chromosomal aberrations are usually considered to derive from unrepaired or misrepaired DNA lesions induced by exogenous or endogenous exposure to DNA-damaging agents. An increase in chromosomal aberrations could also be due to genetic or acquired conditions conferring a higher susceptibility to genetic damage. Elevated levels of chromosomal aberrations in peripheral blood lymphocytes may be seen as an indicator of an early phase of carcinogenesis, where various genetic alterations are also generated in different tissues (6,7). We showed that a high frequency of chromosomal aberrations in peripheral blood lymphocytes, and in particular of chromosome-type aberrations, is associated with increased risk of cancer. The fact that this association does not depend on the time elapsed from the test is consistent with the hypothesis that the level of chro- 170 mosomal aberrations is predictive of cancer risk rather than being an early manifestation of a clinically undetected cancer. The available literature points toward the independence from exposure to carcinogens of the chromosomal aberration–cancer association; that is, the prediction of cancer risk associated with chromosomal aberration frequency is the same in exposed and unexposed subjects (5,7,8,9,10,11,12,13). The presence of interaction between exposure to carcinogens and the predictivity of CAs has been another issue largely debated in the literature (14,15,16,17,18). The presence of a stronger association between CA frequency and risk of cancer in radon-exposed workers than in other workers or controls, which has been already reported (9,15), is not consistent with the findings of the Nordic and Italian cohorts, in which the association between increased CA frequency and cancer risk appeared to be independent from exposure to carcinogens or smoking habit (7). The findings from the present study of Italian chohort (15) were not conclusive in this direction because the predictivity of CA frequency observed in subjects exposed to various classes of carcinogens did not significantly differ from the group of non exposed subjects. That study (14) confirmed previous reports of an association between the extent of chromosomal damage and the risk of cancer. In contrast to most previous reports, this association appeared to be limited to the presence of CSAs, and the magnitude of the excess risk might be lower than previously described. Also, the higher risks found in the group exposed to ionizing radiation is a peculiar finding of that cohort and deserves a deeper insight (14,18,19). CONCLUSION The possibility that the implementation of occupational preventive programs of chromosomal aberrations frequency focused on workers with high CA frequency might have modified their risk of cancer is a plausible explanation of these results, and it will be further evaluated with ad hoc studies, reconstructing occupational lives of subjects with the highest frequency of CA at their first cytogenetic analysis. I. Aganović-Mušinović et al. 7. Mitelman F, Johansson B, Mertens F. Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nat Genet. 2004;36:331-4. 8. Bonassi S, Znaor A, Norppa H, Hagmar L. Chromosomal aberrations and risk of cancer in humans: an epidemiological perspective. Cytogenet Genome Res. 2004;104:376-82. 9. Bonassi S, Hagmar L, Strömberg U, Montagud AH, Tinnerberg H, Forni A, et al. Chromosomal aberrations in lymphocytes predict human cancer independently from exposure to carcinogens. European Study Group on Cytogenetic Biomarkers and Health Cancer Res. 2000;60:1619-25. 10.Hagmar L, Brøgger A, Hansteen IL, Heim S, Högstedt B, Knudsen L, et al. Cancer risk in humans predicted by increased levels of chromosome aberrations in lymphocytes: Nordic Study Group on the Health Risk of Chromosome Damage. Cancer Res. 1994; 54:2919-22. 11.Hagmar L, Bonassi S, Strömberg U, Brøgger A, Knudsen LE, Norppa H, et al. Chromosomal aberrations in lymphocytes predict human cancer—a report from the European Study Group on Cytogenetic Biomarkers and Health (ESCH). Cancer Res. 1998; 58: 4117-21. 12. Hagmar L, Strömberg U, Bonassi S, Hansteen IL, Ehlert Knudsen L, Lindholm C, Norppa H. Impact of types of lymphocyte chromosomal aberrations on human cancer risk. Results from Nordic and Italian cohorts. Cancer Res. 2004;64:2258-63. 13.Rossner P, Boffeta P, Ceppi M, Bonassi S, Smerhovsky Z, Landa K, et al. Chromosomal aberrations in lymphocytes of healthy subjects and risk of cancer. Environ Health Perspect. 2005;113:517-20. 14. Bonassi S, Abbondandolo A, Camurri L, Dal Pra L, De Ferrari M, Degrassi F, et al. Are chromosome aberrations in circulating lymphocytes predictive of future cancer onset in humans? Preliminary results of an Italian cohort study. Cancer Genet Cytogenet. 1995;79:133–5. 15. Bonassi S, Ugolini D, Kirsch-Volders M, Strömberg U, Vermeulen R, Tucker JD. Human population studies with cytogenetic biomarkers: review of the literature and future prospectives. Environ Mol Mutagen. 2005;10.1002/em.20115. 16. Bonassi S, Hagmar L, Strömberg U, Montagud AH, Tinnerberg H, Forni A, Heikkilä P, et al. Chromosomal damage in peripheral blood lymphocytes of newly diagnosed cancer patients and healthy controls. Carcinogenesis. 2010;31:1238-1241. 17.Smerhovsky Z, Landa K, Rössner P, Brabec M, Zudova Z, Hola N, et al. Risk of cancer in an occupationally exposed cohort with increased level of chromosomal aberrations. Environ Health Perspect. 2001;109: 41-5. 18.Wykes SM, Piasentin E, Joiner MC, Wilson GD, Marples B. Low-dose hyperradiosensitivity is not caused by a failure to recognize DNA double-strand breaks. Radiat Res. 2006;165:516–24. 19.Littlefield L, McFee A, Sayer A, O’Neill P, Kleinerman R, Maor M. Induction and persistence of chromosome aberrations in human lymphocytes exposed to neutrons in vitro or in vivo: implications of findings in ‘retrospective’ biological dosimetry. Radiat Protect Dosimetry. 2000;88:59–68. Conflict of interest: none declared. REFERENCES 1. Albertini RJ, Anderson D, Douglas GR, Hagmar L, Hemminki K, Merlo F, et al. IPCS guidelines for the monitoring of genotoxic effects of carcinogens in humans. Mutat Res. 2000;463:111-72. 2. Obe G, Pfeiffer P, Savage JR, Johannes C, Goedecke W, Jeppesen P, et al. Chromosomal aberrations: formation, identification and distribution. Mutat Res. 2002;504:17–36. 3. Palitti F. Mechanisms of the origin of chromosomal aberrations. Mutat Res. 1998;404:133–7. 4. Pfeiffer P, Goedecke W, Obe G. Mechanisms of DNA double-strand repair and their potential to induce chromosomal aberrations. Mutagenesis. 2000;15:289-302. 5. Brøgger A, Hagmar L, Hansteen IL, Heim S, Högstedt B, Knudsen L, et al. An inter-Nordic prospective study on cytogenetic endpoints and cancer risk. Nordic Study Group on the Health Risk of Chromosome Damage. Cancer Genet Cytogenet. 1990;45:85-92. 6. Moorhead PS, Nowell PC, Mellman WJ, Battips DM, Hungerford DA. Chromosome preparations of leukocytes cultured from human peripheral blood. Exp Cell Res. 1960;20:613-6. Reprint requests and correspondence: Izeta Aganović-Mušinović, MD Center for Genetics Medical Faculty University of Sarajevo Čekaluša 90 71000 Sarajevo Bosnia and Herzegovina Phone: +387 33 226 472 lok.156 Email: [email protected] Original article Medical Journal (2014) Vol. 20, No. 3, 171 - 174 Morphometric analysis of arterial Willis ring in patients with varying degrees of occlusion of the internal carotid artery Morfometrijska analiza arterija Willisovog prstena sa različitim stepenom okluzije unutrašnje karotidne arterije Alma Voljevica*, Elvira Talović Department of Anatomy, Faculty of Medicine University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT SAŽETAK In 1664, since the time of Thomas Willis, it is known that the arterial ring at the base of the brain (later named by this anatomy) is the most important part of the collateral cerebral blood flow. His discovery of the valvular mechanism is particularly evident at the time of occurrence of different occlusive diseases of the internal carotid artery. In this paper, the analysis focuses on the carotid angiogram of 75 patients and recorded various forms of occlusive disease of the internal carotid artery, which are presented by the method of serial angiography by Seldinger which were excluded from the archives of the Department of Radiology, Clinical Center University of Sarajevo. For morphometric analysis of blood vessels, we used a specially designed software program ELLIPSE. The most prominent changes were registered in the area of the front and rear communicating artery. The largest diameter of the front communicating artery was seen in patients with unilateral occlusion of the internal carotid artery, while the greatest increase of gain in the back communicating artery was observed in patients with bilateral occlusion of the same artery. This study confirmed so far the repeatedly expressed assertion that the valvular mechanism of the Willis ring is significant with all types of occlusive changes that require arteries which are contained by it. Još od davne 1664. godine, od vremena Tomasa Willisa, poznato je da je arterijski prsten na bazi mozga (kasnije nazvan po ovom anatomu) najvažniji dio kolateralnog moždanog krvotoka. Njegov valvularni mehanizam naročito dolazi do izražaja u momentu nastanka različitih okluzivnih oboljenja unutrašnje karotidne arterije. U ovom radu analizi je podvrgnuto 75 angiograma karotidnog sliva pacijenata kod kojih su zabilježeni različiti oblici okluzivnih bolesti unutrašnje karotidne arterije, prikazanih metodom serijske angiografije po Seldingeru izuzetih iz arhive Katedre za radiologiju Kliničkog centra Univerziteta u Sarajevu. Za morfometrijsku analizu krvnih sudova korišten je posebno dizajnirani softwerski program ELLIPSE. Najizraženije promjene registrovane su u području prednje i stražnje komunikantne arterije. Najveći promjer prednje komunikantne arterije zabilježen je kod pacijenata sa unilateralnom okluzijom unutrašnje karotidne arterije, dok je najveći porast vrijednosti u stražnjoj komunikantnoj arteriji zabilježen kod osoba sa bilateralnom okluzijom iste arterije. Ovo istraživanje je potvrdilo do sada više puta izrečenu tvrdnju da valvularni mehanizam Wilisovog prstena dolazi do izražaja kod svih vrsta okluzivnih promjena koje zahvataju arterije koje ga sačinajvaju. Key words: Willis ring, cerebral arteries, serial angiography, morphometry, internal carotid artery occlusion Ključne riječi: Willisov prsten, cerebralne arterije, serijska angiografija, morfometrija, okluzija unutrašnje karotidne arterije INTRODUCTION level of the anastomosed blood vessels of the brain of Willis’ circle (for example communicating arteries) there is no mixing of blood, due to hemodynamic balance between anastomosed arterial systems. However, under some certain conditions there is a functional disturbance of this balance and blood can transfer from one system to another. Thus, in flexion or extension of the head, compression of vertebral arteries is formed, and during the rotation and lateral flexion, the compression of internal carotid artery or compression of common carotid artery occur (3). In the case of occlusion of a cerebral artery, blood transferring from one system to another can be much more intense, leading to an increase in the diameter of collateral vessels in order that the The intensity of research surrounding the arterial ring at the base of the brain (circulus arteriosus cerebri Willisi) has not decreased since 1664, when for the first time, the arterial ring was described in detail and its collateral function was demonstrated (1, 2). As known, two arterial systems are involved in the construction of a ring: a system of internal carotid artery (arteriae Ipsilateral) and system of vertebral arteries (arteriae vertebrales). It is also known that the collateral function of the Willis’ circle is manifested in physiological and pathological conditions. This claim is asserted in the study in which it was found that under normal circumstances, at the 172 blood vessels should respond functionally to current situation. In recent years, a lot of attention has been devoted to the assessment of hemodynamic status of cerebral circulation, and monitoring of the condition is possible through the usage of many modern diagnostic procedures. Some of the most frequent diagnostic procedures are MR-angiography (4), serial angiography, and transcranial color Doppler (5, 6). By applying last two methods in combination with compression test on the internal carotid artery, it is possible to analyze the collateral ability of Willi’s ring. Aim: the main goal of this study is to measure the diameters of the blood vessels that enter the system of Willis ring among patients with varying degrees of occlusion and stenosis of the internal carotid artery, by using a specially designed software program, whose value could be used in clinical practice to assess the condition of the cerebral circulation system. A. Voljevica et al. Figure 1 Surrounding display of Ellipse software program used in this study. MATERIALS AND METHODS As for the material for this paper, there are 75 angiogram carotid arteries of patients with disturbed cerebrovascular status displayed by using the serial angiography method by Seldinger obtained from the archives (retrospective study) Department of Radiology, Clinical Center University of Sarajevo. Seventy-five patients who were treated by the method of serial angiography, were selected from a possible 157 patients examined by the angiogram and grouped into four categories according to the degree of narrowing, the pathological process of the affected carotid artery. I category consisted of 28 patients who were registered as stronger unilateral or bilateral stenosis of the internal carotid artery (S) II category consisted of 29 patients with unilateral occlusion of the internal carotid artery (A) III category consisted of 13 patients with unilateral internal carotid artery occlusion combined with stronger contralateral stenosis (OS) IV category consisted of 5 patients with bilateral occlusion (OO). Among the categories of patients we created two subgroups; one subgroup consisted of 40 patients who were registered as anamnestic symptoms of cerebrovascular of insufficiency, so this group was labelled symptomatic patients (SS), while the other subgroup consisted of 35 patients who were not registered as symptoms of cerebrovascular insufficiency, but the lesions on the internal carotid artery was registered accidentally, so this group was labelled asymptomatic patients (AS). In the course of recording, a compression test on the internal carotid artery opposite side was performed on all of the patients to show the front and rear communicating artery. All scans obtained were transferred to the specially designed software program Ellipse (Figure 1). In this manner, easier storage of the images that are used for morphometric analysis was enabled. Morphometric measurements were used to obtain data on the value of the diameters of the blood vessels that enter system of Willis’ circle among patients with disturbed cerebrovascular status. For this measurement program the Line System was used. The measurements were made on those scans that provided the best visualization of certain blood vessels. For each vessel three measurements were made in order to obtain the mean value. All data are statistically processed, and the results are shown through charts and tables. RESULTS Using the specially designed software program, measurements of the diameters of the blood vessels that enter the system of Willis ring among patients with varying degrees of occlusion and stenosis arteriae carotis internae (categories of subjects from I to IV) were carried out. The obtained values were compared with values of diameters of blood vessels of Willis ring among subjects of control category (100 subjects with normal cerebrovascular status whose values are published in the paper: Voljevica, et al. (7). Table 1 Diameters of blood vessels expressed in mm. Dimeters of blood vessels expressed in mm Blood >60years S (n=28) O (n=29) OS (n=13) OO (n=5) vessels (n=100) AcoA 1.13±0.28 1.20±0.33 1.33±0.38 1.34±0.36 1.50±0.25 A1 SS 1.78±0.41 1.63±0.51 1.90±0.42 1.84±0.67 2.02±0.60 A1 AS 1.78±0.41 1.86±0.37 2.82±0.60 2.58±0.79 1.78±0.33 PCoA SS 1.29±0.42 1.40±0.44 1.55±0.45 1.60±0.42 1.76±0.41 PCoA AS 1.29±0.42 1.25±0.32 1.45±0.66 1.39±0.64 1.95±0.32 P1 SS 1.79±0.45 1.91±0.43 2.79±0.44 2.63±0.61 2.63±0.42 P1 AS 1.79±0.45 1.92±0.49 2.41±0.59 2.62±0.58 2.66±0.39 AS - asymptomatic patients; SS - symptomatic patients; The values ± indicate standard deviation (± SD) Those patients with stenosis of the internal carotid artery have the complete configuration of Willis ring increased, but there is no statistically significant increase in the diameter of blood vessels that enter its composition. The level of significance is p <0.05. Among such patients inferiority of diameters of precomunacating segment of front cerebral artery compared to the control group of subjects were reported, which is probably caused by atherosclerotic process. Values of diameters of other vessels were slightly higher when compared to the control group subjects. Among patients with occlusion of the internal carotid artery with or without contralateral stenosis, increased collateral flow through the anterior segment of the circle of Willis’ circle was reported, resulting with a statistically significant increase of the radius Morphometric analysis of arterial Willis Ring in patients with varying degrees of occlusion of the Internal carotid artery of the anterior communicating artery as well as precommunicating anterior cerebral artery compared to the control group of patients. The level of significance is p<0.001. We have to note that these values provided for the patients without symptoms were for about 0.2 ± 0.14 mm greater than among patients with symptoms. Among patients with bilateral occlusion of the internal carotid artery, increasing blood flow was identified through the rear segment of the Willis ring, resulting in a significant increase in the radius of the rear communicating artery, and of precommunicating part of the posterior cerebral artery. The level of significance is p<0.001. 3,00 ACoA 2,80 2,60 A1 SS 2,40 A1 AS 2,20 2,00 PCoA SS 1,80 PCoA AS 1,60 P1 SS 1,40 1,20 P1 AS 1,00 >60god S O OS OO Figure 2 Increase of diameters of blood vessel. Figure 1 shows the increase of the diameters of certain blood vessels of Willis ring depending on the type of disease that affects the internal carotid artery. The most visible changes are registered in the front and back of the communicating artery as seen in the chart. The anterior communicating artery shows the largest diameter in patients with unilateral occlusion, and the largest increase in value is achieved by back communicating artery among patients with bilateral occlusion of the internal carotid artery. DISCUSSION Previous studies have shown that patients with significantly reduced blood flow in the internal carotid artery or the basilar artery, collateral arteries can maintain cerebral perfusion in the area of vascularization court which is affected. The primary collateral, such as arteriae cerebri anterior and arteriae cerebri posterior, respond very quickly by greater blood flow and changing the direction of blood flow (8). Previous research has shown that among patients with asymptomatic internal carotid artery occlusion, the diameters of anterior communicating artery increase so that the larger diameter of the artery may have a protective role in patients with unilateral occlusion of the internal carotid artery (9). Also, it was found that in patients with unilateral occlusion of the internal carotid artery presence of collateral flow through the posterior communicating artery circle of Willis is associated with a lower prevalence of border infarct (border zone infarcts), and in asymptomatic patients, increase collateral function has not been observed (9). Based on research conducted in this area, which were based on the morphometric measurements of the arteries of Willis ring in 173 patients with occlusion or stenosis of the corotid artery, it was determined that enhanced flow through communicating segments of Willis ring leads to an increase in the diameter of the blood vessels. In patients registering with unilateral stenosis, boosting flow through the anterior communicating artery did not lead to a statistically significant increase either in the diameter of this, or of other blood vessels that enter Willis ring. In contrast, in patients with unilateral occlusion of the internal carotid artery with or without contralateral stenosis, collateral flow through the anterior segment of the circle of Willis was increased, with a statistically significant increase of the diameter of the anterior communicating artery and precommunicating segments of anterior cerebral artery compared to the control group subjects. The level of significance is p<0.001. We have noted that these values in patients without symptoms are for about 0.2 ± 0.14 mm greater than in patients with symptoms of the disease. In patients with bilateral occlusion of the internal carotid artery, there was a higher percentage flow through the posterior segment of the Willis ring, resulting in a significant increase in the diameter of the rear communicating artery, and of precommunicating segments of the posterior cerebral artery. The level of significance is p<0.001. These results are fully in accordance with the claims of researchers (10,11,12), which, based on their research, came to the conclusion that the increased blood flow through the communicating segment of the Willis ring leads to an increase in the caliber of the arteries. Specifically, the authors suggest that arterial stenosis that affects the arteries, leads to a gradual narrowing of the lumen, which then leads to the inclusion of compensatory mechanisms, including, dilatation of blood vessels and increased blood flow through dilated blood vessel functioning. The same authors also found that compensatory, hemodynamic, metabolic and neural mechanisms are of great importance and their effectiveness determines whether the ischemic tissue can remain capable of living. CONCLUSION At the end we can conclude that our research confirmed previous research results related to Willis ring, and it means that protective mechanism has no match in whole organism, but for its normal establishment of collateral circulation at the ring level the existence of the entire configuration is necessary. Research showed that the biggest change in diameter of back communicating artery are noticed among asymptomatic patients with occlusion of the inner carotid artery with and without contralateral stenosis and it goes up to 46% compared to the mean value. In contrast, the smallest percentage changes are registrated among asymptomatic patients with bilateral occlusion on P1 segment of the back cerebral artery, and it goes up to 15% compared to the mean value. Slightly bigger changes are registrated on P1 segment of back cerebral artery among symptomatic patients with unilateral occlusion and it goes up to 16% compared to the mean value. Identical results are obtained also among group of subjects with bilateral occlusion on back communicating artery of asymptomatic patients and on P1 segment of the back cerebral artery among symptomatic patients. Conflict of interest: none declared. 174 A. Voljevica et al. REFERENCES 1. Ardakani SK, Dadmehr M, Nejat F, Ansari S, Eftekhar B, Tajik P, et al. The cerebral arterial circle (circulus arteriosus cerebri): an anatomical study in fetus and infant samples. Pediatr Neurosurg. 2008;44(5):388–92. 2. Eftekhar B, Dadmehr M, Ansari S, Ghodsi M, Nazparvar B, Ketabchi E. Are the distributions of variations of circle of Willis different in different populations? Results of an anatomical study and review of literature. BMC Neurol. 2006 Jun 24;6:22. 3. Lazorthes G, Gouaze A, Santini JJ, Salamon G. Le cercle artériel du cerveau (circulus arteriosus cerebri) Anat Clin. 1979;1:241–257. 4. Macchi C, Catini C, Federico C, Gulisano M, Pacini P, Cecchi F, et al. Magnetic resonance angiographic evaluation of circulus arteriosus cerebri (circle of Willis): a morphologic study in 100 human healthy subjects. Ital J Anat Embryol. 1996;101(2):115–23. 5. Baumgartner RW, Baumgartner I, Mattle HP, Schroth G. Transcranial collor-coded duplex sonography in the evaluation of collateral flow through the circle of Willis. Am J Neuradiol. 1997;18(1):127-33. 6. Hoksbergen AW, Legemate DA, Ubbink DT, de Vos HJ, Jacobs NJ. Influence of the collateral function of the circle of Willis on hemispherical perfusion during carotid occusion as assessed by transcranial colour-coded duplex ulrasonography. Eur J Vasc Endovasc Surg. 1999;17(6):486-92. 7. Voljevica A. Talović E. Morphometric analysis of Willis circle arteries. Archives of Pharmacy Practice. 2013;4(2). 8. Abdelaziz M, Ahmed AI. Three dimensional magnetic resonance angiography of the circle of Willis: anatomical variations in general Egyptian population. The Egyptian Yournal of Radiology and Nuclear medicine. 2011;42(3):405-412. 9. Hendrikse J, Hartkamp MJ, Hillen B, Mali WP, van der Grond J. Collateral ability of the circle of Willis in patients with unilateral internal carotid artery occlusion: border zone infarcts and clinical symptoms. Stroke. 2001;32:2768–73. 10. Cassot F, Vergeur V, Bossuet P, Hillen B, Zagzoule M, Marc-Vergnes JP. Effects of anterior communicating artery dameter on cerebral hemodinamics in internal carotid artery disease. Circulation. 1995;92(10):3122-31. 11. Hedera P, Bujdakova J, Traubner P, Pancak J. Stroke risik factors and development of collateral flow in carotid occlusive disease. Acta Neurol Scand. 1998;98(3):182-6. 12. Dickey PS, Kailasnath P, Bloomgarden G, Goodrich I, Chaloupa J. Computer modeling of cerebral blood flow following internal carotid occlusion. Neurol Res. 1996; 18(3):259-66 Reprint requests and correspondence: Alma Voljevica, MD Institute of Anatomy „Prof. Dr Hajrudin Hadžiselimović” Faculty of Medicine University of Sarajevo Čekaluša 90 71000 Sarajevo Bosnia and Herzegovina Phone: + 387 33 665 949 143 Fax: + 387 33 203 670 Email: [email protected] Bosnia and Herzegovina versions of Guidelines for Patients! Bosanskohercegovačka verzija Vodiča za pacijente! Original article Medical Journal (2014) Vol. 20, No. 3, 175 - 179 Evaluation of clinical and laboratory characteristics of childhood lymphoma Evaluacija kliničkih i laboratorijskih karakteristika limfoma dječije dobi Edo Hasanbegović*, Nermana Čengić, Meliha Sakić, Adela Tunić, Senada Mehadžić Pediatric Clinic, Clinical Center University of Sarajevo, Patriotske lige 81, 71000 Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT SAŽETAK The aim of this study is to evaluate the basic epidemiological and clinical characteristics of lymphoma in childhood at the Department of Hematooncology, Pediatric Clinic, Clinical Center University of Sarajevo (CCUS), in ten year period. Patients and Methods: the study included 58 patients, of both gender, aged 0-15 years, diagnosed with lymphoma at the Department of Hematooncology, Pediatric Clinic of CCUS, in the period from January 1st 2004 to December 31st 2013. The retrospective study of patients with lymphoma in childhood was conducted. The results were presented using tables and charts, with number of cases and percentages. Statistical analysis of significant differences was performed using Fisher and Chi-square test. The values of p<0.05 or on the level reliability of 95% were considered statistically significant. Results: our study included 58 patients, 37 (63.80%) boys and 21 (36.20%) girls. Most of the patients were in the age group of 8-15 years, namely 38 (65.50%) patients. The leading symptom of lymphoma in childhood was lymphadenopathy, which was presented in 45 (77.58%) patients, followed by subfebrile temperature in 19 (32.75%), paleness in 16 (27.59%), hepatosplenomegaly in 13 (22.41%), and weight loss in 12 (20.69%) patients. The following elevated values were noted: LDH in 16 patients with HL and 14 with NHL, and Cu in 15 patients with HL and 10 with NHL. Majority of the patients with HL were diagnosed in stage II of disease, 12 (37.50%) patients, and 11 (34.40%) in stage IV. Majority of patients with NHL were diagnosed in stage II, 13 (50%), and 8 (30.80%) in stage IV. Conclusion: clinical diagnostic methods and modern therapy at the Pediatric Clinic of CCUS contribute to good prognosis for patients suffering from lymphoma in childhood. Cilj rada je evaluirati osnovne epidemiološke i kliničke karakteristike limfoma dječije dobi na Hematoonkološkom odjelu Pedijatrijske klinike Kliničkog centra Univerziteta u Sarajevu (KCUS) u desetogodišnjem periodu. Ispitanici i metode: istraživanje je obuhvatilo djecu kod kojih je dijagnostikovan limfom na Pedijatrijskoj klinici KCUS-a u periodu od 01.01.2004. do 31.12.2013. Retrospektivnom analizom oboljelih od limfoma dječije dobi, provedeno je kliničko ispitivanje kojim je obuhvaćeno 58 pacijenta u dobi od 0-15 godina, 37 dječaka i 21 djevojčica. Dobiveni rezultati su predstavljeni tabelarno i grafički, brojem i procenatualnom vrijednošću. Fišerovim testom je testirana razlika od normalne distribucije, a kao statistički značajna razlika smatran je (p<0.05). Rezultati: istraživanjem je obuhvaćeno 58 djece, 37 (63.80%) dječaka i 21 (36.20%) djevojčica. Najviše oboljelih bilo je u dobnoj skupini 8 - 15 godina i to 38 (65.50 %). Vodeći simptom limfoma dječije dobi je limfadenopatija koja je bila prisutna kod 45 (77.58%) pacijenata, zatim subfebrilnost kod 19 (32.75%), blijedilo 16 (27.59%), hepatosplenomegalija 13 (22.41%), te gubitak tjelesne težine kod 12 (20.69%) pacijenata. Kod 16 pacijenata sa HL i 14 pacijenata sa NHL bile su povišene vrijednosti LDH, a Cu u serumu kod 15 pacijenata sa HL i 10 pacijenata sa NHL. Najviše pacijenata oboljelih od HL-a je dijagnosticirano u II stadiju bolesti i to 12 (37.50%), a u IV stadiju 11 (34.40%) pacijenata. Najviše pacijenata oboljelih od NHL-a je dijagnosticirano u II stadiju i to 13 (50%), te u IV stadiju 8 (30.80%). Zaključak: kliničko–dijagnostičke metode i savremena terapija na Pedijatrijskoj klinici KCUS-u doprinose dobroj prognozi za pacijente oboljele od limfoma dječije dobi. Key words: Lymphoma, Hodgkin’s, Non Hodgkin’s, child Ključne riječi: Limfom, Hodgkin, Non Hodgkin, dijete INTRODUCTION dren. Lymphomas are divided into Hodgkin’s lymphoma (HL) and Non Hodgkin’s lymphoma (NHL) which are so different diseases in epidemiology, biology, diagnostic approach, treatment and prognosis, that they are treated quite separately. NHL represent about 60% of children’s lymphomas (1, 2). Hodgkin’s lymphoma is the most common malignant lymphoma, characterized by hyperplasia fields of lymphoid tissue in which there are Reed-Sternberg (RS) cells. It usually starts as a painless lymphadenopathy, usually in the neck, and later the disease expands In the general population, neoplasms in children represent 1% of all malignancies. By cause of death, they are in second place right after the accidents, with a prevalence of 10,60%. In children, the most common neoplasms are: leukemias, brain tumors and lymphomas. Lymphomas are the primary neoplasias of the lymphatic system, which are usually manifested by painless enlargement of the lymph nodes. They represent 10 - 13% of newfound malignancies in chil- 176 to other lymph nodes and may cause infiltration extra - lymphatic organs and tissues. Lymph nodes are much bigger and stronger than in benign lymphadenopathy, which is usually seen in children. General symptoms such as fever > 38 ° C, body weight loss > 10% in the last 6 months, night sweats, itchy skin, also called B symptoms, are not so common in children. The etiology of the disease is not clear. Most probably it is important influence of genetic predisposition and environmental factors, among which socio-economic and infectious factors are the important once. In almost 75% of the HL examples in childhood it is possible to prove the involvement of Epstein-Barr virus. In order to determine the treatment, the stage of the disease is determined on the basis of diagnostic biopsy and anatomical distribution. Intra-abdominal disease is normally diagnosed radiologically (ultrasound, CT, MRI) (3). Four types of HL are differentiated histopathologically: lymphocyte predomination, nodular sclerosis, mixed cellularity and lymphocyte depletion. Lymphocyte predomination has the most favorable prognosis and lymphocyte depletion the least favorable. Lymphocyte depletion in children is rare. The treatment of HL has dramatically improved in the past 40 years. With the combination therapy, which includes chemotherapy and radiotherapy, permanent cure is achieved in 80% of the patients. The most frequently applied protocols for the treatment of HL in children are: ABVD (Adryamicin, Bleomycin, Vincristine, DTIC), ChlVPP (Chlorambucil, Vinblastine, Procarbasid, Pronison), COPP (Ciclofosfamid, Oncovin, Procarbazine, Pronison) (4, 5). Non Hodgkin’s lymphomas (NHL) are clonal malignancies of lymphocytes. NHL are heterogeneous group of lymphoproliferative neoplasms marked by the emergence of malignantly altered lymphocytes in the lymph node, and rarely primary in other organs. It is characterized by rapid growth, early dissemination and a high degree of malignancy. Extremely rare occurs in children younger than 2 years after which the frequency increases gradually during childhood. Its peak is reached between the 7-10 year. NHL is 2-3 times more frequent in boys than in girls. According to the cell lines which belong to Non Hodgkin’s lymphoma is divided into B-NHL and T-NHL group. The World Health Organization (WHO) has classified NHL in children at four main types: B-cell Non Hodgkin’s lymphoma (Burkitt and non-Burkitt’s lymphoma), diffuse large B-cell lymphoma, lymphoblastic lymphoma, anaplastic large cell lymphoma. Five-year survival in patients who were diagnosed with NHL younger than twenty years was 86% (6, 7, 8). The aim of the study was to evaluate the basic clinical and laboratory characteristics of lymphoma in childhood at the Pediatric Clinic of CCUS in the ten year period. MATERIALS AND METHODS The study included children diagnosed with malignant lymphoma (Hodgkin and Non Hodgkin’s lymphoma), at the Department of Hematooncology, Pediatric Clinic of CCUS, in the period from January 1st 2004 to December 31st 2013. A total of 58 patients was analyzed, 37 boys and 21 girls, aged 0 - 15 years. The retrospective study of patients with childhood lymphoma was conducted. The results were presented using tables and charts, with number of cases and percentages. Statistical analysis of significant differences was E. Hasanbegović et al. performed using Fisher and Chi-square test. The values of p<0.05 or on the level reliability of 95% were considered statistically significant. The following was analyzed: • gender and age of the patients with Hodgkin (HL) and Non Hodgkin’s lymphoma (NHL) • clinical features of the patients • laboratory parameters • histopathologic classification • classification according to the degree of lymphoma spreading RESULTS Table 1 Gender distribution of children with lymphoma. Lymphoma boys girls total p-value HL % NHL % Total % 17 53.10 20 76.90 37 63.80 15 46.90 6 23.10 21 36.20 32 100.00 26 100.00 58 100.00 0.724 Chi-square test χ2 0.125 0.006 7.538 Table 1 shows the gender distribution of children with HL or NHL in ten year period. Malignant lymphoma was diagnosed in 58 patients, 37 (63.80%) boys and 21 (36.20%) girls. There was a statistically significant difference between the groups of boys and girls with NHL (p = 0.006; Chi-square = 7.538). Table 2 Age distribution of children with lymphoma. Age Lymphoma HL % NHL % Total % p-value 0-1 years 0 0 0 0 0 0 n/a 2-7 years 8-15 years 9 28.10 11 42.30 20 34.50 0.655 0.2 23 71.90 15 57.70 38 65.50 0.194 1.684 total p-value 32 100.00 26 100.00 58 100.00 0.013 Chi-square test χ2 6.125 0.433 0.615 0.018 5.586 Chi-square test χ2 Table 2 shows the age distribution of children with malignant lymphoma. Most of the patients were in the age group of 8 - 15 years, 38 patients (65.50%). There was a statistically significant difference in the total morbidity of malignant lymphoma between the age group of 2-7 and 8-15 years (p = 0.018; Chi-square = 5.586) and morbidity of HL between the age group of 2-7 and 8-15 years (p = 0.013, Chi-square = 6.125). Table 3 Clinical signs and symptoms of patients with ma- lignant lymphoma. p-value Lymphoma HL NHL Lymphadenopathy 26 19 0,297 Loss of appetite 7 3 0,206 Subfebrile temperature 9 10 0,819 Weakness 4 8 0,248 Hepatosplenomegaly 7 6 0,782 Weight loss 7 5 0,564 Paleness 11 5 0,134 Cough 3 6 0,317 Dryness of the oral mucosa 2 0 n/a Excessive sweating 2 1 0,564 Pain in the abdomen 3 5 0,48 Pain in the bones 1 5 0,102 177 Evaluation of clinical and laboratory characteristics of childhood lymphoma Table 3 shows the representation of symptoms of patients with malignant lymphoma. The most frequent symptoms were lymphadenopathy (HL 26, NHL 19 patients), subfebrile temperature (HL 9, 10 NHL patients), paleness (HL 11, NHL 5 patients) and hepatosplenomegaly (HL 7, NHL 6 patients). There was no statistically significant difference between the number of patients with HL and NHL with these symptoms. Table 4 Laboratory parameters. Laboratory parameters HL NHL p-value LDH 16 14 0,715 Ferritin 4 1 0,18 Beta 2 globulin 5 4 0,739 Serum Cu 15 10 0,75 Table 4 shows nonspecific laboratory parameters. In 16 patients with HL and 14 with NHL levels of LDH were elevated, and Cu serum levels in 15 patients with HL and 10 with NHL. There was no statistically significant difference between laboratory parameters and the type of lymphoma. p = 0.01, p < 0,05 Figure 1 Histopathological classification of Hodgkin’s lymphoma (HL). Figure 1 shows number of patients in relation to histopathological type of Hodgkin’s lymphoma. Most patients with HL belonged to the histopathological type of nodular sclerosis, 16 (50.0%) patients, and to mixed cellularity 11 (34.40%) patients. There was a statistically significant difference between the incidence of histopathological classifications of patients with HL (p = 0.01, p <0.05). p = 0.239, p>0.05 Figure 2 Histopathological classification of Non-Hod gkin’s lymphoma (NHL). Figure 2 shows the relationship between the two histopathological types of Non Hodgkin’s lymphoma. B-NHL was present in the majority of patients, 16 patients (61.50%) compared to T-NHL which was present in 10 (38.50%) patients. There was no statistically significant difference between the incidence of histopathological classifications of patients with NHL (p = 0.239, p> 0.05). p = 0.804, p > 0.05 Figure 3 Classification of Hodgkin’s lymphoma (HL) according to the clinical stage of disease progression (The Ann Arbor staging classification of Hodgkin’s lymphoma). Figure 3 shows the number of patients classified according to the Ann Arbor staging classification of Hodgkin’s lymphoma. Most patients were diagnosed in stage II, 12 patients (37.50%), followed by the 11 patients (34.40%) in stage IV and 9 (28.10%) in stage III. There was no statistically significant difference between clinical stages of HL (p = 0.804, p> 0.05). p = 0.152, p>0.05 Figure 4 St. Jude’s classification of Non Hodgkin’s lymphoma (NHL) according to the clinical stage of disease progression. Figure 4 shows the number of patients classified according to the clinical stage of disease progression. Most patients were diagnosed in stage II, 13 patients (50.0%) and 8 (30.80%) in stage IV. There was no statistically significant difference between clinical stages of NHL (p = 0.152, p> 0.05). DISCUSSION In our study, malignant lymphoma was diagnosed in 58 patients, 37 (63.80%) boys and 21 (36.20%) girls. HL was diagnosed in 32 patients, 17 boys (53.10%) and 15 girls (46.90%), which corresponds to the literature stating approximately equal ratio of morbidity in boys and girls. NHL was diagnosed in 26 children, 20 boys (76.90%) 178 and 6 girls (23.10%). Statistical analysis performed by using Fisher and Chi-square test showed that there was a significant difference between the number of boys and girls (p = 0.006; Chi-square = 7.538) suffering from NHL. Pourtsidis A, Pedrosa MF, et al. reported 2,5-3 times more affected boys compared to girls, aged up to 15 years (9, 10). The highest number of patients was in the age group of 8-15 years, 38 children (65.50%). In this group there were 23 patients (71.90%) with HL and 15 (57.70%) patients with NHL. In the age group of 2-7 years, there were 20 patients, which is 34.50% of all patients. Of these, 9 patients were with HL (28.10%), and 11 (42.30%) with NHL. Statistical analysis showed that there was a significant difference (p = 0.013; Chi-square = 6.125) between the age groups of patients with HL, as well as the difference between the age groups of the total number of patients (p = 0.018, Chi-square = 5.586), which corresponds to the literature. Howard SC, Metzger ML, et al. stated that the greatest incidence of HL and NHL was in the age group of 2-10 years, rarely occured before the age of two, and more often after the age of ten (11). There was no statistically significant difference between the age groups of patients with NHL (p = 0.43, Chi-square = 0.615) in our study. The main clinical symptom that dominated in HL and NHL was painless enlargement of the lymph nodes (lymphadenopathy). In children with HL lymphadenopathy was present in 26 cases, and in children with NHL in 19 cases. After lymphadenopathy, the most common associated symptoms were subfebrile temperature: HL 9, NHL 10; hepatosplenomegaly: HL 7, NHL 6; and weight loss: HL 7, NHL 5 (all these symptoms occured equally). The difference between HL and NHL was noticed in the occurrence of symptoms such as loss of appetite, paleness, weakness, cough and pain in the bones. Thus, for example, in HL: loss of appetite was registered in 7 patients, paleness in 11, compared to NHL: 3 patients with loss of appetite and 5 with paleness. While, in NHL more symptomatology occurred such as weakness: 8 patients, cough 6, pain in the bones 5, compared to HL: weakness 4 patients, cough 3 and pain in the bones 1 patient, the difference was evident, but not so relevant for statistically significant difference. Schwartz CL, Büyükpakmukcu M, et al. reported that the most common symptoms of lymphoma were lymphadenopathy, fever, loss of appetite, weight loss, weakness with night sweating and itchiness of the skin (1,12). The following non-specific laboratory parameters of lymphoma were monitored: lactate dehydrogenase (LDH), ferritin, β2-globulin and cuprum (Cu) in serum (2). The increase in their values indicated to worsening of the disease and its activity. LDH was elevated in 16 cases of HL and in 14 cases of NHL. Ferritin was elevated in 4 patients with HL and in 1 patient with NHL. β2-globulin was elevated in five patients with HL and in 4 with NHL, and Cu serum levels in 15 patients with HL and 10 patients with NHL. There was no statistically significant difference between the two groups of patients. The study conducted by Vinjamaram S et al. found that laboratory parameters in NHL such as LDH, β2-globulin, serum Cu were significant during the screening test, in monitoring the effects of therapy to the final cure. Ye QD, Pan C, et al. confirmed that laboratory parameters in HL, LDH, serum Cu, ferritin, β2-globulin E. Hasanbegović et al. were very important for prognosis, course and outcome of disease. These two studies showed that these laboratory parameters for both, HL and NHL, played a very important role in monitoring the disease and that there was no statistically significant difference between subtypes of lymphoma, which is consistent with our research (13,14). From the point of pathohistology, REAL (Revised European-American Lymphoma) classification is in use now, modified and accepted by the World Health Organization (WHO), which differs nodular form of lymphocyte predomination and classical Hodgkin’s lymphoma. Classical HL is divided into nodular sclerosis, lymphocyte predomination, mixed cellularity and lymphocyte depletion. It was noticed that nodular sclerosis was represented in the majority of cases, specifically in 16 cases (50.0%), followed by mixed cellularity in 11 patients (34.4%), while the lymphocyte predomination and depletion were represented in a smaller number. There was a statistically significant difference between the incidence of histopathologic classifications of patients with HL (p = 0.01, p <0.05). Obralić et. al reported that the most common was nodular type, with the representation of 40-70%, followed by mixed cellularity (30-50%), lymphocyte predomination (5-10%) and lymphocyte depletion with 1-5% (15). Our results correlate with the results in the international literature. Out of 26 patients with NHL, 16 (61.50%) had B-NHL, and 10 patients (38.50%) T-NHL. Murphy SB, et. al reported the incidence of B-NHL > 60%, or more precisely (65-70%), and of T-NHL <40%, or more precisely (30-35%) (7). The results of our study are approximate to the relevant literature. According to the clinical stage of disease progression, Hodgkin’s lymphoma was classified by the Ann Arbor classification system. Most new cases were diagnosed in stage II of the disease, 12 (37.50%), then in stage IV, 11 (34.40%), and in stage III, 9 patients (28.10%). There was no cases of HL diagnosed in the first stage. Xing PY, et al. noted that patients diagnosed with HL were 28.40% in stage I, 34.80% in stage II, 19.70% and 17.10% in stage III and IV (16). According to our research, most of Hodgkin’s lymphoma (HL) was diagnosed in stage II and IV, while according to international literature, HL in children was most represented in the first and second stage. According to the clinical stage of disease progression, non-Hodgkin’s lymphoma was classified by St. Jude’s classification system. The highest number of new cases were diagnosed at the time when they were already in stage II of disease, 13 (50%). There were 8 (30.80%) patients in stage IV and 5 (19.20%) in stage III. Adamson P, Murphy RF, et al. reported the results according to stages: I (18%), II (21%), III (43%) and IV (18%) (17). Non Hodgkin’s lymphoma (NHL) according to our results was the most represented in stage II, while according to relevant international literature, NHL was the most common in stage III. CONCLUSION Clinical diagnostic methods and modern therapy at the Pediatric Clinic of CCUS contribute to good prognosis for patients suffering from lymphoma in childhood. Conflict of interest: none declared. 179 Evaluation of clinical and laboratory characteristics of childhood lymphoma REFERENCES 1. Büyükpakmukcu M. Non-Hodgkin’s lymphomas. In: Cancer in Children: Clinical manegment. Fourth Edition, Voute P.A., Kalifa C, Barrett A. Eds. Oxford, Oxford University Press 1999:119-136. 2. Pizzo A, Poplack GD. Principles of Paediatric Oncology. 5th ed. Philadelphia: Lippincott Williams - Wilkins;2005. 3. Saunders C. Hsu, Monika L. Metzger, Melissa M. Hudson et al. Comparison of Treatment Outcomes of Childhood Hodgkin Lymphoma in Two US Centers and a Center in Recife, Brazil. Pediatric Blood Cancer 2007;49(2):139-44. 4. DeVita VT. A selective history of the therapy of Hodgkin’s disease. Br J Hematol 2003; 122(5): 718-27. 5. Thomson AB, Wallace WH. Treatment of paediatric Hodgkin’s disease: a balance of risks. Eu J Cancer 2002; 38(4):468-77. 6. Vats TS. Pediatric Non-Hodgkin’s lymphomas in children: diagnosis and current management. Indian Pediatrics 2001; 38(6):583-8. 7. Cairo MS et al. Non-Hodgkin lymphoma in children. In Kufe DW. Cancer medicine E. 6. London: BC Decker Inc, 2003; 374-87. 8. Hasanbegović E, Šabanović S. The results of Hodgkin lymphoma treatment in children in the period 1997-2006. Bosn J Basic Med Sci. 2008 Feb;8(1):72-5. 9. Pourtsidis A, Doganis D, Baka M, Bouhoutsou D, Varvoutsi M, Synodinou M, et al. Differences between younger and older patients with childhood hodgkin lymphoma. Pediatr Hematol Oncol. 2013 Sep;30(6):532-6. 10. Pedrosa MF, Pedrosa F, Lins MM, Pontes Neto NT, Falbo GH. Non-Hodgkin’s lymphoma in childhood: clinical and epidemiological characteristics and survival analysis at a single center in Northeast Brazil. J Pediatr (Rio J). 2007 Nov-Dec;83(6):547-54. 11. Cairo MS et al. Non-Hodgkin lymphoma in children. In Kufe DW. Cancer medicine E. 6. London: BC Decker Inc, 2003; 374-87. 12.Schwartz CL. The management of Hodgkin disease in the young child. Curr Opin Pediatr. 2003;15(1):10-6. 13.Vinjamaram S. Diagnosis signs and symptoms, laboratory studies in a patient with suspected NHL. Sep 20 2006;24(27):4418-25. 14.Ye QD, Pan C, Xue HL, Chen J, Zhou M, Jiang H, ET AL. [Outcomes of 104 children with B-cell non-Hodgkin lymphoma]. Zhonghua Xue Ye Xue Za Zhi. 2013 May;34(5):399-403. 15.Obralić N. Limfomi: Morbus Hodgkin, non-Hodgkin limfomi. U Mušanović M, Obralić N: Onkologija. Bošnjački institut, Sarajevo, Bosna i Hercegovina, 2002; 373396. 16. Office for National Statistics. Cancer Statistics registrations: Registrations of cancer diagnosed in 2008, England. Series MB1 no.39.2011. 17. Adamson P, Bray F, Costantini AS, Tao MH, Weiderpass E, Roman E. Time trends in the registration of Hodgkin and non-Hodgkin lymphomas in Europe. Eur J Cancer. 2007;43(2):391-401. Reprint requests and correspondence: Edo Hasanbegovic, MD, PhD Pediatric Clinic Clinical Center University of Sarajevo Patriotske lige 81 71000 Sarajevo Bosnia and Herzegovina Phone: +387 33 566 448 Email: [email protected] Original article Medical Journal (2014) Vol. 20, No. 3, 180 - 184 Importance of noninvasive markers in the assessment of portal hypertension as a liver cirrhosis complication Značaj neinvazivnih markera u procjeni portalne hipertenzije kao komplikacije jetrene ciroze Nenad Vanis*, Sanjin Glavaš, Amila Mehmedović, Rusmir Mesihović, Nađa Zubčević, Srđan Gornjaković, Azra Husić-Selimović, Aida Saray, Nerma Zahiragić Clinic of Gastroenterohepatology, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT SAŽETAK Timely detection and treatment of complications associated with liver cirrhosis, including portal hypertension and esophageal varices results in the improvement of quality of life of already sick patients. Frequent endoscopic exams are unpleasant for patients due to their invasive method, and their high costs make additional burden on the healthcare system. Recent researches have focused on the investigation of sensitivity and specificity of a numerous noninvasive parameters in the assessment of the presence and size of the esophageal varices, including the risk of bleeding. The objective of this study was to identify noninvasive parameters obtained through combining laboratory reports and the results of ultrasound morphometric measures in the assessment of esophageal varices presence in patients suffering from liver cirrhosis. Materials and methods: The present study included 40 patients diagnosed with liver cirrhosis and portal hypertension confirmed based on laboratory tests, proximal endoscopy and abdominal ultrasound. We analyzed the level of ammonia and the number of platelets in blood as well as presence of splenomegaly. Results: in 90% of the patients with liver cirrhosis and diagnosed portal hypertension increased level of ammonia in blood was detected, in over 80% of them reduced level of platelets in blood was registered, and over 80% of them suffered from splenomegaly. It was also confirmed that in over 90% of the referent patients two of the three analyzed parameters deviate from normal reference values. Furthermore, it was confirmed that affiliation to MELD score did not affect the ammonia levels in serum (p>0,05). Conclusion: in over 90 % of the patients diagnosed with portal hypertension and esophageal varices at least two of the three analyzed parameters were present (hyperammonemia, thrombocytopenia and splenomegaly). It was confirmed that affiliation to MELD score did not affect the ammonia levels in serum. Pravrovremeno otkrivanje i tretman komplikacija ciroze jetre, među koje spada i portalna hipertenzija, te variksi jednjaka poboljšava kvalitet života već oboljelih pacijenata. Učestali endoskopski pregledi su zbog invazivnosti pregleda neprijatni za bolesnike, a uz to zbog visoke cijene opterećuju zdravstveni sistem. U fokusu posljednjihm istraživanja je proučavanje senzitivnosti i specifičnosti brojnih neinvazivnih parametara u procjeni prisustva i veličine varikoziteta jednjaka, a time i rizika od krvarenja. Cilj rada bio je identifikacija neinvazivnih parametara dobijenih kombinacijom laboratorijskih nalaza i rezultata ultrazvučnih morfometrijskih mjerenja u proceni postojanja varikoziteta jednjaka kod oboljelih od ciroze jetre. Podaci i metode: u studiju je uključeno 40 pacijenata sa dijagnozom jetrene ciroze i kod kojih je na osnovu laboratorijskih pretraga, proksimalne endoskopije i ultrazvučnog pregleda abdomena potvrđena portalna hipertenzija. Ispitivan je nivo amonijaka i broj trombocita u krvi, te prisutnost splenomegalije. Rezultati: kod pacijenata sa cirozom jetre i dijagnosticiranom portalnom hipertenzijom više od 90% je imalo povišen nivo amonijaka u krvi, više od 80% smanjen broj trombocita u krvi te više od 80% pacijenata je imalo splenomegaliju. Također je potvrđeno da kod više od 90% pomenutih pacijenata dva od analizirana tri parametra odstupaju od referentnih vrijednosti. Potvrđeno je da pripadnost MELD klasi nema uticaja na vrijednost NH3 u serumu (p>0,05). Zaključak: kod pacijenata sa portalnom hipertenzijom i variksima jednjaka u više od 90% prisutna su najmanje dva od posmatrana tri parametra (hiperamonijemija, trombocitopenija i splenomegalija). Potvrđeno je da pripadnost MELD klasi nema uticaja na vrijednost NH3 u serumu. Key words: liver cirrhosis, portal hypertension, esophageal varices, ammonia level Ključne riječi: ciroza jetre, por talna hiper tenzija, variksi jednjaka, nivo amonijaka INTRODUCTION treatment of portal hypertension, significantly influence the patients’ life quality. Clinical importance of portal hypertension is defined based on the increase of portal pressure gradient to over 10-12mmHg, (V), given that the physiological value of the portal pressure gradient amounts to 1-5 mmHg. Portal hypertension as a complication related to the progression of liver cirrhosis, is a very important and complex medical issue. Timely detection and treatment of liver cirrhosis complications, including the 181 Importance of noninvasive markers in the assessment of portal hypertension as a liver cirrhosis complication Portal hypertension leads to the establisment of portosystemic collaterals and esophageal varices, which are the most common liver cirrhosis complications present in 50 to 80% of cases. Bleeding esophageal varices often occur in the first year after the diagnosis was set (1). Lethality of variceal bleeding is 17−57% (2−4). The bleeding can be predicted based on the assessment of the varices size and appearance (red cherry spots) (5, 6), and the bleeding incidence can be reduced by application of nonselective beta blockers (7, 8). Furthermore, it is believed that prophylactic endoscopic variceal ligitation reduces the incidence of the first variceal bleeding and mortality of the patients with large varices (9, 10). Accordingly, it is recommended that patients suffering from liver cirrhoses be subjected to endoscopic screening, spacifically annual screening is recommended for patients with minor esophageal varices, and once in two years for patients without varices ( 11,12). However, endoscopic exams are unpleasant for patients due to their invasive method and their high costs make additional burden on the healthcare system. Therefore, the researchers have recently focused on the investigation of sensitivity and specificity of a numerous noninvasive parameters in the assessment of the presence and size of the esophageal varices, including the risk of bleeding. Aim: the aim of this study was to identify noninvasive parameters obtained through combining laboratory reports and the results of ultrasound morphometric measures in the assessment of esophageal varices presence in patients suffering from liver cirrhosis. Conclusion: in over 90 % of patients diagnosed with portal hypertension and esophageal varices at least two of the three observed parameters (hyperammonemia, thrombocytopenia and splenomegaly) were present. MATERIALS AND METHODS Observational, clinical and retrospective study was conducted which included 40 randomly selected patients diagnosed with liver cirrhoses of different etiology, hospitalized and treated at Clinic for Gastroenterohepatology of the Clinical Center University of Sarajevo in the period from 2009 to 2013. There were 65% of male and 35% of female patients with the average age of 57.18±9,95. The patients most represented in the sample were in the 60 to 69 age group (34%), while the least represented were those in the age group from 30 to 39 years (3%). All patients were subjected to basic laboratory tests, proximal endoscopy and abdominal ultrasound. In all 40 patients the presence of different level of oesophageal varices progression was registered, as a complication associated with portal hypertension. The patients were selected according to their demographic variables, sex and age, MELD score, platelet count and level of ammonia in blood, as well as the presence or lack of splenomegaly. With regard to MELD score, platelet count and level of ammonia in blood the measured values were registered, whereas the presence or lack of splenomegaly was identified. Based on the measured MELD score, the patients were divided in two groups which were monitored and compared: Group 1: Patients with MELD score 0-15, comprising 48% of overall sample. Group 2: Patients with MELD score ≥16, comprising 52% of patients. The average values of MELD score amounted to 17,23±5.9. The average level of ammonia in blood was 76,3 ±32,1. Hyperammonemia was present in 84% of patients included in the study. The average platelet count was 119,7±80,84, while thrombocytopenia (<150) was present in 75% of patients. The size of patients’ spleen was also registered as well as the presence or lack of splenomegaly. Figure 1 presents the structure of sample based on splenomegaly presence. Spleen enlargement was registered in 75% of patients from the sample. 25% Splenomegalia: NE Splenomegalia: DA 75% Figure 1 Structure of sample based on splenomegaly presence. Given that it would be interesting to examine the cases with deviations in two of three observed values, the patients from the sample were divided in 4 groups: 0, 1, 2 or 3 symptoms were registered. Figure 2 presents the structure of the sample based on a number of symptoms. 8% 5% 0 1 2 54% 33% 3 Figure 2 Structure of sample based on a number of symptoms. The Figure shows the prevailance of patients with all three symptoms present (54%). It is also significant that 87% of patients from the sample had two or three associated symptoms registered. Results of the conducted descriptive analyses influenced the testing of accuracy of hypotesis related to the outspread of thrombocytopenia, hyperammonemia and splenomegaly in patients diagnosed with liver cirrhosis and portal hypertension: Hypotesis 1: hyperammonemia is present in over 90% of patients with portal hypertension and esophageal varice. Table 1 shows the test results based on proportion of hyperammonemia in population diagnosed with liver cirrhosis and portal hypertension. Table 1 Unilateral test based on proportion of hyperammonemia in the basic party. Value of parameter in sample Predicted parameter value in population Standard error First type error Level of significance z theoretic z empiric 0,85 0,90 0,047 0,05 (5%) 0,95 (95%) -1,645 -1,064 Given that z empiric > z theoretic, the conclusion is that the set hypotesis can be accepted. Hypothesis 2: thrombocytopenia is present in over 80% of the patients with portal hypertension and esophageal varices. 182 N. Vanis et al. Table 2 shows the test results based on proportion of thrombocitopenia in thepopulation of patients with liver cirrhosis and portal hypertension. Table 2 Unilateral test based on proportion of thrombocitopenia in the basic party. Value of parameter in sample Predicted parameter value in population Standard error First type error Level of significance z theoretic z empiric 0,75 0,80 0,045 0,05 (5%) 0,95 (95%) -1,645 -1,111 Given that z empiric > z theoretic, the set hypotesis is accepted on the level of significance of 95%. Hypotesis 3: splenomegaly is present in over 80% of the patients with portal hypertension and esophageal varices. Table 3 shows results of the unilateral test based on proportion of splenomegaly in population with liver cirrhosis and portal hypertension. Table 3 Unilateral test based on proportion of splenomegaly in the basic party. Value of parameter in sample Predicted parameter value in population Standard error First type error Level of significance z theoretic z empiric 0,75 0,80 0,045 0,05 (5%) 0,95 (95%) -1,645 -1,111 Given that z empiric > z theoretic, the set hypotesis can be accepted on the referent level of significance. Hypotesis 4: in over 90% of the patients with portal hypertension and esophageal varices two of the three analyzed symptoms are present (hyperammonemia, thrombocytopenia and splenomegaly). Table 4 shows results of unilateral tests based on proprtion of the patients with minimum two of the three analyzed symptoms. Table 4 Unilateral tests based on proportion of the patients with minimum two out of three symptoms in the basic party. Value of parameter in sample Predicted parameter value in population Standard error First type error Level of significance z theoretic z empiric 0,75 0,80 0,045 0,05 (5%) 0,95 (95%) -1,645 -1,111 In this case too z empiric > z theoretic. Accordingly the forth hypothesis is accepted on the level of significance of 95%. Given the role of the MELD score level in patients with liver cirrhosis and portal hypertension we tested the difference between the level of ammonia in blood in respect to a previously defined MELD classification (relatively low (0-15) and relatively high (16 and more) MELD score). With the purpose of the test results comparison, the first step was to test the assumption of „normality“. Results of Kolmogorov-Smirnov tests are presented in Table 5. Table 5 Results of Kolmogorov-Smirnov test for normality of variables. NH3 76,30 32,10 0,694 0,721 Means Standard deviation Kolmogorov-Smirnov Z p-value Based on the obtained p-value we can conclude that the ammonia level in blood satisfy the assumption of normality. In that regard and for testing the difference in respect to classification based on the level of MELD score t-test was used for standard difference between the two independent samples. The results of the test are presented in Table 6. Table 6 Results of t-test for standard difference of ammo nia based on MELD score classification. Leven e's test for equality of T-test on the equality of variances means Variable F p-value t p-value NH3 Equality of 0,140 0,710 -0,594 0,556 variances is purported Based on a high p-value (p=0.556>0.05) we can conclude that there is no significant statistical difference between the ammonia values in groups with relatively low and relatively high MELD score values. The results were checked with chi-square test for independence (χ2-test). Table 7 contains the results of the test application. Table 7 Results of χ2-test influence on MELD score class on presence of hyperammonemia. MELD class 0-15 16 and more Total Result of 2 - test No 4 2 6 Hyperammonemia Yes 15 19 34 Total 19 21 40 2 =1,040 p-value=0,308 Given that p-value is over 0,05, it is confirmed that the affiliation to MELD class did not affect the values of ammonia. DISCUSSION Liver cirrhosis is a chronic and progressive disease leading to development of portal hypertension, and development of esophageal varices is the most important complication of portal hypertension. Patients diagnosed with liver cirrhosis should be regularly monitored for the presence of esophageal varices, if the presence of portal hypertension has been identified. Given that esogastroduodenoscopy is an invasive and costly examination, and with a view of disburdening the endoscopic units, recent investigations have been focused on noninvasive markers for assessment of probability of the presence and level of esophageal varices. It is very important to identify the risk of bleeding esophageal varices with the assistance of noninvasive markers. The present study included examinees-patients diagnosed with liver cirrhosis, of different etiology, with verified esophageal varices. Statistical analyses of the results showed that majority of male population (65%) was represented in the sample, the represented age structure was from 60 to 69 years (345), whereas the age structure from 30 to 39 (3%) was the least represented which corresponds to range of the most represented liver cirrhosis in population. The total sample was divided in two groups, according to MELD score, with over half of the patients from the sample (52%) having Importance of noninvasive markers in the assessment of portal hypertension as a liver cirrhosis complication a relatively high MELD score (over 16). The presence of hyperammonemia was registered in 85% of examinees of the total sample, whereas the presence of thrombocytopenia was registered in 75% of the patients. Splenomegaly was registered in 75% of the patients from the sample. Taking into account the role of MELD score level in patients diagnosed with liver cirrhosis and portal hypertension the difference was analyzed between the level of ammonia in blood in respect to previously defined MELD classification (relatively low (0-15) and relatively high (16 and more) MELD score). In over 90% of the patients with portaql hypertension and esophageal varices at least two of the three observed symptoms were present (hyperammonemia, thrombocytopenia and splenomegaly). It was confirmed that affiliation to MELD class did not affect the ammonia values (p>0,05). It is evident that there is a clear correlation between the existence of esophageal varices and increased level of ammonia in blood, and the reduced number of platelets in blood. Furthermore, it is evident that high percentage of the patients with the confirmed esophageal varices suffer from spenomegaly. In the past investigations, the most frequently used noninvasive parameters were the number of platelets and splenomegaly. Specifically, Zaman et al. showed that patients with a platelet count under 88000/mm3 are five times more at risk of the existance of more expressed esophageal varices as opposed to patients with higher platelet count (13). Nq FH, et al. have identified the correlation between the existence of ascites, thrombocytopenia, hyperbilirubinemia and larger varices in Chiness population (14). Chalasani N, et al. have also established that trombocitopeny and splenomegaly are predictors of largest varices, where the platelet count with the highest discriminatory significance was 68000/mm3 (11). Splenomegaly and hypersplenism are common in patients diagnosed with liver cirrhosis with portal hypertension (11), and thrombocytopenia is a normal manifestation of hypersplenism with high specificity, but low sensitivity for the presence of portal hypertension (15). It is believed that thrombocytopenia mechanism is primarily sequestration and holding of platelets in enlarged spleen. However, Madhotra et al. established tha 32% of patients may have platelet count under 68 000/mm3 without detectable spelomegaly, which is explained with the reduced syntesis of thrombopoetin in these patients (12). Furthermore, it was established that level of thrombopoetin and platelet count are normalized following liver transplantation (16). Other possible factors for this phenomena are the existence of anti-platelet antibodies in circulation and platelet – connected immunoglobulins, which can be found in patients with liver diseases (17). On the other hand, based on ultrasound measurements of craniocaudal projection of liver it was established that it is liable to a small intra and inter- observatory variability unlike Doppler assessment of the hepatic diameter (18,19). Integration of the two parameters, platelet count and size of the ultrasound assessed spleen, resulted in a new pathophysiology significant parameter, which can be easily calculated and applicable in clinical practice. In their retrospective and prospective study Giannini et al. (20, 21) have showed that this index is sensitive for predicting the presence and size of varices. The same group of authors consider that the use of noninvasive parameters in diagnostic algoritm is useful primarily for identification of patients not suffering from esophageal varices. Based on the study results these 183 authors have presented cutoff value of their index of 909. In other words, patients with index over 909 should not receive prophylactic treatment with beta- blockers, given that there is a small probability for these patients to suffer from esophageal varices. These patients should only occasionally be subjected to endoscopic examination, which is of great medico-social importance. Also, ultrasound parameters obtained through doppler assessment of hepatic diameter are used for the assessment of portal hypertension. The results of these studies are contradictory, but it is considered that congestive index, obtained by division of speed of flow in port vein and diagonal section of port vain (22- 24), as well as hepatic arterial pulsatility index (25), are in correlation with the level of portal hypertension. Hovewer, doppler ultrasound examination require better training and ultrasound equipment with better technical possibilities. In the present study combined laboratory and ultrasound parameters were used in correlation with the presence of esophageal varices, and it was confirmed with high sensitivity and specificity that in over 90% of patients with portal hypertension and esophageal varices at least two of the three observed parameters (hyperammonemia, thrombocytopenia and splenomegaly) were present. It was confirmed that affiliation to MELD class did not affect the ammonia values in serum. This study contributes to investigation of prediction of esophageal varices presence, which has significant clinical implications. CONCLUSION In over 90% of patients with portal hypertension and esophageal varices at least two of the three observed parameters (hyperammonemia, thrombocytopenia and splenomegaly) were present. It was confirmed that affiliation to MELD class did not affect the ammonia values in serum. It is proper to use these parameters, both individually and in combination, as criteria for the selection of patients for endoscopic screening for esophageal varices, requiring further endoscopic treatment or monitoring. Conflict of interest: none declared. REFERENCES 1. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. N Engl J Med. 1988;319(15):983–9. 2. Graham DY, Smith JL. The course of patients after variceal hemorrhage. Gastroenterology 1981; 80(4): 800–9. 3. D’Amico G, Luca A. Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding. Baillieres Clin Gastroenterol. 1997;11(2):243–56. 4. Jensen DM. Endoscopic screening for varices in cirrhosis: findings, implications, and outcomes. Gastroenterology. 2002;122(6):1620–30. 5. Bhasin DK, Malhi NJ. Variceal bleeding and portal hypertension: much to learn, much to explore. Endoscopy. 2002;34(2):119–28. 6. Merkel C, Zoli M, Siringo S, van Buuren H, Magalotti D, Angeli P. Prognostic indicators of risk for first variceal bleeding in cirrhosis: a multicenter study in 711 patients to validate and improve the North Italian Endoscopic Club (NIEC) index. Am J Gastroenterol 2000; 95(10): 2915–20. 7. D’Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology. 1995;22(1):332–54. 8. Tripathi D, Hayes PC. Review article: a drug therapy for the prevention of variceal 184 hemorrhage. Aliment Pharmacol Ther. 2001;15(3): 291–310. 9. Khuroo MS, Khuroo NS, Farahat KL, Khuroo YS, Sofi AA, Dahab ST. Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding. Aliment Pharmacol Ther 2005; 21(4): 347–61. 10.Psilopoulos D, Galanis P, Goulas S, Papanikolaou IS, Elefsiniotis I,Liatsos C. Endoscopic variceal ligation vs. propranolol for prevention of first variceal bleeding: a randomized controlled trial. Eur J Gastroenterol Hepatol. 2005;17(10):1111–7. 11.Chalasani N, Imperiale TF, Ismail A, Sood G, Carey M, Wilcox CM. Predictors of large esophageal varices in patients with cirrhosis. Am J Gastroenterol 1999; 94(11): 3285–91. 12. Madhotra R, Mulcahy HE, Willner I, Reuben A. Prediction of esophageal varices in patients with cirrhosis. J Clin Gastroenterol 2002;34(1):81–5. 13. Zaman A, Hapke R, Flora K, Rosen HR, Benner K.Factors predicting the presence of esophageal or gastric varices in patients with advanced liver disease. Am J Gastroenterol 1999; 94(11):3292–6. 14. Ng FH, Wong SY, Loo CK, Lam KM, Lai CW, Cheng CS. Predicting oesophagogastic varices in patients with liver cirrhosis. J Gastroenterol Hepatol. 1999;14(8):785– 90. 15. Thomopoulos KC, Labropoulou-Karatza C, Mimidis KP, Katsakoulis EC, Iconomou G, Nikolopoulou VN. Non-invasive predictors of the presence of large oesophageal varices in patients with cirrhosis. Dig Liver Dis. 2003;35(7):473–8. 16. Martin TG 3rd, Somberg KA, Meng YG, Cohen RL, Heid CA, de Sauvage FJ. Thrombopoietin levels in patients with cirrhosis before and after orthotopic liver transplantation. Ann Intern Med. 1997; 127(4):285-8. 17.Goulis J, Chau TN, Jordan S, Mehta AB, Watkinson A, Rolles K. Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after orthotopic liver transplantation. Gut. 1999;44(5):754–8. 18. Winkfield B, Aube C, Burtin P, Cales P. Inter-observer and intraobserver variability in hepatology. Eur J Gastroenterol Hepatol. 2003;15(9):959–66. 19. O’Donohue J, Ng C, Catnach S, Farrant P, Williams R. Diagnostic value of Doppler assessment of the hepatic and portal vessels and ultrasound of the spleen in liver disease. Eur J Gastroenterol Hepatol. 2004;16(2):147–55. N. Vanis et al. 20.Giannini E, Botta F, Borro P, Risso D, Romagnoli P, Fasoli A.Platelet count/ spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis. Gut. 2003;52(8):1200–5. 21.Giannini EG, Zaman A, Kreil A, Floreani A, Dulbecco P, Testa E. Platelet count/ spleen diameter ratio for the noninvasive diagnosis of esophageal varices: results of a multicenter, prospective, validation study. Am J Gastroenterol. 2006;101(11):2511– 9. 22. Bolondi L, Li Bassi S, Gaiani S, Barbara L. Doppler flowmetry in portal hypertension. J Gastroenterol Hepatol. 1990;5(4):459−67. 23.Martins RD, Szejnfeld J, Lima FG, Ferrari AP. Endoscopic, ultrasonographic, and US-Doppler parameters as indicators of variceal bleeding in patients with schistosomiasis. Dig Dis Sci. 2000;45(5):1013–8. 24. Aube C, Winkfield B, Oberti F, Vuillemin E, Rousselet MC, Caron C. New Doppler ultrasound signs improve the noninvasive diagnosis of cirrhosis or severe liver fibrosis. Eur J Gastroenterol Hepatol. 2004;16(8):743–51. 25.Schneider AW, Kalk JF, Klein CP. Hepatic arterial pulsatility index in cirrhosis: correlation with portal pressure portal pressure. J Hepatol. 1999;30(5):876–81. Reprint requests and correspondence: Nenad Vanis, MD, PhD Clinic of Gastroentereohepatology Clinical Center University of Sarajevo Bolnička 25 71000 Sarajevo Bosnia and Herzegovina Phone: + 387 33 297 911 Email: [email protected] Professional article Medical Journal (2014) Vol. 20, No. 3, 185 - 190 Antimicrobial susceptibility of common isolated microorganisms in hip surgical wound Antimikrobna osjetljivost najčešće izolovanih mikroorganizama iz hirurških rana kuka Tarik Muharemović¹*, Mersiha Bašić-Muharemović², Šukrija Zvizdić3, Sadeta Hamzić3 General Hospital „Prim. Dr Abdulah Nakaš“, Kranjčevićeva 12, 71000 Sarajevo, Bosnia and Herzegovina, Institute for the Protection of Women and Motherhood of Canton Sarajevo, Josipa Vancaša 1, 71000 Sarajevo, Bosnia and Herzegovina, 3 Faculty of Medicine, University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina 1 2 *Corresponding author ABSTRACT Introduction: the development of orthopedics and traumatology results in an increase of surgical procedures, which consequently results in an increase of complications in terms of surgical wound infection. There was a prevailing opinion that if patients survive the operation, and if infection and sepsis occurs, death was almost inevitable consequence. Changes requiring surgical treatment on the hip are usually trauma, but also a large number of congenital and acquired hip diseases. The most frequent postoperative complication is wound infection. Infection of surgical wounds has been a significant problem since the existence of surgery. Infection of surgical wounds (Surgical Site Infections, SSIS) is an infection that occurs 30 days after the surgery, and one year after the implantation of operating foreign body (implant), in the part of the body where the surgery was performed. The Center for Disease Control and Prevention (CDC) has defined three types of these infections, adding recently a fourth type: incision, surface, deep and organic infections. Antibiotic prophylaxis elected should act on the most common causes of surgical-site infections, but not necessarily on all possible causes. Materials and Methods: the study is a prospective–retrospective, clinical-microbiological study, performed at the General Hospital „Prim. Dr. Abdulah Nakaš“ in Sarajevo, from January 2007 to April 2012. The study involved the patients observed and surgically treated at the Department of Orthopedics and Traumatology of the General Hospital „Prim. Dr. Abdulah Nakaš“ in Sarajevo. The target group consists of 60 subjects of both sexes and different age. Each patient included in the survey was subjected to microbial processing of biological materials taken in a standard way, prepared and microscoped. Results: all 60 patients were divided into groups according to their diagnoses, of which 23 (38.33%) patients were diagnosed with femur neck fracture, 15 (25.00%) with pertrochanteric fracture, 11 (18.33%) patients with coxarthrosis, 5 (8.33%) with intertrochanteric fracture, 3 (5.00%) with subtrochanteric fracture and 3 (5.00%) patients had other diagnosis. Results of microbiological analysis of the number of agents from the surgical wound, showed that one type of microorganism caused the infection detected in 50 (83.3%), and two infection agents in 10 (16.7%) patients. Of the total of 50 patients with microbiologically proven one type isolates from hip surgical wounds, 23 (46.0%) were diagnosed with femoral neck fracture, 11 (22.0%) patients were diagnosed with coxarthrosis, 9 (18.0%) with pertrochanteric fracture, 4 (8.0%) with intertrochanteric fracture, and 3 (6.0%) with subtrochanteric fractures, etc. Conclusion: the fracture of the femoral neck is the most common type of injury or disease in which the microorganism is isolated from the hip surgical wounds. Implantation of subtotal hip prosthesis is the most common type of surgery in which microorganisms are isolated from hip surgical wounds. The majority of patients were over 80 years. The most common microorganism isolated from hip surgical wounds was Acinetobaceter spp., followed by Staphylococcus aureus. Isolated strains Acinetobaceter spp showed the highest antimicrobial susceptibility to Imipenem with 84.6%, and the highest antimicrobial resistance to ciprofloxacin with 92.6%. Isolated strains of Staphylococcus aureus expressed the highest antimicrobial susceptibility to vancomycin and amikacin with 100.0%, and the highest antimicrobial resistance to sulfometoksazol-trimetoprim with 75.0%. Pseudomnas aeruginosa isolated strains showed the highest antimicrobial susceptibility to cefazolin, with 100.0%, and the highest antimicrobial resistance to cefuroxime, ceftriaxon, cefotaxime and sulfometoksasol-trimetoprim, with 100.0%. Key words: hip surgical wound, wound infections, antimicrobial susceptibility SAŽETAK Uvod: razvojem ortopedije i traumatologije povećava se broj operativnih zahvata, s čime se povećava i broj komplikacija u smislu infekcije hirurških rana. Prije je vladalo mišljenje, ako pacijenti i prežive operaciju, te ako nastupi infekcija i sepsa, smrt je bila gotovo neizbježna posljedica. Promjene koje zahtijevaju hiruški tretman na zglobu kuka su najčešće traume, ali i također veliki broj prirođenih i stečenih bolesti kuka. Kao najčešća postoperativna komplikacija spominje se infekcija rane. Infekcija hirurške rane je značajan problem od kada postoji hirurgija. Infekcija hirurških rana (eng. Surgical Site Infections, SSIs) je infekcija koja se javlja 30 dana nakon operativnog zahvata, odnosno godinu dana nakon operativne ugradnje stranog tijela (implantata), na dijelu tijela na kojem je izvršena operacija. Centar za kontrolu i prevenciju bolesti (Center for Disease Control and Pre- 186 vention, CDC) definirao je tri vrste ovakvih infekcija, a odnedavno je dodana i četvrta vrsta, površinske, duboke incizijske i organske. Antibiotik izabran za profilaksu trebao bi djelovati na najčešće uzročnike infekcija hirurškog mjesta, ali ne mora nužno djelovati na sve moguće uzročnike. Materijal i metode: istraživanje je prospektivno - retrospektivno, kliničko-mikrobiološka studija, izvedena u Općoj bolnici „Prim. dr. Abdulah Nakaš“ u Sarajevu, u periodu od pet godina i četiri mjeseca, tj. od januara 2007. godine do aprila 2012. godine. U istraživanje su uključeni ispitanici operisani i observirani na Odsjeku za ortopediju i traumatologiju Hirurškog odjeljenja Opće bolnice „Prim. dr. Abdulah Nakaš“ u Sarajevu. Ciljanu skupinu čini 60 ispitanika, oba spola i različite životne dobi. Od svakog pacijenta (ispitanika) uključenog u istraživanje vršena je mikrobiološka obrada bioloških materijala uzetih na standardan način nakon čega se pravio preparat koji se bojio po Gramu, te mikroskopirao. Rezultati: svih 60 pacijenata podijeljeni su u grupe prema dijagnozama, od čega je prelom vrata femura imalo 23 (38.33%) pacijenata, peritrohanterni prelom 15 (25.00%), koksartrozu 11 (18.33%) pacijenata, intertrohanterni prelom 5 (8.33%), subtrohanterni prelom 3 (5.00%) i ostalo 3 (5.00%). Rezultati mikrobiološkog ispitivanja broja uzročnika iz hirurških rana, pokazuju da je jedan uzročnik infekcije dokazan kod 50 (83.3%), a dva uzročnika infekcije kod 10 (16.7%) ispitanika. Od ukupno 50 pacijenata sa mikrobiološki dokazanom jednom vrstom INTRODUCTION The development of orthopedics and traumatology results in an increase of surgical procedures, which consequently results in an increase of complications in terms of surgical wound infection (1). There was a prevailing opinion that if patients survive the operation, and if infection and sepsis occurs, death was almost inevitable consequence. Because of that the surgery was reserved only for life endangered patients. In the late years of the 19th century, with the advent of Louis Pasteur and application of sterilization methods by Joseph Lister, surgeons were able to operate with significantly reduced risk of infection. Consequently, surgeons become more confident and began to explore the operational procedures in which they previously were not allowed to engage. Later, in the twentieth century, administration of the antibiotic prophylaxis has begun (2,3). Changes requiring surgical treatment on the hip are usually trauma, but also a large number of congenital and acquired hip diseases. Commonly referred congenital hip disease are: •Congenital (developmental) dislocation of the hip, •Epiphiseolisis of the femoral caput, •Legg-Calve-Perthes disease, etc. (4). Most frequently referred acquired diseases are: •Inflammatory diseases (acute septic arthritis, chronic rheumatoid arthritis, tuberculosis of the hip joint, etc.), •Posttraumatic conditions (femoral neck pseudoarthrosis, post-traumatic arthrosis of the hip, post-traumatic necrosis of the femoral head, collum angle changes, etc.), •Degenerative Diseases (coxarthrosis, hip neurogenic arthropathy, etc.), T. Muharemović et al. izolata iz hirurške rane kuka, 23 (46.0%) bilo je sa dijagnozom prelom vrata femura, 11 (22.0%) pacijenata imalo je dijagnozu koksartroza, 9 (18.0%) imalo je dijagnozu pertrohanterni prelom, 4 (8.0%) bilo je sa dijagnozom intertrohanterni prelom i 3 (6.0%) bilo je sa dijagnozom subtrohanterni prelom i ostalo. Zaključak: prelom vrata femura najučestaliji je tip povrede ili oboljenja kod kojeg je izolovan mikroorganizam iz hirurške rane kuka. Implantacija parcijalne proteze kuka najučestaliji je tip operativnog zahvata kod kojeg je izolovanmikroorganizam iz hirurške rane kuka. Najveći broj pacijenata bio je starosne dobi preko 80 godina. Najčešće izolovani mikroorganizam iz hirurške rane kuka je Acinetobaceter spp., a potom slijedi Staphylococcus aureus. Izolovani sojevi Acinetobaceter spp. iskazali su najvišu antimikrobnu osjetljivost na Imipenem sa 100.0%, a najvišu antimikrobnu rezistenciju na ciprofloxacin sa 92.6%. Izolovani sojevi Staphylococcus aureus-a iskazali su najvišu antimikrobnu osjetljivost na vankomicin i amikacin sa 100.0%, a najvišu antimikrobnu rezistenciju na Sulfometoksazol-trimetoprim sa 75,0%. Izolovani sojevi Pseudomnas aureus-a iskazali su najvišu antimikrobnu osjetljivost na cefazolin, sa 100.0%, a najvišu antimikrobnu rezistenciju cefuroxime, ceftriaxon, cefotaxime i sulfometoksasol-trimetoprim, sa 100.0%. Ključne riječi: hirurška rana kuka, infekcije rane, antimikrobna osjetljivost •Other diseases (idiopathic aseptic necrosis of the femoral head in adults, acetabular protrusion, Coxa saltans, hip chondromatosis, etc.) (4). The most frequently mentioned postoperative complication is wound infection (1). Infection of surgical wounds has been a significant problem since the existence of surgery. Surgical Site Infections (SSIS) are infections that occur not later than 30 days after the surgery, and one year after the implantation of operating foreign body (implant) in the part of the body where the surgery was performed (5). The Center for Disease Control and Prevention (CDC) has defined three types of these infections, recently adding a fourth type of infection: incision, surface, deep, and organic (6,7). Nosocomial infections continue to be a major health, economic and social problem (8). Growing number of surgical procedures in the area of the hip joint result in an increase of postoperative complications of which infection is the most frequently referred. It is important to make distinction between superficial wound infection and deep infection. The rate of deep infections in patients fitted with orthopedic implants ranges from 0.6 to 2.3% , while the infection rate in some institutions rnges up to 10% (9). As a possible causes of infection of surgical wounds of patients undergoing hip surgery, the most commonly isolated pathogens are certain representatives of Gram - positive cocci and Gram - negative bacill (10). Frequently referred Gram - positive cocci are Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus spp, and other, while frequently referred Gram - negative bacilli are Haemophilus influenzae, Enterobacteriaceae (Escherichia coli, Shigella spp, Salmonella, Enterobacter spp, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Cit- Antimicrobial susceptibility of common isolated microorganisms in hip surgical wound 187 robacter spp, Hafnia spp, Serratia spp), Pseudomonas aeruginosa, Acinetobacter spp, etc. Among mushrooms, which are potentially possible causes of wound infections, the most commonly isolated is Candida albicans (11). The most common cause of serious infections of surgical wounds, affecting not only the skin, is Staphylococcus aureus. It is estimated that about 50% of severe infections after orthopedic surgical procedures is caused by S. aureus, and about 50% of these infections are caused by methicillin- resistant S. aureus (MRSA), which is resistant to most antibiotics of certain groups (12,13). Risk-factors for the development of infections are comorbidities (diabetes, rheumatoid arthritis), extreme obesity, immunosuppressive therapy, older age, use of corticosteroids before surgery, malnutrition, inadequate sterilization, inadequate handling of sterile material, concomitant infection or recent surgery. The above risk factors significantly increase the chance of infection after surgery on the hip (14). Infections after the hip surgery may occur as early and late infections. Early infections occur, not later than one month following the operation, and late infections occur more than one month after surgery. Described are also cases when the infection was first demonstrated several years after surgery (15). When selecting antibiotics in surgical prophylaxis, it is important to take into account certain specific circumstances. With pure selective surgical procedure, in which there is no damage to the tissue that contains the normal micro flora, antibiotics are not indicated. In these cases, the risk of possible side effects resulting from the application of antibiotics is greater than the benefit of any prophylaxis. Exceptions are only the procedures in which bone or joint implants are implanted (16). Antibiotic prophylaxis elected should act on the most common causes of surgical-site infections, but not necessarily on all possible causes. The choice of antimicrobial drug depends mostly on anatomical accommodation of surgical procedure, duration and type of surgery. In addition, a drug used in prophylaxis should be different from the drugs used in the treatment of the same anatomical region, in order to prevent the emergence of bacterial resistance and preserve those drugs which are effective in the treatment of infection of each anatomical region (17). The aim of the study is to show the antimicrobial susceptibility of microorganisms isolated from the hip surgical wounds. disease, accompanying diseases, etc. Each patient included in the survey was subjected to microbial processing of biological materials taken in a standard way, prepared and microscoped (18). During the wound treatment the collected material was inoculated in culture medium and incubated under appropriate conditions and for appropriate time. Isolation and identification of infectious agents was carried out using the standard microbiological methods. Swabs taken from the relevant biological materials were sown on blood agar, Endo agar or McConkey agar, and incubated for 24-48 hours at the temperature of 35-37 C. The samples taken were processed in accordance with the primary and secondary microbiological studies. The agents were identified based on the characteristic appearance of colonies, biochemical and antigenic test strains. For each isolated microorganism species testing of their antimicrobial susceptibility / resistance to appropriate antimicrobials was done (18). In our study, samples of surgical wounds were not analyzed for the presence of anaerobic pathogens. Each of the isolated pathogens is examined by the appropriate disk diffusion method for its sensitivity / resistance to the appropriate representatives of the group of antimicrobial drugs, the method according to the Kirby - Bauer by the NCCLS (18). Based on the collected data the statistical analysis was performed. SPSS 17.0 program for Windows (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis of the data. MATERIALS AND METHODS The study is a prospectively - retrospective, clinical- microbiological study, performed at the General Hospital „Prim. Dr Abdulah Nakaš“ in Sarajevo, from January 2007 to April 2012. The study involved patients observed and surgically treated at the Department of Orthopedics and Traumatology of the General Hospital „Prim. Dr Abdulah Nakas“ in Sarajevo. The target group consisted of 60 subjects of both sexes and different age. From an objective medical examination, anamnesis and available medical documentation, insight into the type of disease and injury was obtained, as well as the type of surgical treatment. In addition, basic information about the patient was collected as well as information on type of therapy, presence of complications of the underlying RESULTS All 60 patients were divided into groups according to their diagnoses, of which 23 (38.33%) patients were diagnosed with femur neck fracture, 15 (25.00%) with pertrochanteric fracture, 11 (18.33%) patients with coxarthrosis, 5 (8.33%) with intertrochanteric fracture, 3 (5.00%) with subtrochanteric fracture and 3 (5.00%) patients had other diagnosis (Figure 1). Figure 1 Rate of representation between types of injuries or illnesses. From the total of 60 patients treated for isolated microorganisms from surgical wounds, 21 (35.0%) belonged to the age group up to 74 years, 13 (21.7%) patients belonged to the age group of 75-79 years, while 26 (43.3%) patients belonged to the age group of 80 and over (Figure 2). 188 T. Muharemović et al. Figure 2 Rate among type of injury or disease by age of patients. Table 1 Type of surgical procedure. TYPE OF SURGICAL PROCEDURE No. % 26 43.3 Partial hip repleacement 12 20.0 Osteosinthesis with condylar plate 10 16.6 Total cementless hip repleacement 4 6.7 Total cemented hip repleacement 4 6.7 Osteosinthesis with angular plate 4 6.7 Other procedures Total 60 100.0 From the total of 60 patients surgically treated for microorganisms isolated from hip surgical wounds, in respect to the type of surgery, during the investigation there was a total of 26 (43.3%) patients with implantation of partial endoprosthesis, 4 (6.7%) patients with implantation of total bone cement prosthesis, 10 (16.6%) with implantation of total prosthesis without bone cement, 12 (20.0%) patients underwent the surgery osteosynthesis with a condylar plate, in 4 (6.7%) patients surgery osteosynthesis with angular plate was performed, while 4 (6.7%) patients were assigned to the group of other surgical procedures (Table 1). Results of the microbiological analysis of the number of pathogens isolated from the hip surgical wound showed that one pathogen was proved as a cause of the infection detected in 50 (83.3%) patients, and two pathogens in 10 (16.7%) patients. Of the total of 50 patients with microbiologically proven one type isolates from hip surgical wounds, 23 (46.0%) were diagnosed with femoral neck fracture, 11 (22.0%) patients were diagnosed with coxarthrosis, 9 (18.0%) with pertrochanteric fracture, 4 (8.0%) with intertrochanteric fracture, and 3 (6.0%) with subtrochanteric fractures, etc. Of the total of 10 patients with microbiologically proven two types of isolates from hip surgical wound, 3 (30,0%) patients were diagnosed with fracture neck of femur, 6 (60.0%) with pertrohanter- Table 2 Overview of microbial positive isolates (one or two isolated pathogens). Femoral neck fractures Number of isolated microorganism ONE TWO TOTAL 20 3 23 (40.0%) (30.0%) Coxarthrosis 11 (22.0%) 0 (0.0%) 11 Pertrohanteric fractures 9 (18.0%) 6 (60.0%) 15 Intertrohanteric fractures 4 (8.0%) 1 (10.0%) 5 Other 6 (12.0%) 0 (0.0%) 6 TOTAL 50 (83.3%) 10 (16.7%) 60 (100%) TYPE OF INJURY OR DISEASE nic fracture, and 1 (10,0%) patient with two agents was from the intertrochanteric fracture group (Table 2). It did not happen that two pathogens causing the hip wound infection were isolated in patients diagnosed with coxarthrosis. Out of the total of 70 isolated and identified bacterial isolates, the most represented was the bacterium Acinetobacter spp in 27 (45.8%) cases, followed by Staphylococcus aureus in 20 (33.9%) cases, Pseudomonas aeruginosa in 7 (11.9%) cases, Enterococcus faecalis in 6 (10.2%) cases, Proteus mirabillis in 3 (5.1%) case, Staphylococcus epidermidis in 3 (5.1%) case, and 2 (3.4%) cses with isolates of Klebsiella spp, and 1 (1.7%) isolate of Serratia marcescens and Streptococcus viridans, respectfully (Figure 3). Figure 3 Frequency rate of microorganism species isolated from hip surgical wounds. Table 3 Results of antimicrobial susceptibility testing of isolated Acinetobacter species strains. S Antibiotik Total tested (100,0%) No I R % No % No % 37,0 3 11,1 14 51,9 3,7 14,8 11,1 11,1 7,4 11,1 11,1 23,1 84,6 16,7 1 0 0 0 0 0 0 3 1 6 3,7 0,0 0,0 0,0 0,0 0,0 0,0 11,5 3,8 25,0 25 23 24 24 25 24 24 17 3 14 92,6 85,2 88,9 88,9 92,6 88,9 88,9 65,4 11,5 58,3 80,8 0 0,0 5 19,2 Broj Amoxicil lin + 10 Clav. Kiselina 27 Ampicilin 27 1 Cefalotin 27 4 Cefazolin 27 3 Cefuroxim 27 3 Ciprofloksacin 27 2 Ceftriaxon 27 3 Cefotaxime 27 3 Gentamicin 26 6 Imip enem 26 22 Sulfometoksazol -trimetoprim 4 24 Meropenem 26 21 Table 4 Results of antimicrobial susceptibility testing on Staphylococcus aureus isolated strains. Antimicrobial susceptibility of common isolated microorganisms in hip surgical wound Table 5 Results of antimicrobial susceptibility testing on Pseudomonas aeruginosa isolated strains. S Antibiotik Total tested (100,0%) I No % No R % No % Amoxicillin + Clav. Kiselina 7 3 42,9 2 28,6 2 28,6 Ampicillin Ampicillin + Sulbactam Cefalotin Cefazolin Cefuroxim Ciprofloksacin Ceftriaxon Cefotaxime Gentamicin Imipenem Sulfometoksaz. -trimetoprim Meropenem 7 7 7 7 7 7 7 7 7 7 7 7 1 4 1 7 0 1 0 0 1 6 0 6 14,3 57,1 14,3 100,0 0,0 14,3 0,0 0,0 14,3 85,7 0,0 85,7 0 0 0 0 0 0 0 0 2 0 0 0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 28,6 0,0 0,0 0,0 6 3 6 0 7 6 7 7 4 1 7 1 85,7 42,9 85,7 0,0 100,0 85,7 100,0 100,0 57,1 14,3 100,0 14,3 DISCUSSION All 60 patients were divided into groups according to their diagnose, of which 23 (38.33%) patients were diagnosed with fracture neck of femur, 15 (25.00%) with peritrohanteric fracture, 11 (18.33%) patients with coxarthrosis, 5 (8.33%) with intertrochanteric fracture, 3 (5.00%) with subtrochanteric fracture and 3 (5.00%) were diagnoses otherwise. According to a research conducted by the Department of Health of the State of New York in September 2011, which included 167 hospitals, and where 26,286 hip operations were reported in the period of January-December 2010, the percentage of infection was 1.12%. The above percentage is related only to hip aloarthroplastic surgery. Of these 31% were superficial, 42% deep and 27% infection organic space. A similar percentage was also reported in 2008 and 2009. From the isolated pathogen in New York, USA, Staphylococcus aureus was the most frequent with 54.4% followed by MRSA with 26.4%, Enterococcus spp with 9.2%, etc. (19). Most authors still describe the percentage of infection of 1-2%, but it generally refers to a deep infection. Some authors refer to the percentage of infection of approximately 10%, which is very rare (20,21,22). Out of the total of 70 isolated and identified bacterial isolates, the most represented was the bacterium Acinetobacter spp in 27 (45.8%) cases, followed by Staphylococcus aureus in 20 (33.9%) cases, Pseudomonas aeruginosa in 7 (11.9%) cases, Enterococcus faecalis in 6 (10.2%) cases, Proteus mirabillis in 3 (5.1%) case, Staphylococcus epidermidis in 3 (5.1%) case, and 2 (3.4%) cses with isolates of Klebsiella spp, and 1 (1.7%) isolate of Serratia marcescens and Streptococcus viridans, respectfully. The percentage of patients with an isolate obtained from the hip surgical wounds was far greater in the operations that were carried out immediately due to trauma than in those patients in whom surgery was elective. Infections were common in patients with comorbidity and elderly patients. Care of the patients who develop surgical site infections after discharge, is significantly more expensive than the care of the patients without infection, given that the patients with infection visit the general practitioner and emergency hospital centers 7.5 times more often, than those without infection. It is therefore necessary 189 to develop a strategy for the prevention of these infections, as well as all other infections incurred in health care institutions, as part of national programs developed so far in many countries, aimed at patient safety. Frequently used ceftriaxone, applied in perioperative prophylaxis, expressed antimicrobial susceptibility in 21 (35.0%) patients, and cefazolin, a drug that is the method of choice in preoperative prophylaxis, showed sensitivity in 20 (33.3%) patients. CONCLUSION Femoral neck fracture is the most common type of injury or disease with positive isolate from the hip surgical wounds, represented in 23 (38.3%) cases. Implantation of partial hip endoprothesis is the most common type of surgical procedure in which the microorganism were isolated from hip surgical wounds, represented in 26 ( 43.3% ) cases. The largest number of patients aged over 80, a total of 26 (43.3%), was with positive isolation. Most frequently isolated microorganism from the hip surgical wounds is Acinetobaceter spp (45.8% of cases), followed by Staphylococcus aureus in 33.9%, Pseudomonas aeruginosa in 11.9% and Enterococcus faecalis in 10.2% of cases. Acinetobaceter spp isolated strains expressed the highest antimicrobial susceptibility to Imipenem, with 84.6%, and the highest antimicrobial resistance to ciprofloxacin, with 92.6%. Staphylococcus aureus isolated strains expressed the highest antimicrobial sensitivity to vancomycin and amikacin with 100.0%, and the highest antimicrobial resistance to sulfometoksasol-trimetoprim, 75.0%. Pseudomnas aeruginosa isolated strains showed the highest antimicrobial susceptibility to cefazolin, with 100.0%, and the highest antimicrobial resistance to cefuroxime, ceftriaxon, cefotaxime and sulfometoksasol-trimetoprim, with 100.0%. Conflict of interest: none declared. REFERENCES 1. Banović D. et al., Traumatologija koštano-zglobnog sistema. Beograd: Zavod za udžbenike i nastavna sredstva; 1998;533-619. 2. Guidelines for Perioperative Antibiotic Prophylaxis. In: Abrutyn E, Goldmann DA, Scheckler WE. Infection Control Reference Service. 2nd ed. Philadelphia: W.B. Saunders; 2001;343-5. 3. Prpić I. et al. Infekcije u kirurgiji za medicinare. Zagreb: Školska knjiga; 2002;58-63. 4. Pećina M. Et al. Ortopedija. Zagreb: Naklada Ljevak; 2004;286-324. 5. Centers for Diesase Control and Prevention, Surgical Site Infection (SSI) http:/www.cdc.gov/ncidod/dhqp/ FAQ_SSI html (10. Januar 2011). 6. Konjhodžić F. et al. Infekcije u hirurgiji. Sarajevo: Institut za naučnoistraživački rad i razvoj KCUS; 2001;217-219. 7. Gross P. Dramatic improvments in healthcare quality you can do it too. In Mayhall GC, editor. Hospital epidemiology and infection control. Baltimore: Wiliams and Wilikins; 2004;99-105. 8. Roy MC, Perl TM. Basic of surgical-site infection surveillance. Infect control Hosp Epidemiol. 1997; 18(9): 659-68. 9. Francetić I, Sardelić S, Bukovski-Simonoski S, Santini M., Betica-Radić Lj. et al. Lijec Vjesn. 2010;132(7-8):203-17. 10. Bešlagić E. et al. Medicinska mikrobiologija. Sarajevo: Medicinski fakultet Univerziteta u Sarajevu; 2010;166:193-264. 11.Graves N, Halton K, Curtis M, Doidge S, Larison D, McLaws M, et al. Costs of surgical site infections that appear after hospital discharge. Emerg Infect Dis. 2006;12(5):831-4. 190 T. Muharemović et al. 12.Gillespie WJ, Walenkamp G. Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD000244. 13. Š. Đozić, S. Đozić. Endoproteza kuka - Implantati i rehabilitacija. Sarajevo: Farmaceutski fakultet; 2009;11-13. 14. Hukić M. et al. Prevencija i kontrola infekcija u zdravstvenim ustanovama. Sarajevo: TDP Sarajevo; 2010;47-57; 96-98. 15. Grubor P. Hirurški pristupi u ortopediji. Banja Luka: Medicinski fakultet Banja Luka; 2010;141-155. 16.Mohamed Daabiss. American Society of Anaesthesiologists physical status classification physical status classification. Indian J Anaesth. 2011;55(2):111–115. 17. Zvizdić Š, Bešlagić E, Kapić E. Mikrobiologija s parazitologijom. Priručnik za studente farmaceutskog fakulteta. Sarajevo: Farmaceutski fakultet, 2006. 18. Hospital acquired infectiones. New York State, Department of Health, Albany, NY; September 20, 2011. 19. Van Kasteren ME, Manniën J, Ott A, Kullberg BJ, de Boer AS, Gyssens IC. Antibiotic Prophylaxis and the Risk of Surgical Site Infections Following Total Hip Arthoplasty: Timely Administration Is the Most Important Factor. Clin Infect Dis. 2007; 44: 921927. 20.Hollenbeak CS, Lave JR, Zeddies T, Pei Y, Roland CE, Sun EF. Factors associated with risk of surgical wound infections. Am J Med Qual. 2006;21:29S-34S. 21.http://www.hipsandknees.com/hip/hipsurgerycomplications.htm 22.Yokoe DS, Noskin G, Miner AL, Kenneth E, Sands K, Yokoe DS, Freedman J, Thompson K, James M, Plat R. Enhanced identification of postoperative infections among inpatients. Emerg Infect Dis. 2004;10:1924-30. Reprint requests and correspondence: Tarik Muharemović, MD General Hospital „Prim dr. Abdulah Nakaš“ Kranjčevićeva 12 71000 Sarajevo Bosnia and Herzegovina Email: [email protected] Bosnia and Herzegovina is high risk region for fatal CVD events! Bosna i Hercegovina pripada visoko rizičnom regionu za fatalne KV ishode! Professional article Medical Journal (2014) Vol. 20, No. 3, 191-193 Five-year work of the birthing unit of the Clinic for Gynecology and Obstetrics; perinatal report Petogodišnji rad porođajne sale Klinike za ginekologiju i akušerstvo; perinatalni izvještaj Mohamad Abou El-Ardat*, Ejub Bašić, Nermin Hadžić, Fatima Gavrankapetanović, Lejla Imširija, Eldar Mehmedbašić, Amela Hodža Clinic of Gynecology and Obstetrics of the Sarajevo University Clinical Center, Patriotske lige 81, 71000 Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT SAŽETAK The Clinic of Gynecology and Obstetrics of the Clinical Center University of Sarajevo is a tertiary level of health care with over 3,500 infants born every year. The birthing unit of the Clinic provides 24/7 service throughout the year. It has the most contemporary equipment for vaginal delivery, with 10 beds and rooms for delivery in the presence of a husband (spause). Also, there are ORs that can be accessed directly from the delivery room, if required. This paper provides a presentation of the work of the birthing unit within the Clinic in the period from 2009 to 2013, frequency of deliveries ending in surgical procedures, manner and number of deliveries, and presentation of other manual methods and interventions applied during delivery. Over the five year period (2009-2013) a total of 17,157 women gave birth in the birthing unit of the Clinic of Gynecology and Obstetrics of CCUS, or to be specific, there were 5.526 (32.21%) Caesarean sections (C-sections) and 11.631 (or 67.79%) vaginal deliveries. Over the five-year period, 17.356 babies were born in the Clinic of CCUS. Most of the babies were born in 2009. The highest number of twins was recorded in 2013 (n=89), and triplets in 2010 (n=7). The highest perinatal mortality rate was recorded in 2013 (7.4 ‰), and the lowest in 2010 (4.3 ‰). In the last three years, the perinatal mortality was around 7 ‰, which matches the perinatal mortality rates in European hospitals. Following the period of low birth rate, in the past few years the number of deliveries in the Clinic recovered, nearing the average from 2009. The C-section rate is still very high. However, this number stabilized in 2013 at around 30%, which exceeds all epidemiological indicators. Perinatal mortality has been stable over the last three years, coinciding with the European Union incidence rate. Klinika za ginekologiju i akušerstvo Kliničkog centra Univerziteta u Sarajevu (KCUS) predstavlja tercijalni nivo zdravstvene zaštite sa preko 3500 poroda na godišnjem niovu. Porođajna sala Klinike za akušerstvo je organizovana tako da pruža usluge 24h dnevno u toku cijele godine. U porođajnoj sali se nalazi najsavremenija oprema za vaginalni porod, sa ukupno 10 porođajnih kreveta, sa prostorijom za porod uz prisustvo supruga (partnera). U sklopu Klinike za ginekologiju i akušerstvo nalaze se i operacione sale do kojih se direktno dolazi iz porođajne sale, u hitnim slučajevima. Ovim istraživanjem je dat detaljni prikaz rada porođajne sale Klinike za ginekologiju i akušerstvo od 2009-2013 godi-ne, učestalost operativnog dovršetka poroda, način i broj poroda, te prikaz ostalih manuelnih tehnika i inetervencija koje su primjenjene tokom poroda. U petogodišnjem periodu (2009-2013. godine) u porođajnoj sali Klinike za ginekologiju i akušerstvo KCUS-a porođeno je ukupno 17157 žena. Od ukupnog broja poroda carskim rezom je porođeno 5526 (32,21%) žena, a vaginalno je porođeno 11631 (67.79%) žena. U petogodišnjem periodu na Klinici za akušerstvo KCUS rođeno je 17356 beba. Najveći broj beba je rođen u 2009. godini. Najveći broj gemina je bilo u 2013. godini (n=89), dok je najveći broj tripleta zabilježen u 2010 godini (n=7). Najveći perinatalni mortalitet je zabilježen u 2013. godini (7.4‰), a najmanji u 2010. godini (4.3 ‰). Perinatalni mortalitet se kretao u istim vrijednostima od oko 7‰ u posljednje tri godine što se poklapa sa vrijednostima perinatalnog mortaliteta evropskih porodilišta. Nakon pada broja poroda, posljednjih godina broj poroda na Klinici za akušerstvo se oporavlja te se vraća na prosječni broj iz 2009. godine. Procenat carskih rezova i dalje je jako visok, ali je u 2013. godini došlo do stabilizacije sa prosječnih oko 30%, što prevazilazi sve epidemiloške parametre. Perinatalni mortalitet je u posljedne 3 godine konstantan te se podudara sa incidencom porodilišta Evropske unije. Key words: delivery, Caesarean section, perinatal mortality Ključne riječi: porod, carski rez, perinatalni mortalitet INTRODUCTION officially opened on 25 November 2010. The Birthing Center of the Clinic of Gynecology and Obstetrics provides 24/7 service throughout the year. It has the most contemporary equipment for vaginal delivery, with 10 beds and rooms for delivery in a the presence of a husband (spause). Also, there are ORs that can be accessed directly from the delivery room in case of emergency. The Clinic of Gynecology and Obstetrics of CCUS is a tertiary level of health care with over 3,500 infants born every year. During the 1992-1995 war, the building of the Clinic was destroyed and the Clinic was moved to another location within CCUS. In 2010, the original building of the Clinic in Jezero (Sarajevo) was restored and 192 Figure 1 Delivery room. For centuries pregnancy has been causing fear of negative outcome for either the mother or the baby. Unfortunately, this was very common in the past. All of us, who have ever been present at a delivery, know that there is nothing more natural and normal than a natural birth. We also know that nothing is abnormal as an abnormal birth. It is unbelievable how one can become the other in the blink of an eye (1). Research objective: thorough presentation of the work of the Birthing Center within the Clinic of Gynecology and Obstetrics in the period from 2009 to 2013, frequency of deliveries ending in surgical procedures, manner and number of deliveries, and presentation of other manual methods and interventions applied during delivery. MATERIALS AND METHODS The research was carried out at the Clinic of Gynecology and Obstetrics of CCUS in the period from 2009 to 2013. A database has been created using the data collected from the birthing center, which keeps all delivery-related data (parity, delivery method, interventions during delivery, information about infants). The data were entered into MS Excel and then exported to the SPSS software (v20.0) for statistical analysis. Chi-squared test was used for statistical evaluation of qualitative data. Research findings: over the five year period (2009-2013) a total of 17,157 women gave birth in the Birthing Center of the Clinic for Gynecology and Obstetrics of CCUS, namely there were 5,526 (32.21%) Caesarean sections (C-section), and 11,631 (67.79%) vaginal deliveries. Table 1 Number of deliveries (vaginal–C-section) during the observed period. 2009 2010 2011 2012 2013 Vaginal delivery 2,809 1,995 2,148 2,101 2,578 % 71.88% 66.68% 64.66% 65.33% 69.32% No. 1,099 997 1,174 1,115 1,141 C-section % 28.12% 33.32% 35.34% 34.67% 30.68% No. 3,908 2,992 3,322 3,216 3,719 Total % 100.00% 100.00% 100.00% 100.00% 100.00% The highest birth rate was recorded in 2009 (3,908), and the lowest in 2010 (2,992). The average number of deliveries during the period under review was 3,431. The chi-squared test showed a statistical difference in the number of deliveries during the analyzed years, χ2=163.577; df=4; p<0.05. The C-sections rate grew linearly in the period from 2009 (28.12%) to 2011, when the highest number of C-sections was recorded (35.34%). After that, the trend of C-sections began to drop, especially in 2013 (30.68%). M. Abou El-Ardat et al. Graph 1 Number of deliveries during the observed period. Graph 2 C-section percentage share vs. total number of de liveries. Table 2 shows the frequency of surgeries per year during the period under review. The Chi-squared test showed that there was a statistical difference in the number of surgeries compared to the period under review, χ2=31.118; df=4; p<0.05. The highest number of surgeries was recorded in 2013 (355), and the lowest in 2010 (222). It is also important to say that the most usual procedure was manual exploration of the uterus. Frequency of forceps delivery dropped over the years and reached zero in 2013. Table 2 Frequency of obstetric surgical procedures over the five-year period. 2009 2010 2011 2012 2013 Manual aid – breech birth 12 12 14 15 31 7 2 13 21 30 VE Forceps 1 3 3 3 0 Manual exploration of 201 163 204 197 244 uterus Lysis placentae manualis 58 42 53 49 50 Obstetric surgeries - total 279 222 287 285 355 Over the five-year period, 17,356 babies were born in the Clinic of Gynecology and Obstetrics of CCUS. Most of the infants were born in 2009. The highest number of twins was recorded in 2013 (n=89), and triplets in 2010 (n=7). Table 3 Number of infants born during the observed period. Singleton Twins Triplets The highest preterm birth rate was recorded in 2012 (11.29%), and the lowest in 2013 (4.65%). Table 4 Number of full-term and preterm births. 2009 2010 2011 2012 2013 Full-term 3675 2826 3128 2907 3546 Preterm 257 220 237 370 173 6.54% 7.22% 7.04% 11.29% 4.65% 2009 3802 66 1 2010 3405 72 7 2011 3365 72 2 2012 3156 59 1 2013 3628 89 2 Five-Year Work of the Birthing Center of the Clinic for Gynecology and Obstetrics Statistically speaking, the frequency of infants born weighing between 500 and 1000g remained stable during the observed period. Table 5 Birth weight overview. 500-1000g 1000-2500g >2500g 2009 32 257 3643 2010 30 220 2796 2011 33 237 3095 2012 31 240 3006 2013 23 323 3465 The highest perinatal mortality rate was recorded in 2013 (7.4‰), and the lowest in 2010 (4.3‰). In the last three years, the perinatal mortality was around 7‰, which matches the perinatal mortality rates in European hospitals. Graph 3 Perinatal mortality analysis. 193 at 16.65‰ in 1996 and 9.60‰ in 2007 (2). The study on C-Section and perinatal mortality rate carried out at the Maichin Dom (7) in Bulgaria in the period from 1976 to 2000 showed that C-section rate growth from 4.8% to 24.4% reduced the perinatal mortality from 27.7‰ to 11.4‰. In normal pregnancies, perinatal mortality was between 8 and 11% with a C-section frequency between 15 and 16%. In high-risk pregnancies the perinatal mortality rate remained the same, but with the C-section frequency it was between 24 and 26%. “No correlation between caesarean section rates and perinatal mortality of singleton infants over 2,500 g” is a study carried out in Island, which provided new information about obstetrics trends (8). Island is one of the countries with the lowest perinatal mortality rate. The data were collected from the Island birth registry for the period of 20 years, i.e. 1987-2006. Perinatal mortality stood at ca 2‰ per annum, ranging between 0.8 and 4.1‰. The C-section delivery rate ranged between 11.9% and 16.7%, without correlating with the perinatal mortality rate. Among primiparae, the C-section delivery rate increased from 13.1 to 17.8% without correlating with the perinatal mortality, which stood at ca 1.7‰. CONCLUSION DISCUSSION The Birthing Center of the Clinic of Gynecology and Obstetrics is a 24/7 institution staffed with experienced obstetricians. In 2012, at the Clinic for Gynecology and Obstetrics, 3,216 women gave birth, of which 35% were subject to C-section. During the 2009-2013 period, 17,157 women gave birth in this Center: 32.21% through C-section, and 67.79% via vaginal birth. The highest number of births was recorded in 2009, and the lowest in 2010. The highest C-section rate was recorded in 2011 (35.34%) and the lowest in 2009 (28.12%). Abadžić’s research findings showed that the number of C-sections in the Clinic of Gynecology and Obstetrics of the CCUS in 1996 was 8.57%, and 27.75% in 2007. This indicates that the number of C-sections tripled over the 12-year period (2). The growth trend continued in 2012. We have been witnesses of increase in C-section births in the last few years. When it comes to developed countries, Australia and the USA have the highest C-section rate (28.5% and 29.1%) (3). Similar trends have occurred in Latin America, especially in Mexico (25.7%) and Brazil (27.9%) and other developing countries including India (Kerala) (21.4%) (4,5). Even though the “optimum C-section rate” is still a subject of many discussions, the World Health Organization (WHO) has proposed the rate of 15% (5). Fatušić et al. in their retrospective study carried out in the Clinic of Gynecology in Tuzla, reviewed the medical documents on C-section deliveries performed over the course of a five year period (1984-1988). Their findings showed no C-section epidemics. During that period, 6.47%, or 1,819 of C-sections were performed. Out of the total percentage, 90.22% (1,641) were unplanned C-sections, while 9.78% (178) were planned in advance (6). As already stated, during the observed period, 17,356 infants were born. The perinatal mortality rate grew and stands at 7‰ as of 2011 (the same trend was preserved in 2013). In her research, Abadžić proved that the perinatal mortality rate stood Following the period of low birth rate, in the past few years the number of deliveries in the Clinic of Gynaecology and Obstetrics „recovered“, nearing the average from 2009. The C-section rate is still very high. However, this number stabilized in 2013 at around 30%, which exceeds all epidemiological indicators. Perinatal mortality has been stable over the last three years, coinciding with the European Union incidence rate. Conflict of interest: none declared. REFERENCES 1. Dornan J. Managing Obstetric Emergencies and Trauma course manual; RCOG press-London; 2007 (Foreword xix;178-179) 2. Abadžić N. Perinatološki parametri i karakteristike gravida porođenih carskim rezom, Magistarski rad, Medicinski fakultet, Univerzitet u Sarajevu, 2012. 3. Berghela V, Baxter JK, Chauhan SP. Evidence-based surgery for cesarean delivery. Am J Obstet and Gynecol. 2005;193(5):1607-17. 4. Cesarean section history, US National Library of medicine, Part 1, 2009. 5. Cyr RM. Myth of the ideal cesarean section rate: commentary and historic perspective. Am J Obstet and Gynecol. 2006;194(4): 932-6. 6. Fatušić Z. Minimalna hirurška trauma u toku Carskog reza, Perinatalni dani BiH 2007. 99-109 7. Dimitrov A. Rate of cesarean section and perinatal infant mortality at “Maichin dom”. Akush Ginekol (Sofia). 2003;42(6):3-6. 8. Jonsdottir G, Smarason AK, Geirsson RT, Bjarnadottir RI. No correlation between cesarean section rates and perinatal mortality of singleton infants over 2.500 g. Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik, Iceland. Acta Obstet Gynecol Scand. 2009;88(5):621-3. Reprint requests and correspondence: Mohamad Abou El-Ardat, MD Clinic of Gynecology and Obstetrics Clinical Center University of Sarajevo Patriotske lige 81, 71000 Sarajevo Bosnia and Herzegovina Phone: +387 33 250 285 Email: [email protected] Review article Medical Journal (2014) Vol. 20, No. 3, 194 - 196 Oral precanceroses: clinical histopathological correlation Oralne prekanceroze: kliničko patološka korelacija Dedić A¹*, Hodžić M¹, Avdić M², Hadžić S¹, Pašić E¹, Gojkov-Vukelić M.¹, Kantardžić A¹ 1 Department of Periodontology and Oral Medicine, Faculty of Dentistry University of Sarajevo, Bolnička 4a, 71000 Sarajevo, Bosnia and Herzegovina; ²Department of Periodontology, New Mowsat Hospital, Kuwait *Corresponding author ABSTRACT SAŽETAK Oral precanceroses are on the rise in the world and in our country. Precancerous oral lesions represent morphologically altered tissue in which cancerization occurs at a much higher probability than in the seemingly unaltered oral mucosa of the contralateral side. This paper points to a number of etiopathogenetic mechanisms, with a special focus on the proto-oncogenic and oncogenic mechanisms. The aim of this paper is to present the clinical-histopathologic correlation of leukoplakia and lichen. The significance of progression of dysplasia and strategic diagnostic protocol are important for early detection of oral precanceroses. With strategic diagnostic protocol and recommendations for doctors, we expect to overcome numerous dilemmas in the differential diagnosis of oral precanceroses. Sophisticated histopathological methods and a multidisciplinary approach are the gold standard for exact diagnosis. Key words: oral precanceroses, oncogene, histopathological findings Oralne prekanceroze imaju tendencu rasta u svijetu i kod nas. Prekancerozne oralne lezije označavaju morfološki promijenjeno tkivo u kojem se kancerizacija pojavljuje s mnogo većom vjerovatnoćom nego u naizgled nepromijenjenoj oralnoj sluznici kontralateralne strane. Rad ukazuje na brojne etiopatogenetske mehanizme sa posebnim fokusom na protoonkogene i onkogene. Cilj rada je prezentirati kliničko-patohistološku korelaciju leuko-plakije i lichena. Značaj progresije displazije i strateški dijagnostički protokol su značajni za ranu detekciju oralnih prekanceroza. Uz strateški dijagnostički protokol i preporuke za ljekare, očekujemo prevazilaženje brojnih dilema u diferencijalnoj dijagnozi oralnih prekanceroza. Sofisticirane patohistološke metode i multidisciplinaran pristup su zlatni standard za egzaktnu dijagnozu. INTRODUCTION antigens in the epithelial cells may be the earliest initial indicators of premalignant or malignant orientation of the oral epithelium (2). According to the World Health Organization (WHO), oral precanceroses are divided into: oral precancerous lesions and oral precancerous conditions. Oral precancerous lesions are pathological changes that can transform into malignant lesions. Precancerous oral lesions represent morphologically altered tissue in which cancerization occurs at a much higher probability than in the seemingly unaltered oral mucosa of the contralateral side (1). Possible etiopathogenetic mechanisms for cancerization of oral mucosa It has been shown that free radicals play the primary role in the development of premalignant and malignant diseases of all tissues, including the oral mucosa. Free radicals are byproducts of oxygen which are released together with the energy necessary for living cells in the process of oxidation of tissue, and are generally very unstable. Free radicals can damage all cellular elements. In the initial stages of premalignant and malignant diseases, they damage the cellular DNA, and then run a number of cellular reactions which release additional free radicals. They are constant irritants during the long latency period of development of malignant tumors. Therefore, they are slowly but surely destroying the affected tissue in the premalignant stage. The latest research confirms the importance of secretory status in etiopathogenesis of premalignant and malignant diseases. It is important to note that the differences in the expression of blood group Ključna riječ: oralne prekanceroze, onkogen, patohistološki nalaz Oncogenes Oncogenes are genes whose activities lead to the disturbance of the regulation of cell division, causing malignant tumors. They occur through mutation of normal cellular genes, the so-called proto-oncogenes involved in controlling the cell cycle. Protein products of proto-oncogenes play a key role in the regulation of proliferation and differentiation of cells. Proto-oncogenes are responsible for autonomous growth of malignant cells that are unresponsive to normal control mechanisms even without any external growth factors (3). Proto-oncogenes become oncogenes through translocation or transposition (1); amplification (2); dotted mutation (3). From: Pavlica M.,Web udžbenik: Genetika,2012.(2) 195 Oral precanceroses: clinical histopathological correlation Clinical histopathological correlation of oral precanceroses Erythoplakia Cause unknown; Smoking is associated with the emergence of erythroplakia Age: Usually occurs between 50 and 70 years of age High risk localization: Oral cavity floor, tongue, retromolar region, the soft palate Histopathology: Squamous cell carcinoma 50% High degree of dysplasia or Ca in situ 40% Mild to moderate dysplasia 10% Biopsy required (4,5) Clinical - histopathological correlation Erythroplakia – buccal mucosa Erythroplakia – tongue Progression of dysplasia From: Regezi J. A., Sciubba, J. J., Jordan, R. C. K. Oral pathology: Clinical pathologic correlations. 2008. St. Louis,Mo: Saunders Elsevier (4) Lichen ruber planus Erythroplakia - ph finding Leukoplakia Risk factors Smoking, alcohol, nutrition, unknown Localization: Vestibulum, buccal and palatal mucosa, alveolar ridge, lips and tongue, oral cavity floor Locations with a high risk for malignant transformation: Oral cavity floor > tongue > lips > palate > cheeks > vestibulum > retromolar region Age: Usually over 40 years of age Microscopic diagnosis Hyperkeratosis - 80% Dysplasia - 12% Ca in situ - 3% (4,6,7) Cause unknown; Destruction of basal keratinocytes by T cells Clinical presentation Adults; relatively common (0.2-2% of the population); parasites for a long time Characteristic white keratosis stretch marks Form: reticular, erosive (ulcerative), plaque, papular, erythematosus (atrophic) Pain: in erosive forms (ocasionally in erythematosus form) Potential risk for malignant transformation Increased in erosive forms of lichen (0.4 to 2.5%) Pathology Combination of mucositis and hyperkeratosis. IgM deposition in the basal membrane, and less frequently of IgA and C3 Therapy Observation, local and systemic corticosteroids, or other immunosuppressive drugs - Levamisole tbl. (4,8,9) Clinical - histopathological correlation Erosive form of lichen (10) Bullous form of lichen (10) Clinical - histopathological correlation Proliferative verrucous leukoplakia Hyperkeratosis Idiopathic leukoplakia of the lateral side of tongue Mild degree of dysplasia Leukoplakia of the tongue, cobblestone form High degree of dysplasia Hyperkeratosis, lymphocytic infiltrate and basal Immunohistochemical detection of CD3 antigen with T cell dominance in the inflammatory infiltrate (4) Strategic clinical and diagnostic protocol Anamnesis Visual perception Visual observation Early detection - Toluidine Blau test Assessment of quantitative and qualitative salivary status Native, microbiological and Ph finding of Candida albicans Clinical - histopathological correlation (efflorescence → biopsy) Ph finding of dysplasia (mild, moderate, severe) 196 A. Dedić et al. Idiopathic leukoplakia: Diagnosis and management CONCLUSION Early detection of efflorescence initiation is significant in prevention of development of oral precanceroses. Procedures for sophisticated diagnostic histopathological methods constitute fundamental knowledge and a gold standard relevant in the exact verification of oral precanceroses. A multidisciplinary approach is a clinical imperative in the treatment of oral precanceroses. Conflict of interest: none declared. REFERENCES From: Regezi J. A., Sciubba, J. J., Jordan, R. C. K. Oral pathology: Clinical pathologic correlations. 2008. St. Louis,Mo: Saunders Elsevier (4) Recommendations for doctors How to identify precanceroses? Inspection and visualization of efflorescence Macroscopic morphological characteristics of efflorescence (at the level of mucosal tissue, below and above the level of mucosal tissue) Time factor → risk factor → length of efflorescence White lesions: PLAQ → EROSION → ULCUS → COBBLESTONE → NODULES → INDURATION Imbalance of humoral and cellular immunity Can not be removed 1. Cekić A. et al. Oralna medicina. Zagreb: Školska knjiga; 2005. 2. Pavlica M. Web udžbenik: Genetika, 2012. 3. Radović S, Dorić M, Tomić-Ćuk I, Babić M, Kuskunović S. Dijagnostičke procedure u patologiji. Medicinski fakultet Univerziteta u Sarajevu. 2012., Sarajevo 4. Regezi JA, Sciubba, JJ, Jordan RCK. Oral pathology: Clinical pathologic correlations. 2008. St. Louis, Mo: Saunders Elsevier. 5. Reichart PA, Philipsen HP. Oral erythroplakia-a review. Oral Oncol. 2005;41:551-561. 6. Scully C, Sudbo J, Speight PM: Progress in determining the malignant potential of oral lesions. J Oral Pathol Med. 2003;32:251-256. 7. Zakrzewska JM, Lopes V, Speight P, Hooper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82(4):396-401. 8. Boisnic S, Frances C, Branchet MC, Szpirglas H, Le Charpentier Y. Immunohistochemical study of oral lesions of lichen planus: diagnostic and pathophysiologic aspects, Oral Surg Oral Med Oral Pathol. 1990;70(4):462-5. 9. Barker JN, Mitra RS, Griffiths CE, Dixit VM, Nickoloff BJ. Keratinocytes as initiators of inflammation. Lancet 1991;337:211-214. 10. Dedić A. Autoimune oralne bolesti: praktikum. Sarajevo: Institut za naučnoistraživački rad i razvoj KCUS; 2010. - Monitor the efflorescence - Control check-ups (every 3 months) - Continuous motivation and education for oral hygiene - Risk factors - smoking, alcohol, UV rays - CAUTION - Medications - side effects - CAUTION - Complete dental treatment of the patient until prosthetic restoration (fixed prosthetics) (10). This strategic doctrinal code of ethics and diagnostic aims at overcoming the many dilemmas in differential diagnosis of precancerous lesions Erythroplakia of the tongue Squamous carcinoma of the tongue Reprint requests and correspondence: Amira Dedić, MD, PhD Department of Periodontology and Oral Medicine Faculty of Dentistry in Sarajevo University of Sarajevo Bolnička 4a 71000 Sarajevo Bosnia and Herzegovina Phone:+387 33 214 249 Email: [email protected]; [email protected] Case report Medical Journal (2014) Vol. 20, No. 3, 197-199 Staged surgical treatment of combined osteoarticular and vascular injury of the shoulder Fazni hirurški tretman kombinovane koštano zglobne i vaskularne ozljede ramena Amel Hadžimehmedagić1*, Ismet Gavrankapetanović2, Haris Vranić1, Mehmed Jamakosmanović2 Clinic for Cardiosurgery, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2Clinic for Orthopedics and Traumatology, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina 1 *Corresponding author ABSTRACT SAŽETAK This case report describes a staged surgical treatment of combined osteoarticular and vascular injury of the right shoulder. Initial surgical treatment at Trauma Department of the Regional Hospital failed. Humeral head was still out of joint, axillar artery suture caused acute arterial occlusion, and brachial plexus was compressed so the patient was referred to our hospital. After completed diagnostics surgery was indicated. Our plan was to resolve both injuries in two stages so we decided to proceed with the operative treatment of the vascular injury in the first stage, and postpone final fracture treatment for the second stage. Implantation of reversible shoulder endoprosthesis was postponed until it was evident that neurovascular recovery was achieved. In the treatment of these combined injuries we recommend staged procedure. Prikaz slučaja opisuje fazni hirurški tretman kombinovane koštano-zglobne i vaskularne ozljede desnog ramena. Primarni hirurški tretman u regionalnoj bolnici nije dao zadovoljavajući rezultat. Glavica humerusa je i dalje zauzimala izvanzglobnu poziciju, a neadekvatan šav aksilarne arterije je izazvao akutnu arterijske okluziju i kompresiju brahijalnog pleksusa, te je pacijent je upućen u našu bolnicu. Nakon kompletiranja dijagnostike indiciran je hirurški tretman. Naš plan je osmišljen tako da se hirurški zbrinu obje povrede, ali u dvije faze, tako smo odlučili da se vaskularne ozljede zbrinu u prvoj fazi, i odloži tretman završne obrade loma za drugu fazu. Implantacija ramene endoproteze je odgođena do momenta kada je bilo nedvojbeno da je postignut potpuni neurovaskularni oporavak. U tretmanu ovakvih kombinovanih povreda preporučujemo faznu proceduru. Key words: humeral neck fracture, axillary artery lesion, arthroplasty INTRODUCTION Proximal humeral fractures represents only 5% of all fractures seen at the emergency departments, and 15% of them are associated with axillary artery and nerve structures injuries (1). This injuries can lead to heavy bleeding, neurological palsy and severe perypheral limb ischemia. Early diagnosis and exact treatment is fundamental for the restoration of peripheral circulation and motor function. Possibility of unexpected intraoperative events and problematic outcome, implicates to have high index of suspicion when dealing with proximal humeral fractures even when typical clinical signs of neurovascular injury are absent (2). This is even more difficult when history of blunt low-energy trauma is present in a healthy young patient. This report involves a patient suffering from osteoarticular and associated neuro-vascular injury of the right shoulder. CASE REPORT A 31 year old male sustained an anatomical humeral neck frac- Ključne riječi: prelom vrata humerusa, lezija aksilarne arterije, artroplastika ture after blunt trauma, falling from height (Figure 1). Figure 1 Anteroposterior radiograph at regional medical center after initial procedure. 198 Initial treatment was performed in a regional medical center two weeks before admission to our hospital. According to a written report, initially absent clinical signs of associated neurovascular injury led to conservative treatment and Dessault immobilization for two days. Unsuccessful conservative treatment and immobilization was followed by surgical treatment of humeral head migrated in the axillary fossa. When the conservative treatment failed, open reduction and stabilization of the fracture was indicated. In such position sharp bony fragment lacerated the mid-portion of the axillary artery and made complete compression of the axillary vein. Surgical approach to the fracture site revealed vascular lesion and severe bleeding which resulted in a direct suture of arterial vessel wall. This was followed by unsuccessful attempt to perform reduction of the humeral head. This "unexpected" intraoperative diagnosis of vascular injury caused a switch in surgical plan and the patient was referred for a final treatment at Clinic for Orthopedic and Traumatology of the Clinical Center University of Sarajevo. Pulselessness, signs of the first degree forearm ischemia, and compromissed deep venous blood flow were noticed at the admission. Signs of mild neurological injury with generalized motor weakness in the arm, neuropraxia of the brachial plexus, were also present. MRC scale 2 was found most likely due to direct consequences of the injured artery. We explaned it primarelly by ischemic syndrome and due to developing hematoma causing swelling and compression on the nerve structures placed in common fascial sheath. No other motor deficiency was detected in the right arm. The patient suffered from severe pain as a result of a swollen and tender shoulder. The x-ray confirmed fracture dislocation with the humeral head migration into the axillary fossa (Figure 2). Figure 2 Anteroposterior radiograph at admission showing head dislocation into axillary fossa. MATERIALS AND METHODS Transfemoral angiography showed 6 cm length of interruption of the arterial tree at the midportion level of axillary artery with rich blood vessel collateral network feeding distal arterial tree (Figure 3). Upon evaluation of clinical and radiological findings, two staged surgery was suggested. We concluded that dislocated humeral head A. Hadžimehmedagić et al. Figure 3 Angiogram showing complete obliteration of the flow through right axillary artery. still positioned in the axillary fossa caused segmental arterial thrombosis with complete obliteration of the flow after the initial suture of the vessel wall. The likelihood of the avascular necrosis was high and preoperative strategy was to remove humeral head and perform vascular reconstruction of the vessel in the first stage. Figure 4 Intraoperatively taken image showing a vascular necrosis of humeral head. We used the same surgical approach through the deltoid-pectoral groove. As expected, approach to humeral head showed its avascular necrosis due to lasting dislocation in axillary fossa (Figure 4). Once the humeral head was removed an extensive arterial bleeding occurred. Bleeding was control by clamping after extending the surgical approach along Morencheim line through the pectoral muscle. After resection of the damaged and trombosed segment of artery (4 cm in length), an arterial reconstruction was performed using synthetic graft (PTFE 7 mm in diameter). Interposition of the graft was done in a usual way by a proximal and distal termino-terminal eversive anasthomosis using Prolen 6/0 suture. Postoperatively a normal radial artery pulse was found. Signs of ischemia, cyanosis and venous obstruction were resolved, with Staged surgical treatment of combined osteoarticular and vascular injury of the shoulder only mild paresthesias present. The patient was discharged with a "hanging shoulder" and the second stage treatment was postponed until a neurological and a vascular recovery was confirmed with angiography and EMG (Figure 5). Figure 5 Angiogram taken upon neurovascular recovery showing functional synthetic graft. A follow up angiogram (Figure 5) showed a potent graft and ”hanging shoulder”. Twelve weeks after the first stage we performed the second stage surgical treatment. By using lateral approach to the shoulder, total arthroplasty was done with hydroxyl apatite coated cementless reverse total endoprosthesis (total reverse endoprosthesis Lima LTO s.p.a) (Figure 6). Figure 6 Anteroposterior radiograph showing reverse shoulder endoprosthesis in place. Postoperatively the shoulder was placed in 0°- abduction, 0°rotation and in sling for 2 weeks. Recovery was assisted by physiotherapy with the aim to achieve active-assited flexion/abduction up to 90°, avoiding external rotation and with 45° of internal rotation. Unrestricted motion was allowed after 8 weeks when active flexion was 70°, abduction 95°, internal rotation 30° and external rotation 20°. Patient was pain free, clinical examination and radiograph taken 199 showed no loosening. Neurovascular status of the right arm was equal when compared to the other non-injured arm. DISCUSSION Proximal humeral fractures represents only 5% of all fractures seen at the emergency departments, and 15% of them are combined with neurovascular injury. Treatment of uncommon injuries provided in inexperienced medical center reveals several pitfalls that could and should be avoided in the future and by that provide favorable treatment outcomes for the patient. In order to avoid delay in diagnosis and reduce risk of increasing severity of the injury, Doppler ultrasound scanning initially and arteriography if necessary should be routinely part of the initial procedure when dealing with proximal humeral fractures (3,4). This diagnostic procedure, along with close clinician follow up is necessary in patients suffered from proximal humeral fractures even when no significant clinical signs of neurovascular injury are present (4,5). CONCLUSION When dealing with major neurovascular artery injury secondary to displaced proximal humeral fractures requiring arthroplasty we recommend staged procedure, where major vascular injury involving arterial reconstruction should be resolved first, followed by final treatment of the fracture involving arthroplasty in the second stage. Furthermore, follow up of this and other similar reported cases will in the future give us better and long term results in the cases in which primary implantation of reverse shoulder endoprosthesis was performed. Conflict of interest: none declared. REFERENCES 1. Palm DS, Parikh PP, Schoonover B, Lebamoff D, McCarthy MC. Axillary arterial entrapment and brachial plexus injury due to proximal humeral fracture. Injury Extra. 2013;44(8):67–69. 2. Goyal VD, Sharma V, Kalia S, Sehgal M. Axillary Artery Injury Caused by Fracture of Humerus Neck and Its Repair Using Basilic Vein Graft. Case Rep Surg. 2014;2014:430583. 3. Stenning M, Drew S, Birch R. Low-energy arterial injury at the shoulder with progressive or delayed nerve palsy. J Bone Joint Surg Br. 2005;87(8):1102–6. 4. Yagubyan M, Panneton JM. Axillary artery injury from humeral neck fracture: a rare but disabling traumatic event. Vasc Endovascular Surg. 2004;38(2):175–84. 5. Modi CS, Nnene CO, Godsiff SP, Esler CN. Axillary artery injury secondary to displaced proximal humeral fractures: a report of two cases. J Orthop Surg (Hong Kong). 2008;16(2):243-6. Reprint requests and correspondence: Amel Hadžimehmedagić, MD, PhD Clinic for Cardiosurgery Clinical Center University of Sarajevo Bolnička 25 71000 Sarajevo Bosnia and Herzegovina Phone:l +387 33 297 682 Email: [email protected] Case report Medical Journal (2014) Vol. 20, No. 3, 200-202 Perivascular epithelioid cells tumor; case report of uncommon clear cell neoplasm ligamentum teres uteri Perivaskularni epitelioidni stanični tumori; prikaz slučaja neuobičajene svijetlostanične neoplazije ligamentum teres materice Faika Mujanović-Glamočanin1*, Spahić Amir2 Department for Gynecology and Obstetrics, Cantonal Hospital Travnik, Kalibunar bb, 72270 Travnik, Bosnia and Herzegovina, Department for Pathology, Public Hospital Travnik, Kalibunar bb, 72270 Travnik, Bosnia and Herzegovina 1 2 *Corresponding author ABSTRACT SAŽETAK Neoplasms with perivascular epithelioid cell differentiation are mesenchymal tumors that consist of histologically and immunohistochemically different perivascular epithelioid cells (PEComa). PEComa are described in different organs and are considered to be widely present tumors. Clinical presentation is not specific and accurate preoperative diagnosis is hard to achieve. PEComa can be very aggressive disease and lead to appearance of metastasis even after couple of years. At this moment surgical resection appears to be the most adequate manner of treatment, while radiotherapy and chemotherapy (without surgical resection) did not show significant results. Case report in our study describes a patient with non specific symptoms, extreme general weakness and CT scan showing large tumor mass in projection of right ovary. Final diagnosis was made after surgery by histopathological analysis with immunochemical profile. According to the WHO data 200 cases of this neoplasm was described so far, and this was the first case documented in Bosnia and Herzegovina. Neoplazme sa perivaskularnom epitelioidnostaničnom diferencijacijom (PEComa) su mezenhimalni tumori sastavljene od histološki i imunohistohemijski različitih perivaskularnih epitelioidnih stanica. PEComi su opisani u različitim organima i smatraju se sveprisutnim tumorima. Klinička prezentacija nije specifična i tačnu preoperativnu dijagnozu je teško odrediti. PECom može biti vrlo agresivna bolest i dovesti do metastaza i nakon nekoliko godina. Hiruško odstranjenje tumora za sada se čini najadekvatnijim načinom liječenja, dok samo chemio i radio terapija (bez hiruškog tretmana) nisu pokazali značajne rezultate. Prikaz slučaja u našoj studiji je pacijentica sa nespecifičnim simptomima, izražene opšte slabosti organizma i CT prikazom velike tumorske mase u projekciji desnog jajnika. Do konačne dijagnoze PEComa dođe se postoperativno patohistološkom i imunohistohemijskom analizom. Prema podacima WHO do sada je objavljeno 200 slučajeva ove naoplazme, a predmetni slučaj je prvi registrovani u Bosni i Hercegovini. Key words: perivascular epithelioid cells tumor, mesenchymal tumors INTRODUCTION The term PEComa as a concept was firstly introduced by Zamboni in 1996, and in 2003 the WHO defined PEComa as a mesenchymal tumor. One hypothesis states that the neoplasm is derived from undifferentiated neural crest cells with smooth muscle cells and melanocytes. The second assumption is that a PEComa has myoblastic origin, and the third one that it is of pericytic origin. Neoplasms with perivascular epithelioid-cell differentiation are mesenchymal tumors composed of histologically and immunohistochemically different epithelioid perivascular cells (1,2,3). The family of neoplasms with perivascular epithelioid-cell differentiation includes: •angiomyolipoma (AML) •clear cell “sugar” lung tumor (CCST), •lymphangioleiomyomatosis (LAM), •clear cell myomelanocytic tumor of falciform ligament / ligamentum teres (CCMMT), Ključne riječi: perivaskularni epitelioidni stanični tumori, mezenhimalni tumori •uncommon clear cell tumors. Up to date PEComa were described as pancreas, rectal, abdominal serosa, uterine, external female genital organs, and thigh and heart tumors. Some of these lesions according to the WHO classification were listed as renal (AML), liver (AML) and lung (CCST, LAM) tumors. Epidemiologically, neoplasms with perivascular epithelioid cell differentiation are extremely rare. In 80-90% of cases they occur in women of 46 years on average. There are reports for approximately 200 neoplasms with perivascular epithelioid cell differentiation (4,5,6,7,8,9). Neoplasms with perivascular epithelioid cell differentiation (PEComa) which were previously reported developed in retroperitoneum, abdominal-pelvic region, uterus and gastrointestinal tract. Clinically, clear cell myomelanocytic tumors of the falciform ligament / ligamentum teres (CCMMT) are presented as painful abdominal mass. Uterine PEComa are presented with a vaginal bleeding. Other neoplasms with a perivascular epithelioid cell differenti- Perivascular epithelioid cells tumor; case report of uncommon clear cell neoplasm ligamentum teres uteri ation (PEComa) are basically painless masses. Clinical presentation is nonspecific, and therefore the exact diagnosis is difficult to make. Accurate diagnosis requires histopathology and immunohistochemical analysis, and it is set following surgical procedure. Grade of tumor malignancy is determined by the tumor size; (larger than 5 cm) mitotic activity (higher than 1/50 HPF) and necrosis (10). Immunohistochemical PEComa demonstrates expression of the myogene and melanocytic marker, such as HMB45, HMSA-1, Melan A/ Mart, Mitf and actin. Surgical treatment followed by chemotherapy and radiotherapy shows significant results. CASE REPORT Patient R.A, 50 years old, in menopausal age. Personal history: patient is complaining of weakness during the last year, weight loss of about 20 kg, pain in lower abdomen, sedimentation rate test rises to three digit values (125/135), and chronic sideropenic anemia. Cervical cone biopsy performed five years ago (CIN III), patient was positive to hepatitis C antigen. Gynecological finding: multipara, vaginal portion of the uterus shows scaring, uterus is visualized with right adnexa, size of baby head, can be moved, left tube and ovary shows no pathological changes. Abdominal CT prior to surgical procedure: in the area of right ovary there is a clearly marked area of soft tissue density which in contrast sequence receives contrast medium and its central parts are hypodense. The diameter of this area is 65x60 mm. Urine bladder has normal position, shape and width of the wall. Parenchymatous organs and digestive tube without changes. There are no pathologically enlarged nodes along large blood vessels. Work diagnosis: Tumor ovarii lateris dextri. Surgical procedure was suggested and performed: Tumerectomia. Hysterectomia totalis abdominalis cum adnexectomiam bill. Surgical finding: between right ovary, uterine fundus and posterior wall of the urine bladder there is a tumor, size about 10 cm, closely linked to all surrounding organs and especially to the urine bladder wall, in a shape of cauliflower, of fragile consistency. Surgically primary location of the tumor can not be precisely defined. After the surgery patient received the course of antibiotics, analgesics and fluid compensation, Clivarin 0,25, and three doses of full blood type „O“ RhD negative. Postoperative course went without complications, patient afebrile, regular diuresis, peristaltic returned. Surgically removed tumor mass consisted of grayish tissue particles, of moderately hard consistency and homogenous structure with area of necrosis and hemorrhage with the largest tissue sample size measuring 85x50x20mm, and the smallest one 10x5mm. Microscopically, perivascular epithelioid cells (PECs) are characterized with perivascular location, often with radial pattern of the cells around the blood vessel lumen while the stroma among the aggregates of the neoplastic cells is scarce and infiltrated with abundant inflammatory cells dominated with lymphocytes (Figure 2). Typically, perivascular epithelioid cells in immediate perivascular localization are mostly epithelioid and spindle cells that remind of smooth muscle cells. Most of the changes had relative relation of epithelioid and spindle cells (Figure 1). 201 Figure 1 PEComa. Ratio of epithelioid and spindle cells (H&E, x10). Figure 2 PEComa. Perivascular radial pattern PECs (H&E,x10). Perivascular epithelioid cells (PECs) have clear to granular, slightly eosinophilic cytoplasm, round to oval nuclei with small nucleoli, even though hyperchromasia and irregularity of nuclei is visible (Figure 4). Tumor cells demonstrate emphasized nuclear atypia, frequent mitotic activity and presence of necrotic degenerative changes (Figure 3). Perivascular epithelioid cells (PECs) form nest like architecture (Figure 1, Figure 4). Figure 3 PEComa shows a picture of atypia, pleomorphism of nuclei with coarse chromatin, small nucleoli and mitoses (HE, x20). Figure 4 PEComa has clear to granulated, easily eosinophil- ic cytoplasm (HE,x20). 202 Single perivascular epithelioid cells (PECs) demonstrate emphasized pleomorphy in their forms with large nuclei of vesicular and bizarre shapes, granular chromatin with prominent one or two nucleoli and frequent mitotic activity (6MF/10HPF) (Figure3). Immunohistochemical profile of neoplastic cells demonstrate positivity to Vimentine and SMA, respectively focal positivity to S-100, HHF35 and Calponin (courtesy and approval of Professor Svjetlana Radovic, Institute for Pathology, Faculty of Medicine, University of Sarajevo). Following the obtained histopathological diagnosis of neoplastic mass the patient was referred to the Oncologist who prescribed chemotherapy and radiotherapy after cystoscopy and abdominal CT. Cystoscopy: regular finding. Abdomen CT: no residual disease, urinary bladder normal position, form, size, width of the wall. After urination negligible amount of residual urine. Gynecological finding: palpatory and in specula normal findings. Vaginal scar regular finding. PAP smear showed inflammation. Applied chemotherapy: VI Taxotera cycles a 120 mg, Gemcitabin 1600 mg with standard hydration and premedication and post-medication. During IV cycle patient had neutropenia, pretibial edema and diarrhea. After diuretic therapy with potassium, antibiotics, B vitamin the chemotherapy was resumed. Applied radiotherapy: irradiated lesser pelvis with box isocentric technique with TT 46 Gy, and endocavitary boost on HDR with TD 20 Gy. Control CT of the abdomen: no secondary metastatic changes. Laboratory findings were within referral ranges. Gynecological finding and control cystoscopy showed no pathological findings. Patients felt well, no complaints, gained 20 kilograms. Further treatment: control visits to Oncologist and Gynecologist every six months. DISCUSSION Neoplasms with perivascular epithelioid cell differentiation are mesenchymal tumors that consist of histologically and immunohistochemically from different perivascular cells. There are reports by the WHO for approximately 200 neoplasms and up to date there has been no reports of this neoplasm in Bosnia and Herzegovina. Cases of this neoplasm were reported in uterus, falciform ligament, small and large intestines, pancreas and pelvic wall respectively in vulva, thigh and heart, while this report describes a case of PEComa in retrovesical area with intimate relation to surrounding organs. Clinical symptoms were non specific. Location of the tumor was established before the surgical procedure via CT scan of pelvis and abdomen and after that a surgical procedure was done based on the work diagnosis: Tu ovarii lat.dex. During the surgery a primary location of the tumor could not be established due to the intimate contact with urinary bladder, uterus and right ovary, and it was reported that the tumor was located in retrovesical area. The urinary bladder wall remained intact during the surgery and the uterus was detached from the tumor and surgically removed. Tumor size was about 10 cm. Histologically it had mitotic potential and areas of necrosis pointed to the highly malignant mass. After the surgical procedure, followed by histopathological diagnosis with immunohistochemical finding and completed oncologi- F. Mujanović-Glamočanin et al. cal treatment which obviously gave favorable results, general status of the patient was satisfying, taken into account referral laboratory blood findings, brining the weight back to normal values and no recidive and no metastasis of this neoplasm. Patient is still under the supervision of the Gynecologist and Oncologist. CONCLUSION There are difficulties in therapeutical work due to the rare nature of the disease and therefore an international study is needed to resolve this issue. Conflict of interest: none declared. REFERENCES 1. World Health Organization Classification of Tumours 2013, Pathology & Genetics, Tumours of Soft Tissue and Bone, Chapter 9: Tumours of Uncertain Differentiation 221-223. 2. World Health Organization Classification of Tumours 2002, Pathology & Genetics, Tumours of Soft Tissue and Bone, Chapter 9: Tumours of Uncertain Differentiation 221-223. 3. Beak JH, Chung MG, Jung DH, Oh JH. Perivascular epithelioid cell tumor (PEComa) in the transverse colon of an adolescent: a case report. Tumori. 2007; 93(1):106-8. 4. Folpe AL, Kwiatkowski DJ. Perivascular epithelioid cell neoplasms: pathology and pathogenesis. Hum Pathol. 2010;41(1):1-15. 5. Bonetti F, Martignoni G, Colato C, Manfrin E, Gambacorta M, Faleri M, et al. Abdominopelvic sarcoma od perivascular epithelioid cells. Report of four cases in young women, one with tuberous sclerosis. Mod Pathol. 2001;1486):563-8. 6. Goh SG, Ho JM, Chuah KL, Tan PH, Poh WT, Riddell RH. Leiomyomatosis-like lymphangioleiomyomatosis of the colon in a female with tuberous sclerosis. Mod Pathol. 2001;14(11):1141-6. 7. D´Andrea V, Lippolis G, Biancari F, Ruco LP, Marzullo A, Wedard BM, et al. A uterine pecoma: a case report. G Chir. 1999;20(4):163-4. 8. Folpe Al, Goodman ZD, Ishak KG, Paulino AF, Taboada EM, Meehan SA, Weiss SW. Clear cell myomelanocytic tumor of the falciform ligament/ligament teres: a novel member of the perivascular epithelioid clear cell family of tumors with a predilection for choldren and young adults. Am J Surg Pathol. 2000;24(9):1239-46. 9. Folpe AL, McKenney JK, Li z, Smith SJ, Weiss SW. Clear cell myomelanocytic tumor of the thigh: report of a unique case. Am J Surg Pathol. 2002;26(6):809-12. 10.Tazelaar HD, Batts KP, Srigley JR. Primary extrapulmonary sugar tumor (PETS): a report of four cases. Mod Pathol. 2001;14:615-22. Reprint requests and correspondence: Faika Mujanović-Glamočanin, MD Department for Gynecology and Obstetrics Cantonal Hospital Travnik Kalibunar bb 72270 Travnik Phone: +387 61 726 000 E-mail: [email protected] Case report Medical Journal (2014) Vol. 20, No. 3, 203 - 204 Blunt chest trauma and pericardial tamponade Tupa trauma grudnog koša i tamponada perikarda Dragan Milošević1*, Duško Golić1, Dragan Rakanović1,Vojislav Vujanović1, Dušan Janičić2 Clinic of Anesthesia and Intensive Care, Clinical Center Banja Luka, Zdrave Korde 1, 78000 Banja Luka, Bosnia and Herzegovina, Clinic of Thoracic Surgery, Clinical Center Banja Luka, 12 beba 1, 78000 Banja Luka, Bosnia and Herzegovina 1 2 *Corresponding author ABSTRACT SAŽETAK Blunt chest trauma can cause a spectrum of cardiac injuries, ranging from asymptomatic arrhythmias to rupture of the cardiac chambers or great blood vessels. Pericardial tamponade is an acute life-threatening complication of blunt chest trauma with a high mortality rate despite aggressive treatment. It is generally accepted that early recognition, prompt diagnosis and immediate treatment of cardiac tamponade are critical for survival of those patients. The case in our study was a male, aged 44, admitted to ICU after blunt chest trauma, 40 minutes after an accident. Tupa trauma grudnog koša može izazvati širok spektar srčanih ozljeda, od asimptomatskih aritmija do rupture srčanih šupljina i velikih krvnih sudova. Tamponada perikarda se javlja kao jedna od akutnih - životno ugrožavajućih komplikacija tupe traume i praćena je visokim mortalitetom uprkos agresivnom tretmanu. Opšte prihvaćen stav je da su rano prepoznavanje, brza dijagnostika i hitan tretman presudni za preživljavanje ovakvih pacijenata. Slučaj iz naše studije je muškarac, 44 godine star, primljen u JIL nakon tupe traume grudnog koša, četrdeset minuta nakon incidenta. Key words: blunt chest trauma, pericardial tamponade, early recognition, treatment Ključne riječi: tupa trauma grudnog koša, tamponada perikarda, rana dijagnoza, tretman INTRODUCTION ography showed no signs of pulmonary effusion, pneumothorax or broken ribs. ECG showed microvoltage, central venous pressure was 22 mmH2O. Paradoxal pulse was present. Complete blood count and urine output was normal. Haemodynamic instability was still present and we reasonable suspected pericardium tamponade and decided to perform surgergical procedure, specifically the left thoracotomy. Initial treatment and diagnostic procedure took twenty minutes. In the operating theatre, before induction of anesthesia, arterial blood pressure was 76/46 mmHg, heart rate 135 bpm, oxygen saturation 89%. For premedication we used fentanil 100 mcg, and “crush” induction technique with barbiturate, succinil holin, and rapid intubation with double lumen endotracheal tube (“left” tube). The patient’s position was right lateral due to performing left antero-lateral thoracotomy. Fluid resuscitation was performed with caution due to the presence of cardiogenic shook (Hartman sol.500 ml). After thoracotomy and collapsed left lung, the surgeon performed pericardiocentesis with fenestration and got approximately 300 ml of hemorrhagic fluid from the pericard. From that moment patient’s condition rapidly improved with established haemodynamic stability TA 135/89, mmHg, heart rate 90 bpm, ECG normovoltage and central venous pressure 13 mmH2O. There were no signs of miocard trauma. After double chest drainage, and chest closing, the laparoscopic exploration of abdominal cavity was performed wich confirmed the ultrasound examination result. Following the surgical procedure the patient was awaken at ICU, with hemodynamic stability. The following day the patient was transferred to the thoracic surgery department with stabile vital signs. On the third and fifth postoperative day the thoracic drain was extracted, and ten days Trauma is a leading cause of death, morbidity and hospitalisation in developed civilisations. According to the USA data trauma is responsible for one hundred tousand deaths per year (1). The same source indicates that incidence of chest trauma is 12 on one million population per day, with 33% of them requiring hospitalisation. Chest trauma causes 50% motrality in polytrauma patients, of whom 25% accounted for blunt chest trauma (1,2). Blunt chest trauma can affect one or more structures of chest: wall, ribs, clavicula, sternum, thoracic cavity with pleura, lungh, tracheobronchial elements, esophagus, heart and great blood wesseles (2). High central venous pressure, low arterial pressure, silent heart sounds – classic signs of pericard tamponade, are not allways present, and can be unreliable signs in life treatened polytrauma patients (3). CASE REPORT A male, aged 44, was admitted at ICU after blunt chest trauma, forty minutes after an accident at work (he was hit in the chest by a trunk). Upon the admission he was conscious, hypotensive (80/50 mmHg), tachycardic (130 bpm), tachypnoic (respiratory rate 22/ min), with swollen neck vessels, auscultator clear respiratory sound, silent heart sound, and oxygen saturation 90%. We perform initial treatment of polytrauma (oxygen via mask, kristalloid infusion 1000 ml), with radiographic and ultrasound examination of the thoracic and abdominal cavity. Ultrasound evaluation of abdominal and chest showed no presence of fluid, parenchymal organs preserved echo structure, while pericard was not suitable for analysis. Chest radi- 204 after the accident he was discharged from hospital. The surgical procedure lasted for approximately 50 minutes, and the overall time from the accident to postoperative time at ICU amounted to less than two hours. Figure 1 Left thoracotomy, pericard fenestration. DISCUSSION Pericardium tamponade is an acute life-threatening condition requiring percutaneous or surgical pericardiocentesis (4). Existing signs of cardiac tamponade may be unreliable, and the presence of normal clininical parameters can not exclude cardiac tamponade development. Initial chest radiography is not reliable in many cases, and even the ultrasound examination, despite its high specifity (90%), is not always superior diagnostic procedure (5-9). These procedures may delay urgently needed surgical intervention. Laboratory findings in many cases may show normal values. CK levels determination has low sensitivity, specifity and low positive predictive values (9,10). D. Milošević et al. REFERENCES 1. Centres for Disease Control and Prevention. Accidents/Unintentional Injuries. CDC Web site. Available at: http://www.cdc.gov/nchs/FASTAT/acc-inj.htm. Accessed May 2013. 2. Goalay TJ, Dente CJ, Feliciano DV. Toso vascular trauma at an urban level I trauma center. Prespect Vasc Surg Endovasc Ther. 2006;18(2):102-12. 3. Varahan SL, Farah GM, Caldeira CC, Hoit BD, Askari AT. The double jeopardy of blunt chest trauma: a case report and review. Echocardiography 2006;23(3):235-9. 4. Karmy-Jones R, Jurkovich GJ, Nathens AB, Shatz DV, Brundage S, Wall MJ Jr, et al. Timing of urgent thoracotomy for hemorrhage after trauma: a multicenter study. Arch Surg. 2001 ;136(5):513-8. 5. Cook AD, Klein JS, Rogers FB, Osler TM, Shackford SR. Chest radiographs of limited utility in the diagnosis of blunt traumatic aortic laceration. J Trauma. 2001;50(5):843-7. 6. Paydar S, Johari HG, Graffarpasand F, Shahidian D, Debhozorgi A, Ziaeian B, et al. The role of rutine chest radiography in initial evaluation of stable blunt trauma patients. Am J Emerg Med. 2012;30(1):1-4. 7. Breen JF. Imaging of pericardium. J Thorac Imaging. 2001;16(1):47-54. 8. Chirillo F, Totis O, Cavarzerani A, Bruni A, Farnia A, Sarpellon M, et al. Usefulness of transthoracic and transoesophageal echocardiography in recognition and management of cardiovascular injuries after blunt chest trauma. Heart. 1996;75(3):301-6. 9. Ansari MZ, Chaudhry MA, Signal A, Joshi R. Unusual cardiac injury following blunt chest trauma. Eur J Emerg Med. 20018(3):229-31. 10. Sybradni KC, Cramer MJ, Burgersdijk C. Diagnosing cardiac contusion: old wisdom and new insights. Heart. 2003;89(5):485-9. 11.Fitzgerald M, Spencer J, Johnson F, Marasco S, Atkin C, Kossmann T. Definitive management of acute cardiac tamponade secundary to blunt trauma. Emerg Med Australas. 2005;17(5-6):494-9. 12.Baum VC. The patient with cardiac trauma. J Cardiothorac Vasc Anesth 2000;14(1):71-81. CONCLUSION Fundamental history, rapid available diagnostic based on clinical condition, and inability to establish hemodinamic stability after fluid resuscitation are sufficient for a reasonable doubt accompanied by urgent surgical treatment as a basic condition for survival (11,12). Physicians who treat polytraumatic patients must think about possibility of cardiac tamponade developing. The time is a very important facor, which in our case was less than two hours from the accident to postoperative treatment at ICU (4). It depense on functioning of all the links in the chain from the first aid to intrahospital treatment. Pericardium tamponade is an acute life – threatening condition, relatively easy to treat when timely recognised. Conflict of interest: none declared. Reprint requests and correspondence: Milošević Dragan MD, MSc Clinic of Anesthesia and Intensive Care Clinical Center Banja Luka Zdrave Korde 1 78000 Banja Luka, RS Bosnia and Herzegovina Phone:+387 51 343 238 Email: [email protected] Case report Medical Journal (2014) Vol. 20, No. 3, 205 - 207 A heart murmur which saved a life Šum na srcu koji je spasio život Amir Omerbašić1*, Mirsad Đugum1, Mirela Tuce1, Aida Kriještorac1, Edin Omerbašić2, Mirza Halimić2 „Poliklinika Atrijum“, Džemala Bijedića 185, 71000 Sarajevo, Bosnia and Herzegovina, Heart Center, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina 1 2 *Corresponding author ABSTRACT SAŽETAK A 45-year old female appears with symptoms of breathlessness and rapid fatigue which has progressed. She is diagnosed with COPD (chronic obstructive pulmonary disease), anemia and anxiety-depressive syndrome. She takes bronchodilators and iron supplements but does not feel any better. With auscultation a pansystolic murmur grade 2/6 is found in the tricuspid valve area without progression to other areas. Echocardiography reveals a gigantic tumor that takes up almost the entirely left atrium and partly protrudes into the left ventricle. Within an hour the patient was operated. The tumor was removed entirely, with dimensions of 7x5x4 cm, connected with a thin stem to the interatrial septum. Postoperative the patient feels very well. Pacijentica, 45 godina, javlja se sa simptomima otežanog disanja i brzog zamaranja koji progrediraju, te je šest mjeseci vođena pod dijagnozom HOBP–a (hronične opstruktivne bolesti pluća), anemije i anksiozno-depresivnog sindroma. Prethodno pacijentica bez ikakavih kliničkih simptoma. Istoj se ordiniraju bronhodilatatori i preparati željeza nakon kojih se pacijentica ne osjeća bolje. Auskultacijom srca čuje se pansistolni šum stepena 2/6 u području trikuspidne valvule bez širenja. Ultrazvukom srca otkriva se gigantski tumor koji zauzima skoro u cjelosti lijevu pretkomoru i jednim svojim dijelom prolabira u lijevu komoru. U roku od jednog sata od postavljanja dijagnoze pacijentica biva operirana. Operativnim zahvatom se odstrani tumorska masa u cjelosti, dimenzija 7x5x4 cm koja je bila vezana tankom peteljkom za interatrijalni septum. Postoperativni tok prolazi uredno. Key words: Left atrial myxoma, echocardiography, heart murmur Ključne riječi: Miksom lijevog atrija, ehokardiografija, srčani šum INTRODUCTION tole, partially obstruct the inflow of blood to the ventricles, or may, depending on body position (left side body position) completely and permanent obstruct the valve, resulting drop of pressure and/or short–term loss of consciousness. They, however, can fully let the blood flow into the ventricle, if the patient lies horizontally on the back, which means that these patients tolerate that position of the body much better than those one who have a real mitral stenosis (5). Auscultatory finding, called “tumor plop”, is a typical low - frequency noise, which can be heard at the beginning or middle of diastole and seems to arise due to a sudden stop of the tumor after hitting the wall of the chamber. Myxoma may be clinically manifested with peripheral or pulmonary embolism, as well as with general signs or symptoms that include fever, weight loss, cachexia, weakness, arthralgia, rash, thickened fingers, Raynaud’s phenomenon, hypergammaglobulinemia, anemia, polycythemia, leukocytosis, increased sedimentation, thrombocytopenia or thrombocytosis. Not surprisingly, the myxoma is often mistakenly diagnosed as endocarditis, collagen vascular disease or tumors outside the heart (6). Two-dimensional transthoracic or transesophageal echocardiography is useful in the diagnosis of cardiac myxoma and allows the determination of localization of the tumor and its size, which is very important while planning surgical removal. The method of choice in the treatment of patients with myxoma is surgical removal of the tumor with cardiopulmonary bypass. Primary benign tumors account for about 75% of all tumors of the heart, of which 27% are endocardial myxoma, 75% are with the localization in the LA. Myxoma are the most common type of primary tumors of the heart, they occur in all age groups, they make one-third to one-half of all cases of tumors found at the autopsy and about three-quarters of all tumors treated surgically. Very often they are found in patients “post–mortem” after a stroke. The diagnosis is not always easy to set up because of its uncharacteristic symptoms. Atrial myxoma are often associated with the processes of embolization in 30–40% of cases. They are more often represented in middle–aged women (1,2,3,4). Pathological, myxoma have a gelatinous structure, composed of myxoma cells immersed in the stroma which is rich with glycosaminoglycans, with an average diameter of 4-8 cm. Most are solitary tumors localized in the atrium, especially the left one, where they grow near the fossa ovalis attached to the interatrial septum. In most cases myxoma are represented with obstructive, embolic or constitutional signs and symptoms. The most common clinical presentation mimics mitral valve disease or stenosis due the prolapse of the tumor through the mitral valve or mitral regurgitation due a trauma caused by the tumor. Depending on their weight, shape and insertions, the tumor can rhythmically and intermittently in the dias- 206 A. Omerbašić et al. Myxoma recurrences occur in approximately 12–22 % in hereditary forms and about 1–2% in other forms. Recurrence of the tumor probably arises because of multifocal lesions in the first and inadequate resection in another form. CASE REPORT We present a case of a 45 year old female who was scheduled for a medical examination because of breathlessness and rapid fatigue. Further investigation discovered that the patient had a weight loss of 10 kg within the last 6 months, she often felt palpitations and bloating in the stomach. The symptoms were present for six months during which the patient went to several medical examinations in different institutions of health and was diagnosed with COPD (chronic obstructive pulmonary disease) and anemia. After taking bronchodilators and iron supplements, which were prescribed from different doctors, she didn’t feel any better and was afterwards diagnosed with anxiety - depressive syndrome. During the physical examination in our clinic a pansystolic murmur grade 2/6 was found in the tricuspid valve area, without further progression to other areas. This heart murmur was not found until then and it was a indication for us to do a transthoracic echocardiography (TTE). Blood pressure (120/80 mmHg), heart rate (62/min) and ECG of the patient were normal. Figures 1, 2 and 3 show a large left atrial mass attached to the interatrial septum with severe mitral insufficiency. Figure 1 Figure 2 Figure 3 Echocardiography revealed a gigantic tumor, with dimensions of 67 x 53 mm, that took up almost the entirely left atrium and partly protruded into the left ventricle. Tumor mass followed the kinetics of the left ventricle and gave the impression that it was connected with a thin stem to the interatrial septum. Dimensions of the left atrium were slightly increased (LAD 4.8 cm) with the presence of severe mitral regurgitation, moderate tricuspid insufficiency, pulmonary hypertension and a small pericardial effusion. An emergency surgery was performed. The tumor was removed entirely, with dimensions of 7.0 x 5.5 x 4.0 cm, connected with a thin stem to the interatrial septum. Histopathologic analysis confirmed a myxoma. Figure 4 shows the extracted tumor from the left atrium. Figure 4 Postoperative the patient had episodes of atrial fibrillation that were successfully treated with cardioversion after which the patient was in a permanent sinus rhythm without need for a pace maker and without any symptoms. DISCUSSION Left atrial myxoma gives a different clinical picture and can imitate a range of cardiovascular diseases. The clinical picture depends on the localization, mobility and size of the tumor (7). Symptoms may be completely missing, but sudden death is also possible. Myxoma of the heart is often followed by a series of general symptoms 207 A heart murmur which saved a life and nonspecific laboratory tests, so-called paraneoplastic syndrome. Fatigue, periodic fever, weight loss, joint pain and skin rash often appear. In this case, the patient did not show characteristic symptoms of atrial myxoma even though he had such dimension. Sometimes the occurrence of shortness of breath (dyspnea), coughing and coughing up blood (hemoptysis) is possible. Fatigue, malaise and edema of the lower extremities is common. Sometimes accumulation of free fluid in the abdomen (ascites), dizziness and fainting appears (8). The patient in this case presented only shortness of breath and fatigue and misled the doctors to think more of a respiratory problem rather than cardiovascular one. Although „tumor plop“, a late diastolic murmur, is usually found in the case of left atrial myxoma, we heard a pansystolic murmur grade 2/6 because of its large dimensions. Laboratory test are not specific and can show leukocytosis, anemia, increased sedimentation, CRP and interleukin 6. Our patient had only anemia. Diagnosis is based on ultrasound findings (echocardiography), transthoracic as in our case, or transesophageal , and finally confirmed by pathological examination. CONCLUSION This case shows a patient who was misdiagnosed only due lack of basic methods of physical examination, in this case, auscultation of the heart. Auscultation of the heart is a very important part of the physical examination that can not be left out. Each newly discovered heart murmur should undergo a ultrasound of the heart in order to timely detect difficult diagnosis. In this case we want to emphasize the importance of basic physical examination and ultrasound of the heart as a primary method of testing the origin of any heart murmur. The importance of this case lies in the fact that a myxoma tends to embolic incidents and sudden cardiac death and as such should be promptly detected and removed. This case is also significant because the gigant tumor mass did not make any embolic process or lead to sudden cardiac death, which is very rare for a myxoma with such large dimensions. Conflict of interest: none declared. REFERENCES 1. Arhiva pacijenata Poliklinika Atrijum, Sarajevo 2013. godina 2. Arhiva pacijenata KCUS – Centar za srce, Sarajevo 2013. godina 3. Jurilj R, Božić I. Ehokardiografija: Bolest endokarda. Medicinska naklada Zagreb 2007;14:326. 4. Harrison TR, et al. Načela interne medicine. Oboljenja kardiovaskularnog sistema. Izdanje 15, Beograd i Banja Luka 2004;240:1373. 5. Burke AP, Virmani R. Cardiac myxoma: a clinicopathologic study. Am J Clin Pathol. 1993;100(6):671-80. 6. Vrhovac B, et al. Interna medicina. Kardiovaskularni sistem: Tumori srca. Zagreb 1997; V.12:699 7. Internet stranica: http://www.stetoskop.info/Miksom-srca-1029-c37-sickness.htm 8.Internet stranica: http://www.simptomi.rs/index.php/bolesti/17-tumori-i-maligne-bolesti/645-miksom-miksomi-tumo-tumori-srce-srca-leva-pretkomoa-trijalni-simptomi-medicina-zdravlje-lekar-trudnoca-bolesti-ishrana-dijeta-dijagnoza-uzrok-posledica-lecenje-terapija-beograd-srbij Reprint requests and correspondence: Amir Omerbašić, MD Poliklinika Atrijum Džemala Bijedića 185 71000 Sarajevo Bosnia and Herzegovina Email: [email protected] Our contribution to the reduction of cardiovascular diseases in Bosnia and Herzegovina! Naš prilog redukciji kardiovaskularnih bolesti u Bosni i Hercegovini! Case report Medical Journal (2014) Vol. 20, No. 3, 208-210 Clinical picture of autoimmune hepatitis and cholangitis in a pregnant woman during pregnancy and after delivery Klinička slika autoimunog hepatitisa i holangitisa kod trudnice tokom trudnoće i nakon poroda Lejla Imširija*, Naima Imširija, Sanjin Deković, Fatima Gavrankapetanović, Edin Idrizbegović Clinic of Obstetrics, Clinical Center University of Sarajevo, Patriotske lige 81, 71000 Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT SAŽETAK A primigravida diagnosed with autoimmune hepatitis and cholangitis was monitored at the Clinic where she gave birth on her due date. During the entire pregnancy she was subjected to regular and multi disciplinary controls followed by immunosuppressive therapy in correlation with the liver tests. The required findings were generally accurate during the entire pregnancy but the expected deterioration in the liver test findings occurred following the delivery. Prvorotka sa dijagnozom autoimunog hepatitisa i cholangitisa je praćena na klinici za porodiljstvo gdje je i porođena u terminu. Tokom cijele trudnoće je redovno, multidisciplinarno kontrolirana te je ordinirana imunosupresivna terapija u korelaciji sa nalazom jetrenih proba. Traženi nalazi su tokom cijele trudnoće uglavnom bili uredni ali je nakon poroda došlo do očekivanog pogoršanja u nalazima jetrenih proba. Key words: pregnancy, autoimmune hepatitis, cholangitis Ključne riječi: trudnoća, autoimuni hepatitis, cholangitis INTRODUCTION CASE REPORT Autoimmune hepatitis is a chronic inflammatory disease involving the loss of tolerance to the liver tissue which results in destruction of the liver parenchyma. It is characterized with necroses and inflammation in periportal parts of lobules, hypergammaglobulinemia and presence of auto antibodies. The disease is more frequent in women and immunogenetics connection with haplotype A1-B8DR3 or DR4 has been registered (1–3). Extra hepatitis syndromes are also frequently present. There is no specific test for diagnosing autoimmune hepatitis but there is a set of diagnostic criteria based on which the International Association for Autoimmune Hepatitis in 1999 formulated a numeric system for diagnosing potential or positive disease (4). Sclerosing cholangitis is a chronic progressive holistic disease of intrahepatic and extrahepatic bile ducts. Diffuse inflammation, fibrosis and obliteration of the entire biliary tree finally result in secondary biliary liver cirrhosis. Incidence rates are from 2 to 8 per 100,000 people (5). These two patological conditions of hepatobiliary system especially deteriorate during the pregnancy and particulary after delivery. This report describes a case of a pregnant woman whose pregnancy was monitored at the Clinic of Obstetric of the Clinical Center University of Sarajevo. A primigravida, previously diagnosed with autoimmune hepatitis and cholangitis, reported to the admission unit of the Clinic of Obstetric, Clinical Center University of Sarajevo (CCUS). She was diagnosed with the disease at the age of 15 and had been under regular control of the responsible Hepatologist. Her pregnancy was monitored by practitioners of the Pathology department, which involved accurate and regular control of the liver enzymes and parameters for the purpose of the therapy adjustment. The team responsible for monitoring the patient’s condition also included two Hepatologists and the Clinic Internist. During the pregnancy she was under intensive clinical and laboratory controls which involved monitoring of all parameters related to the disease. The patient gave spontaneous birth at 40 week of gestation, following the spontaneous rupture of the membranes. The second and third stage of the labor went well and 24 hours later she was discharged from the Clinic of Obstetrics. One month after delivery, in a good general health and in a proper obstetric status, the patient was referred under further responsibility of the practicing Hepatologist. Clinical picture of autoimmune hepatitis and cholangitis in a pregnant woman during pregnancy and after delivery Figure 1 Values of ASAT during the pregnancy and after delivery. Figure 2 Values of ALAT during pregnancy and after de- livery. Figure 3 Values of GGT during pregnancy and after deliv- ery. Descriptive-statistical analysis was used for presenting values of liver enzymes in the patient during pregnancy and after delivery. The average AST values ranged from approximately 32,78 U/L during the pregnancy, while after delivery their value significantly increased and amounted to 60 U/L (p<0,05). The average ALT value during the pregnancy (48,9 U/l) and after delivery (124,75 U/L), significantly differ, and it also significantly increased after delivery. Although GGT value statistically significantly increased after deliver (during the pregnancy 158,09 U/L; after delivery 188 U/L), the av- 209 erage value during delivery was also significantly higher then the reference values. The same related to ALP values during the pregnancy and after delivery. The values of liver enzymes during the pregnancy were maintained within certain borders through application of medicamentous therapy, but their value statistically significantly increased immediately after delivery. Figure 4 Values of ALP during pregnancy and after delivery. Figure 5 Values of PV during pregnancy and after delivery. Whereas average PV values during the pregnancy (1,07) and after delivery (13,37) statistically significantly differ (p<0,05), there was no statistically significant difference in the value of bilirubin during the pregnancy and after delivery (Figure 6). Figure 6 Levels of bilirubin during pregnancy and after de livery. 210 L. Imširija et al. CONCLUSION During the pregnancy the patient received the therapy consisting of Decortin, Imuran and Ursofalk. Dosage of Decortin was reduced during the pregnancy and before delivery, and due to high values of the liver enzymes after delivery it was again restored to 5mg. Imuran was administered by mid pregnancy in a dosage of 50-100 mg. It is important to note that Ursofalk was administered continuously, starting from the third trimester until after delivery in a dosage of 1500mg. Only this triple therapy could partly maintain the liver enzymes in their reference values, or in the values under control of the practitioner, and clinically stable condition of the patient could be maintained by adjusting the dosage. Incidence of pregnant women with AIH and Cholangitis is small but it can be connected with serious complications during pregnancy and after delivery. Therefore, those pregnant women must be treated in third level institutions. Regular pregnancy monitoring by a team comprising not only a Gaenecologist but also a Hepatologist and an Internist may result in a positive outcome, as described in the present case report. DISCUSSION REFERENCES Pathogenesis of autoimmune hepatitis has not been fully explained, but there is a generally accepted concept that external factors constitute a “trigger” for development of autoimmune hepatitis in the presence of the genetic predisposition. However, the disease most often occurs spontaneously sui generis without prior exposure to a virus or some other agent. Autoimmune liver diseases as well as other autoimmune diseases are more frequent in women (6). Women are four times more likely to develop autoimmune hepatitis. It is likely that hormones play important role, taking into account that some autoimmune diseases develop after menopause, while other improve during pregnancy and deteriorate after delivery (7). Nevertheless, the most significant part in the development of autoimmune hepatitis as well as other autoimmune diseases is attributed to certain haplotypes of alleles of the main histocompatible complex which point to crucial importance of class II antigens in the clinical expression of these diseases (1-3). The manner in which certain alleles of human leukocyte antigen (HLA) participate in the development of autoimmunity has not yet been established. Structural analysis of molecule of the major histocompatibility complex and the complex with peptides is the bases for studying associations with certain autoimmune diseases and for therapy consideration. This research has shown that functions of hormones excreted during pregnancy successfully stabilize autoimmune hepatitis and cholangitis, while the clinical picture deteriorates after pregnancy which requires timely action of a practitioner in adjustment of the therapy to be used by a puerpera. 1. Agarwal K, Czaja AJ, Jones DE, Donaldson PT. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology. 2000;31(1):49–53. 2. Manns MP, Vogel A. Autoimmune hepatitis, from mechanisms to therapy. Hepatology. 2006;43(2 Suppl 1):S132-44. 3. Heathcote EJ. Management of primary biliary cirrhosis – the American Association for the Study of Liver Diseasespractice guidelines. Hepatology. 2000;31(4):100513. 4. Kaya M, Angulo P, Lindor KD. Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system. J Hepatol. 2000;33(4):537-42. 5. Kneser JM, Bantel H, Manns MP. Diagnostic and therapeutic management of autoimmune hepatitis. Hepatology Rev. 2005;2:80-7. 6. Vergani D, Alvarez F, Bianchi FB, Cançado EL, Mackay IR, Manns MP, et al. Liver autoimmune serology: a consensus statement from the committeefor autoimmune serology of the International Autoimmune Hepatitis Group. J Hepatol. 2004;4184):677-83. 7. Poupon R. Autoimmune overlapping syndromes. Clin Liver Dis. 2003;7(4):865-78. Conflict of interest: none declared. Reprint requests and correspondence: Lejla Imširija-Idrizbegović, MD, MSc Clinic of Obstetrics Clinical Center University of Sarajevo Patriotske lige 81 71000 Sarajevo Bosnia and Herzegovina Phone: +387 61 190 622 Email: [email protected] Instructions to authors 211 INSTRUCTIONS TO AUTHORS Journal “Medical Journal” publishes original research articles, professional, review and educative articles, case reports, criticism, reports, and Bosnian/Croatian/Serbian language. Authors take responsibility for all the statements and attitudes in their articles. If article was written by several authors, it is necessary to provide full contact details (telephone numbers and email addresses) of the corresponding author for the cooperation during preparation of the text to be published. Authors should indicate whether the procedures carried out on humans were in accordance with the ethical standards of medical deontology and Declaration of Helsinki. Articles that contain results of animal studies will only be accepted for publication if it is made clear that ethics standard were applied. Measurements should be expressed in units, according to the rules of the SI System. Manuscript submission should be sent to Editorial Board and addressed to: “MEDICINSKI ŽURNAL” Institut za naučnoistraživački rad i razvoj Kliničkog centra Univerziteta u Sarajevu Bolnička 25 71000 Sarajevo Bosna i Hercegovina e-mail: [email protected]; [email protected] COVER LETTER Apart from the manuscript, the authors should enclose a cover letter, with the signed statements of all authors, to the Editorial Board of “Medical Journal” stating that: 1. the work has not been published or accepted for publication previously in another journal, 2. the work is in accordance with the ethical committee standards, 3. the work, accepted for publication, becomes ownership of “Medical Journal”. PREPARATION OF MANUSCRIPT disk (Word Windows), or e-mail. Spacing: 1,5: left margin: 2,5 cm; right margin: 2,5 cm; top and bottom margin: 2,5 cm. program in which they are prepared. Articles are written in-extenso in English. The manuscript should be submitted on a good quality CD disc, or by e-mail, together with two printed copies (if it is possible). Sent CD disks will not be returned to the authors. ARTICLE CONTAINS: TITLE OF THE ARTICLE IN ENGLISH LANGUAGE TITLE OF THE ARTICLE IN BOSNIAN/SERBIAN/CROATIAN (B/S/C) LANGUAGE First name and last name of author and co-authors Name and address of institution in which author/co-authors are employed (same for all authors) in B/S/C and English language as well as the address of corresponding author at the end of the paper. Summary in B/S/C language with the precise translation in English. Abstract of approximately 200-250 words should concisely describe the contents of the article. Key words ARTICLE BODY The main body of the article should be systematically ordered under the following headings: INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION 212 - CONCLUSION REFERENCES INTRODUCTION Introduction is a concise, short part of the article, and it contains purpose of the article relating to other published articles with the same topic. It is necessary to quote the main problem, aim of investigation, and/or main hypothesis which is investigated. MATERIALS AND METHODS protocol and type of clinical investigation, place and period of investigation. Main characteristics of investigation should be described (randomization, double-blind test, cross test, placebo test), standard values for tests, time framework (prospective, retrospective study), selection and number of patients – criteria for inclusion and exclusion from the study. RESULTS and directly incorporated in the text, at the exact place, with ordinal number and concise heading. Table should have at least two columns DISCUSSION Discussion is concise and refers to own results, in comparison with the other authors’ results. Citation of references should follow Vancou- CONCLUSION Conclusion should be concise and should contain most important facts, which were obtained during investigation and its eventual clinical REFERENCES – Instructions for writing references References should follow the format of the requirements of Vancouver rules. number in parenthesis at the end of the sentence according to the order of entering. Every further referring to the same reference, number numbers in the order of entering in the text (entering reference number). Journal’s title is abbreviated using Index Medicus abbreviations. It is very important to properly design references according to instructions that may be downloaded from addresses National Library of Medicine Citing Medicine http://www.ncbi.nlm.nih.gov/books/bv.fcg?rid=citmed.TOC&depth=2, or International Committee of Medical Journal Editors Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Sample References http://www.nlm.nih.gov/bsd/uniform_requirements.html. Instructions to authors 213 UPUTSTVA AUTORIMA Časopis “Medicinski žurnal” objavljuje originalne naučne radove, stručne, pregledne i edukativne, prikaze slučajeva, recenzije, saopćenja, stručne obavijesti i drugo iz područja svih medicinskih disciplina. Rad in-extenso (cjelokupan) piše se na engleskom jeziku, uz sažetak i naslov rada koji uz engleski trebaju biti napisani i na našim jezicima (bosanski, hrvatski i srpski). Autori su odgovorni za sve navode i stavove u njihovim radovima. Ukoliko je rad pisalo više autora, potrebno je navesti tačnu adresu (uz telefonski broj i e-mail adresu) onog autora s kojim će uredništvo sarađivati pri uređenju teksta za objavljivanje. Ukoliko su u radu prikazana istraživanja na ljudima, mora se navesti da su provedena u skladu s načelima medicinske deontologije i Deklaracije iz Helsinkija. Ukoliko su u radu prikazana istraživanja na životinjama, mora se navesti da su provedena u skladu s etičkim načelima. Prilikom navođenja mjernih jedinica, treba poštovati pravila navedena u SI sistemu. Radovi se šalju Redakciji na adresu: “MEDICINSKI ŽURNAL” Institut za naučnoistraživački rad i razvoj Kliničkog centra Univerziteta u Sarajevu Bolnička 25 71000 Sarajevo Bosna i Hercegovina e-mail: [email protected]; [email protected] POPRATNO PISMO Uz svoj rad, autori su dužni Redakciji “Medicinskog žurnala” dostaviti popratno pismo, koje sadržava vlastoručno potpisanu izjavu svih autora: 1. da navedeni rad nije objavljen ili primljen za objavljivanje u nekom drugom časopisu, 2. da je istraživanje odobrila Etička komisija, 3. da prihvaćeni rad postaje vlasništvo “Medicinskog žurnala”. OPSEG I OBLIK RUKOPISA Windows), ili e-mail. Prored: 1,5: lijeva margina: 2,5 cm; desna margina: 2,5 cm; gornja i donja margina: 2,5 cm. obavezno napisati na engleskom jeziku, a sažetak i naslov još i na našem jeziku. Rad se dostavlja na CD-u, i/ili e-mailom, uz dva štampana primjerka (ako je moguće). CD se ne vraća. RAD SADRŽI: NASLOV RADA NA ENGLESKOM JEZIKU NASLOV RADA NA NAŠEM JEZIKU Ime i prezime autora i koautora Naziv i puna adresa institucije u kojoj je autor-koautor/i zaposlen/i (jednako za sve autore), na engleskom jeziku, te na kraju rada navedena adresa kontakt-autora. Sažetak na našem jeziku, kao i na engleskom - max. 200–250 riječi, s najznačajnijim činjenicama i podatcima iz kojih se može dobiti uvid u kompletan rad. Ključne riječi - Key words, na našem jeziku i na engleskom, ukupno do pet riječi, navode se ispod Sažetka, odnosno Abstracta. SADRŽAJ Sadržaj rada mora biti sistematično i strukturno pripremljen i podijeljen u poglavlja i to: UVOD MATERIJAL I METODE REZULTATI DISKUSIJA ZAKLJUČAK LITERATURA 214 UVOD Uvod je kratak, koncizan dio rada i u njemu se navodi svrha rada u odnosu na druge objavljene radove sa istom tematikom. Potrebno je navesti glavni problem, cilj istraživanja i/ili glavnu hipotezu koja se provjerava. MATERIJAL I METODE literaturi. U kliničko-epidemiološkim studijama opisuju se: uzorak, protokol i tip kliničkog istraživanja, mjesto i vrijeme istraživanja. Potrebno je opisati glavne karakteristike istraživanja (npr. randomizacija, dvostruko slijepi pokus, unakrsno testiranje, testiranje s placebom itd.), standardne vrijednosti za testove, vremenski odnos (prospektivna, retrospektivna studija), izbor i broj ispitanika – kriterije za uključivanje i isključivanje u istraživanje. REZULTATI ose u tekst gdje im je mjesto, s rednim brojem i konciznim naslovom.Tabela treba imati najmanje dva stupca s obrazloženjem što prikazuje; DISKUSIJA Piše se koncizno i odnosi se prvenstveno na vlastite rezultate, a potom se nastavlja upoređivanje vlastitih rezultata s rezultatima drugih autora, pri čemu se citiranje literature navodi po važećim Vankuverskim pravilima. Diskusija se završava potvrdom zadatog cilja ili hipoteze, odnosno njihovim negiranjem. ZAKLJUČAK Treba da bude kratak, da sadrži najbitnije činjenice do kojih se došlo u radu tokom istraživanja i njihovu eventualnu kliničku primjenu, kao i LITERATURA - Upute za citiranje - pisanje literature Literatura se obavezno citira po Vankuverskim pravilima. Svaku tvrdnju, saznanje ili misao treba potvrditi referencom. Reference u tekstu treba označiti po redoslijedu unošenja arapskim brojevima u zagradi na kraju rečenice. Ukoliko se kasnije u tekstu pozivamo na istu referencu, navodimo broj koji je referenca dobila prilikom prvog unošenja/pominjanja u tekstu. Literatura se popisuje na kraju rada, rednim brojevima pod kojim su reference unesene u tekst (ulazni broj reference), a naslov časopisa se skraćuje po pravilima koje određuje Index Medicus. Ukoliko je citirani rad napisalo više autora, navodi se prvih šest i doda “et al.”. Vrlo je važno ispravno oblikovati reference prema uputama koje se mogu preuzeti na adresama National Library of Medicine Citing Medicine http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=citmed.TOC&depth=2 , ili International Committee of Medical Journal Editors Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Sample References http://www.nlm.nih.gov/bsd/uniform_requirements.html. 215 Instructions to authors Novi Evropski vodič za prevenciju tromboembolizma kod A Fib CHA2DS2-VASc skor za procjenu rizika od tromboembolizma kod A Fib! Risk factor-based point-based scoring system - CHA2DS2 -VASc Risk factor Score Congestive heart failure/LV dysfunction 1 Hypertension 1 Age >75 2 Diabetes mellitus 1 Stroke/TIA/thrombo-embolism 2 Vascular disease* 1 Age 65–74 1 Sex category (i.e. female sex) 1 Maximum score 9 *Prior myocardial infarction, peripheral artery disease, aortic plaque. Actual rates of stroke in contemporary cohorts may vary from these estimates. Major i non-major riziko fakori za procjenu tromboembolizma kod A Fib! Risk factors for stroke and thrombo-embolism in non-valvular AF Major risk factors Previous stroke TIA or systemic embolism Clinically relevant non-major risk factors CHF or moderate to severe LV systolic dysfunction [e.g. LV EF � 40%] Hypertension Age �75 years Diabetes mellitus Age 65-74 years Female sex Vascular disease AF = atrial fibrilation; EF = ejection fraction (as documented by echocardiography, radio nuclide ventriculography, cardiac catheterization, cardiac magnetic resonance imaging, etc.); LV = left venticular; TIA = trasient ischaemic attack. Algoritam antikoagulantne terapije nakon procjene CHA2DS2VASc i major risk faktora! Choice of Anti-coagulant Atrial fibrilation Yes Valvular AF* Yes No (i.e. non-valvular AF) <65 years and lone AF (including females) No Assess risk of stroke (CHA2DS2-VASc score) * Includes rheumatic valvular AF, hypertrophic cardiomyopathy, etc. 0 ** Antiplatelet therapy with aspirin plus clopidogrel, or less effectively - aspirin only, may be considered in patients who refuse any OAC 1** �2 Oral anticoagulant therapy Assess bleeding risk (HA S-BLED score) Consider patient values and preferences No antithrombotic therapy NOAC VKA NOAC - Novel Oral Anticoagulants, VKA - Vitamin K Antagonists Prijedlog mreže Primarne Perkutane Koronarne Intervencije za Bosnu i Hercegovinu! Prijedlog mreže Primarne Perkutane Koronarne Intervencije za Federaciju Bosne i Hercegovine!