Impact of gene polymorphisms on cardiovascular diseases in patients with end stage renal disease

UVOD: Hronična bubreţna bolest (HBB) je nezavistan faktori rizika za kardiovaskularne bolesti. Cilj ovog rada je da se ispita efekat polimorfizama gena za homocistein MTHFR 677C>T, MTHFR 1298 A>C, interleukin 6 -174G>C, interleukin 10 -1082G>A i -819T>C i fetuin 742 C>T i 766 C>G na koncentracije homocisteina, IL-6 i IL-10, fetuina i na rane i kasne pokazatelje ateroskleroze, pojavu kalcifikacija na koronarnim arterijama (KKA) i preţivljavanje bolesnika. transplantiranim bubregom (TX). U studiji za IL-6 i IL -10 228 bolesnika (77 HD i 55 na peritoenumskoj dijalizi), a za fetuin 88 (46 sa HBB i 42 Tx) i kontrolnoj grupi 28 zdravih osoba. Odredjivani su polimorfizmi u genima PCR metodom, biohemijske analize, CRP, amiloid A, fetuin-A, homo-cistein, IL-6 i IL-10. Merena je debljine intima medije (IMD) karotidnih arterija i prisustvo plaka, a skor kalci-fikacija multislajsnom tomografijom. REZULTATI: Bolesnici sa MTHFR 677 CT i TT genotipom su imali više vrednosti Hcy, ali bez statističke značajnosti. Ho-mozigoti sa genotipom IL-6 -174CC su imali značajno više koncentracije IL-6 (6,4pg/ml), u odnosu na -174GC+GG genotipove (3,1pg/ml, p=0,30). Koncentracije IL-10 nisu razlikovale prema genotipovima IL-10 -1082G>A i -819T>C. Homozigoti sa genotipom u genu za fetuin 742TT i 766GG su imali najniţe koncentracije fetuina-A (p=0,02). Aterosklerotski plak na karotidnim arterijama je imalo 47% bolesnika. IMD i izraţenost plaka nije se razlikovala medju MTHFR genotipovima. Ispitanici sa plak skorom 1-3 su bili značajno stariji, češće su imali hipertenziju, viši C reaktivni protein i kreatinin, a najznačajniji prediktor je bila starost (B=0,133; pC. Petogodišnje preţivljavanje bolesnika bez mutacije u genu za fetuin 742C>T je bilo 100%, kod bolesnika sa mutacijom 81%, a ukoliko su imali i povišene vrednosti C reaktivnog proteina 50%. ZAKLJUčAK: Ispitivanja u ovom radu nisu pokazala da je polimorfizam u genu za MTHFR značajno povezan sa koncentracijom homocisteina, niti sa parametrima ateroskleroze, heterozigoti MTHFR 677CT su imali lošije preţivljavanje. Polimorfizam IL-6 -174G>C je bio povezan sa koncentracijama IL-6, homozigoti 174CC su im-ali značajno više koncentracije IL-6 i lošije preţivljavanje. Polimorfizmi u genu za fetuin su bili udruţeni sa niţim koncentracijama fetuina-A u krvi i sa lošijim preţivljavanjem.Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. The aim of this study was to examine the effect of gene polymorphisms for homocysteine MTHFR 677C> T, MTHFR 1298 A> C, interleukin 6 -174G> C, interleukin 10 -1082G> A and -819T> C for fetuin 742 C> T and 766 C > G on con-centrations of homocysteine, IL-6 and IL-10, fetuin and on early and late indicators of atherosclerosis, the oc-currence of coronary artery calcifications (COA) and patient survival. METHODS: The Hcy study included 188 patients, 82 treated with hemodialysis (HD) and 106 with kidney transplantation (TX). In the study for IL-6 and IL-10 228 were included (77 HD and 55 on peritoneum dialysis), and for fetuin 88 (46 with HBB and 42 Tx) and the control group of 28 healthy individuals. Polymorphisms in genes were determined by PCR, biochemical analysis, CRP, amyloid A, fetuin-A, homo-cysteine, IL-6 and IL-10. The thickness of the intimate media (IMD) of the carotid arteries and the presence of plaque were measured, and the score was calcified by multislice tomography. RESULTS: Patients with MTHFR 677CT and TT genotype had higher Hcy values, but no statistical signific-ance. Homozygotes with genotype IL-6 -174CC had significantly higher IL-6 concentrations of 6.4pg / ml, compared to -174GC + GG genotypes (3.1pg / ml, p = 0.30). IL-10 concentrations did not differ according to IL-10 genotypes -1082G> A and -819T> C. Homozygotes for mutations in the fetuin gene 742TT and 766GG had the lowest concentrations of fetuin-A (p = 0.02). IMD and plaque expression did not differ among MTHFR genotypes. Subjects with a plaque score of 1-3 were significantly older, more likely to have hypertension, higher C-reactive protein and creatinine, and the most sig-nificant predictor was age (B = 0.133; p C gene poly-morphism. The five-year survival of patients without mutation in the fetus 742C> T gene was 100%, in patients with mutation 81%, and in patients with elevated reactive protein C values 50%. CONCLUSION: The studies in this paper did not show that polymorphism in the MTHFR gene was significant-ly associated with homocysteine concentration or atherosclerosis parameters, MTHFR 677CT heterozygotes had poorer survival. The IL-6 -174G>C polymorphism was associated with IL-6 concentrations, mutation homozy-gotes had significantly higher IL-6 concentrations and poorer survival. Polymorphisms in the fetuin gene 742 C>T and 766C>G were associated with lower blood concentrations of fetuin-A and poorer survival

Influence of immediate release tablet formulation on dissolution profile of paracetamol

Introduction: Paracetamol is analgesic and antipyretic, which is usually in the form of an immediate release tablet formulations. Therapeutic effects in terms of the speed and intensity of the analgesic effect is dependent on speed of liberation from formulation. Aim: The aim of this work was to determine and compare dissolution profiles of 4 paracetamol immediate release tablet formulations and to determine influence of excipients on kinetic of paracetamol dissolution. Materials and Methods: Dissolution profiles of paracetamol tablets were determined using method with paddles and phosphate buffer pH 6.8 as a medium. Release of paracetamol was followed 60 minutes (using 6 time points). Concentration of paracetamol was measured using UV/Vis spectrophotometric method (243 nm). Dissolution profiles were compared using model-independent method (difference factor and similarity factor), statistic method (ANOVA-based method and pair Student's T-test, p<0.05) and model dependent methods (to determinate the release kinetics of paracetamol). Results: All formulations in the first 45 minutes liberated more than 85 % of the labled content. Formulation D, which contained superdesintegrator, released 90% of the content in the first 5 minutes. Though based on values of difference and similarity factors formulations are, not significantly different, ANOVA-based method showed that formulation A and B, B and C, as well as formulation B and D do statistically differ in all 6 time points, meaning they have parallel profiles. The release of paracetamol from formulations A and D is best described by the first order kinetic model, while the release of formulations B and C by the logistic model. Conclusions: The release kinetic of paracetamol is mostly influenced by the type of superdisintegrants and lubricants. Formulation with superdisintegrant technology OptiZorb® demonstrated fastes release rate and thus it is expected to produce the fastest pharmacodynamic effect.

Impact of gene polymorphisms on cardiovascular diseases in patients with end stage renal disease

UVOD: Hronična bubreţna bolest (HBB) je nezavistan faktori rizika za kardiovaskularne bolesti. Cilj ovog rada je da se ispita efekat polimorfizama gena za homocistein MTHFR 677C>T, MTHFR 1298 A>C, interleukin 6 -174G>C, interleukin 10 -1082G>A i -819T>C i fetuin 742 C>T i 766 C>G na koncentracije homocisteina, IL-6 i IL-10, fetuina i na rane i kasne pokazatelje ateroskleroze, pojavu kalcifikacija na koronarnim arterijama (KKA) i preţivljavanje bolesnika. transplantiranim bubregom (TX). U studiji za IL-6 i IL -10 228 bolesnika (77 HD i 55 na peritoenumskoj dijalizi), a za fetuin 88 (46 sa HBB i 42 Tx) i kontrolnoj grupi 28 zdravih osoba. Odredjivani su polimorfizmi u genima PCR metodom, biohemijske analize, CRP, amiloid A, fetuin-A, homo-cistein, IL-6 i IL-10. Merena je debljine intima medije (IMD) karotidnih arterija i prisustvo plaka, a skor kalci-fikacija multislajsnom tomografijom. REZULTATI: Bolesnici sa MTHFR 677 CT i TT genotipom su imali više vrednosti Hcy, ali bez statističke značajnosti. Ho-mozigoti sa genotipom IL-6 -174CC su imali značajno više koncentracije IL-6 (6,4pg/ml), u odnosu na -174GC+GG genotipove (3,1pg/ml, p=0,30). Koncentracije IL-10 nisu razlikovale prema genotipovima IL-10 -1082G>A i -819T>C. Homozigoti sa genotipom u genu za fetuin 742TT i 766GG su imali najniţe koncentracije fetuina-A (p=0,02). Aterosklerotski plak na karotidnim arterijama je imalo 47% bolesnika. IMD i izraţenost plaka nije se razlikovala medju MTHFR genotipovima. Ispitanici sa plak skorom 1-3 su bili značajno stariji, češće su imali hipertenziju, viši C reaktivni protein i kreatinin, a najznačajniji prediktor je bila starost (B=0,133; pC. Petogodišnje preţivljavanje bolesnika bez mutacije u genu za fetuin 742C>T je bilo 100%, kod bolesnika sa mutacijom 81%, a ukoliko su imali i povišene vrednosti C reaktivnog proteina 50%. ZAKLJUčAK: Ispitivanja u ovom radu nisu pokazala da je polimorfizam u genu za MTHFR značajno povezan sa koncentracijom homocisteina, niti sa parametrima ateroskleroze, heterozigoti MTHFR 677CT su imali lošije preţivljavanje. Polimorfizam IL-6 -174G>C je bio povezan sa koncentracijama IL-6, homozigoti 174CC su im-ali značajno više koncentracije IL-6 i lošije preţivljavanje. Polimorfizmi u genu za fetuin su bili udruţeni sa niţim koncentracijama fetuina-A u krvi i sa lošijim preţivljavanjem.Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. The aim of this study was to examine the effect of gene polymorphisms for homocysteine MTHFR 677C> T, MTHFR 1298 A> C, interleukin 6 -174G> C, interleukin 10 -1082G> A and -819T> C for fetuin 742 C> T and 766 C > G on con-centrations of homocysteine, IL-6 and IL-10, fetuin and on early and late indicators of atherosclerosis, the oc-currence of coronary artery calcifications (COA) and patient survival. METHODS: The Hcy study included 188 patients, 82 treated with hemodialysis (HD) and 106 with kidney transplantation (TX). In the study for IL-6 and IL-10 228 were included (77 HD and 55 on peritoneum dialysis), and for fetuin 88 (46 with HBB and 42 Tx) and the control group of 28 healthy individuals. Polymorphisms in genes were determined by PCR, biochemical analysis, CRP, amyloid A, fetuin-A, homo-cysteine, IL-6 and IL-10. The thickness of the intimate media (IMD) of the carotid arteries and the presence of plaque were measured, and the score was calcified by multislice tomography. RESULTS: Patients with MTHFR 677CT and TT genotype had higher Hcy values, but no statistical signific-ance. Homozygotes with genotype IL-6 -174CC had significantly higher IL-6 concentrations of 6.4pg / ml, compared to -174GC + GG genotypes (3.1pg / ml, p = 0.30). IL-10 concentrations did not differ according to IL-10 genotypes -1082G> A and -819T> C. Homozygotes for mutations in the fetuin gene 742TT and 766GG had the lowest concentrations of fetuin-A (p = 0.02). IMD and plaque expression did not differ among MTHFR genotypes. Subjects with a plaque score of 1-3 were significantly older, more likely to have hypertension, higher C-reactive protein and creatinine, and the most sig-nificant predictor was age (B = 0.133; p C gene poly-morphism. The five-year survival of patients without mutation in the fetus 742C> T gene was 100%, in patients with mutation 81%, and in patients with elevated reactive protein C values 50%. CONCLUSION: The studies in this paper did not show that polymorphism in the MTHFR gene was significant-ly associated with homocysteine concentration or atherosclerosis parameters, MTHFR 677CT heterozygotes had poorer survival. The IL-6 -174G>C polymorphism was associated with IL-6 concentrations, mutation homozy-gotes had significantly higher IL-6 concentrations and poorer survival. Polymorphisms in the fetuin gene 742 C>T and 766C>G were associated with lower blood concentrations of fetuin-A and poorer survival

Alzheimer’s Disease and Premature Ovarian Insufficiency

Estradiol promotes neuronal growth, transmission, survival, myelinization, plasticity, synaptogenesis, and dendritic branching and it improves cognitive function. Alzheimer’s disease (AD) is characterized by amyloid plaques, neurofibrillary tangles, and the loss of neuronal connection in the brain. Genomic analysis has concluded that hypoestrogenism influences the APOE gene and increases the risk of AD. Premature ovarian insufficiency (POI) is defined as oligo/amenorrhea in women below 40 years of age, low estradiol, and high-gonadotropin levels. Early symptoms and signs of POI must be detected in time in order to prevent subsequent complications, such as Alzheimer’s disease. Meta-analysis has shown favorable effects of estrogen in preventing Alzheimer’s. We measured some of the typical markers of AD in women with POI such as interleukin 6 (IL-6), interleukin 8 (IL-8), tissue necrosis factor α (TNFα), TAU1, TREM2, and amyloid precursor proteins (APP). While FSH, LH, and IL-8 were significantly higher in POI group, compared to controls, testosterone and DHEAS were lower. A significant decrease in IL-6 was found in the POI group during a 6-month therapy, as well as an increase in amyloid precursor proteins. CONCLUSION: Neurological complications of POI, such as declining short-term memory, cognitive function, and dementia, have to be promptly stopped by initiating estro-progestogen therapy in POI. A long-term continuation of the therapy would be strongly advised

Aging, aluminium and basal forebrain lesions modify substrate kinetics of erythrocyte membrane Na, K-ATPase in the rat

Several studies suggested that the activity of erythrocyte Na, K-ATPase declines with aging. Here, it is postulated that alterations in the substrate kinetics of the erythrocyte membrane Na, K-ATPase could be more aggravated in conditions of brain cholinergic dysfunction seen in Alzheimer's disease than in normal aging. To test this hypothesis, we compared the Na, K-ATPase activity (Vmax/Km parameters) in aged rats with those in young rats with brain cholinergic dysfunction induced by electrolytic-, kainic acid-lesioned nucleus basalis magnocellularis (NBM) or by intracerebroventricular AlCl3 administration. In the above mentioned groups, Vmax values were significantly lower in comparison to the control animals. Furthermore, Km values were significantly higher in animals with electrolytic-induced NBM lesions, AlCl3 treated rats and aged animals. However, Km was significantly lower in kainic acid-induced NBM lesions compared to the control group. The Na, K-ATPase catalytic efficiency, estimated by the ratio Vm/Km, decreased as followed: young animals gt aged animals gt kainic acid lesion gt electrolityc lesion gt AlCl3. Our data suggest that neurodegenerative processes similar to those seen in Alzheimer's disease affect the sodium/potassium pump functionality which might be detected in peripheral blood erythrocyte membranes

Infuence of donor specific transfusion on renal allograft outcome

Donor specific transfusion (DST) is proclaimed to improve graft survival in living related kidney transplantation (LRTx). The aim of the present study was to estimate the influence of DST on LRTx graft function, acute rejection rate (AR) and survival in the early and late post transplant period. Fifty-five LRTx patients (grafted in the same year, and matched for recipients' and donor's age, sex) were included into the study. Ninety pts received DST: 4 patients were excluded from further evaluation (3 developed positive cross match reaction and one patients received cadaver graft) and 15 patients subsequently underwent LRTx from their respective blood donors (group 1). Their outcome was compared with 15 patients who had never been transfused before (group 2) and 25 random transfused patients (group 3). Besides similar patients' and donors' sex and age, kidney transplantations were performed in the same period. Graft functions were followed-up 6-60 months after LRTx. DST protocol consists of 3x150 ml potentially related donor's fresh whole blood at 2-week intervals (DST1, DST2, DST3) with 3 days azathioprine administration (2 mg/kg bw, one day before to one day after DST administration). Donor specific citotoxic antibodies were determined before DST1, at the day of DST2, DST3 and 14 and 28 days after DST3. All patients were grafted at least one month after the DST3. Immunosuppressive protocol consisted of three drugs. There is no difference in HLA mismatches, MLC answer, and pretransplant panel reactive antibodies level between groups. One patient from group 2 lost their graft in the first postTx month (acute tubular necrosis). A better graft function was preserved in patients from groups 1 and 3 than group 2 in the observed periods. Number of patients with acute rejection was unsignificantly different: 5/15 from group 1,12/25 from group 3 but 8/10 patients from group 2. However, the acute rejection rate was lower in patients from group 1. One and five-year graft survival was 100% for grafts from groups 1 and 3, while it is gradually decreased for group 2 grafts: 84.5% and 57%. Our results confirmed the beneficial effect of blood transfusion on LRTx renal graft function and survival and DST on the incidence of acute rejection