Duplication of The SOX3 Gene in an Sry-negative 46,XX Male with Associated Congenital Anomalies of Kidneys and the Urinary Tract: Case Report and Review of the Literature.

Disorders of sex development (DSD) are a group of rare conditions characterized by discrepancy between chromosomal sex, gonads and external genitalia. Congenital abnormalities of the kidney and urinary tract are often associated with DSD, mostly in multiple malformation syndromes. We describe the case of an 11-year-old Caucasian boy, with right kidney hypoplasia and hypospadias. Genome-wide copy number variation (CNV) analysis revealed a unique duplication of about 550 kb on chromosome Xq27, and a 46,XX karyotype, consistent with a sex reversal phenotype. This region includes multiple genes, and, among these, SOX3 emerged as the main phenotypic driver. This is the fifth case reporting a genomic imbalance involving the SOX3 gene in a 46,XX SRY-negative male, and the first with associated renal malformations. Our data provide plausible links between SOX3 gene dosage and kidney malformations. It is noteworthy that the current and reported SOX3 gene duplications are below the detection threshold of standard karyotypes and were found only by analyzing CNVs using DNA microarrays. Therefore, all 46,XX SRY-negative males should be screened for SOX3 gene duplications with DNA microarrays.

Proteomics in diagnosis of prostate cancer.

Prostate cancer (PCa) is the second most frequently diagnosed malignancy in men worldwide. The introduction of prostate specific antigen (PSA) has greatly increased the number of men diagnosed with PCa but at the same time, as a result of the low specificity, led to overdiagnosis, resulting to unnecessary biopsies and high medical cost treatments. The primary goal in PCa research today is to find a biomarker or biomarker set for clear and effecttive diagnosis of PCa as well as for distinction between aggressive and indolent cancers. Different proteomic technologies such as 2-D PAGE, 2-D DIGE, MALDI MS profiling, shotgun proteomics with label-based (ICAT, iTRAQ) and label-free (SWATH) quantification, MudPIT, CE-MS have been applied to the study of PCa in the past 15 years. Various biological samples, including tumor tissue, serum, plasma, urine, seminal plasma, prostatic secretions and prostatic-derived exosomes were analyzed with the aim of identifying diagnostic and prognostic biomarkers and developing a deeper understanding of the disease at the molecular level. This review is focused on the overall analysis of expression proteomics studies in the PCa field investigating all types of human samples in the search for diagnostics biomarkers. Emphasis is given on proteomics platforms used in biomarker discovery and characterization, explored sources for PCa biomarkers, proposed candidate biomarkers by comparative proteomics studies and the possible future clinical application of those candidate biomarkers in PCa screening and diagnosis. In addition, we review the specificity of the putative markers and existing challenges in the proteomics research of PCa.

Severe scoliosis, torticollis and short stature in a woman with Wildervanck Syndrome (WS).

Wildervanck syndrome (WS) combines features of Klippel-Feil syndrome (KFS), sixth nerve palsy, and deafness. This is a case of a 23 year old woman, diagnosed with KFS (a triad of short neck, low posterior hairline and restricted neck movements) at the age of 20 days. The manifestations of the WS in this patient are severe: she has torticollis, and an extremely severe scoliosis. In addition, she is short (-3 SD; parental target height + 0.8SD) and has mixed sensorineural and conductive deafness. She also has ptosis, strabismus and a high myopia. Radiologically, there are multiple coalitions of cervical vertebrae. Intelligence is unaffected (IQ 95), but deafness, strabismus and high myopia forced her early out of school. Karyotype is 46, XX. In brief, this is a patient with severe WS and additional anomalies. Short and/or reduced parental target height is a part of WS.

Genetic, Genomic and Epigenomic Studies of Balkan Endemic Nephropathy (Ben).

BEN is a primary, chronic tubulointerstitial nephritis characterized with chronic anemia, absence of edema, xantoderma, normal blood pressure and normal findings on the fundus oculi. The disease is distributed in restricted areas in Bulgaria, Romania, Croatia, Bosnia, Former Yugoslavia. Despite numerous studies on genetic and environmental factors and their possible involvement in BEN, its etiopathogenesis still remains elusive. Our recent study aim to elucidate the possible epigenetic component in BEN development. Whole genome DNA array methylation analysis was applied to compare the methylation profiles of male and female BEN patients from endemic regions in Bulgaria and Serbia and healthy controls. All three most prominent candidate genes with aberrations in the epigenetic profile discovered with this study are involved in the inflammatory/immune processes and oncogenesis. These data are in concordance with the reported pathological alterations in BEN. This research supports the role of epigenetic changes in BEN pathology. Exome sequencing of 22.000 genes with Illumina Nextera Exome Enrichment Kit revealed three mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients which encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN.

NGS nominated CELA1, HSPG2, and KCNK5 as candidate genes for predisposition to Balkan endemic nephropathy.

Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression leading to terminal renal failure. The results of molecular biological investigations propose that BEN is a multifactorial disease with genetic predisposition to environmental risk agents. Exome sequencing of 22 000 genes with Illumina Nextera Exome Enrichment Kit was performed on 22 DNA samples (11 Bulgarian patients and 11 Serbian patients). Software analysis was performed via NextGene, Provean, and PolyPhen. The frequency of all annotated genetic variants with deleterious/damaging effect was compared with those of European populations. Then we focused on nonannotated variants (with no data available about them and not found in healthy Bulgarian controls). There is no statistically significant difference between annotated variants in BEN patients and European populations. From nonannotated variants with more than 40% frequency in both patients' groups, we nominated 3 genes with possible deleterious/damaging variants--CELA1, HSPG2, and KCNK5. Mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN.

The many faces of rare diseases (RD): meeting report on Rare Disease in South-Eastern Europe, 15-16 November 2013, Skopje, Republic of Macedonia.

The Second meeting on Rare Diseases in South Eastern Europe (SEE) was held in Skope, Macedonia on November 15-16, 2013. Objective and main data: Rare diseases (RD) are a major problem in developed and especially in countries without affluence. 6-8% of every population suffers from RD. The cumulative effect of RDs on the health system of a country is increasing. Diagnosis often remains a challenge and requires international collaboration. Treatment in diseases for which medication exist is often inaccessible to patients because of the high costs. All countries of SEE need screening programs that address more diseases. Patient organizations play a major role in increasing awareness and providing the needed pressure on society to treat treatable RDs. On the other hand, RDs are frequently a source of valuable new molecular insights not only on mechanisms of their etiology and pathology, but sometimes provide an insight on mechanisms of frequent diseases in man. Further efforts are needed in improving all the RD aspects mentioned.

Department of Nephrology at the Medical Faculty, Ss. Cyril and Methodius University, Skopje--creating nephrology protection for the citizens of the Republic of Macedonia.

In January 1975, de facto, the Nephrology Department was founded at the Medical Faculty in Skopje as the first institution of such a type in former Yugoslavia. The Nephrology Department was the driving force for the further development of nephrology in the Republic of Macedonia. D. Hrisoho was the first Director of the Department, and its subsequent Directors were G. Masin, M. Polenakovic, K. Zafirovska and currently A. Sikole. Prior to the establishment of the Nephrology Clinic there had been considerable experience in the diagnosis and treatment of renal patients. The first haemodialysis (HD) in the Republic of Macedonia (RM) was performed in 1959 on a patient with acute renal failure (ARF) using a Kolff-Brigham rotating drum artificial kidney at the Blood Transfusion Institute in Skopje. In 1965 the Renal Unit at the Department of Medicine, Medical Faculty, Skopje obtained a new, modern "Websinger" artificial kidney with a sigma motor pump and possibilities for the use of a disposable Kolff "twin coil" dialyser. Between 1959 and 1971, HD was performed only on patients with ARF. In May 1971, a Unit for Chronic HD was founded at the Renal Unit and the programme of maintenance haemodialysis (MHD) was started with five Stuttgart Fresenius machines and 12 patients dialysed on twin coil dialysers. That was a great incentive for the development of HD in the Republic of Macedonia enforced by the great number of patients with end stage renal disease. Thus in 2007 we have 18 HD centres in the Republic of Macedonia, with 1183 patients. Treatment of the patients with MHD is the greatest success achieved in the Republic of Macedonia in nephrology concerning patients with end stage renal disease. Prior to the treatment with MHD patients were destined to die, whereas now, with this type of treatment, they have a normal life and families. Patients with kidney diseases are examined in outpatients clinics as well as treated in the wards of the Department. All types of vascular accesses, renal biopsies, bone biopsies, kidney ultrasound, plasmapheresis and other investigations are performed every day at the Nephrology Department of the Medical Faculty. On the basis of the results of renal biopsy, a classification of parenchymal renal diseases has been established, as well as appropriate immunosuppressive and other treatments. The nephrology doctrine for primary, secondary and tertiary healthcare has been prepared and has been distributed to all medical centres in the Republic of Macedonia. The first (living donor) renal transplantation was performed in July 1977. Later, living and cadaver donor transplantations were performed, so the Department of Nephrology was complete concerning dialysis and renal transplantation, and it became part of the European centres for diagnosis and therapy of kidney disease. Doctors from the Nephrology Department are among the most productive scientific workers in the Republic of Macedonia and their papers can be found on the internet Pub Med. The Department of Nephrology, together with the Nephrology Association, was the source of knowledge in the area of nephrology and the transfer of knowledge from abroad into Macedonia and vice versa. The Nephrology Association has made a great contribution in the development of nephrology in our country. The most famous European and world nephrologists have participated in the work of our association and have contributed to the development of nephrology not only in Macedonia, but on the Balkans as well.

One hundred years since the birth of academician Dimitar Arsov, founder and nestor of the modern internal medicine in the Republic of Macedonia.

Dimitar Arsov was born in Kriva Palanka on September 28, 1908 and died on July 2, 1974 in Skopje; he had finished elementary education in Kriva Palanka, high school (1922-1926) in Kumanovo, Macedonia and Col-lege of Medicine (1926-1932), Ph. D. University of Paris, Sorbone, France, 1936. He returned to Macedonia in 1937. In 1947 he was elected and Assistant Professor and in 1950 a Docent at the Faculty of Medicine in Skopje. He was appointed Director of the Clinic of Medicine and Head of the Chair of Internal Medicine, who served at those positions in the period 1952-74. In 1958 he was elected Professor of Internal Medicine. The first habilitation of the Medical Faculty in Skopje was defended by D. Arsov in 1954, titled: "The Effects of the Intravenous Epinephrine on the Hypersplenism of Malaria and Cala-Azar". On August 18, 1967, D. Arsov was elected Full Member and also the first member in the field of medicine of the Macedonian Academy of Sciences and Arts. The excellent experience in the work with the patients, precise observation of the symptoms and syndromes of the diseases in each patient, knowing the most advanced therapy at that time enabled D. Arsov to make conclusion for possibility of new therapy and gave him the material for writing scientific papers. In the first half of the 50s, during his regular work, Arsov discovers a new, internationally recognized therapy for rheumatism. Patients of both Cala-Azar and inflammatory rheumatism were treated with small doses of adrenaline therapy and they felt drastic decrease in rheumatism inflammation within one week. This therapy was used a couple of years in several countries around the world. He participated in the undergraduate and graduate studies. He contributed to the development of 2,240 graduated doctors and under his management over 300 doctors specialized in internal medicine and became specialists internists. Under his management, numerous habilitations and dissertations in internal medicine were finished. He contributed also to the development of 25 assistants, 5 docents, 5 full-time professors in internal medicine at the Medical Faculty in Skopje. He has published more than 200 papers from different areas of internal medicine, of which 36 are on the PubMed. He has published 5 books on internal medicine for students and doctors. He was a President and member of several Macedonian medical associations, as well as of medical associations of former Yugoslavia. He was awarded with the highest awards of former Yugoslavia and Macedonia. He was also awarded with international awards, such as: Doctor Honoris Causa by the University in Besancon and Honor and Medal from the City Assembly of Besancon (France). During his management of the Internal clinic the University Internal clinic developed eight different sub-specialist departments: Cardiology, Pneumology, Rheumatology, Nephrology, Hematology, Gastroenterology and Endocrinology with metabolism and Clinical biochemical laboratory. The fast development of subspecialties has led to development of separate clinics for each subspecialty in 1975, so only the Chair of Internal Medicine remained as a connection between the subspecialties for education and scientific research. He was a prolific scientist who after World War II wrote the first scientific and specialist papers and books in the field of internal medicine in Macedonia. He created a school of internal medicine. The scientific and uncompromised attitude towards the expert truth are weaved in the unforgettable face of the Academician Prof. D-r. Dimitar Arsov, scientist, teacher, and doctor. With his vast work in healing the sick and preventing the diseases in the Republic of Macedonia, he became the cornerstone of modern medicine in the Republic of Macedonia. Thus, he truly deserves to be the doyen of internal medicine, one of the leading, most important persons in medicine of the 20th century in our country. Today, his honorary name appears on: Clinic of Rheumatology at the Medical Faculty in Skopje, Medical Center in Kriva Palanka, Scientific Club of the student organization of the Medical Faculty in Skopje.

Morphology of renal interstitial fibroblasts.

INTRODUCTION: Renal fibrogenesis is a process common to all progressive kidney diseases. The main executive cell in this process is the fibroblast, by secreting and remodelling the extracellular matrix. The number of fibroblasts is minor in a healthy kidney interstitium, but it increases during the process of fibrosis. Their morphology and immunophenotype vary due to different intrinsic and extrinsic factors which makes their identification and visualization, as well as determination of their origin, very difficult. MATERIAL AND METHODS: We performed morphological and immunohistochemical analyses on kidney biopsies with interstitial fibrosis, using the following antibodies: Vimentin, α-SMA, S100A4, Cadherin 9 and CD34. We also did light-microscopy analyses of semithin sections of tissue embedded in epoxy resin and stained with Toluidine blue. RESULTS: Our observations show that different cells in the fibroblastic population show positivity for different markers, thus contributing to the theory that there are different subpopulations of fibroblasts, with different origins, that take part in renal fibrogenesis.

Contributions of doctors from Serbia to the establishment and initial development of the Faculty of Medicine in Skopje, Republic of Macedonia.

AIM: To analyse and present the milestone activities and actors, with special emphasis on the contribution of doctors from Serbia to the establishment and initial development of the Faculty of Medicine in Skopje, Macedonia, in the period 1947-60 and beyond. METHOD: A retrospective study based on archive materials, encyclopedias and jubilee publications of the Faculty of Medicine and Faculty of Dentistry in Skopje, other relevant sources of information, and a review of the relevant literature. RESULTS: The Faculty of Medicine in Skopje was founded in 1947 and the first meeting of the Teachers' Council of the Faculty was held on March 17, 1947. The first generation of 153 students was enrolled in the autumn of 1947 and the first lecture was delivered on November 3, 1947. More than 20 doctors from Serbia, half of them faculty staff, had joined the initiative of the Government of Macedonia for establishing the Faculty of Medicine in Skopje in 1947. They played leading roles in creating a number of the faculty departments/chairs, establishing 6 institutes and 6 clinics within the newly established Faculty of Medicine in Skopje in 1947 and in the first 10-15 years of its development. CONCLUSION: The Faculty of Medicine in Skopje, founded in 1947, played a crucial role in the education of medical professionals, in improving the poor health status of the population and the overall further development of the health system and provision of health care to the population of Macedonia. The contribution of the doctors from Serbia to the establishment and initial development of the Faculty of Medicine in Skopje, during the period 1947-1960 and beyond, was remarkable and important.

First scientific meeting of Yugoslav nephrologists, Struga, Republic of Macedonia, 26-28.IX 1977--introduction to the development of nephrology--in former Yugoslavia.

The first scientific meeting of nephrologists in Yugoslavia with international participation was held in Struga, Republic of Macedonia, on Lake Ohrid, 26 to 28 September 1977. During the Third Symposium on Endemic Nephropathy, which was held in Nis on 5 to 8 November 1975 at the Radon Hotel, representatives of the nephrology sections of the republics founded the Yugoslav Society of Nephrology. Academician Vojislav Danilovic from Belgrade was elected as the Association's first President. It was decided that the first scientific meeting of Yugoslav Nephrologists be held in Struga, Macedonia, 1977, and the first Nephrology Congress in Belgrade in 1979. It was also agreed that congresses be held every four years, and to organize scientific meetings between congresses. In this way, the Nephrology Association of Yugoslavia gained the opportunity for a lot of activities every two years. The Proceedings of the First Scientific Meeting of Yugoslav Nephrologists contained 6 plenary lectures and 84 papers presented during the three sections of the scientific meeting, 31 about hypertension and kidneys, 19 about immunology in nephrology and 34 about dialysis. The first scientific meeting of Yugoslav nephrologists with international participation was the first major review of the achievements of Nephrology in Yugoslavia, assessment of its results, work incentives and the creation of a vision for future development. The meeting strengthened the ties among the colleagues, new acquaintances were created, and new ideas for further cooperation appeared.

Personality profiles and depression in haemodialysis patients.

Chronic haemodyalisis is an established treatment of end stage renal disease which maintains the lives of individuals who otherwise would have succumbed to a uraemic death. However, this method of treatment raises certain psychological, social and ethical issues, where depression and stress are the most common. This article is concerned with the evaluation of depression and the psychological characteristics of patients treated by chronic maintenance haemodyalisis. Using two psychometric tests (Beck Depression Inventory and MMPI-201) we obtained a significant incidence of depression (90.63%) in patients recruited from two centres for dia-lysis in Skopje, where even the severe form was unrecognized and untreated. The psychological profiles confirmed hypersensitivity, depressive mood, frequent interpersonal problems, and withdrawal from friends and relatives. Latent aggressiveness could be destructive for their social communications. In order to overcome the depression some response measures such as relaxation training, psychological support, music therapy or peripheral biofeedback are recommended.

Contributions of doctors from Macedonia to the establishment and initial development of the Faculty of Medicine in Skopje, Republic of Macedonia.

AIM: To present an overview of the circumstances, initiatives and milestone activities of the process and actors, with special emphasis on the contribution of doctors from Macedonia to the establishment and initial development of the Faculty of Medicine in Skopje, Macedonia, in the period 1947-60 and beyond. METHOD: A retrospective study based on archive materials, encyclopedias and jubilee publications of the Faculty of Medicine and Faculty of Dentistry in Skopje, other relevant sources of information, and a review of the relevant literature. RESULTS: The Faculty of Medicine in Skopje was founded in 1947 and the first meeting of the Teachers' Council of the Faculty was held on March 17, 1947. The first generation of 153 students was enrolled in the autumn of 1947 and the first lecture was delivered on November 3, 1947. About 15 doctors from Macedonia--faculty staff in the period from 1947-54--had joined the initiative of the Government of Macedonia for establishing the Faculty of Medicine in Skopje, and an additional 22 lecturers from Macedonia, who had been elected in the period from 1955-60, supported its initial development. They played leading roles in the creating and/or development of a number of the faculty departments/chairs, institutes and clinics within the newly established Faculty of Medicine in Skopje in 1947 and in the first 10-15 years of its initial development. CONCLUSION: The Faculty of Medicine in Skopje, founded in 1947, played a crucial role in the education of medical professionals, in improving the poor health status of the population and the overall further development of the health system and provision of health care to the population of Macedonia. The contribution of the doctors from Macedonia to the establishment and initial development of the Faculty of Medicine in Skopje, during the period 1947-60 and beyond, was dominant and essential.

Study of the hepatitis C virus in the republic of macedonia.

Hepatitis C virus (HCV) is a major public health problem. It is a leading cause of chronic liver disease and the most common indication for liver transplantation. The therapy for eradication of HCV infection is successful in only 50.0-80.0% of patients and is highly dependent on the HCV genotype. Molecular detection and characterization of HCV in the Republic of Macedonia started in 1990. Since then, more than 4000 samples have been analyzed at the Research Centre for Genetic Engineering and Biotechnology (RCGEB) "Georgi D. Efremov," Skopje, Republic of Macedonia. The prevalence of HCV infections in the healthy population of the Republic of Macedonia was found to be 0.4%, while it varies between 23.0 and 43.0% in different at-risk groups of patients. The prevalence of HCV genotypes, according to associated risk factors in HCV infected patients from the Republic of Macedonia, was analyzed. We found genotype 1 to be predominant in a group of hemodialysis patients, while genotype 3 was predominant in intravenous (IV) drug users. Association of six polymorphisms in the Oligoadenylate synthetase (OASL)-like interferon-stimulated gene with a sustained virological response was also analyzed. Our preliminary results suggest that non ancestral alleles in four of the six studies polymorphisms in OASL gene are associated with sustained virological response among HCV infected patients in R. Macedonia.

On rare and "super-rare" diseases: an insight from the Republic of Macedonia.

Rare diseases (RD) are becoming increasingly important as possible targets of new forms of treatment, as a valuable source of a novel insight in fundamental lows of biology, and in the specific mechanisms of many diseases. Molecular methods have created a better diagnosis and oftentimes treatment. RDs pose significant problem for the patients, since their problems are often not recognized by the medical community and shunned by the health insurance. The cumulative costs of diagnosis and treatment of RDs is significant for any society, oftentimes bearably acceptable for developing countries.

Rare diseases with renal involvement in the Republic of Macedonia.

Rare diseases (RDs) pose a significant set of problems for patients, since their disease and general social and health situation are often not recognized by the medical community and shunned by health insurance. The sheer number of RDs (5000-8000) and the number of patients (6-8% of the population) are challenging for every society. We wanted to get a better understanding of the rare diseases affecting the kidneys and urinary tract (RDAKUT) in the Republic of Macedonia and we investigated principally the PubMed Central articles of Macedonian medical professionals dealing with RDAKUT, but we also used information on RDAKUT from local sources. A significant number of RDs have been published, demonstrating the awareness and skill of Macedonian medical professionals despite pretty limited diagnostic facilities. We still feel that RDAKUT are underdiagnosed (e.g. Fabry's disease has not yet been reported), and that many patients with RDs have a long way to go before an accurate diagnosis. Increased awareness and ameliorated education are needed by the physicians; while health insurance must include RDAKUT covering their diagnosis and treatment costs. Neonatal screening for ~30 diseases (instead of just hypothyroidism) is also required. Patients' organizations exist and they are active in promoting their interests before of the health authorities.

Renal histopathology and clinical course in patients with Wegener's granulomatosis--single centre experience from the Republic of Macedonia.

The aim of this study was to evaluate the clinical course of patients with Wegener's granulomatosis (WG) with renal involvement, to examine histopatological form seen in renal biopsies and present follow-up of the patients. A retrospective analysis was carried out of 18 patients presenting with WG and active renal disease at the University Nephrology Department, Ss. Cyril and Methodius University, Skopje, R. Macedonia. All patients were ANCA positive and had a percutaneous renal biopsy taken on their admission. 12 patients were male, 6 female, aged 48.61±13.77 (M±SD). All had extrarenal symptoms prior to admission. Oligoanuria was present in 7/18 (38.9%) of the patients, serum urea levels of the whole group were 40.67±18.13 mmol/l (M±SD) and for serum creatinine 691.06±384.93 µmol/l (M±SD). Necrotizing glomerulonephritis with crescents was present in 11/18 (61.11%) of the patients, the others presented diffuse proliferative extracapillary glomerulonephritis. All patients were treated with steroids and cyclophosphamide, and plasmapheresis was performed in 7/18 (38.9%) of the patients. Probability rate for surviving after one month was 0.6111 and after three months 0.3889 (Kaplan-Meier). The current treatment of WG in our study did not prevent serious complications and development of ESRD in a large number of our patients. This systemic disorder is still a serious problem and early diagnosis and alternative strategies for the management of the disease will be an important objective for further studies.

Urothelial carcinoma associated with Balkan endemic nephropathy. A worldwide disease.

Balkan endemic nephropathy (BEN), a familial chronic tubulo-interstitial disease with a slow progression to terminal renal failure, affects people living in the alluvial plains along the tributaries of the Danube River. One of its most peculiar characteristics is a strong association with upper urothelial cancer. An increased incidence of upper urinary tract (UUT) transitional cell cancer (TCC) was discovered among the inhabitants of endemic settlements and in families affected by BEN. In areas where BEN is endemic, the incidence of upper tract TCC is significantly higher, even 100 times, than in non-endemic regions. A high incidence of urothelial cancer in end-stage BEN patients strongly suggests preventive nephro-ureterectomy in all end-stage patients with BEN treated with either transplantation or dialysis. Better understanding of the molecular mechanisms involved in carcinogenesis and tumor progression, has provided a large number of molecular markers of TCC, with a potential diagnostic and prognostic value. Markers that distinguish among TCC, normal urothelium, and benign urothelial conditions are potentially diagnostic, prognostic, and therapeutic targets. The geographic correlation and presence of AA-DNA adducts in both BEN and associated urothelial cancer, support the speculation that these diseases share a common etiology. Dietary exposure to AA is a significant risk factor for BEN and its attendant transitional cell cancer. These are cases of well-known AA induced urothelial carcinoma, and could be detected worldwide. The presence of more than one risk factors is possible and it is important to test etiological hypotheses in different endemic foci, preferably as a multicentric research.

Medical journals in the Republic of Macedonia after the Second World War.

An attempt was made to retrospectively examine the medical journals published in the Republic of Macedonia since the Second World War. An analysis was made of the basic data concerning the journals, most of which are deposited in the Central Library of the Medical Faculty at the Ss. Cyril and Methodius University in Skopje, and a few deposited in the National and the St. Clement of Ohrid University Library in Skopje. Some journal-related data were obtained by searching the electronic databases (mainly Medline/PubMed, Hinari, Ebsco) and the Internet as a global system of network of networks. After the Second World War several attempts at publishing biomedical journals have been made in the Republic of Macedonia. The number of journals has increased especially in the last ten years. Only a few of them have a long-term publishing tradition. In fact, the only journal to maintain continuity in publishing until today is the Macedonian Medical Review, that has been published regularly since 1946 until today. It is an official publication of the Macedonian Medical Society. The Annual of the Medical Faculty in Skopje was published from 1954 to 1997 under this name, and in 1997 it was renamed the Macedonian Journal of Medicine. There was an interruption in its publishing in 1999 and 2000 and it was regularly published until 2007, after which its publication ceased once more. In addition to these two journals, other medicine-related journals that have been published in the Republic of Macedonia (some of them, however, irregularly or they have ceased publication) are Acta Morphologica (since 2004); Physioacta (since 2007); Paediatrics Annual Review (since 1996); Epilepsy (since 1997); Acta Ortopedica et Traumatologica Macedonia (since 1999); MJMS-Macedonian Journal of Medical Sciences (since 2008); Prilozi Macedonian Academy of Arts and Sciences (since 1969); Macedonian Dental Review (since 1977); Dental Review (since 2007); Macedonian Pharmaceutical Bulletin (since 1964); Macedonian Veterinary Review (since 1972); Archives of Public Health (since 2009); Medicus (since 2004); Vox Medici (since 1992); Social Medicine--Professional Journal for Public Health (since 2009); Journal of Special Education and Rehabilitation (since 1997); Balkan Journal of Medical Genetics (since 1998); BANTAO Journal (since 2003); Public Health--Journal for Health Education (1952-1986); Acta Chirurgica Iugoslavica (since 1954); Acta Chirurgica Macedonica (2001-2004); We You and Healthcare (since 2006); Newsletter-Health, Kavadartsi (1999); Medical Review--Professional Journal of the Medical Workers in Shtip (2001); Medicus--Information Newsletter of Public Health, General Hospital Shtip (2006); Medical Bulletin of the Health Service of the Skopje Army Region (1957-1987); Medical Spectrum--Professional Journal of Alkaloid--Skopje (1972-1981); Healthcare Newsletter, Kumanovo (1990-1996); Healthcare, Shtip (1979-1994); Healthcare Platform, Bitola (1975-1984); Journal with papers of the Society of Science and Art, Prilep; Healthcare Newsletter of the Medical Center Prilep (1975-1986); Healthcare Newsletter, Strumica (1978-1988); Contributions, a Journal of the Society of Science and Arts from Bitola; Doctors' Newspaper--Informative and educational newspaper of the Macedonian Medical Association (2010). A number of medical journals appear and after a short period of time disappear. The papers are mainly written in the Macedonian language, and none of the journals are currently indexed in Pub/Med, except for the Prilozi/Contributions of the Macedonian Academy of Sciences and Arts. In our opinion, to improve the quality of the published papers in the Macedonian journals, several goals have to be accomplished: better equipment and facilities in the hospitals, institutes and research centres that would yield better basic research and clinical trials; better basic education on how to write and publish scholarly/scientific papers, which has to be conducted at both undergraduate and postgraduate levels, along with lifelong learning; better peer-review processes; better editorial policy of the journals; compliance with international standards/uniform requirements for manuscripts submitted to biomedical journals; fostering the goals of the World Association of Medical Editors and European Association of Science Editors, etc. If these tasks and goals are realized, then we can build a solid ground to better present our medical results to the world.