Nada Majkic-Singh

Parameters of antioxidative defense in type 2 diabetic patients with cardiovascular complications

OBJECTIVE. Diabetes‐associated oxidative stress is a consequence of both increased production of free radicals and reduced capacity of antioxidative defense. Prolonged hyperglycemia is the major factor in the pathogenesis of atherosclerosis in diabetes which can lead to cardiovascular complications. The aim of this study was to test the parameters of antioxidative defense in type 2 diabetic patients. METHODS. A total of 117 type 2 diabetics with and without cardiovascular complications were examined in order to find out the influence of hyperglycemia, type and duration of complications and duration of diabetes on the extent of disorder of antioxidative parameter values: superoxide dismutase (SOD), glutathione peroxidase (GSH‐Px), glutathione reductase (GR) and total antioxidant status (TAS). RESULTS. Compared to healthy control subjects, type 2 diabetic patients with cardiovascular complications (CVC) had significantly lower SOD (P<0.0001), GSH‐Px (P<0.0001), GR ( P = 0.0002) and TAS values (P<0.0001). In type 2 diabetic subjects with CVC, males had significantly lower SOD (778.7±103.2 U/gHb, P<0.01) and GR activities (52.2±8.9 U/L, P<0.001) compared to females (839.3±94.9 U/gHb; 58.5±9.1 U/L). Significant and positive correlation was found between glucose levels and SOD (r = 0.375 for P<0.05) and GSH‐Px (r = 0.384, P<0.05 ) activity in the group of complications‐free diabetics, while significant negative correlation between glucose and GSH‐Px values (r = −0.382, P<0.05) was found in the group of type 2 diabetics with coronary artery disease (CAD) and hypertension (HTA) and with CAD and acute myocardial infarction (AMI) (r = −0.860 P<0.05), and highly negative correlation between glucose and SOD levels (r = −0.590, P<0.05) in the group of diabetic subjects with CAD, AMI and HTA. Likewise, there was highly significant negative correlation of SOD (r = −0.949, P<0.05) and TAS (r = −0.393 for P = 0.038) with duration of diabetes in the group of diabetics with CAD and HTA. CONCLUSION. Our results confirm the hypothesis that there is reduced antioxidative defense in type 2 diabetics with prominent cardiovascular complications, which negatively correlates with glucose concentrations and duration of diabetes and cardiovascular complications.

Genetic aspects of ischemic stroke: coagulation, homocysteine, and lipoprotein metabolism as potential risk factors

Stroke is one of the most common causes of death and long term disability throughout the world. It may be the outcome of a number of monogenic disorders or, more commonly, a polygenic multifactorial disease. Numerous studies have investigated the role of genetics in the pathogenesis of ischemic stroke, with varied and often contradictory results. The candidate ‘stroke risk’ genes affecting haemostasis (F5, F2, FGA/FGB, F7, F13A1, vWF, F12, SERPINE1, ITGB3/ITGA2B, ITGA2, GP1BA, TPA, TAFI, THBD, PZ, ANX5), homocysteine metabolism (MTHFR, CBS, MTR), and lipid metabolism (apo E, LPL, CETP, ABCA1, apo AI, apo CIII, apo AIV, apo AV, apo B, apo H, apo(a), PON1/2/3, LDLR/LOX-1) are evaluated in this review. By examining meta-analyses and case-control studies, we made a classification of gene/gene polymorphisms according to the degree of association with ischemic stroke risk. The data assembled could be very useful for further meta-analysis and for future clinical applications.

Presepsin (sCD14-ST) in preoperative diagnosis of abdominal sepsis.

Abstract Background: The aim of the study was to identify the diagnostic significance of presepsin in acute abdominal conditions and also to examine the correlation between presepsin, procalcitonin (PCT) and other parameters. Methods: To detect presepsin we used a new rapid method based on a chemiluminescent enzyme immunoassay. The clinical usefulness of presepsin to differentiate bacterial and non-bacterial infection [including systemic inflammation response syndrome (SIRS)] was studied and compared with PCT, C-reactive protein (CRP) and white blood cells (WBC). Results: The presepsin values in different conditions were (mean±standard deviation): healthy group (n=70) 258.7±92.53 pg/mL; SIRS (n=30) 430.0±141.33 pg/mL; sepsis (n=30) 1508.3±866.6 pg/mL. The presepsin values were significantly higher in patients with sepsis than the SIRS group (p<0.0001, Mann-Whitney U-test). The area under the receiver operating characteristics (ROC) curve (AUC) for discriminating of the SIRS from the sepsis patients was 0.996 for presepsin and it was greater than the AUC of PCT (0.912), CRP (0.857) or WBC (0.777). Conclusions: The ROC curve of the SIRS patient without infection and the sepsis patient showed that the presepsin concentration was a significantly sensitive indicator of sepsis and useful marker for the rapid diagnosis of sepsis.

The role of CRP and inflammation in the pathogenesis of age-related macular degeneration.

Age-related macular degeneration (AMD) is a complex, degenerative and progressive disease involving the multiple genetic and environmental factors that can result in severe visual loss. The etiology of AMD is not well understood. Many theories exist and feature mechanisms of oxidative stress, atherosclerotic-like changes, genetic predisposition and inflammation. The most recent clinical studies appointed to a great role of inflammation and C-reactive protein (CRP) in the pathogenesis of AMD. There is a large body of evidence indicating the association of CRP with endothelial dysfunction, oxidative stress and production of reactive oxygen species (ROS), as well as with lipid status disorder in AMD patients. According to recent studies, CRP is definitely not only the inflammatory marker but also a mediator of development of the vascular disorders in the retinal circulation. The results obtained from the present studies may help our understanding the pathogenesis of the retinal vascular disease associated with high levels of CRP.

The association of lipoprotein parameters and C-reactive protein in patients with age-related macular degeneration.

Background: Age-related macular degeneration (AMD) is the most common cause of visual impairment in individuals over 50 years of age, with the prevalence of 0.05% before the age of 50 rising to 30% after 74 years of age. An elevated concentration of plasma lipoproteins is considered to be one of the risk factors of AMD development. The aim of our study was to analyze the concentration of serum lipoproteins – total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), non-LDL cholesterol and triglycerides – as well as apolipoproteins – apoA1, apoB and Lp(a) – along with C-reactive protein (CRP) in patients with AMD in order to explore the possible association of lipid and inflammatory parameters with the pathogenesis of AMD. Material and Methods: In the cross-sectional study in the University clinical setting, 79 patients with AMD, aged 71.47 ± 7.02 years, and 84 aged-matched control subjects were included. The patients underwent complete ophthalmological examination including visual acuity assessment, color fundus photography and fluorescein angiography. Results: Statistical processing data revealed significantly higher total (p = 0.0002), LDL (p = 0.023), non-HDL cholesterol (p = 0.0014) and CRP (p = 0.049) values in AMD patients compared to control subjects. Conclusions: Based on the obtained results, it may be concluded that lipid status disorder and inflammation could play an important role in the development of AMD in elderly people.

What is a Biomarker? From its Discovery to Clinical Application

What is a Biomarker? From its Discovery to Clinical Application The term biomarker in medicine most often stands for a protein measured in the circulation (blood) whose concentration indicates a normal or a pathological response of the organism, as well as a pharmacological response to the applied therapy. From a wider perspective, a biomarker is any indicator that is used as an index of the intensity of a disease or other physiological state in the organism. This means that biomarkers have a very important role in medical research and practice providing insight into the mechanism and course of a disease. Since a large number of biomarkers exist today that are used for different purposes, they have been classified into: 1) antecedent biomarkers, indicating risk of disease occurrence, 2) screening biomarkers, used to determine a subclinical form of disease, 3) diagnostic biomarkers, revealing an existing disease, 4) staging biomarkers, that define the stage and severity of a disease, and 5) prognostic biomarkers, that confirm the course of disease, including treatment response. Regardless of their role, their clinical significance depends on their sensitivity, specificity, predictive value, and also precision, reliability, reproducibility, and the possibility of easy and wide application. For a biomarker to become successful, it must undergo the process of validation, depending on the level of use. It is very important for every suggested biomarker, according to its purpose or its nature, to possess certain characteristics and to meet the strict requirements related to sensitivity, accuracy and precision, in order for the proper outcome to be produced in the estimation of the state for which it is intended. Finally, the development of guidelines for biomarker application is very important, based on well defined and properly conducted assessments of biomarker determination, providing the means by which research is translated into practice and allowing evidence based on facts to promote the clinical application of new biomarkers. Šta je Biomarker? Od Otkrića Do Kliničke Primene Izrazom biomarker u medicini se označava najčešće protein izmeren u cirkulaciji (krvi) čija koncentracija ukazuje na normalan ili patološki odgovor u organizmu, kao i na farmakološki odgovor na primenjenu terapiju. Šire gledano biomarker je bilo koji pokazatelj koji se koristi kako indikator intenziteta nekog oboljenja ili drugog fiziološkog stanja u organizmu. To znači da biomarkeri imaju veoma značajnu ulogu u medicinskim istraživanjima i primeni jer omogućavaju sagledavanje mehanizma i toka bolesti. Pošto danas postoji veliku broj biomarkera koji se koriste u različite svrhe izvršena je njihova podela na: 1) antecedentne biomarkera, koji ukazuju na rizik od nastanka bolesti, 2) »screening« biomarkere, kojima se utvrđuje subklinička forma bolesti, 3) dijagnostičke biomarkere, koji otkrivaju postojeću bolest, 4) »staging« biomarkere, koji definišu stadijum i težinu bolesti i 5) prognostičke biomarkere, koji potvrđuju tok bolesti, uključujući i odgovor na terapiju. Bez obzira na ulogu koju imaju, njihov klinički značaj zavisi od njihove osetljivosti, specifičnosti, prediktivne vrednosti, zatim preciznosti, pouzdanosti, reproducibilnosti, kao i mogućnosti jednostavne i široke primene. Da bi biomarker bio uspešan mora proći kroz put validacije zavisno od nivoa upotrebe. Veoma je značajno da svaki predloženi biomarker zavisno od namene ili njegove prirode ima odgovarajuće karakteristike i da ispunjava stroge zahteve koji se odnose na osetljivost, tačnost i preciznost kako bi se postigao odgovarajući ishod za procenu stanja za koji je namenjen. Shodno navedenom više istraživačkih cenatara i grupa predložilo je način i uputstva za evaluaciju biomarkera uzimajući u obzir prognostičke prema diajgnostičim modelima. Konačno, veoma je značajna izrada uputstava (Guidelines) za primenu biomarkera koja su zasnovana na dobro definisanim i sprovedenim procenama određivanja nekog biomarkera, na koji način su dobijena dobra sredstva putem kojih su preneta istraživanja u praksu a dokazi zasnovani na činjenicama potpomažu kliničku primenu novih biomarkera.

The impact of inflammation to the antioxidant defense parameters in AMD patients

Background and aims: Oxidative stress and inflammation are postulated to be involved in the pathogenesis of the age-related macular degeneration (AMD) although the mechanism linking the oxidation and inflammation is still unknown. The aim of this study was the analysis of the antioxidant capacity measured by levels of the antioxidant enzymes: superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and total antioxidant status (TAS) along with the inflammatory markers such as Creactive protein (CRP), interleukin-6 (IL-6) and fibrinogen in AMD patients in order to analyze the relationship of the inflammatory markers with the antioxidant parameters and their association with AMD. Methods: The cross-sectional study, carried out in the University clinical setting, included 84 patients with the age-related macular degeneration, aged 71.25±7.14 years and 84 aged-matched control subjects (CG). Results: Statistical analysis revealed significantly lower GR (p=0.007) and TAS (p<0.000) values in the group of AMD patients compared to the controls. Logistic regression analysis showed that higher values of inflammatory markers (CRP>3 mg/L, IL>4.9 pg/mL, fibrinogen>3.8 g/L) and lower values of antioxidative parameters (SOD<900 U/gHb, GR<55 U/L and TAS<1.15 mmol/L) were significantly associated with AMD (ORCRP: 1.29, 95% CI 0.54-3.12, p<0.05; ORIL-6: 3.53, 95% CI 1.16–10.75, p=0.024; ORFIB: 3.06, 95% CI 1.78–7.92, p=0.019; ORSOD: 2.39, 95% CI 0.78–7.35, p<0.05; ORGR: 4.04, 95% CI 1.28–12.73, p=0.013; ORTAS: 2.9, 95% CI 1.4–6.3, p=0.032). Conclusions: Based on the results obtained, it may be concluded that the antioxidant defense system was significantly reduced in patients with AMD and the probability to develop AMD was higher in older individuals with lower values of antioxidant parameters and higher values of inflammatory markers.

B-type natriuretic peptide predicts new-onset atrial fibrillation in patients with ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention.

The predictive value of B-type natriuretic peptide (BNP) with respect to the occurrence of new-onset atrial fibrillation (AF) in patients with ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI) is unknown. The aim of this study was to evaluate whether BNP has a predictive value for the occurrence of new-onset AF in patients with STEMI treated by primary PCI. In 180 patients with STEMI treated by primary PCI, BNP concentrations were measured 24h after chest pain onset. The Receiver Operating Characteristic analysis was performed to identify the most useful BNP cut-off level for the prediction of AF. The patients were divided into the two groups according to calculated cut-off level: high BNP group (BNP≥720 pg/mL, n=33) and low BNP group (BNP<720 pg/mL, n=147). The incidence of AF was 5.0%, and occurred more frequently in high BNP group (7/33, 21.2%) than in low BNP group (2/147, 1.4%), (p<0.001). Patients with high BNP were older (p=0.017), had more often anterior wall infarction (p=0.015), higher Killip class on admission (p=0.038), higher peak troponin I (p=0.002), lower left ventricular ejection fraction (p=0.029) than patients with low BNP. After multivariate adjustment, BNP was an independent predictor of AF (OR 3.70, 95% CI 1.40-9.77, p=0.008). BNP independently predicts the occurrence of new-onset AF in STEMI patients treated by primary PCI.

The effect of Hyperglycemia and Oxidative Stress on the Development and Progress of Vascular Complications in Type 2 Diabetes

The effect of Hyperglycemia and Oxidative Stress on the Development and Progress of Vascular Complications in Type 2 Diabetes Oxidative stress is the result of increased production of free radicals, which impair the cell function and cause many pathological conditions and diseases. The development of diabetes, its course and complications are closely associated with an imbalance in pro-antioxidative cell state and change of redox potential. Prolonged exposure to hyperglycemia is currently considered the major factor of the pathogenesis of atherosclerosis in diabetes. Atherosclerosis is the cause of about 80% of mortality in diabetics, and over 75% of all hospitalized diabetic patients have associated cardiovascular complications. Hyperglycemia induces different vascular tissue damage at the cellular level, which potentially accelerates the atherosclerotic processes. The most significant mechanisms responsible for acceleration of atherosclerotic processes in diabetic patients are: a) non-enzymatic protein and lipid glycosylation which interferes with normal function, in the way that it deranges molecular conformation, impairs enzymatic function, reduces the capacity of breakdown and interferes with recognition of protein structures by receptors; b) interaction of glycosylated proteins with their receptors resulting in induction of oxidative stress and pro-inflammatory reactions; c) polyol pathway; d) hexosamine pathway and e) activation of protein kinase C and impaired growth factor expression. Uticaj Hiperglikemije I Oksidativnog Stresa na Nastanak I Razvoj Vaskularnih Komplikacija U Dijabetesu Tipa 2 Oksidativni stres nastaje kao posledica prekomerne produkcije slobodnih radikala, koji oštećuju ćelijsku funkciju i dovode do nastanka mnogih patoloških stanja i bolesti. Nastanak dijabetesa, tok i razvoj kompli-kacija, usko su povezani sa disbalansom pro-antioksidativnog stanja ćelije i promenom redoks potencijala. Prolongirana izloženost hiperglikemiji danas se smatra glavnim faktorom u patogenezi ateroskleroze u dijabetesu. Atero-skleroza je uzrok oko 80% smrtnosti u dijabetičara, a više od 75% hospitalizovanih dijabetičara imaju i prateće kardiovaskularne komplikacije. Hiperglikemija indukuje veliki broj oštećenja vaskularnog tkiva na ćelijskom nivou koji potencijalno ubrzavaju aterosklerotske procese. Istraživanja na ljudima i životinjama rasvetlila su nekoliko mehanizama koja obuhvataju većinu patoloških oštećenja u vaskulaturi: a) neenzimska glikozilacija proteina i lipida koja interferira sa normalnom funkcijom, tako što remeti molekularnu konformaciju, oštećuje enzimsku funkciju, smanjuje kapacitet razgradnje i interferira sa prepoznavanjem proteinskih struktura od strane receptora; b) interakcija glikoziliranih proteina sa njihovim receptorima rezultuje indukcijom oksidativnog stresa i proinflamatornim reakcijama; c) put poliola; d) put heksozamina; i e) aktivacija protein kinaze C i poremećaj ekspresije faktora rasta.

Cardiovascular Mortality in Hemodialysis Patients: Clinical and Epidemiological Analysis

Cardiovascular Mortality in Hemodialysis Patients: Clinical and Epidemiological Analysis Cardiovascular diseases are the leading cause of death in hemodialysis (HD) patients. The annual cardiovascular mortality rate in these patients is 9%, with left ventricular (LV) hypertrophy, ischemic heart disease and heart failure being the most prevalent causes of death. The aim of this study was to determine the cardiovascular mortality rate and estimate the influence of risk factors on cardiovascular mortality in HD patients. A total of 115 patients undergoing HD for at least 6 months were investigated. Initially a cross-sectional study was performed, followed by a two-year follow-up study. Beside the standard biochemical parameters, C-reactive protein (CRP), homocysteine, cardiac troponins (cTn) and the echocardiographic parameters of LV morphology and function (LV mass index, LV fractional shortening, LV ejection fraction) were determined. Results were analyzed using Cox regression analysis, Kaplan-Meier and Log-Rank tests. The average one-year cardiovascular mortality rate was 8.51%. Multivariate Cox regression analysis identified increased CRP, cTn T and I, and LV mass index as independent risk factors for cardiovascular mortality. Patients with cTnT > 0.10 ng/mL and CRP > 10 mg/L had significantly higher cardiovascular mortality risk (p < 0.01) than patients with cTnT > 0.10 ng/mL and CRP ≤ 10 mg/L and those with cTnT ≤ 0.10 ng/mL and CRP ≤ 10 mg/L (p < 0.01). HD patients with high cTnT and CRP have a higher cardiovascular mortality risk. Kardiovaskularni Mortalitet kod Bolesnika na Hemodijalizi: Klinička i Epidemiološka Analiza Kardiovaskularne bolesti su vodeći uzrok smrti bolesnika koji se leče hemodijalizom. Jednogodišnja stopa kardiovaskularnog mortaliteta iznosi 9%, a od kardiovaskularnih bolesti najveću prevalenciju imaju hipertrofija leve komore, ishemijska bolest srca i srčana slabost. Cilj rada je bio da se utvrdi stopa kardiovaskularnog mortaliteta i da se ispita uticaj faktora rizika na razvoj kardiovaskularnog mortaliteta kod bolesnika na hemodijalizi. Ispitano je 115 bolesnika koji se leče hemodijalizom duže od šest meseci. Prvo je obavljena studija preseka, a zatim praćenje bolesnika u dvogodišnjem vremenskom periodu. Parametri ispitivanja obuhvatili su koncentraciju C-reaktivnog proteina, homocisteina, srčanog troponina T i I, kao i ehokardiografske parametre morfologije i funkcije leve komore. Za statističku analizu dobijenih podataka korišćeni su Coxova regresiona analiza, Kaplan-Meierov test i Log-Rankov test. Utvrđeno je da prosečna jednogodišnja stopa kardiovaskularnog mortaliteta iznosi 8,51%. Multivarijantna Coxova regresiona analiza je pokazala da su povećana koncentracija C-reaktivnog proteina, srčanog troponina T i I, i povećan indeks mase leve komore nezavisni faktori rizika za nastanak kardiovaskularnog mortaliteta. Bolesnici kod kojih je koncentracija srčanog troponina T - cTnT > 0,10 ng/mL i koncentracija CRP > 10 mg/L imaju statistički veoma značajno (p < 0,01) veći rizik od kardiovaskularnog mortaliteta u odnosu na bolesnike kod kojih je cTnT > 0,10 ng/mL i CRP ≤ 10 mg/L i statistički veoma značajno (p < 0,01) veći rizik od kardiovaskularnog mortaliteta u odnosuna bolesnike koji imaju cTnT ≤ 0,10 ng/mL i CRP ≤ 10 mg/L. Bolesnici koji se leče hemodijalizom kod kojih je povišena koncentracija srčanog troponina T i C-reaktivnog proteina imaju povećan rizik od kardiovaskularnog mortaliteta.