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Svetlana Ignjatović

Vodiči Za Primenu Tumorskih Markera Kod Karcinoma Dojke

Najbolje validovani markeri karcinoma dojke pripadaju tkivnim markerima i uključuju receptore za estrogen (ER), receptore za progesteron (PR), HER-2, urokinaza plazminogen aktivator (uPA) i plazminogen aktivator inhibitor 1 (PAI-1). Kod svih novodijagnostikovanih pacijenata sa karcinomom dojke određivanje ER, PR i HER-2 je danas obavezno. Mada je merenje uPA i PAI-1 tehnički validovano, do danas nije klinički rasprostranjeno i to uglavnom zbog zahteva za minimalnom količinom svežeg ili sveže zamrznutog tkiva. Određivanje ovih proteina može da se iskoristi kao pomoć pri selekciji »limfni čvor negativnih« pacijenata s karcinomom dojke kojima nije potrebna adjuvantna hemoterapija. Mada se dosta koristi u postoperativnom praćenju i praćenju terapije u poodmaklom oboljenju, klinička vrednost CA 15-3 i drugih serumskih markera nije joŠ uvek validovana u studijama nivoa dokaza I. Nedavna poboljšanja u razumevanju biologije karcinoma dojke i paralelno povećanje mogućih opcija tretmana treba da vode ka poboljšanju ishoda ove veoma hetrogene bolesti. Onkolozi joŠ uvek imaju teškoće u odabiru specifičnih strategija tretmana prema molekularnim karakteristikama oboljenja svakog pacijenta ponaosob.

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Svetlana Ignjatović and Nada Majkić-Singh

Primena »Six Sigma« U Kontroli Kvaliteta Zdravstvenih Laboratorija

Cilj svakog postupka ili proizvodnog sistema je dobijanje dobrog proizvoda. Većina metoda kontrole kvaliteta je inicijalno razvijena da pomogne industrijsku proizvodnju. Ovo ne predstavlja iznenađenje s obzirom da masovna proizvodnja tipično zahteva mnogo ponavljanja koje uključuju kontrolisani redosled operacija. Nisu svi prilazi kontroli kvaliteta podjednako efikasni. Neusaglašenosti koje postoje u laboratorijskom određivanju su u osnovi uzrokovane kako prekomernim varijacijama u procesu, tako i greškama. Ključni nedostatak u primeni metoda statističke kontrole kvaliteta ležKi u činjenici da su neefikasne u detekciji i kontroli grešaka, a one danas predstavljaju najdominatniji uzrok neusaglašenosti većine organizacionih procesa. Statističkom kontrolom kvaliteta mogu efikasno da se kontrolišu varijacije u procesu, ali ne mogu da se detektuju ili spreče greške. »Six Sigma« pripada statističkoj kontroli kvaliteta koja pružKa novu metodologiju za merenje karakteristika procesa, a takođe usavršava prethodne metodologije čime dolazi do unapređenja procesa. MenadžKment zasnovan na »Six Sigma« kvalitetu polako ulazi u zdravstvene organizacije pri čemu nudi realnu nadu za unapređenje razmišljanja i procesa menadžKmenta kvaliteta. Jedan od razloga je što se »Six Sigma« fokusira na defekte koji za uzvrat zahtevaju da ciljevi za dobar kvalitet budu definisani. »Six Sigma» pružKa univerzalnu metodologiju kojom se meri kvalitet time što se broje defektni proizvodi, pri čemu se određuje stopa defektnih proizvoda kao »defekti na milion» (»defects per million» ili »DPM»), a koji se zatim konvertuju u »Sigma metriku» uz korišćenje standradnih tabela koje su dostupne u svakom tekstu vezanom za »Six Sigma». »Sigma metrikom» se »Six Sigma» pojednostavljuje i dobija univerzalni »reper» koji govori o karakteristikama procesa. Na ovaj način svi procesi mogu da se okarakterišu na »Sigma skali.« Tipično se vrednosti nalaze između 2 i 6, pri čemu je cilj postizanje »svets- ke klase kvaliteta» koja iznosi 6. Na osnovu podataka koji potiču iz stvarnog sveta zdravstvenih laboratorija očigledno se možKe zaključiti da je izvođenje operacija na današnjim instrumentima dobro. Nova generacija kliničkih analizatora je postigla jako visoku «Sigma metriku«. Korisnici zdravstvene zaštite mogu da užKivaju u novoj eri napretka sa instrumentima i metodama nivoa 6 Sigma ili višim.

Open access

Marijana Dajak, Svetlana Ignjatović and Nada Majkić-Singh

Funkcija Bubrega - Procena Brzine Glomerularne Filtracije

Brzina glomerularne filtracije (GFR) je široko prihvaćena kao najbolja opšta mera funkcije bubrega. Vodiči američke Nacionalne fondacije za bubreg definišu hroničnu bubrežnu bolest (HBB) bilo sa vrednošću GFR koja je manja od 60 mL/min/1,73 m2 ili sa prisustvom oštećenja bubrega, bez obzira na uzrok, u toku 3 ili više meseci i klasifikuju stadijume težine HBB prema GFR. GFR se može meriti kao urinarni ili plazma klirens egzogenih filtracionih markera kao što je inulin. Međutim, zbog teškoća u primeni, troškova i radijacionog izlaganja, ove metode imaju ograničenu upotrebu u rutinskim laboratorijama. Klirens kreatinina može biti korisna alternativa kada egzogeni markeri nisu dostupni, ali sakupljanje urina u vremenskim intervalima nije pogodno za pacijente i osetljivo je na grešku pri sakupljanju. GFR se često procenjuje klinički iz serumskih koncentracija egzogenog kreatinina ili cistatina C. Cistatin C u serumu još uvek nije adekvatno procenjen kao indeks GFR, a na kreatinin u serumu utiču GFR i faktori nezavisni od GFR, uključujući godine, pol, rasu, telesnu veličinu, ishranu, izvesne lekove i laboratorijske analitičke metode. Prema kliničkim vodičima Nacionalne fondacije za bubreg, kliničke laboratorije bi trebalo da izdaju >>procenjenu<< GFR (estimated GFR), izračunatu iz prediktivnih jednačina, kao dodatak izveštavanja vrednosti markera u serumu. Trenutno preporučena jednačina za procenu je razvijena iz MDRD (Modification of Diet in Renal Disease) studije. Ova jednačina koristi godine, pol, rasu (afro-američka prema ne-afro-američkoj) i koncentraciju kreatinina u serumu, a ne zahteva varijablu za telesnu težinu zato što normalizuje GFR za standardnu telesnu površinu od 1,73 m2. Da bi se postigla poboljšana tačnost preračunate GFR sa ovom jednačinom, preporučuje se da komercijalne metode za kreatinin budu kalibrisane prema sertifikovanim referentnim materijalima i sledljive sa IDMS (isotope dilution mass spectrometry) metodologijom. Za MDRD jednačinu je pokazano da je korisna za pacijente sa HBB, ali njena upotreba je još uvek nejasna za ljude sa niskim vrednostima kreatinina u serumu i visokim vrednostima za GFR, uključujući zdrave pojedince, decu i trudnice. Validacione studije su u razvoju kako bi se procenila MDRD jednačina za druge etničke grupe i različita bolesna stanja.

Open access

Snežana Jovičić, Svetlana Ignjatović and Nada Majkić-Singh

Comparison of Two Different Methods for Cardiovascular Risk Assessment: Framingham Risk Score and Score System

Numerous studies have shown that the major risk factors for coronary heart disease (cigarette smoking, hypertension, elevated serum total cholesterol and low-density lipoprotein cholesterol - LDL, low serum high-density lipoprotein cholesterol - HDL, diabetes mellitus and advancing age), are additive in predictive power. Accordingly, the total risk of a person can be estimated by summing up the risk imparted by each of the major risk factors. Using data obtained from population studies, various risk assessment algorithms have been developed. The aim of this study was to compare the two most common risk scores. Risk assessment for determining 10-year risk in 185 healthy, asymptomatic individuals of both sexes, 30-85 years old, was carried out according to both Framingham (FRS) and SCORE risk scoring. The risk factors included in the calculation of 10-year risk are gender, age, total cholesterol, HDL-cholesterol, systolic blood pressure, treatment for hypertension and cigarette smoking. The determinations of total cholesterol and HDL-cholesterol were made in sera collected after a 12h fasting period using an Olympus AU2700 automated analyzer. The Framingham risk score was determined using an electronic calculator - ATP III Risk Estimator, and the risk status according to SCORE was obtained using charts for the 10-year risk in populations at high risk. Among 185 participants, in 152 (82%) 10-year risk for Coronary Heart Disease (CHD) death was <10%, 24 (13%) had intermediate and 9 (5%) had high risk (⩾20%) according to FRS. According to SCORE, 110 (60%) participants had <1%, 56 (30%) had 1-5% and 19 (10%) had ⩾5% of 10-year risk for cardiovascular death. Different categories of risk were assigned to ~30% of individuals according to different risk assessment models. Differences in risk classification when using two different risk assessment algorithms can be explained with several important issues, including different endpoints, consideration of interactions and incorporation of antihypertensive use. It is important to note that neither FRS nor SCORE have been appropriately adjusted for our population, according to the national cardiovascular mortality rate.

Open access

Olivera Dimitrijević, Blagica Đorić-Stojčevski, Svetlana Ignjatović and Nada Majkić-Singh

C-Reactive Protein in Estimating Inflammatory Status in Patients with Acute Coronary Syndrome

Chronic inflammation plays a key role in the pathogenesis of atherosclerosis, and is considered as a risk factor for the occurrence of acute coronary events, together with traditional risk factors such as age, smoking, hypercholesterolemia, diabetes mellitus and genetic predisposition. In this study, inflammatory status was estimated in patients with acute coronary syndrome. C-reactive protein, erythrocyte sedimentation rate and white blood cell count were measured at admission to the hospital in 25 patients with unstable angina pectoris and 31 patients with acute myocardial infarction, and compared with healthy control group (n = 59). C-reactive protein was the only parameter that differed significantly between all three groups (p < 0.0001), and patients with unstable angina had higher levels (median 7.28 mg/L) than patients with myocardial infarction (4.10 mg/L) and control group (1.07 mg/L). The obtained results show that levels of chronic inflammation in patients with acute coronary syndrome are significantly higher than baseline inflammation levels in a healthy population.

Open access

Snežana Jovičić, Svetlana Ignjatović and Nada Majkić-Singh

Summary

Vitamin D is not technically a vitamin, since it is not an essential dietary factor. It is rather a prohormone produced photochemically in the skin from 7-dehydrocholesterol. Vitamin D and its metabolites may be categorized as either cholecalciferols or ergocalciferols. Cholecalciferol (vi - tamin D3) is the parent compound of the naturally occurring family and is produced in the skin from 7-dehydrocholesterol on exposure to the ultraviolet B portion of sunlight. Vitamin D2 (ergocalciferol), the parent compound of the other family, is manufactured by irradiation of ergosterol produced by yeasts and its potency is less than one-third of vitamin D3’s potency. The steps in the vitamin D endocrine system include the following: 1) the photoconversion of 7- dehydrocholesterol to vitamin D3 in the skin or dietary intake of vitamin D3; 2) metabolism of vitamin D3 by the liver to 25-hydroxyvitamin-D3 [25(OH)D3 ], the major form of vitamin D circulating in the blood compartment; 3) conversion of 25(OH)D3 by the kidney (functioning as an endocrine gland) to the hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3 ]; 4) systemic transport of the dihydroxylated metabolite 1,25(OH)2D3 to distal target organs; and 5) binding of 1,25(OH)2D3 to a nuclear receptor (VDR) at target organs, followed by generation of appropriate biological responses. The activation of vitamin D to its hormonal form is mediated by cytochrome P450 enzymes. Six cytochrome P450 (CYP) isoforms have been shown to hydroxylate vitamin D. Four of these, CYP27A1, CYP2R1, CYP3A4 and CYP2J3, are candidates for the enzyme vitamin D 25-hy - droxylase that is involved in the first step of activation. The highly regulated, renal enzyme 25-hydroxyvitamin D-1a-hy - dro xylase contains the component CYP27B1, which completes the activation pathway to the hormonal form 1,25(OH)2D3. A five-step inactivation pathway from 1,25(OH)2D3 to calcitroic acid is attributed to a single multifunctional CYP, CYP24A1, which is transcriptionally in du - ced in vitamin D target cells by the action of 1,25(OH)2D3. An additional key component in the operation of the vitamin D endocrine system is the plasma vitamin D binding protein (DBP), which carries vitamin D3 and its metabolites to their metabolism and target organs. DBP is a specific, high-affinity transport protein. It is synthesized by the liver and circulates in great excess, with fewer than 5% of the binding sites normally occupied. 1,25(OH)2D3, acts as a ligand for a nuclear transcription factor, vitamin D receptor - VDR, which like all other nuclear receptors, regulates gene transcription and cell function. The widespread presence of VDR, and the key activating (1a-hydroxylase, CYP27B1) and inactivating (24-hydroxylase, CYP24A1) en - zy mes in most mammalian cells means that the cells in these tissues have the potential to produce biological res pon ses, depending on the availability of appropriate amounts of vi - tamin D3. Thanks to this widespread presence of elements of vitamin D endocrine system, its biological features are being recognized outside bone tissue, i.e. calcium and pho - sphate metabolism.

Open access

Iva Perovic Blagojevic, Tatjana Eror, Jovana Pelivanovic, Svetlana Jelic, Jelena Kotur-Stevuljevic and Svetlana Ignjatovic

Summary

Background: Polycystic ovary syndrome (PCOS) is associated with reproductive and metabolic abnormalities. The aim of this study was to analyse risk of cardiovascular disease (CVD) in PCOS, to define individual risk factors and assess their ability to predict risk.

Methods: Fifty-four young women with PCOS (22 obese and 32 normal weight) were compared to 46 respective controls (17 obese and 29 normal weight). Anthropometric parameters, lipid status parameters, inflammation markers, concentrations of glucose, transaminases, sex and anterior pituitary hormones, sex hormone binding globulin (SHBG) and androgens were measured. Cardiovascular Risk Score (CVRS), indices for identifying Non-Alcoholic Fatty Liver Disease (NAFLD) and the Index of Central Obesity (ICO) were calculated.

Results: Significantly higher CVRS values (p<0.05) were found in obese PCOS women compared to normal weight control and normal weight PCOS groups. Anthropometric parameters, lipid status parameters and fibrinogen (p<0.001, p<0.01) were higher in women with higher CVRS. The most significant CVRS predictors in all PCOS women were SHBG, androstenedione, follicle-stimulating hormone (FSH) and dehydroepiandrosterone sulphate (DHEAS). ICO and all NAFLD indices exhibited significant positive correlation with CVRS and a model consisting of these indices provided good diagnostic accuracy (AUC>0.8) in identifying patients with increased cardiovascular risk (CVR).

Conclusions: Obesity is a higher risk for developing CVD than PCOS alone. Anthropometric parameters, lipid parameters, fibrinogen, NAFLD indices and ICO increase CVR in PCOS women. For the prediction of CVR in PCOS, we suggest a combination of NAFLD indices and ICO.

Open access

Janko Pejović, Svetlana Ignjatović, Marijana Dajak, Nada Majkić-Singh and Žarko Vučinić

N-Terminal Pro-B-Type Natriuretic Peptide in Patients with Hypertensive Heart Disease

Patients with hypertensive heart disease have elevated concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The aim of our study was to evaluate NT-proBNP in patients with long-standing hypertension and in patients with signs of hypertensive cardiomyopathy. The study included three groups of 50 subjects: healthy persons (Control Group), patients with hypertension and normal left ventricular systolic function (Group 1) and patients with longstanding hypertension and signs of hyper tensive cardiomyopathy with impaired left ventricular systolic function (Group 2). Our results show a very good correlation (Pearson's test) between NT-proBNP in Group 1 and Group 2 and C-reactive protein (Group 1: r = 0.8424; Group 2: r = 0.6650), systolic blood pressure (Group 1: r = 0.7213; Group 2: r = 0.4856), diastolic blood pressure (Group 1: r = 0.4282; Group 2: r = 0.3989) and ejection fraction (Group 1: r = -0.7390; Group 2: r = 0.9111). ROC analysis revealed that the AUC between the Control Group and Group 1 for NT-proBNP (0.912) was not significantly different (p>0.05) from the AUC for systolic (0.924) and diastolic pressure (0.937). A cut-off value for NT-proBNP of 5.89 pmol/L can be used to reliably distinguish patients of Group 1 from the Control Group, and a cut-off value of 21.67 pmol/L reliably separates patients from Group 1 and Group 2 (in both cases, the AUC is 1.000). Patients in Group 2 who belonged to the II and III New York Heart Association (NYHA) class had significantly higher levels of NT-proBNP than those in NYHA class I (ANOVA test, p=0.001). These data suggest that NT-proBNP is a useful biomarker for distin guishing patients with long-standing hypertension who are at risk of heart failure, allowing optimization and proper treatment of these patients.

Open access

Mirjana Bećarević, Svetlana Ignjatović and Nada Majkić-Singh

Summary

It has been proposed that apoptosis is one of the mechanisms involved in the generation of antiphospholipid antibodies. The presence of antiphospholipid antibodies is the main laboratory criterion for a definite diagnosis of the antiphospholipid syndrome. Annexinopathies are disorders characterized by deregulation of annexins expression levels and function. Annexin A5 has been used as an agent for molecular imaging techniques (visualization of phosphatidylserineexpressing apoptotic cells) in vitro and in vivo in animal models and in patients (injection of human recombinant anxA5 into the patient‘s circulation). Although the determination of titers of anti-annexin A5 antibodies is not mandatory for the diagnosis of the antiphospholipid syndrome, it was reported that patients with primary antiphospholipid syndrome with a history of recurrent abortions had elevated titers of antiannexin A5 antibodies, while the presence of thromboses was not associated with elevated levels of these antibodies

Open access

Marijana Dajak, Svetlana Ignjatović, Biljana Stojimirović, Snežana Gajić and Nada Majkić-Singh

Beta-Trace Protein as a Marker of Renal Dysfunction in Patients with Chronic Kidney Disease: Comparison with Other Renal Markers

Beta-trace protein (BTP), also known as prostaglandin D synthase, is a low-molecular-mass protein which belongs to the lipocalin protein family. It was found to be increased in the serum of patients with renal diseases. The aim of this study was to compare the clinical usefulness of serum levels of beta-trace protein for the detection of renal dysfunction in patients with chronic kidney disease (CKD) with levels of other renal markers: creatinine, cystatin C and β2-microglobulin (B2M). The study included 134 patients with a wide range of renal dysfunction that encompassed all five CKD stages. Obtained data showed that beta-trace protein highly correlated (Spearman test) with creatinine (r = 0.890), cystatin C (r = 0.904) and B2M (r = 0.933) and its levels in serum significantly increased from CKD stage 1 to 5. Furthermore, the values of glomerular filtration rate (GFR) estimated from a BTP-based formula significantly correlated with GFR calculated from creatinine-based and cystatin C-based formulas. ROC analyses showed that BTP had similar diagnostic accuracy for detection of reduced renal function in CKD stages as other renal markers, for estimated GFRs of < 30, < 60 and < 90 mL/min/1.73 m2. The areas under the ROC curves (AUC) for BTP, for these GFR limits, were from 0.983 to 0.917 and they were not significantly different from AUCs for other renal markers. The results of this study showed that BTP may be a useful and reliable serum marker for identifying the magnitude of renal dysfunction in patients with CKD and may have its place beside serum cystatin C and creatinine as an alternative endogenous GFR marker.