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Prema podacima iz 2011 godine, u Srbiji je približno 630 000 ljudi (8,6%) obolelo od dijabetes melitus-a, a procenjuje se da će taj broj porasti na 730 000 (10,2%) do 2030 godine. Preko 90% obolelih ima tip 2 dijabetes melitus (T2DM). Prva linija medikamentne terapije predstavljaju bigvanidi čiji je najznačajniji predstavnik metformin. Prema literaturnim podacima, u oko 10-30% sluĉajeva, kontinuirana upotreba metformina ima za posledicu smanjenu intestinalnu apsorpciju vitamina B12. Tačan patofiziološki mehanizam koji dovodi do metforminom indukovane malapsorpcije vitamina B12 nije u potpunosti ispitan i poznat i postoji nekoliko aktuelnih teorija s ciljem objašnjenja ovog kompleksnog problema. Cilj rada je bio utvrđivanje nivoa, dinamike, trenda i učestalosti promena vitamina B12, holotranskobalamina (B12 aktiv), homocisteina i folne kiseline tokom kontinuirane primene metformina tokom godinu dana. Studija praćenja je sprovedena u Centru za laboratorijsku medicinu a u saradnji sa Klinikom za endokrinologiju, dijabetes i bolesti metabolizma, Kliničkog centra Vojvodine. Ovom studijom je obuhvaćeno 50 ispitanika obolelih od T2DM a u momentu uvođenja metformina. Svim ispitanicima je određivana koncentracija vitamina B12, B12 aktiva, homocisteina i folne kiseline, u momentu uvođenja terapije kao i nakon 4, 8 i 12 meseci primene metformina. Za dvanaest meseci kontinuirane primene metformina, utvrđen je kontinuirani pad i redukcija vrednosti ukupnog vitamina B12 za 25.29 %, odnosno vrednosti B12 aktiva za 23.26 %. U toku ispitivanja, utvrđen je kontinuirani trend porasta vrednosti homocisteina u krvi, s statistički značajnim porastom vrednosti homocisteina nakon osam meseci primene metformina. Pošavši od predpostavki da metformin istovremeno blokira apsorpciju vitamina B12 u gastrointestinalnom traktu kao i raspoloživost iz postojećih, tkivnih rezervi, zatečene količine ovog vitamina u ciljnim ćelijama se postepeno redukuju i troše, rezultujući krajnjem snižavanju nivoa metabolički aktivnih oblika kobalamina, te posledičnoj akumulaciji homocisteina kako u ćelijskom, tako i u vanćelijskom prostoru. Na osnovu dobijenih rezultata ispitivanja može se predložiti opservacija nivoa ukupnog vitamina B12 i homocisteina u krvi pre uvođenja metformina u terapiju tipa 2 dijabetes melitusa kao i dvanaest meseci nakon toga. Na osnovu nivoa jednogodišnjeg pada koncentracija ukupnog vitamina B12, porasta koncentracija homocisteina, kao i drugih kliničkih i laboratorijskih parametara, može se razmatrati opcija uvođenja supstitucione terapije vitaminom B12 ili dalja opservacija nivoa vitamin B12 u krvi i ćelijskom prostoru., According to data from 2011, in Serbia, approximately 630.000 people (8.6%) were diagnosed with diabetes mellitus, and it is estimated that this number will increase to 730.000 (10.2%) by 2030. Over 90% are type 2 diabetes mellitus (T2DM) patients. The first line of medication therapy is metformin. According to the literature data, in about 10-30% of cases, continuous use of metformin causes impared intestinal absorption of vitamin B12. The exact pathophysiological mechanism leading to metformin induced malabsorption of vitamin B12 has not been fully known, and there are several current theories to explain this complex problem. The aim of this study was to determine the level, dynamics, trend and frequency of changes in blood levels of total vitamin B12, holotranscobalamin (B12 active), homocysteine and folic acid during continuous application of metformin, over a year. The study was carried out at the Center of Laboratory Medicine in cooperation with the Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Vojvodina. This study included 50 T2DM patients at the time of the introduction of metformin therapy. Levels of vitamin B12, holotranscobalamin, homocysteine and folic acid are determined before and after 4, 8 and 12 months of metformin administration, to all subjects. After a year of metformin use, the level of total vitamin B12 has been reduced by 25.29%, as well as holotranskobalamin by 23.26%. During the study, a continuous elevation of homocysteine levels was determined, with statistically significant increase in homocysteine values after eight months of metformin administration. Starting from the assumption that metformin blocks the absorption of vitamin B12 in the gastrointestinal tract as well as the availability of existing tissue reserves, the amount of this vitamin in the target cells is gradually reduced, resulting in an extremely low level of metabolically active forms of this vitamin and the consequent accumulation of homocysteine in intracellular and extracellular space. On the basis of the obtained test results, it may suggest observation of the level of total vitamin B12 and homocysteine prior to the introduction of metformin in T2DM therapy and after one year thereafter. Based on the level of one-year decline of total vitamin B12 and the increase of homocysteine concentrations, as well as other clinical and laboratory parameters, substitution therapy with vitamin B12 or further monitoring of laboratory parameters of vitamin B12 metabolism may be proposed.

The results obtained show that the frequency of the heterozygous MDR1 C3435T is significantly higher in COPD patients in comparison to the control group (p

Introduction The Mediterranean fever gene (MEFV) has special importance in autoinflammatory diseases (AID) etiology. The MEFV gene codes for protein pyrin, one of the inflammasome regulators in the innate immune cells. Mutations and R202Q polymorphism of the MEFV gene alter pyrin function, consequently leading to a dysregulation of interleukin-1β release, activation of NF-κB, apoptosis, as well leukocytes oxidative burst. Mutations M680I, M694V, M694I, V726A and E148Q represent the largest percentage of all mutations. Although the R202Q polymorphism in heterozygous form is a benign alteration, several studies confirmed that R202Q homozygotes may develop AID. Familial Mediterranean fever is the most common hereditary autoinflammatory disease with MEFV gene mutations. However, these mutations are determined in a number of other diseases, where they predispose a proinflammatory state, such as: Behcet's disease, Henoch-Schonlein purpura, ulcerative colitis, systemic lupus erythematosus, multiple sclerosis, etc. The acute phase of AID is caracterised by increased body temperature, abdominal pain, arthralgia, myalgia, erysipeloid rash, fatigue, etc. There is an inflammatory reaction in the blood and increased oxidative stress, detected through the decreased antioxidant activity and increased levels of oxidatively modified molecular products. However, various clinical presentation in the presence of the same MEFV mutations in different individuals, as well as disease in heterozygotes, led to a reconsideration of the role and significance of MEFV gene changes. It is found that mutation carriers have a tendency for febrile episodes, frequent occurrence of rheumatic diseases, and increased levels of acute phase reactants. It is assumed that still unknown modifying genes or environmental factors are partially responsible for AID in heterozygotes. Aim The aim of this study was to investigate the presence and distribution of the MEFV gene mutations and R202Q polymorphism in healthy population in Serbia. Also, the intention was to determine the incidence of recurrent fevers and other clinical signs of inflammation in persons with mutations and R202Q polymorphism, and compare with persons without these changes. In addition, it was investigated whether persons with MEFV changes have altered oxidative stress parameters and what is their association with inflammatory events. Methods The study enrolled 100 healthy subjects. The investigation protocol included: collection of health data (using the official Eurofever project questionnaire) and collection of blood samples to perform genetic test and analysis of oxidative stress parameters. DNA was extracted from peripheral blood leukocytes. DNA sequencing was performed using ABI PRISM 310 automated sequencer (Applied Biosystems, USA). Thiobarbituric acid reactive substances test (TBARS) in plasma was performed by the spectrophotometric method of Andreeva et al. TBARS in erythrocytes were determined by spectrophotometric method of Jain et al. Advanced oxidation protein products (AOPP) were determined spectrophotometricaly and calibrated by chloramine-T solution by the method of Witko-Sarsat V et al. Determination of superoxide dismutase (SOD) was performed with pyrogallol method (McCord J, Fridovich I). Catalase activity was determined by catalase ELISA kit (Enzo Life Sciences), following the manufacturer's instructions. Results Out of 100 examined subjects 11% had MEFV gene mutation: 6% heterozygous E148Q/N mutation and 5% K695R/N. There were 10% of R202Q polymorphism homozygotes and 45% heterozygotes. Unexpectedly, the carrier frequency of mutations and R202Q polymorphism was relatively high for a healthy population in Serbia. Regarding clinical manifestations, persons with the mutations and R202Q homozygotes reported more frequently: febrile episodes of unknown cause (p=0.027), diffuse abdominal pain (p=0.015), peritonitis (p=0.019) and fatigue (p=0.012) in comparison with persons without these gene changes. Individuals with the MEFV gene mutations had more frequently recurrent febrile episodes (p=0.048), diffuse abdominal pain (p=0.017), peritonitis (p=0.008) and fatigue (p=0.032). R202Q homozygotes have experienced significantly more often repeated episodes of fever (p=0.022), diffuse abdominal pain (p=0.009) and lymphadenopathy (p=0.035). Recurrent fever and nonspecific abdominal pain are the most common symptoms in most AID with MEFV gene mutations and suggest the existence of a modified immune response in these persons. Individuals with the MEFV mutations and R202Q homozygotes had significantly higher concentration of erythrocytes TBARS compared with persons without these gene changes (p=0.03), suggesting the existence of increased oxidative damage of erythrocyte membranes. Also, the plasma SOD activity was significantly higher in these individuals (p=0.049), and in R202Q homozygotes particular (p=0.001), which may be due to increased induction of extracellular SOD. Changes in oxidative stress parameters in the MEFV changes carriers were significantly associated with biochemical parameters of inflammation (leukocytes count with erythrocyte TBARS (p=0.009) and erythrocyte sedimentation rate and SOD levels (p=0.031)). Conclusion The MEFV gene mutations are present in 11% of healthy persons in Serbia, those are E148Q/N in 6% and K695R/N in 5% of people. There are 10% homozygote for R202Q polymorphism and 45% heterozygote R202Q carriers in Serbian population. Persons with E148Q and K695R heterozygous MEFV gene mutations and R202Q homozygous polymorphism have frequently febrile episodes of unknown cause, as well as other non-specific manifestations of inflammation. The mutations carriers and R202Q homozygotes have significantly higher values of erythrocyte TBARS and plasma SOD activity, compared with persons without aforementioned genetic changes. Frequent occurrence of non-specific inflammation manifestations in mutation carriers and R202Q homozygotes indicates that these MEFV gene changes are a predisposition for development of inflammation. Changes in oxidative stress parameters indicate the existence of a mild oxidative stress and stimulation of the innate immune response together with possible changes in specific leukocyte functions in these individuals.

Introduction. Renal replacement therapy remains the treatment of option for patients in end stage renal disease. The most frequent cause of late allograft loss is cardiovascular disease, which constitutes the leading cause of death of renal transplant recipients (RTR). When compared with the general population, RTR show a four-fold greater risk for CVD, and a two-fold higher risk for cardiovascular death. Renal transplant dysfunction can be considered as a traditional risk factor, while high sympathetic activity and accumulation of the endogenous inhibitor of endothelial NO synthase (eNOS), asymmetric dimethylarginine (ADMA) are factors peculiar to chronic renal failure. eNOS can be strongly inhibited by ADMA, whose accumulation in plasma may play an important role in endothelial dysfunction. ADMA is an uremic toxin that can be considered as parameter of endothelial dysfunction. ADMA, also, causes local vasoconstriction when infused intra-arterially. Symmetric dimethylaginine (SDMA) does not inhibit NOS directly, and is also elevated in patients with renal failure, its levels, better than ADMA, correlate with glomerular filtration rate (GFR). ADMA was proposed to be a marker for atherosclerotic changes, and for the assessment of cardiovascular morbidity and mortality. Atherosclerosis is today described as a disease where inflammation is the dominant pathological and biochemical alteration. The development of the atherosclerotic plaque is closely linked to expression of different cellular adhesion molecules (CAMs), that are essential mediators, playing a central role in the recruitment of inflammatory cells to the site development. Many factors were demonstrated to increase concentration of cellular adhesion molecules: hypertension, immunosuppressive therapy, autoimmune disease and cell mediated allograft rejection. These CAMs can be measured in plasma and therefore may represent promising biomarkers that may reflect underlying endothelial activation and vascular inflammation. Besides inflammation many studies have generally suggested a positive association between dyslipidemia and end stage renal disease and advanced chronic kidney failure. Renal disease is associated with profound abnormalities in lipids and lipoprotein metabolism and in renal transplant recipients hyperlipidemia is a well known feature. It has been suggested that dyslipoproteinemia observed in kidney disease contributes to the progression of glomerular and tubular lesions, with deterioration to end stage renal disease. Factors that induce post-transplant dyslipidemia include age, body weight, pre-transplant lipid levels, presence of proteinuria and allograft dysfunction. Standard immunosuppressive therapy usually consists of triple drug therapy of three drug classes: calcineurin inhibitors, anti-proliferative agents and corticosteroids. Corticosteroids and cyclosporine, besides the nephrotoxic effect, seem to be one of the main contributing factors that influence the post-transplant lipidemic profile. Cyclosporine plays an independent role in elevating cholesterol levels by modulating the low density lipoprotein (LDL) receptors. Corticosteroids, cyclosporine and tacrolimus (to a lesser degree than cyclosporine) increase post-transplant cholesterol and triglycerides levels, usually in dose dependent fashion. Elevated total and LDL cholesterol occur in about 60% and hypertriglyceridemia in about 35%, whereas low high density (HDL) cholesterol is present in only 15% of renal transplant recipients. Enhanced sympathetic activity is frequently reported in end stage renal disease, and such activation declines, but does not normalize, after successful kidney transplantation. Renalase is a new flavoprotein that regulates sympathetic tone and blood pressure. It is secreted by the kidney and is reported that has monoamine oxidase (MAO) activity, therefore may metabolize catecholamines. Cardiomyocytes, liver and skeletal muscles also secrete renalase, and it was found in peripheral nerves, central nervous system, adrenals, adipose tissue, 12.5-day-old embryo and endothelium. It circulates in the blood as a proenzyme waiting for elevated catecholamines for activation. The purpose of the study was to observe parameters of endothelial dysfunction (parameters of chronic inlammation and nitrosative stress), lipid profile disturbances and the level of sympathetic activity in the stable renal transplant recipients, to assess correlations between renal dysfunction and inflammatory biomarkers, lipid profile disturbances, nitrosative stress and sympathetic activity, as well as potential differences in these parameters in regard to immunosuppressive protocol, and among them to hypothesize the best independent predictor, and predictors of early renal dysfunction after multivariate modeling (adjustment for age, body mass index, hypertension, smoking and diabetes mellitus). Methods. We enrolled 73 renal transplant recipients, who were greater than 12 months post-renal transplant surgery, had a stable graft function, no clinically present cardiovascular disease and were on standard immunosuppression. The study was conducted between March and November 2012 at the Clinic for Nephrology, Dialysis and Transplantation, Clinical Centre Nis. Ethics Committee of Medical Faculty Nis approved the study and fully informed written consent was obtained from each patient. Results. Significant differences were found between clinical and control group in sistolic blood pressure, (p

U našoj i svestskoj istoriografiji objavljen je veliki broj studija i naučnih radova u kojima je proučavana epilepsija i njeni vidovi lečenja u različitim vremenskim periodima. Neke od tih studija prilaze epilepsiji sa istorijske tačke gledišta i pokušavaju da rasvetle različite metode tradicionalne narodne medicine. Brojnija istraživanja pripadaju savremenoj naučnoj medicini (ispitivanje farmakološkog dejstva aktivnih principa lekovitog bilja, kao i antikonvulzivnog dejstva pojedinih lekovitih biljaka na životinjskim modelima i kliničkim studijama). Manji broj studija je posvećen lečenju epilepsije u srednjovekovnoj medicini. Ovu studiju možemo svrstati u studije medicine i dodirnih grana jer se radi o studiji iz istorije medicine koja je urađena multidisciplinarnim pristupom sa stanovišta etnologije, farmacije (fitoterapije), religije, filozofije, književnosti i drugih. Cilj ove studije je izvođenje komparativne analize epilepsije i metoda njenog lečenja u srpskim srednjovekovnim zemljama u prošlosti i u savremenoj medicini. Metod rada će obuhvatiti komparativnu analzu epilepsije u srpskim zemljama u srednjem veku i drugim evropskim zemljama toga doba na osnovu podataka dobijenih izučavanjem srednjovekovnih spisa (hagiografija, biografija, kodeksa), zakonskih spisa koji se odnose na epilepsiju i dokumenta o uređenju srpskih srednjovekovnih manastirskih bolnica. Proučavanje obuhvata srpske zemlje u periodu srednjeg veka, od IX do sredine XV veka. A number of studies and scientific papers in which the epilepsy and its treatment in different historical periods were studied are published both in our and in the world historiography. The epilepsy is approached by some of these studies from a historical point of view with attempt to shed light on the different methods of the traditional folk medicine. Numerous studies belong to the modern scientific medicine (research of the effects of the pharmacologically active principles of medicinal herbs; anticonvulsant effects of some medicinal plants in animal models and in clinical studies). A smaller number of studies were devoted to the treatment of epilepsy in medieval medicine. This study can be classified as the study in the field of the history of medicine and the common branches. This study is characterized with ultidisciplinary approach from the standpoint of ethnology, pharmacology, phytotherapy, religion, philosophy, literature and others. The aim of this study is to perform a comparative analysis of epilepsy and methods for its treatment between them in Serbian medieval countries and in contemporary medicine.

Introduction: Kidney diseases are the biggest health problem nowadays. Endemic nephropathy (EN) is a chronic tubulointerstitial kidney disease, undetectable at the beginning and with slow development to terminal renal failure. The real cause of the disease is still not known. Although the importance of inheritance is underlined, the effects of environmental factors (aristolochic acid, a mycotoxin) and the presence of disorders of the immune system are more likely to be involved in disease pathway. Aim: We aimed to establish qualitative and quantitative differences of proteins in urine of patients with the endemic nephropathy, diabetic nephropathy, acute prerenal kidney injury, and their importance in the diagnostics. The acute and chronic effects of aristolochic acid 1 and ochratoxin A on tubulocytes are important for establishing the mechanisms of kidney damage and the potential biomarkers. Methods: Proteomic technology was used, and the results were confirmed by Western blot, dot blot, immunofluoroscence and immunohistochemisry analyses of cells and tissue samples. Importance: The use of proteomic technologies of urine proteins in patients and healthy controls gives a new data for the identification of diagnostic and prognostic markers of kidney damage. This study shows the presence of significant differences in the proteins of the respondents, which can be used as diagnostic and differential diagnostic parameters. Study of toxic effects of aristolochic acid 1 and ochratoxin A permited a better understanding of the mechanisms of kidney disease, but first of all, a better expanation of molecular pathway in the initiation and during development of endemic nephropathy and associated urothelial cancer.