Severe digital malformations in a rare variant of fibrodysplasia ossificans progressiva.

A 16-year-old girl with a history of nontraumatic swelling of both forearms, osteochondromas of the knees, heterotopic ossification of the neck and back, severe malformations of all digits with hypoplastic or absent nails, alopecia partialis of the scalp, and moderate cognitive impairment was seen for diagnostic evaluation. Whole exome sequencing identified an activating mutation of ACVR1 (c.983G > A; p.Gly328Glu) which confirmed a suspected FOP variant. The delayed diagnosis of an FOP variant in this patient could have been avoided if the significance of severe digital malformations had been recognized, especially in the setting of progressive heterotopic ossification.

Urinary peptide biomarker panel associated with an improvement in estimated glomerular filtration rate in chronic kidney disease patients.

Background: An improvement in the glomerular filtration rate (GFR) of chronic kidney disease patients has been an underestimated clinical outcome. Although this may be considered as an unexpected disease course, it may provide some insights into possible mechanisms underlying disease remission and/or regression. Therefore, our aim was to identify urinary peptide biomarkers associated with an improvement in estimated GFR (eGFR) over time and to improve patient stratification. Methods: Capillary electrophoresis coupled with mass spectrometry (CE-MS) was employed to evaluate the urine peptidome of patients with different types of renal diseases. In total, 376 patients with a slope/year between -1.5% and +1.5% were designated as non-progressors or stable, while 177 patients with a > 5% slope/year were designated as patients with an improved eGFR for state-of-art biomarker discovery and validation. Results: We detected 384 significant peptide fragments by comparing the CE-MS data of the stable patients and those with improved renal function in our development cohort. Of these 384, a set of 141 peptides with available amino acid sequence information were used to generate a support vector machine-based classification panel. The biomarker panel was applied to our validation cohort, achieving a moderate area under the curve (AUC) value of 0.85 (81% sensitivity and 81% specificity). The majority of the peptides (78%) from the diagnostic panel arose from different types of collagen. Conclusions: We have developed a panel of urinary peptide markers able to discriminate those patients predisposed to improve their kidney function over time and possibly be treated with more specific or less aggressive therapy.

LHX4 Gene Alterations: Patient Report and Review of the Literature.

LHX4 mutations are rare in combined pituitary hormone deficiency, and even rarer in isolated GHD. We describe a 14 years old boy who was referred for investigation of short stature. Convergent strabismus, nystagmus was present. At the age of 5 years his gait was unstable. A progressive myopathy ensued. Tests of pituitary reserve showed partial IGHD (8.2 ng/ml). Other pituitary hormones were within normal range. Muscle biopsy showed congenital myopathy of undefined etiology. MRI of the brain revealed the empty sella syndrome. Targeted resequencing with a panel containing probe sets for enrichment and analysis of > 4,800 clinically relevant genes, targeting 12Mb of the human genome revealed the c.250C>T (R84C) LHX4 mutation. His father is healthy, with no myopathy or pituitary deficiencies, but has the same LHX4 mutation. This report extends the range of phenotypes associated with LHX4 gene mutations. To the best of our knowledge, we are the first to report on congenital myopathy in an LHX4 gene mutation. Forthwith, we offer a comprehensive review of the patients published so far with their clinical and genetic characteristics.

Proteomics analysis of malignant and benign prostate tissue by 2D DIGE/MS reveals new insights into proteins involved in prostate cancer.

BACKGROUND: The key to a more effective diagnosis, prognosis, and therapeutic management of prostate cancer (PCa) could lie in the direct analysis of cancer tissue. In this study, by comparative proteomics analysis of PCa and benign prostate hyperplasia (BPH) tissues we attempted to elucidate the proteins and regulatory pathways involved in this disease. METHODS: The samples used in this study were fresh surgical tissues with clinically and histologically confirmed PCa (n = 19) and BPH (n = 33). We used two dimensional difference in gel electrophoresis (2D DIGE) coupled with mass spectrometry (MS) and bioinformatics analysis. RESULTS: Thirty-nine spots with statistically significant 1.8-fold variation or more in abundance, corresponding to 28 proteins were identified. The IPA analysis pointed out to 3 possible networks regulated within MAPK, ERK, TGFB1, and ubiquitin pathways. Thirteen of the identified proteins, namely, constituents of the intermediate filaments (KRT8, KRT18, DES), potential tumor suppressors (ARHGAP1, AZGP1, GSTM2, and MFAP4), transport and membrane organization proteins (FABP5, GC, and EHD2), chaperons (FKBP4 and HSPD1) and known cancer marker (NME1) have been associated with prostate and other cancers by numerous proteomics, genomics or functional studies. We evidenced for the first time the dysregulation of 9 proteins (CSNK1A1, ARID5B, LYPLA1, PSMB6, RABEP1, TALDO1, UBE2N, PPP1CB, and SERPINB1) that may have role in PCa. The UBE2N, PSMB6, and PPP1CB, involved in cell cycle regulation and progression were evaluated by Western blot analysis which confirmed significantly higher abundances of UBE2N and PSMB6 and significantly lower abundance of PPP1CB in PCa. CONCLUSION: In addition to the identification of substantial number of proteins with known association with PCa, the proteomic approach in this study revealed proteins not previously clearly related to PCa, providing a starting point for further elucidation of their function in disease initiation and progression.

Proteomics analysis of urine reveals acute phase response proteins as candidate diagnostic biomarkers for prostate cancer.

Despite the overall success of prostate specific antigen (PSA) in screening and detection of prostate cancer (PCa), its use has been limited due to the lack of specificity. The principal driving goal currently within PCa research is to identify non-invasive biomarker(s) for early detection of aggressive tumors with greater sensitivity and specificity than PSA. In this study, we focused on identification of non-invasive biomarkers in urine with higher specificity than PSA. We tested urine samples from PCa and benign prostatic hyperplasia (BPH) patients by 2-D DIGE coupled with MS and bioinformatics analysis. Statistically significant (p < 0.05), 1.8 fold variation or more in abundance, showed 41 spots, corresponding to 23 proteins. The Ingenuity Pathway Analysis showed significant association with the Acute Phase Response Signaling pathway. Nine proteins with differential abundances were included in this pathway: AMBP, APOA1, FGA, FGG, HP, ITIH4, SERPINA1, TF and TTR. The expression pattern of 4 acute phase response proteins differed from the defined expression in the canonical pathway. The urine levels of TF, AMPB and HP were measured by immunoturbidimetry in an independent validation set. The concentration of AMPB in urine was significantly higher in PCa while levels of TF and HP were opposite (p < 0.05). The AUC for the individual proteins ranged from 0.723 to 0.754. The combination of HP and AMBP yielded the highest accuracy (AUC = 0.848), greater than PSA. The proposed biomarker set is quickly quantifiable and economical with potential to improve the sensitivity and specificity of PCa detection.

Balkan nephropathy.

Balkan endemic nephropathy (BN), frequently associated to upper urothelial cancer, is a familial chronic tubulointerstitial disease with insidious onset and slow progression to end-stage renal disease. After 60 years of research, its cause remains the major unanswered question. Etiology assumes polygenic susceptibility to the disease in interaction with multiple environmental factors. Chronic intoxication with Aristolochia is the major environmental risk factor for this disease. The mycotoxin hypothesis considers that BN is produced by ochratoxin A. The Pliocene lignite hypothesis assumes that the disease is caused by long-term exposure to organic toxins leached from coal nearby the endemic villages. Exome sequencing of 22,000 genes revealed that mutant genes (CELA1, HSPG2, and KCNK5) in BN patients encode proteins involved in basement membrane/extracellular matrix and vascular tone, which are tightly connected to the process of angiogenesis. SEC61G, IL17RA, and HDAC11 proved to be differently methylated throughout all patient-control pairs. The acetylation of histone lysine residues was detected and found increased at specific sites of H3 and total H4 histones isolated from urothelial cells of patients with BN. The results of molecular biological research will allow the discovery of genetic markers of BN and associated urothelial cancer, permitting early detection of BN-predisposing mutations and identification of susceptible individuals who might be at risk of exposure to environmental agents. The research of gene-gene and gene-environment interactions could lead to further studies to determine the precise risk for BN.

Consensus statement on screening, diagnosis, classification and treatment of endemic (Balkan) nephropathy.

Currently used diagnostic criteria in different endemic (Balkan) nephropathy (EN) centers involve different combinations of parameters, various cut-off values and many of them are not in agreement with proposed international guidelines. Leaders of EN centers began to address these problems at scientific meetings, and this paper is the outgrowth of those discussions. The main aim is to provide recommendations for clinical work on current knowledge and expertise. This document is developed for use by general physicians, nephrologists, urologist, public health experts and epidemiologist, and it is hoped that it will be adopted by responsible institutions in countries harboring EN. National medical providers should cover costs of screening and diagnostic procedures and treatment of EN patients with or without upper urothelial cancers.

Whole genome methylation array analysis reveals new aspects in Balkan endemic nephropathy etiology.

BACKGROUND: Balkan endemic nephropathy (BEN) represents a chronic progressive interstitial nephritis in striking correlation with uroepithelial tumours of the upper urinary tract. The disease has endemic distribution in the Danube river regions in several Balkan countries.DNA methylation is a primary epigenetic modification that is involved in major processes such as cancer, genomic imprinting, gene silencing, etc. The significance of CpG island methylation status in normal development, cell differentiation and gene expression is widely recognized, although still stays poorly understood. METHODS: We performed whole genome DNA methylation array analysis on DNA pool samples from peripheral blood from 159 affected individuals and 170 healthy individuals. This technique allowed us to determine the methylation status of 27 627 CpG islands throughout the whole genome in healthy controls and BEN patients. Thus we obtained the methylation profile of BEN patients from Bulgarian and Serbian endemic regions. RESULTS: Using specifically developed software we compared the methylation profiles of BEN patients and corresponding controls and revealed the differently methylated regions. We then compared the DMRs between all patient-control pairs to determine common changes in the epigenetic profiles.SEC61G, IL17RA, HDAC11 proved to be differently methylated throughout all patient-control pairs. The CpG islands of all 3 genes were hypomethylated compared to controls. This suggests that dysregulation of these genes involved in immunological response could be a common mechanism in BEN pathogenesis in both endemic regions and in both genders. CONCLUSION: Our data propose a new hypothesis that immunologic dysregulation has a place in BEN etiopathogenesis.

International Conference: "Renal Aspects of Disaster Relief", Ohrid, R. Macedonia, May 24-26, 1996.

The International Conference Renal Aspects of Disaster Relief, Ohrid, R. Macedonia, May 24-26, 1996 united doctors and engineers in order to better build settlements, and in case of an earthquake, how to help the injured.Plans have been proposed for the treatment of the injured with fluid and dialysis, as well as how to organize the non-governmental organizations and the population to assist the medical staff in optimizing the treatment of the injured.Members of the Renal Disaster Relief Task Force of the International Society of Nephrology and the European Renal Best Practice were tasked with preparing guidelines for medical staff and the population to address earthquake injuries.

The Importance of the World Kidney Day World Kidney Day - 11 March 2021 - Living Well with Kidney Disease.

World Kidney Day (WKD) is a global campaign to raise awareness of the importance of our kidneys to overall health and to reduce the frequency and impact of kidney disease and associated health problems worldwide. Kidney disease is a non-communicable disease (NCD) and currently affects around 850 million people worldwide. One in ten adults has chronic kidney disease (CKD). The global burden of CKD is increasing, and is projected to become the 5th most common cause of years of life lost globally by 2040. CKD is a major cause of catastrophic health expenditure. The costs of dialysis and transplantation consume 2-3% of the annual healthcare budget in high-income countries. Crucially, kidney disease can be prevented and progression to end-stage kidney disease can be delayed with appropriate access to basic diagnostics and early treatment. This year World Kidney Day continues to raise awareness of the increasing burden of kidney diseases worldwide and to strive for kidney health for everyone, everywhere. During the pandemic with COVID 19 patients kidneys are also damaged, apart from the respiratory tract and other organs. It can lead to an increase in acute renal failure and consequent chronic kidney insufficiency, as well as number of deaths. Therefore, it is important to evaluate the renal function in each patient with COVID 19 virus. In the Republic of North Macedonia from 2006 to present day nephrologists and other medical personnel devoted to the early diagnosis, prevention and treatment of renal disease have participated in the activities of the World Kidney Day. These activities were supported by the Macedonian Society of Nephrology, Dialysis, Transplantation and Artificial Organs, the Department of Nephrology at the Medical Faculty, the Macedonian Academy of Sciences and Arts, the Government of the Republic of North Macedonia, non-governmental nephrology organizations (NEFRON) and the media. There were lectures and presentation devoted to the various theme of the WKD, publications in journals, as well as activities for examination of the renal function of patients in the medical centers. The activities during the WKD contributed to the improvement of the nephrological protection of the citizens of the Republic of N. Macedonia.

Prof. Peter Ivanovich, MD, FRCP - A Friend of Doctors Nephrologists from North Macedonia.

Prof. Peter Ivanovich was born in Tacoma, Washington, USA on November 9, 1928, and died in Chicago on November 16, 2019. After being educated by the father of chronic hemodialysis, Belding Scribner, in Seattle, P. Ivanovich devotes himself to the study of hemodialysis and its treatment in patients with chronic terminal renal failure. From 1971 he worked at the Northwestern University School of Medicine in Chicago where he created a hemodialysis unit at the Veteran Affairs Hospital. In the well-equipped hemodialysis unit, the latest hemodialysis techniques were studied and new drugs were tested. Numerous doctors from all over the world, as well as from Macedonia, visited and researched at the unit with P. Ivanovich. P. Ivanovich has frequently visited Macedonia and the former Yugoslavia, where he participated with his lectures. He helped in the development of nephrology in the Balkan Peninsula. Significant is his participation in the First Scientific Meeting of the Nephrologists of Yugoslavia, Struga, 26-28. IX 1977 and in the creation of BANTAO in Ohrid on 9. IX 1993 - during the First Congress of the Macedonian Society of Nephrology, Dialysis, Transplantation and Artificial Organs. Prof. P. Ivanovich is in the lasting memory of the nephrologists of North Macedonia as a renowned nephrologist, cosmopolitan and friend of patients and doctors.

A Scientific Symposium "Artificial Organs Today: From in Vitro Assessment to Human Therapies" on the Occasion of the Celebration of the 40th Anniversary of the Macedonian Academy of Sciences and Arts.

On the occasion of the celebration of the 40th anniversary of the Macedonian Academy of Sciences and Arts (MASA) the Macedonian Society of Nephrology, Dialysis, Transplantation and Artificial Organs (MSNDTAO) organized a one day symposium titled: "Artificial Organs Today: From in vitro assessment to human therapies", on September 28, 2007 at the Macedonian Academy of Sciences and Arts. The following sessions were held: Artificial Organs in Front of the Ageing Populations; System Requirements for Artificial Organ Technology; Tools for Artificial Organ Technology; Extracorporeal Blood Circuits in Organ Replacement Therapies; Treatment Options for Blood Purification Therapies. Presentation were delivered by: Horst Klinkmann, Germany; Jörg Vienken, Germany; Jens Hartmann, Austria; Udo Losert, Austria; Jan Wojcicki, Poland; Helmut Mann and Siegfried Stiller, Germany; Beat Walpoth, Switzerland; Juan F. del Cañizo, Spain; Borce Georgievski, Macedonia; Bernd Stegmayr, Sweden; Momir Polenakovic, Macedonia; Petar Kes, Croatia; Aleksandar Sikole, Macedonia; Wolfgang Ramlow, Germany; Dieter Falkenhagen, Austria. These meetings are significant for the application and development of the artificial organs in patients.

Artificial Organs 2000 ESAO.

Artificial Organs 2000 Satellite Symposium of European Society for Artificial Organs (ESAO) was organized by the Macedonian Society for Nephrology, Dialysis, Transplantation and Artificial Organs (MSNDTAO) and the Macedonian Academy of Sciences and Arts (MASA) on November 25-26, 2000 on the occasion of the 25th Anniversary of the Department of Nephrology of the Ss. Cyril and Methodius University, Skopje, R. Macedonia.The main topics of this symposium were: Blood-purification techniques, Artificial Kidney, Metabolic- and Cardiac-Assist Systems as well as Biomaterials to be used for Artificial Organs.H. Klinkmann (Glasgow, United Kingdom), D. Falkenhagen (Krems, Austria), U. Baurmeister (Wuppertal, Germany), V. Bonomini, S. Stefoni (Bologna, Italy), R. Vanholder (Ghent, Belgium), S. Stiller (Aachen, Germany), H. Mann, H. Melzer (Aachen, Germany), J. Pop-Jordanov, N. Pop-Jordanova (Skopje, R. Macedonia), B. Stegmayr (Umea, Sweden), M. Mydlik, K. Derzisova, O. Racz, A. Sipulova, J. Boldizsar, E. Lovasova, M. Hribikova (Kosice, Slovak Republic), A. Jörres (Berlin, Germany), M. Polenakovic (Skopje, R. Macedonia), J. Vienken (Bad Homburg, Germany), S. Bowry (Bad Homburg, Germany), E. Piskin (Ankara, Turkey), J. Klinkmann, W. Schimmelpfennig, H. Lantow, W. Rigger. (Teterow, Germany), A. Sikole (Skopje, R. Macedonia), A. Oncevski, P. Dejanov, V. Gerasimovska, M. Polenakovic (Skopje, R. Macedonia), J. Wojcicki (Warsaw, Poland), K. Affeld (Berlin, Germany), G. Rakhorst et al. (Groningen, The Netherlands), Z. Mitrev (Skopje, R. Macedonia), S. Kedev, G. Guagliumi, O. Valsecchi, M. Tespili (Skopje, R. Macedonia, Bergamo, Italy) have presented their papers at the Symposium. The presentations provoked a fruitful discussion and it was concluded that they should be published.The papers were published in the International Journal of Artificial Organs of the European Society for Artificial Organs (ESAO) as a special issue on "Artificial Organs 2000 ESAO Satellite Symposium -Skopje, R. Macedonia", Guest Editors: M. H. Polenakovic, Skopje and J. Vienken, Bad Homburg; Vol. 25, No. 5, 2002.

Prof. Dimitar Hrisoho, Md, Phd, Founder of Nephrology in the R. N. Macedonia.

Prof. Dr. Dimitar T. Hrisoho was born on June 11, 1924 in Bitola, R. Macedonia. He died in Struga on September 22, 1986, and was buried in Skopje. He completed primary and secondary education in Bitola. He graduated from the Medical Faculty in Belgrade in 1951 as one of the best students of his generation (average grade of 9.75). In 1953 he was employed at the Internal Clinic of the Medical Faculty in Skopje, where in 1955 he passed the specialist exam in internal medicine. He successfully defended his habilitation "Polyarthritis chronica evolutiva" and his doctoral dissertation "Clinical features of Vitina nephropathy". The doctoral dissertation indicates that Vitina nephropathy is a new site of the Balkan Endemic Nephropathy entity and that more genetic testing of patients were needed. Based on numerous clinical and scientific researches published in over 200 papers, he was elected a Full Professor of internal medicine at the Medical Faculty of the Ss. Cyril and Methodius University in Skopje in 1971. In 1970, he formed the nephrology section of the Macedonian Medical Association (MMA), which grew into the nephrology Association of MMA. Through the Association, the education of the medical staff from the field of nephrology was performed. He also set up a bio-cybernetics association. He achieved his vision and desire to transfer and apply the achievements of modern nephrology in the diagnosis and treatment of kidney patients in Macedonia at the Clinic of Nephrology of the Medical Faculty in Skopje, which was the first specialized institution established for examination and treatment of kidney patients in the former Yugoslavia and the Balkans. The Clinic educated nephrological staff and examined and treated kidney patients with new methods and drugs that positively affected the development of nephrology as a subspecialty of the internal medicine. D. Hrisoho was actively involved in the introduction of new methods for examination of kidney patients, as well as in the treatment of patients with acute and chronic renal insufficiency with dialysis since 1965. He also participated in the first two kidney transplantations from living donors performed in 1977. He wrote a chapter on "kidney examination", printed in the book of Prof. A. J. Ignjatovski "Fundamentals of Internal Propedeutics" Part III, published by "Prosvetno delo", 1963, in Skopje. This is the first text to investigate a patient with kidney disease published in a textbook in R. Macedonia. In 1984 he published the textbook "Clinical Nephrology" printed by the University of the Ss. Cyril and Methodius University in Skopje. Prof. D. Hrisoho organized the First Scientific Meeting of Yugoslav Nephrologists with international participation, from 26 to 28 September 1977, in Struga, R. Macedonia. The meeting was attended by prominent nephrologists from the former Yugoslavia, the Balkans, Europe and the United States, among them: J.S. Cameron from UK, J.L. Funck-Brentano from France, M. Burg and P. Ivanovich from the USA, R. Kluthe from Germany and A. Puchlev from Bulgaria. The scientific meeting was the largest nephrology event until then organized in the former Yugoslavia. The meeting provided an exchange of experiences with world-renowned nephrologists. D. Hrisoho presented the paper Artificial intelligence in nephrology. The author tried to apply bio-cybernetics in nephrology. Prof. D. Hrisoho was Vice Dean of the Medical Faculty in Skopje in the period 1963-1965 and Vice Rector of the University of the Ss. Cyril and Methodius University in Skopje in the period 1974-1975. Prof. Hrisoho was also active in socio-political organizations. For his medical, educational and scientific activities he received several awards and recognitions in the country and abroad. Thus, the work of Prof. D. Hrisoho was permanently embedded in the nephrology of R. Macedonia.

Sixth Congresses of the Macedonian Society for Nephrology, Dialysis, Transplantation and Artificial Organs (MSNDTAO) - Stimulus for the Development of Nephrology in N. Macedonia.

The Macedonian Society for Nephrology, Dialysis, Transplantation and Artificial Organs (MSNDTAO) was established on September 1, 1992 in order to stimulate the development of nephrology and to unite experts from all professions interested in the research and treatment of kidney patients. Momir H. Polenakovic was elected President of MSNDTAO.The First congress of MSNTAO was held in Ohrid from October, 7 to 10, 1993 in hotel "Desaret" under the auspices of the first President of R. Macedonia, Kiro Gligorov. During the Congress, the Balkan Cities Association of Nephrology, Dialysis, Transplantation and Artificial Organs (BANTAO) was formed on October 9, 1993. The idea of cooperation with the Department of Nephrology from the Ege University, Izmir, R. Turkey was promoted. Some of the presented papers were published in the Proceedings "Nephrology '93" as a supplement to the Macedonian medical review. The "Doctrine for performing nephrological activity in the Republic of Macedonia" was also promoted.The Second congress of MSNDTAO was held in Struga, R. Macedonia from September, 6 to 10, 1997 together with the Second BANTAO Congress. Selected papers were printed in the Macedonian Medical Review.The Third congress of MSNDTAO was held from May, 30 to June 2, 2001 in Skopje, at the Macedonian Academy of Sciences and Arts (MASA). Proceedings of papers was also published.In 2011 M. H. Polenakovic was elected Honorary President of MSNDTAO for life, and Goce Spasovski was elected the current President of MSNDTAO.The Fourth congress of MSNDTAO was held in Ohrid from June, 21 to 24, 2012 together with the Fourth Meeting of the South-Eastern European Pediatric Nephrology Working Group (SEEPNWG).The Fifth congress of MSNDTAO was held from June, 9 to 12, 2016 in Skopje, at MASA together with the 6th Southeastern European Pediatric Nephrology Working Group (SEPNWG) Meeting and IPNA (International Pediatric Nephrology Association) Teaching Course. The VIII Macedonian-Croatian Nephrology Days were also held during the Congress.The Sixth congress of MSNDTAO was held from September, 26 to 29, 2019 along with the 15th BANTAO Congress, in Skopje, at MASA. The Congress also marked the 80th anniversary of the birth of M. H. Polenakovic.Apart from the participants from R. Macedonia, the congress was attended by renowned nephrologists from Europe and the world.A novelty of the last congresses was the organization of 9 CME (Continuing Medical Education) courses with famous lecturers. CME courses supported by the ERA-EDTA and / or the ISN were as follows: 2005 - Ohrid (BANTAO), 2006 - Skopje (MSNDTAO), 2009 - Skopje (MSNDTAO), 2010 - Skopje (ERA-EDTA - ESAO), 2011 Skopje (ERA-EDTA - EUTox group), 2012 - Ohrid (MSNDTAO), 2014 -Skopje (MSNDTAO), 2016 - Skopje (MSNDTAO), 2018 - Skopje (MSNDTAO - ERA-EDTA & ISN), 2019 - Skopje (BANTAO - ISN & ERA-EDTA).In addition to the congresses, MSNDTAO has held meetings with nephrological associations from the neighboring countries as Croatia, Serbia, Albania and Kosovo.The congresses of MSNDTAO contributed to the introduction and education of doctors in the diagnosis and treatment of kidney patients. They were a strong stimulus for the development of nephrology in R. Macedonia and beyond.

Heterotopic ossifications and Charcot joints: Congenital insensitivity to pain with anhidrosis (CIPA) and a novel NTRK1 gene mutation.

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV), is a rare and severe autosomal recessive disorder. We report on an adult female patient whose clinical findings during childhood were not recognized as CIPA. There was neither complete anhidrosis nor a recognizable sensitivity to heat. Tumorlike swellings of many joints and skeletal signs of Charcot neuropathy developed in adolescence which, together with a history of self-mutilation, led to a clinical suspicion of CIPA confirmed by identification of a novel homozygous variant c.1795G > T in the NTRK1 gene in blood lymphocytes. Both parents were heterozygous for the mutation. The variant predicts a premature stop codon (p.Gly599Ter) and thus represents a pathogenic variant; the first reported in the Southeastern European population.

Fifty years of research in Balkan endemic nephropathy: where are we now?

Despite broad investigations into the possible role of genetic factors, environmental agents and immune mechanisms, the etiology of Balkan endemic nephropathy (BEN) is only partially understood. An increased incidence of upper urothelial cancer in patients with BEN and in populations from endemic settlements has been demonstrated. Genetic studies have landed support for genetic predisposition to BEN. The similarity of the morphological and clinical pattern of BEN and Chinese herbs nephropathy has raised the possibility of a common etiologic agent, aristolochic acid (AA), described in 1969 by Ivic and confirmed by a recent study of AA-DNA adducts. Ochratoxin A (OTA) is studied extensively as the etiologic agent of BEN. Weathering of low-rank coals nearby the endemic villages produces water-soluble polycyclic aromatic hydrocarbons and aromatic amines, similar to metabolic products of acetaminophen, which has a causal relationship with analgesic nephropathy. AA is confirmed as the etiologic agent of BEN; however, it may not be the sole risk factor. More research is needed on the patterns of BEN over time and between different endemic places. Therefore, it is important to test etiological hypotheses in different endemic foci, preferably as a multicentric research. An international approach to solving the etiology of BEN is needed in the coming years. The geographic correlation and presence of AA-DNA adducts in both BEN and associated urothelial cancer support the hypothesis that these diseases share a common etiology.

Acad. Prof. Yucel Kanpolat, Distinguished and Internationally Recognized Neurosurgeon and Friend of the Republic of Macedonia.

The sad news about the death of Acad. Yucel Kanpolat (September 17, 2016), a famous scholar, a pioneer in the field of neurosurgery, and a friend of the Republic of Macedonia, saddened the members of the Editorial Board of the journal PRILOZI of the Department of Medical Sciences of the Macedonian Academy of Sciences and Arts, of which he was a member, as well as the other members of the Academy. Yucel Kanpolat was an international figure, linking Turkey to almost every country in the world. Neurosurgery has lost a very special surgeon, scientist and humanitarian. During the visit to the Macedonian Academy of Sciences and Arts in 2011, we discussed the cooperation between the Turkish Academy of Sciences and the Macedonian Academy of Sciences and Arts, which he respected very much, as well as the role of the academies. He delivered a lecture on The Mission of Academia in the Age of Science, PRILOZI, MASA, XXXII, 2, p. 7-10 (2011), which we reprint in addition.

Prof. Aleksandar Josifovich Ignjatovski, Founder and First Director of the Clinic for Internal Medicine and the First Head of the Department of Internal Medicine at the Faculty of Medicine in Skopje, R. Macedonia.

Aleksandar J. Ignjatovski was born in the Smolensk Region, Russia, on 18.03.1875. He graduated from the Faculty of Medicine in St. Petersburg in 1899 where he started specialization in internal medicine and continued in Berlin, Heidelberg, Munich and Paris. In 1905 he was elected assistant professor in St. Petersburg, continued as an associate professor in Odessa in 1908 and a full-time professor in 1912 in Warsaw. During the October Revolution, he was the Head of the Internal Clinic in Rostov, and in 1920 he emigrated to Belgrade. In 1922 he was appointed full professor and Director of the First Internal Clinic at the Faculty of Medicine in Belgrade, which he established, developed and managed until his retirement in 1946. In 1948 he moved to Skopje as a full professor and first Director of the Internal Clinic at the Faculty of Medicine in Skopje. He studied the pathogenesis of arteriosclerosis and first proved it experimentally, and published a paper in 1908, indicating that it was associated with higher blood cholesterol level. He also dealt with immunobiology and infectious diseases, in particular tuberculosis and tetanus. Prof. A. Ignjatovski was an excellent clinician, teacher and scientist, who published over 80 papers. His most important textbooks are "Clinical Semiotics and Symptomatic Therapy", in two editions, in Russian (1919) and in Serbian (1929-37), and "The Basics of Internal Propedeutics" in three volumes, published in Skopje in 1952, 1954 and 1963. The work of Prof. A. Ignjatovski, as a leading clinician and a great teacher and scientist, is embedded in the development of internal medicine, and medicine in general, in Russia, Serbia and Macedonia. The bright memorial of the founder and first director of the Internal Medicine Clinic and the first Head of the Department of Internal Medicine at the Faculty of Medicine in Skopje has been permanently incorporated in the history of medicine in R. Macedonia. Prof. A. Ignjatovski died on 18.08.1955.

Ideas and Spirit of the Balkan Cities Association of Nephrology, Dialysis, Transplantation and Artificial Organs (Bantao) Connect Nephrologists from the Balkan Cities - From the Foundation to the 15th Bantao Congress.

The Balkan Cities Association of Nephrology, Dialysis, Transplantation and Artificial Organs (BANTAO) was established in Ohrid, Republic of Macedonia on October 9, 1993 during the First Congress of the Macedonian Society of Nephrology, Dialysis, Transplantation and Artificial Organs (MSNDTAO). The idea of the founders was that such Society would have a clear impact on several aspects of practice and research in nephrology and artificial organs in the Balkans, firstly, by increasing its international visibility and potential collaborative work, and recognition by international organizations. Secondly, such a society would facilitate the exchange of experience and knowledge between experts in our area. In addition, it would be a very positive symbolic act showing that collaborative work for the betterment of life is possible and desirable in our area and that coming together will bear better fruits at the human and cultural levels. It will also send a very clear signal to the outside world that the Balkans can be a place of collaboration and mutual understanding. Several international bodies such as the International Society of Artificial Organs and the International Faculty of Artificial Organs have signaled their interest in and support for the creation of such a society. Despite the turbulent times in the Balkan Peninsula, the First BANTAO Congress was held in Varna from September 22 to 24, 1995, which was an impressive event. F. Valderrabano, Chairman of the EDTA-ERA registry reported on that event with a lot of sympathy in the paper entitled "Nephrologists of the Balkan countries meet across political frontiers and war fronts - an example to politicians. The foundation of and the Second Congress of BANTAO were also well accepted by the colleagues nephrologists from Russia. The Second Congress was held on September 6-10, 1997 in Struga, the Third BANTAO Congress was held on September 18-20, 1998 in Belgrade, the Fourth Congress of BANTAO was held in Izmir on November 14-16, 1999, the Fifth Congress of BANTAO was held in Thessaloniki on September 30 - October 3, 2001, the 6th BANTAO Congress was held in Varna, on October 6-9, 2003, the 7th BANTAO Congress was held in Ohrid, on September 8-11, 2005, the 8th BANTAO Congress was held in Belgrade, on September 16-19, 2007, the 9th BANTAO Congress was held in Antalya, November 18-22, 2009, the 10th BANTAO Congress was held in Chalkidiki, October 13-15, 2011, the 11th BANTAO Congress was held from 26 to 29 September 2013 in Timisoara on the 20th Anniversary of the foundation of BANTAO, the 12th BANTAO Congress was held on October 15-18, 2015 in Opatija, the 13th BANTAO Congress was held on 4-8 October, 2017 in Sarajevo, the 14th BANTAO Congress was held on September 20-23, 2018, in Budva and the 15th BANTAO Congress was held in Skopje, 26-29 September 2019. Another milestone in the life of BANTAO was the appearance of the BANTAO journal in 2003, which has been published biannually since then. In the past 17 years there have been 33 editions of the journal and seven supplements reporting BANTAO congresses. The editors of the journal past and present are: 2003-2005 (Dimitar Nenov); 2005-2009 (Ali Basci); 2009-(Goce Spasovski). Up to date, more than 400 papers have been published. The BANTAO journal is registered on EBSCO, DOAJ, SCOPUS, and has become a strong 'glue' among nephrologists from the Balkan cities. The BANTAO congresses and the BANTAO journal have succeeded in elevating nephrology knowledge and thus increased the standards of nephrology patient care throughout the Balkans. Standing above the divisive forces of politics, language and war, BANTAO gives a living example that collaboration and humility are feasible in times of maddening destruction, and are transformative.