Matrix Remodeling Enzymes as Potential Fluid Biomarkers of Neurodegeneration in Alzheimer's Disease.

This study investigated the diagnostic accuracy of plasma biomarkers-specifically, matrix metalloproteinase (MMP-9), tissue inhibitor of metalloproteinase (TIMP-1), CD147, and the MMP-/TIMP-1 ratio in patients with Alzheimer's disease (AD) dementia. The research cohort comprised patients diagnosed with probable AD dementia and a control group of cognitively unimpaired (CU) individuals. Neuroradiological assessments included brain magnetic resonance imaging (MRI) following dementia protocols, with subsequent volumetric analysis. Additionally, cerebrospinal fluid (CSF) AD biomarkers were classified using the A/T/N system, and apolipoprotein E (APOE) ε4 carrier status was determined. Findings revealed elevated plasma levels of MMP-9 and TIMP-1 in AD dementia patients compared to CU individuals. Receiver operating characteristic (ROC) curve analysis demonstrated significant differences in the areas under the curve (AUC) for MMP-9 (p < 0.001) and TIMP-1 (p < 0.001). Notably, plasma TIMP-1 levels were significantly lower in APOE ε4+ patients than in APOE ε4- patients (p = 0.041). Furthermore, APOE ε4+ patients exhibited reduced hippocampal volume, particularly in total, right, and left hippocampal measurements. TIMP-1 levels exhibited a positive correlation, while the MMP-9/TIMP-1 ratio showed a negative correlation with hippocampal volume parameters. This study sheds light on the potential use of TIMP-1 as a diagnostic marker and its association with hippocampal changes in AD.

Bleeding Index and Monocyte Chemoattractant Protein 1 as Gingival Inflammation Parameters after Chemical-Mechanical Retraction Procedure.

OBJECTIVE: A widely used chemical-mechanical method of gingival retraction can cause gingival tissue damage. The aim of this study was to test the influence of the chemical-mechanical gingival retraction procedures on the gingival bleeding index (GBI) and the salivary concentration of monocyte chemoattractant protein 1 (MCP-1) as an indicator of inflammatory changes in the gingiva. MATERIALS AND METHODS: The effects of 2 different retraction agents (aluminum chloride and ferric sulfate) were compared, particularly their tissue damaging effect during tooth preparation. Therefore, GBI values and the salivary concentration of MCP-1 were assessed during the chemical-mechanical method of gingival retraction in a homogenous group of respondents. The subjects (n = 60) were divided into 2 experimental groups (G1 and G2) regarding the need for tooth preparing and making artificial crowns. Each group was further divided into 2 subgroups (R1 and R2) according to the type of the gingival retraction agent used (aluminum chloride and ferric sulfate). RESULTS: Compared to the values at the study start, a statistically significant increase in GBI and salivary MCP-1 (p < 0.001) 1 day after gingival retraction agent application was observed in both experimental groups. After 72 h, the values were lower than in the second observation period but still statistically significantly higher compared to the study start (p < 0.001), which indicated the reversibility of the tissue changes. CONCLUSION: Higher values of the investigated parameters were observed in the group of subjects with prepared teeth, and clinical changes were more pronounced after the use of ferric sulfate.

The association of CAT-262C/T polymorphism with catalase activity and treatment response in juvenile idiopathic arthritis.

Oxidative stress is believed to be of great importance for both the etiology and the persistence of juvenile idiopathic arthritis (JIA). The aim of this study was to investigate the association of -262C/T polymorphism of the catalase (CAT) gene with JIA, as well as to evaluate whether this polymorphism can influence plasma CAT activity and outcome in JIA patients treated with etanercept. A total of 154 subjects (60 JIA patients and 94 healthy volunteers) were screened for CAT-262C/T gene polymorphism using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Plasma CAT activity was determined using the spectrophotometric method according to Goth, prior to and 12 months after anti-TNF (etanercept) therapy. Clinical outcome was assessed using the JIA ACR (American College of Rheumatology) response criteria. The genotype and allele frequency distributions of CAT-262C/T polymorphism in the patients were significantly different from those of the controls (p = 0.014, p = 0.006). The TT genotype (polymorphic homozygous) was associated with a 4.36-fold higher likelihood of having JIA (95% CI 1.545-12.323, p = 0.005) as compared to the CC genotype (wild-type). At month 12 of treatment, JIA patients, carriers of the CC genotype, showed significantly higher plasma CAT activity (p = 0.004) and achieved the JIA ACR 70 response more often (p = 0.003) than the patients, carriers of the CT/TT genotype. This is the first study implying the possible association of CAT-262C/T polymorphism with JIA. The results suggest the potential protective effect of the CC genotype, with regard to CAT activity and treatment outcome.

The Relevance of Vascular Endothelial Growth Factor, Hypoxia Inducible Factor-1 Alpha, and Clusterin in Carotid Plaque Instability.

BACKGROUND: Stroke is one of the leading causes of morbidity and mortality. Thromboembolism, as a major cause of carotid artery-related stroke, can be caused by plaque rupture which is associated with neoangiogenesis within the carotid plaque. AIM: We sought to investigate a possible correlation between angiogenesis-related factors and preoperative neurological manifestations in patients with internal carotid artery stenosis, for a better understanding of thromboembolism in internal carotid artery stenosis-related stroke. METHODS: This study included 54 patients (asymptomatic, n = 20 and symptomatic, n = 34) undergoing carotid endarterectomy for high-grade internal carotid artery stenosis. In the retrieved carotid plaques, angiogenesis-related factors (vascular endothelial growth factor [VEGF], hypoxia inducible factor-1 alpha [HIF-1α], and Clusterin) were measured by immunohistochemistry and quantified by real-time polymerase chain reaction. RESULTS: We demonstrated the expression of VEGF, HIF-1α, and Clusterin by endothelial cells and smooth muscle cells in the carotid plaques. Noteworthy, mRNA VEGF levels were .7-fold higher in symptomatic patients (P = .017) compared to asymptomatic patients. In contrast, mRNA Clusterin levels were 1.8-fold lower (P = .021). Levels of mRNA HIF-1α were 1.5-fold higher in asymptomatic patients, but no statistical significance was reached between the 2 groups. CONCLUSIONS: Our results show an association between VEGF and Clusterin and neurological symptoms of patients with high-grade carotid artery stenosis.

Vitamin D Receptor Gene Polymorphisms in Serbian Patients With Bronchial Asthma: A Case-Control Study.

Vitamin D and single nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR) gene are potentially involved in the pathogenesis of bronchial asthma (BA); however, precise mechanisms by which vitamin D reduces the inflammation and the role of VDR SNPs in BA are not completely understood. The aim of this study was to examine the possible associations of FokI, BsmI, ApaI, and TaqI SNPs with BA. A total of 168 subjects were screened for VDR SNPs using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. The obtained results showed statistically significant differences in the distribution of FokI genotypes (df = 2; P = 0.008) and alleles (P = 0.002; OR = 0.446; 95%CI = 0.264-0.752) between patients and controls. Distributions of BsmI, ApaI, and TaqI genotypes and alleles did not show statistical differences. BsmI, ApaI, and TaqI SNPs are in linkage disequilibrium (LD) in the whole studied group, as well as in BA patients and controls. The strongest LD was observed between BsmI and TaqI (r2 = 0.69 for all subjects in the study; r2 = 0.75 in BA; r2 = 0.64 in controls), while lower values of LD were observed for BsmI and ApaI, and ApaI and TaqI SNPs. This is the first study that examined the association of VDR SNPs (FokI, BsmI, ApaI, and TaqI) in Serbian patients with BA indicating protective effect of FF genotype and F allele of FokI SNP on BA development. J. Cell. Biochem. 118: 3986-3992, 2017. © 2017 Wiley Periodicals, Inc.

Degree of contralateral carotid stenosis improves preoperative risk stratification of patients with asymptomatic ipsilateral carotid stenosis.

OBJECTIVE: The benefit of carotid surgery in asymptomatic patients with high-grade internal carotid artery stenosis (ICAS) is subject of intense debate, and thus improved preoperative risk stratification is mandatory. This study aimed to investigate the predictive value of contralateral ICAS (cl-ICAS) for the preoperative clinical presentation of patients with ipsilateral ICAS (primary outcome). METHODS: This study was a post hoc analysis of a prospective cohort comprising 485 consecutive patients undergoing carotid endarterectomy for high-grade ICAS. Patients were classified by their clinical presentation, ie, asymptomatic (n = 213) or symptomatic (within 6 months of surgery; n = 272, comprising both transient ischemic attack [TIA; n = 163] and stroke [n = 109]). We investigated the association of cl-ICAS with the primary outcome in adjusted regression models. RESULTS: Mean ipsilateral degrees of ICAS were similar in both groups (84% ± 10% vs 84% ± 11%; P = .92), whereas contralateral degrees were significantly higher in the symptomatic group (29% ± 34% vs 38% ± 39%; P = .008). After multivariable regression analysis, cl-ICAS >60% conferred a three times higher preoperative stroke risk (odds ratio, 3.31; 95% confidence interval, 1.98-5.54; P < .001). Inclusion of cl-ICAS significantly improved (P = .001) ipsilateral combined TIA and stroke risk prediction based on established risk factors (area under the curve, 0.66; 95% confidence interval, 0.60-0.72; P < .001). CONCLUSIONS: Our study identifies a high contralateral degree of ICAS as an independent predictor of preoperative ipsilateral TIA and stroke in patients with ipsilateral high-grade ICAS. Therefore, such patients might rather benefit from elective carotid surgery and intensive postoperative medical care.

Randomized controlled trial comparing the combination of a polymeric membrane dressing plus negative pressure wound therapy against negative pressure wound therapy alone: The WICVAC study.

Negative pressure wound therapy (NPWT) is the treatment of choice for chronic wounds; yet, it is associated with considerable workload. Prompted by its nonadhesive and wound-healing properties, this study investigated the effect of an additional polymeric membrane interface dressing (PMD; PolyMem WIC) in NPWT. From October 2011 to April 2013, 60 consecutive patients with chronic leg wounds or surgical site infections after revascularization of lower extremities were randomly allocated to either treatment with conventional NPWT (control arm) or NPWT with an additional PMD (intervention arm). The primary outcome was wound healing achieved within 30 days, the secondary endpoints included: number of days between dressing changes, wound-related pain, cost efficiency, and occurrence of adverse events (ClinTrials.gov Identifier: NCT02399722). Forty-seven patients completed follow-up. No difference in wound healing was observed (p > 0.05) between both study arms. The additional PMD allowed significantly longer wearing times (days) between dressing changes (intervention: 8.8 ± 0.5, control: 4.8 ± 0.2; p < 0.001). Pain was slightly higher in patients randomized to NPWT alone (VAS score: 4.8 ± 2.9) compared to NPWT + PMD (VAS score: 3.0 ± 2.9, p = 0.063). No wound infections were observed. Costs were reduced by 34% per patient in the intervention arm. These results suggest that the combination of NPWT and an additional interface PMD is a safe and economic method for the treatment of chronic wounds, which requires significantly fewer dressing changes for a comparable wound healing.

B-Vitamin Serum Concentrations Predicting Long-Term Overall and Stroke-Free Survival after Carotid Endarterectomy.

BACKGROUND: Both deficiency and, according to recent reports, excess of vitamin B12 (B12) are associated with increased mortality. Thus, it is difficult to estimate the effect of B12 on overall survival, which also depends on folate (FA) in homocysteine lowering. This study aimed to assess FA and B12 serum concentrations associated with long-term survival of vascular surgery patients by means of a prognostic index (PI). METHODS: This single-center, prospective cohort study comprised 485 consecutive carotid surgery patients. B-vitamin baseline concentrations of B12 and FA were used to compute a PI for postoperative overall survival from January 2003 to January 2012 (mean observation period 102.3 months). RESULTS: Increasing B12 serum concentrations showed a nonlinear association with overall survival (P = .033). A B vitamin-based PI significantly predicted overall (hazard ratio [HR] per standard deviation = 1.97, confidence interval [CI] 1.37-2.82; P < .001), cardiovascular (HR = 3.03, CI 1.78-5.14; P < .001), and stroke-free survival (HR = 2.20, CI 1.22-3.98; P = .009), and revealed that the highest adverse event-free survival was predicted by high FA (16.3 ± 12.9 ng/mL) but only moderate B12 (360.3 ± 156.0 pmol/L) baseline concentrations. CONCLUSIONS: Prediction of increased long-term overall, cardiovascular, and stroke-free survival is based on high FA but only moderate B12 serum concentrations. Excessive B12 concentrations might harbor a potential harm and are no requisite for low homocysteine concentrations. The association between B vitamins and survival might serve either as a tool for risk stratification or, if causative, as effective therapy, if optimal dosing of B vitamins is provided and on-treatment concentrations, including homocysteine and renal functions, are closely monitored.

Ratio of Apolipoprotein A-II/B Improves Risk Prediction of Postoperative Survival After Carotid Endarterectomy.

BACKGROUND AND PURPOSE: Even in patients with high-grade carotid stenosis, cardiovascular morbidity causes more deaths than strokes do. Despite successful low-density lipoprotein (LDL) cholesterol lowering, a significant risk of atherosclerotic cardiovascular disease remains, eventually rendering other lipid or lipoprotein ratios more efficient treatment targets. This study aimed to investigate the predictive value of the ratio of serum apolipoprotein A-II/B for overall mortality (primary outcome) of carotid surgery patients. METHODS: This single-center, nonrandomized, prospective cohort study comprised 327 consecutive patients undergoing carotid endarterectomy for high-grade internal carotid artery stenosis. Baseline lipoprotein concentrations were measured, and patients were observed for the occurrence of the primary outcome until the census date (January, 2003 to January, 2012; median follow-up, 102.3 months). RESULTS: The ratio of apolipoprotein A-II/B (hazard ratio, 0.74 per SD; confidence interval, 0.60-0.91; P=0.004) showed the highest association with the primary outcome compared with other lipid-risk parameters, significantly improving a prognostic model based on major cardiovascular risk factors, including LDL, high-density lipoprotein, and triglycerides in terms of overall performance, calibration, and discrimination. This led to a significantly improved reclassification of 8.9% of all patients (net reclassification improvement, 0.137; P=0.006 and integrated discrimination improvement, 0.041; P<0.001) and of 13.6% of patients with a serum baseline concentration of <100 mg/dL LDL (net reclassification improvement, 0.270; P=0.030 and integrated discrimination improvement, 0.061; P=0.002). CONCLUSIONS: Apolipoprotein A-II/B significantly improves risk prediction of overall survival, also in carotid surgery patients with lower LDL levels. Consequently, this ratio might provide an efficient diagnostic tool and eventually a treatment target for actual lipid-lowering therapies, which has to be addressed in future randomized controlled trials.

The Use of Agmatine Provides the New Insight in an Experimental Model of Multiple Sclerosis.

The aim of the study is to investigate the hypothesis that agmatine (AGM) enhances blood brain barrier (BBB) compounds properties in experimental autoimmune encephalomyelitis (EAE), which is an established animal model for studying multiple sclerosis (MS). Wild-type (WT) and knockout (KO) CBA/H iNOS-/- mice, 3 months old (15 ± 5 g) were used for EAE induction by myelin basic protein (MBP) dissolved in complete Freund's adjuvant (CFA). The animals were divided into control, CFA, EAE, EAE + AGM and AGM groups. After the development of full clinical remission, the animals were sacrificed and the immunohistochemical and biochemical examinations were performed in brain homogenates. We had noticed the increased expressions of occludin in WT and KO mice with EAE + AGM, compared to EAE groups in which these expressions were significantly decreased compared to the controls. The significant elevations of matrix metalloproteinases (MMPs)-MMP-3 and MMP-9 in WT and KO EAE animals were decreased during AGM treatment in both groups. AGM application post EAE in WT and KO mice caused decreased level of Iba-1 stain, compared to EAE groups. The obtained results suggest beneficial AGM effects in EAE on BBB components, which might be useful for novel therapeutic strategies in MS.

Arginase activity and lecithin/sphingomyelin (l/s) ratio in the amniotic fluid of pregnant women.

Arginase activity is important in polyamines and nitric oxide production which are required for the normal growth of placenta and embryo. A considerable arginase activity is observed in amniotic fluid in women at the end of pregnancy. Lecithin to sphingomyelin (L/S) ratio is widely used in order to assess fetal lung immaturity and prevention of neonatal respiratory distress syndrome, the major cause of neonatal morbidity and mortality. The purpose of our study was to determine if there is a relationship between arginase activity and L/S ratio in amniotic fluid. The study included 170 pregnant women, 18-43 years old, with normal and pathological pregnancy. The arginase activity was measured on the basis of the determination of the amount of liberated ornithine from arginine as substrate. The L/S ratio was done by using a thin layer chromatography. Increased level of arginase activity correlates with the fetal lung maturity. Arginase activity and L/S values may be useful biochemical data, for intrauterine baby maturity.

Dissecting the immune response of CD4+ T cells in Alzheimer's disease.

The formation of amyloid-ß (Aß) plaques is a neuropathological hallmark of Alzheimer's disease (AD), however, these pathological aggregates can also be found in the brains of cognitively unimpaired elderly population. In that context, individual variations in the Aß-specific immune response could be key factors that determine the level of Aß-induced neuroinflammation and thus the propensity to develop AD. CD4+ T cells are the cornerstone of the immune response that coordinate the effector functions of both adaptive and innate immunity. However, despite intensive research efforts, the precise role of these cells during AD pathogenesis is still not fully elucidated. Both pathogenic and beneficial effects have been observed in various animal models of AD, as well as in humans with AD. Although this functional duality of CD4+ T cells in AD can be simply attributed to the vast phenotype heterogeneity of this cell lineage, disease stage-specific effect have also been proposed. Therefore, in this review, we summarized the current understanding of the role of CD4+ T cells in the pathophysiology of AD, from the aspect of their antigen specificity, activation, and phenotype characteristics. Such knowledge is of practical importance as it paves the way for immunomodulation as a therapeutic option for AD treatment, given that currently available therapies have not yielded satisfactory results.

Melatonin protects rat thymus against oxidative stress caused by exposure to microwaves and modulates proliferation/apoptosis of thymocytes.

The aim of the study was to evaluate the effect of melatonin on oxidative stress, DNA fragmentation, apoptsis and proliferation in thymus tissue of rats exposed to microwaves. Wistar rats were divided in four groups: I - treated with saline; II - treated with melatonin; III - microwaves exposed; IV - microwaves exposed and melatonin treated. Melatonin (2 mg/kg i.p.) was administered daily. Animals were sacrificed after 20, 40 and 60 days. A significant increase in malondialdehyde and carbonyl group content, as well as decrease in catalase and increase in xanthine oxidase activity were registered under microwave exposure. Melatonin prevented the increase in malondialdehyde and carbonyl group content, and reversed the effect on catalase and xanthine oxidase activity. Both, alkaline and acid DNase activity were increased due to microwave exposure. Furthermore, microwaves caused increase in apoptosis rate (detected using Annexin V-FITC/PI kit) and reduced proliferative capacity of thymocytes (induced by ConA). However, melatonin caused decrease in alkaline and acid DNase activity, decrease in apoptotic rate and increase in proliferation rate of thymocytes. Melatonin exerts protective effects on rat thymocytes by modulating processes of apoptosis and proliferation, and causes decrease in DNA fragmentation and oxidative stress intensity under exposure to microwaves.

Dexamethasone decreases the spermidine and spermine concentrations and polyamine oxidase activity in rat thymus.

BACKGROUND: Glucocorticoids (GCs) exert a wide range of anti-inflammatory, immunosuppressive, and antineoplastic activities. The aim of our investigation was to elucidate the effect of dexamethasone, a synthetic GC, on polyamine metabolism in the rat thymus. METHODS: Male albino Wistar rats, weighing 180-230 g, were divided into two groups: control and experimental. The experimental group received dexamethasone intraperitoneally for 3 days, in a daily dose of 4 mg/animal. The last dose of the hormone was applied on the 3rd day, 1 h before killing. The control group received 0.9% NaCl instead of the hormone. The animals were killed by decapitation. The thymus was removed quickly and rinsed with ice-cold saline. Polyamines were extracted using butanol. The amount of polyamines was investigated by electrophoresis. For the estimation of polyamine oxidase (PAO) activity, 10% water homogenate was prepared. RESULTS: Our results suggested that dexamethasone supplementation of experimental animals for 3 days significantly decreased the spermine (Sp) and spermidine (Spd) levels in rat thymus tissue (Sp Control, 362.56±25.33 nmol/g wet weight; Sp Exp. Group, 313.01±21.16 nmol/g wet weight; Spd Control, 673.81±30.95 nmol/g wet weight; Spd Exp. Group, 410.21±17.26 nmol/g wet weight). PAO activity significantly decreased under hormone influence in comparison with the control group (PAO Control, 0.449±0.121 U/mg prot.; PAO Exp. Group, 0.312±0.096 U/mg prot.). CONCLUSIONS: The decrease in polyamine amounts in the rat thymus is not due to the change in PAO activity.

Histopathology of chironomids exposed to fly ash and microplastics as a new biomarker of ecotoxicological assessment.

In the last few decades, industrial pollution has gained extensive attention in terms of its effect on the aquatic environment. This imposes the need to develop sensitive biomarkers for early detection of pollutant toxicity in ecotoxicological assessment. The advantages of histopathological biomarkers are many, including quick reaction to the presence of contaminants, and the small number of individuals needed for efficient analysis. The present study analyzed the negative effect of lignite coal fly ash (LCFA) and microplastic particles (MPs) on Chironomus riparius, a suggested model organism by the Organization for Economic Cooperation and Development (OECD). This study aimed to perform histological analyses of larval tissues and target potential changes in treated groups that could serve as promising histopathological biomarkers of the contaminant's negative effects. Following that, other known sensitive sub-organismal biomarkers were analyzed and paired with the histopathological ones. Histological analysis of larvae showed a significantly decreased length of microvilli in midgut regions II and III in both treatments. Treatments with MPs affected oxidative stress parameters: thiobarbituric acid reactive substances (TBARS), advanced oxidation protein products (AOPP), superoxide dismutase (SOD), and hemoglobin levels, while LCFA significantly affected all tested sub-organismal biomarkers (DNA damage, levels of AOPP, SOD, and hemoglobin), except catalase (CAT) and TBARS. When observing histological slides, a significant shortage of brush border length in the posterior parts of the midgut was detected in all treatments. In the case of LCFA, the appearance of intensive vacuolization of digestive cells with inclusions resembling apoptotic bodies, in mentioned regions was also detected. This study demonstrated high sensitivity of brush border length to the MPs and LCFA exposure, complementary to other tested sub-organismal biomarkers. Revealing the great potential of this histopathological biomarker in ecotoxicological studies contributes to the international standard ecotoxicology assessment of emerging pollutants.

Protective effects of glutathione and lipoic acid against cadmium-induced oxidative stress in rat's kidney.

Cadmium is a widespread, toxic industrial pollutant. The proximal tubule of the mammalian kidney is a major target of Cd-induced toxicity. We analyzed the effects of cadmium exposure on the model system of experimental animals, the thiobarbituric acid (TBA)-reactive substance (TBARS) level, and the activity of xanthine oxidase (XO) and catalase in kidney of rats, with and without glutathione and lipoic acid (LA). The experimental animals were classified into six groups, regarding cadmium, glutathione, and LA intake. The concentration of TBARSs in the homogenate was determined by spectrophotometric method according to Nabavi et al. The specific activity of XO was determined spectrophotometrically by the method of Aygul et al. Catalase activity in tissues was determined by spectrophotometric method according to Nabavi et al. The increased level of TBARS and the increased activity of XO in kidney tissue in cadmium poisoning are statistically significant compared to control (p < 0.001). Glutathione and LA applied along with cadmium lowered TBARS concentration and reduced XO activity (p < 0.001). Catalase activity in the kidney tissue was increased in the group, which was administered cadmium (p < 0.001). In conclusion, glutathione and LA, as physiological antioxidants applied with cadmium, have reduced the level of lipid peroxide and the activity of XO, and can be used as protectors in conditions of cadmium poisoning.

Importance of a functional measure in the evaluation of patients in a memory clinic: Validation of the Serbian version of the Amsterdam instrumental activities of daily living questionnaire.

INTRODUCTION AND AIM: The Amsterdam instrumental activities of daily living questionnaire (A-IADL-Q) was developed as a sensitive tool in detecting a functional decline in early dementia. The aim of our study was to analyze the validity and reliability of the Serbian translation of the short version of A-IADL-Q in a population of memory clinic patients. MATERIAL AND METHODS: We have included 160 subjects with Alzhemier's disease (AD) dementia, mild cognitive impairment (MCI), or normal cognition (NC). All patients were examined by a neurologist, screened for cognitive impairment (MMSE) and depression, and referred to laboratory testing, neuroimaging examination, and neuropsychological assessment. Informants (close friends or relatives) completed Serbian language versions of the A-IADL-Q -Short version and the Lawton-Brody Instrumental Activities of Daily Living (LB-IADL) scale. Reliability analysis was performed by assessing internal consistency and reproducibility (test-retest reliability). Construct validity was assessed as the impact of gender, аgе, education, diagnosis, cognitive and functional measures on A-IADL-Q scores. RESULTS: The internal consistency of the Serbian version of A-IADL-Q was acceptable (Cronbach's alpha 0.82), Test-retest reliability of the A-IADL-Q was excellent (ICC=0.92, 95% CI 0.84-0.98, p < 0.001). There was no statistically significant difference in A-IADL-Q scores between male and female subjects (t = 1.183; p = 0.241), while the difference was registered between subjects with different education levels (F=12.955; p < 0.001) and diagnosis (F=209.433; p < 0.001). There was a strong and statistically significant correlation between A-IADL-Q and MMSE scores (tau-b= 0.638; p < 0.001) and IADL-Q and LB-ADL scores (tau-b=0.714; p < 0.001). A significant multiple regression model was found (F(4, 155) = 103.692;p < 0.001), which explained 72.1% of the A-IADL-Q score variance with MMSE score and age as significant predictors. CONCLUSION: The Serbian adaptation of the A-IADL-Q-short version is a reliable and valid measure of instrumental activities of daily living in patients with dementia and mild cognitive impairment. This easy-to-administer instrument is useful for the early diagnostics of dementia syndrome in a memory clinic population.

Association of vitamin D receptor genetic variants with bone mineral density and inflammatory markers in rheumatoid arthritis.

BACKGROUND AND AIMS: Vitamin D receptor (VDR) genetic variants are considered to have a role in the pathogenesis of rheumatoid arthritis (RA). This study examines an association of FokI, BsmI, ApaI and TaqI with RA, as well as with bone mineral density (RA with normal bone mineral density, RA-NBMD; RA with associated osteopenia, RA-OSTP; and RA with associated osteoporosis, RA-OP) and inflammatory markers. MATERIALS AND METHODS: VDR genetic variants were tested in 248 subjects using the PCR-RFLP method. RESULTS: Significant differences were observed in the distribution of FokI genotypes between RA patients (p < 0.001), or subgroups (RA-NBMD, RA-OSTP, RA-OP) (p = 0.035, p = 0.02, p < 0.001, respectively) and controls. Prevalence of FokI f allele was significantly higher in RA group (p < 0.001) and subgroups (p = 0.003, p = 0.021, p < 0.001, respectively) compared to controls. An increased susceptibility to RA-OSTP was revealed in BsmI/ApaI Ba (AC) haplotype carriers (p = 0.012). A significantly higher erythrocyte sedimentation rate values were obtained in FokI FF compared to Ff + ff carriers (54.57 ± 23.73 vs. 22.83 ± 12.42; p < 0.001) within the RA-NBMD subgroup. CONCLUSION: The results of the study indicate an association of RA with FokI genetic variant and increased susceptibility to RA in f allele carriers, as well as to RA-OSTP in BsmI/ApaI Ba (AC) haplotype carriers.

Effect of the Interrelation between CYP3A5 Genotype, Concentration/Dose Ratio and Intrapatient Variability of Tacrolimus on Kidney Graft Function: Monte Carlo Simulation Approach.

Background: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. Aim: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C0/D) over 6-12 months on reduced estimated glomerular filtration rate (eGFR) values in the late period after kidney transplantation (Tx), applying Monte Carlo (MC) simulation. Methods: The previously published linear regression was the basis for MC simulation, performed to determine how variations in significant predictors affect the distribution of eGFR from 13 to 36 months post-transplantation. The input C0/D values were derived from CYP3A5 genotype subgroups. Results: Patients characterized by high Tac IPV and low mean C0/D over 6-12 months could have been at greater risk of lower eGFR values in a three-year period following Tx compared to the other patient groups. This effect was more pronounced in patients with a lower eGFR at the 6th month and a history of acute rejection. The proven contribution of CYP3A5 expresser genotype to low C0/D values may suggest its indirect effect on long-term graft function. Conclusion: The findings indicate that simultaneous assessment of Tac IPV, C0/D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period.