Search

Research objective: to estimate results of treatment of patients with the localized form of a cancer of a prostate at a combination of a transurethral resection (TURP) and HIFU of an ablation. Objects and research methods: From February, 2009 to February, 2014 of 100 patients with the localized form of a cancer of a prostate were selected for research: 26 patients were included into HIFU and 74 group in group of the combined treatment (TURP+HIFU). Selection criteria for HIFU ablation were the localized cancer of a prostate concerning which earlier it wasn't carried out treatments, and level of a PSA at the time of statement of the diagnosis 15 ng/ml. All patients corresponding to these by criteria, were considered as candidates for treatment and inclusion in the analysis. The nadir and stability of PSA, the histologic conclusion, IPSS, quality of life and complication were estimated at time of postoperative supervision. Results: Statistically significant influence of a combination TURP+HIFU for the term of transurethral drainage of a bladder (a median of 40 days against 7 days), incontience frequency (15.4% against 6.9%), infections of urinary ways (47.9% against 11.4%) and IPSS change during the postoperative period (on the average 8.91 against 3.37) is noted. During the short period of supervision it wasn't observed considerable changes in relation to efficiency: in HIFU group the frequency of repeated sessions made 25%, in TUR/HIFU group 4%. Conclusion: HIFU therapy is modern, minimum invasive method of a cancer therapy of a prostate. The combination of a transurethral resection and HIFU ablation significantly reduces the frequency of the complications connected with treatment. Maintaining the patient after combined TURP and HIFU ablation is comparable with maintaining the patient after usual TURP.

The aim of the study is to improve the treatment of patients with male reproductive organs pathology, formed by chronic brucellosis infection. Material and methods: We have analyzed the dynamics of the clinical manifestations of diseases of the scrotal organs, data of physical and ultrasound studies, semen parameters, the quality of life in 22 patients with chronic brucellosis and the presence of orchitis / orchiepididymitis against conventional therapy (10 patients), and combined treatment with the inclusion of cycloferon (i/m, 2 injection rate from 5 (0.25g) with a break 10 days) — 12. Results: We have proved ability of cycloferon to reduce the severity of the inflammatory process in the testis and epididymis, with improving of spermatogenesis and the quality of life for patients. We have marked the reduction in the number of exacerbations of chronic orchitis / orchiepididymitis 2.4 times after the course of cycloferon, its good tolerability of patients, no side effects. Conclusion: Using these results, the presence of anti-inflammatory and immunomodulatory potencies, cycloferon can be recommended in treatment of inflammatory lesions of the scrotal organs in patients with chronic brucellosis.

The current aspects of ultrasonic diagnostics and monitoring in treatment of urolithiasis and obstructive syndrome were considered on the basis of the analysis of native and foreign literature. The reaction of hemodynamic parameters of the kidney to obstruction of the upper urinary tract and the impact of the shock waves on renal parenchyma were under the study. The potential of Doppler in the evaluation of renal blood flow both before and after surgery were highlighted in the article

Stroke is a disease whose consequences have a considerable impact on the quality of the patient’s life. It is a widespread disease that has a disabling impact on life and, in addition to physical changes, brings about a number of psychological and cognitive processes.

Objective: To evaluate a contribution of selected laboratory parameters for a prediction of progressive and erosive development in patients with early rheumatoid arthritis (RA).Methods: In a prospective study baseline levels of antibodies to cyclic citrullinated peptide (anti-CCP), IgM, IgA, and IgG rheumatoid factors (RFs) were measured by enzyme linked immunosorbent assay (ELISA) in 104 patients with RA with disease duration <2 years. Antikeratin antibodies (AKA) and antiperinuclear factor (APF) were detected by indirect immunofluorescence. Patients were divided into two groups based either on the presence or absence of erosions or according to progression of Larsen score at the end of the 24 months' follow up.Results: Sixty seven (64%) patients developed radiographic erosions, 49 (47%) had progression in Larsen score, and 36 (35%) progressed by more than 10 Larsen units. Significant differences in erosions and progression between the two groups were detected for anti-CCP, AKA, APF, IgM RF, IgA RF, and IgG RF. Baseline Larsen score correlated significantly with anti-CCP, IgM RF, and IgA RF levels, and all measured antibodies correlated with the progression >10 units. The combination of anti-CCP and IgM RF increased the ability to predict erosive and progressive disease.Conclusion: The data confirmed that measurement of anti-CCP, AKA, APF, and individual isotypes of RFs was useful for prediction of structural damage early in the disease course. Combined analysis of anti-CCP and IgM RF provides the most accurate prediction. [ABSTRACT FROM AUTHOR]

Abstract Background Levels of pentosidine (representative of advanced glycation end-products) in sera of patients with rheumatoid arthritis are increased when compared with sera of other diagnoses or healthy controls. These levels have been reported to correlate with clinical indices of rheumatoid arthritis activity and with laboratory markers of inflammation. The purpose of this study was to find out if these findings pertain to other advanced glycation end-products. Methods We have developed two immunoassays based on new monoclonal antibodies to advanced glycation end-products. Antibody 103-E3 reacts with an unidentified antigen, formed in the reaction of proteins with ribose, while antibody 8-C1 responds to Nε-(carboxyethyl)lysine. We have used these monoclonal antibodies to measure levels of advanced glycation end-products in sera of patients with rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, and healthy controls. We calculated the correlations between advanced glycation end-product levels in rheumatoid arthritis sera and the Disease Activity Score 28 (DAS28), age, disease duration, CRP, anti-CCP, rheumatoid factor and treatment with corticosteroids, respectively. Results Levels of both glycation products were significantly higher in sera of patients with rheumatoid arthritis when compared with sera of patients with systemic lupus erythematosus, osteoarthritis, or the healthy controls. Neither the level of Nε-(carboxyethyl)lysine nor the level of the 103-E3 antigen in rheumatoid arthritis sera correlated with the DAS28-scored rheumatoid arthritis activity. The levels of both antigens in rheumatoid arthritis sera did not correlate with age, gender, corticosteroid treatment, or levels of CRP, anti-CCP antibodies, and rheumatoid factor in sera. Conclusions We report highly specific increases in the levels of two advanced glycation end-products in sera of patients with rheumatoid arthritis. This increase could be explained neither by rheumatoid arthritis activity nor by inflammation. We propose a working hypothesis that presumes the existence of a link between advanced glycation end-product formation and induction of autoimmunity.

Abstract Dexamethasone (DEX) is known to induce diabetes and dyslipidemia. We have compared fasting triacylglycerol and cholesterol concentrations across 20 lipoprotein fractions and glucose tolerance in control (standard diet) and DEX-treated 7-month-old males of two rat strains, Brown Norway (BN) and congenic BN.SHR-(Il6-Cd36)/Cub (BN.SHR4). These two inbred strains differ in a defined segment of chromosome 4, originally transferred from the spontaneously hypertensive rat (SHR) including the mutant Cd36 gene, a known target of DEX. Compared to BN, the standard-diet-fed BN.SHR4 showed higher cholesterol and triacylglycerol concentrations across many lipoprotein fractions, particularly in small VLDL and LDL particles. Total cholesterol was decreased by DEX by more than 21% in BN.SHR4 contrasting with the tendency to increase in BN (strain*DEX interaction p = 0.0017). Similar pattern was observed for triacylglycerol concentrations in LDL. The LDL particle size was significantly reduced by DEX in both strains. Also, while control BN and BN.SHR4 displayed comparable glycaemic profiles during oral glucose tolerance test, we observed a markedly blunted DEX induction of glucose intolerance in BN.SHR4 compared to BN. In summary, we report a pharmacogenetic interaction between limited genomic segment with mutated Cd36 gene and dexamethasone-induced glucose intolerance and triacylglycerol and cholesterol redistribution into lipoprotein fractions.

Background: Levels of pentosidine (representative of advanced glycation end-products) in sera of patients with rheumatoid arthritis are increased when compared with sera of other diagnoses or healthy controls. These levels have been reported to correlate with clinical indices of rheumatoid arthritis activity and with laboratory markers of inflammation. The purpose of this study was to find out if these findings pertain to other advanced glycation end-products.Methods: We have developed two immunoassays based on new monoclonal antibodies to advanced glycation end-products. Antibody 103-E3 reacts with an unidentified antigen, formed in the reaction of proteins with ribose, while antibody 8-C1 responds to Nepsilon-(carboxyethyl)lysine. We have used these monoclonal antibodies to measure levels of advanced glycation end-products in sera of patients with rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, and healthy controls. We calculated the correlations between advanced glycation end-product levels in rheumatoid arthritis sera and the Disease Activity Score 28 (DAS28), age, disease duration, CRP, anti-CCP, rheumatoid factor and treatment with corticosteroids, respectively.Results: Levels of both glycation products were significantly higher in sera of patients with rheumatoid arthritis when compared with sera of patients with systemic lupus erythematosus, osteoarthritis, or the healthy controls. Neither the level of Nepsilon-(carboxyethyl)lysine nor the level of the 103-E3 antigen in rheumatoid arthritis sera correlated with the DAS28-scored rheumatoid arthritis activity. The levels of both antigens in rheumatoid arthritis sera did not correlate with age, gender, corticosteroid treatment, or levels of CRP, anti-CCP antibodies, and rheumatoid factor in sera.Conclusions: We report highly specific increases in the levels of two advanced glycation end-products in sera of patients with rheumatoid arthritis. This increase could be explained neither by rheumatoid arthritis activity nor by inflammation. We propose a working hypothesis that presumes the existence of a link between advanced glycation end-product formation and induction of autoimmunity. [ABSTRACT FROM AUTHOR]

Background: All-trans retinoic acid (ATRA, tretinoin) is a vitamin A derivative commonly used in the treatment of diverse conditions ranging from cancer to acne. In a fraction of predisposed individuals, the administration of ATRA is accompanied by variety of adverse metabolic effects, particularly by the induction of hyperlipidemia. We have previously derived a minimal congenic SHR.PD-(D8Rat42-D8Arb23)/Cub (SHR-Lx) strain sensitive to ATRA-induced increase of triacylglycerols and cholesterol under condition of high-sucrose diet. SHR-Lx differs only by 7 genes of polydactylous rat (PD/Cub) origin from its spontaneously hypertensive rat (SHR) progenitor strain., Methods: Adult male rats of SHR and SHR-Lx strains were fed standard diet (STD) and experimental groups were subsequently treated with ATRA (15 mg/kg) via oral gavage for 16 days, while still on STD. We contrasted the metabolic profiles (including free fatty acids, triacylglycerols (TG) and cholesterol (C) in 20 lipoprotein fractions) between SHR and SHR-Lx under conditions of standard diet and standard diet + ATRA. We performed transcriptomic analysis of muscle tissue (m. soleus) in all groups using Affymetrix GeneChip Rat Gene 2.0 ST Arrays followed by Ingenuity Pathway Analysis and real-time PCR validation., Results: In response to ATRA, SHR-Lx reacted with substantially greater rise in TG and C concentrations throughout the lipoprotein spectrum (two-way ANOVA strain * RA interaction significant for C content in chylomicrons (CM), VLDL and LDL as well as total, CM and HDL-TG)., Conclusions: According to our modeling of metabolic and signalization pathways using differentially expressed genes we have identified a network with major nodes (including Sirt3, Il1b, Cpt1b and Pparg) likely to underlie the observed strain specific response to ATRA.

To investigate the burden of ankylosing spondylitis in the Czech Republic as a baseline for future health economic evaluations. Data were obtained from two cross-sectional studies Beda I (2005) and Beda II (2008), performed in 1,008 and 509 patients, respectively. Methodology used was Cost-of-Illness prevalence-based analysis bottom-up approach. Analysis was performed from payer (health insurance companies) and societal perspective (including productivity costs using friction cost approach). Mean age of sample in Beda I and Beda II was 50.2 and 52.5 years, male were present by 61.0 and 62.7 %; average disease duration was 23.0 and 26.4 years, respectively. Mean total annual costs per patient in the sample were €4,782 in Beda I and €5806 in Beda II. Average direct costs per patient in the sample per year are estimated at €1,812 (Beda I) and €2,588 (Beda II) with the average productivity costs €2,970 (Beda I) and €3,218 (Beda II). We observed a small decrement in percentage (6.7 %) of productivity costs for Beda II as an influence of higher consumption of biologic drugs, hence higher direct costs and possible productivity preservation. The largest direct cost burdens were spa procedures (45.3 %, Beda I) and biological drugs (52.8 %, Beda II). Unique analysis of the burden of the AS in the Central-Eastern Europe presents health care resource and cost consumption by comparing two cross-sectional prevalence-based studies. Further analysis should be carried to obtain data connecting health status with costs consumption in order to analyse the AS from this perspective.

Objectives: The risk of activation of latent tuberculosis infection (LTBI) is increased in patients treated with anti-TNF-α drugs. Tuberculin skin test (TST) and Quantiferon-TB Gold test (QFT) are used to detect LTBI before and during anti-TNF-α treatment. We describe here a relation of these tests at various timepoints and also longitudinal QFT data., Methods: Study group consisted of 305 patients with several rheumatic inflammatory diseases treated and/or scheduled for anti-TNF-α drugs. The QFT was performed in 303 patients during therapy and in 177 patients also during screening. The TST was used in 284 patients. Both tests simultaneously were utilised in 360 instances., Results: Twenty-two patients were QFT positive; 3.9% before and 5.9% during anti-TNF-α treatment. Two patients who became QFT positive developed active tuberculosis. The TST was positive in 42% and 38% of patients before and during treatment, respectively. There was poor agreement between the two tests. Patients on glucocorticoids had a negative TST more frequently. The IFN-γ response to mycobacterial antigens significantly increased after application of tuberculin, but never reached the positive threshold. There was a significant increase in mitogen-induced IFN-γ production after initiation of anti-TNF-α therapy., Conclusions: Poor correlation between the QFT and TST renders the TST non-specific for LTBI. QFT is more specific to detect LTBI and conversion to a positive result may predict active TB. An increase in IFN-γ production in response to mycobacterial antigens is seen when the TST is performed before the QFT. Mitogen-induced IFN-γ production increases after initiation of anti-TNF-α therapy.

Dexamethasone (DEX) is known to induce diabetes and dyslipidemia. We have compared fasting triacylglycerol and cholesterol concentrations across 20 lipoprotein fractions and glucose tolerance in control (standard diet) and DEX-treated 7-month-old males of two rat strains, Brown Norway (BN) and congenic BN.SHR-(Il6-Cd36)/Cub (BN.SHR4). These two inbred strains differ in a defined segment of chromosome 4, originally transferred from the spontaneously hypertensive rat (SHR) including the mutant Cd36 gene, a known target of DEX. Compared to BN, the standard-diet-fed BN.SHR4 showed higher cholesterol and triacylglycerol concentrations across many lipoprotein fractions, particularly in small VLDL and LDL particles. Total cholesterol was decreased by DEX by more than 21% in BN.SHR4 contrasting with the tendency to increase in BN (strain*DEX interaction p = 0.0017). Similar pattern was observed for triacylglycerol concentrations in LDL. The LDL particle size was significantly reduced by DEX in both strains. Also, while control BN and BN.SHR4 displayed comparable glycaemic profiles during oral glucose tolerance test, we observed a markedly blunted DEX induction of glucose intolerance in BN.SHR4 compared to BN. In summary, we report a pharmacogenetic interaction between limited genomic segment with mutated Cd36 gene and dexamethasone-induced glucose intolerance and triacylglycerol and cholesterol redistribution into lipoprotein fractions.

Endogenous retroviruses (ERVs) contribute to a range of germline, as well as somatic mutations in mammals. However, autonomous retrotransposition of potentially active elements has not been demonstrated in the rat genome. We cloned an insertion that disrupted the normal splicing of the Cntrob gene that was subsequently identified as a nonautonomous, novel endogenous retrovirus of the RnERV-K8e family. The RnERV-K8e family is closely related to the recently reported MmERV-K10c elements, but differs from the autonomous mouse MusD or IAP families. In addition, we identified a novel, unexpectedly close relative of RnERV-K8e in the mouse, suggesting ERV-K cross-species transmission between mice and rats. We cloned a potentially autonomous RnERV-K8e element identified by in silico analysis and, using an in vitro retrotransposition assay, demonstrated that it is capable of retrotransposition. This particular element (named Rat-rho, pronounced "retro") encodes a retroviral envelope gene (env); however, env is not required for de novo retrotransposition events. Significant levels of RnERV-K8e-associated genetic polymorphisms were detected among inbred rat strains, suggesting ongoing retrotransposition in the rat genome. This study identifies an ERV-K-type family in rats that shows obvious signs of recent activity. Ongoing retrotranspositional activity may significantly add to genomic variability among inbred rat strains.

Aims: Therapeutic administration of retinoids is often accompanied with undesirable side effects, including an increase in lipid levels in up to 45% of treated patients. We tested the hypothesis of whether spontaneously hypertensive rat (SHR) and congenic SHR.PD-(D8Rat42-D8Arb23)/Cub (SHR-Lx) strains, differing only in a 14-gene region of chromosome 8 and previously shown to display differential sensitivity to the teratogenic effects of retinoic acid, could serve as a pharmacogenetic model set of the metabolic side effects of retinoid therapy., Materials & Methods: Male, 15-week old rats (n = 12/strain) of SHR and SHR-Lx strains were fed a high-sucrose diet for 2 weeks and subsequently treated either with all-trans retinoic acid (15 mg/kg) or only with a vehicle for 16 days (n = 6/strain/treatment), while still on the high-sucrose diet. We assessed the morphometric and metabolic profiles of all groups, including glucose tolerance tests, levels of insulin, adiponectin, free fatty acids, concentrations of triglycerides and cholesterol in 20 lipoprotein fractions under conditions of both high-sucrose diet and high-sucrose diet plus all-trans retinoic acid administration., Results & Conclusion: SHR-Lx displayed substantially greater sensitivity to a number of all-trans retinoic acid-induced metabolic dysregulations compared with SHR, resulting in impairment of glucose tolerance, increased visceral adiposity, and substantially greater increase of circulating triglyceride concentrations, accompanied by a shift towards their less favorable distribution into the lipoprotein fractions. These observations closely mimic the common side effects of retinoid therapy in humans, rendering SHR-Lx an experimental pharmacogenetic model of atRA-induced dyslipidemia.

Lx mutation in SHR.Lx rat manifests in homozygotes as hindlimb preaxial polydactyly. It was previously mapped to a chromosome 8 segment containing the Plzf gene. Plzf (promyelocytic leukemia zinc finger protein) influences limb development as a direct repressor of posterior HoxD genes. However, the Plzf coding sequence is intact in the Lx mutants. Using linkage mapping in F2 hybrids, we downsized the segment containing Lx to 155 kb and sequenced conserved noncoding elements (CNEs) inside. A 2,964-bp deletion in Plzf intron 2, never detected in control animals, is the only candidate for Lx. The deletion removes the most deeply conserved CNE in the 155-kb segment, suggesting a regulatory influence on Plzf expression. Correspondingly, using in situ hybridization and quantitative real-time polymerase chain reaction, we found a decrease of Plzf expression in Lx/Lx limb buds with concomitant anterior expansion of expression domains of its targets, Hoxd10-13 genes, in the absence of ectopic Sonic hedgehog expression. Upstream regulation of Plzf in limb buds is currently unknown. We present here the first candidate Plzf cis-regulatory sequence., ((c) 2009 Wiley-Liss, Inc.)

Introduction: Thiazolidinediones are increasingly used drugs for the treatment of Type 2 diabetes. The individual response to thiazolidinedione therapy, ranging from the variable degree of metabolic improvement to harmful side-effects, is empirical, yet the underlying mechanisms remain elusive. In order to assess the pharmacogenomic component of thiazolidinediones' metabolic action, we compared the effect of rosiglitazone in two genetically defined models of metabolic syndrome, polydactylous (PD) and BN.SHR4 inbred rat strains, with their insulin-sensitive, normolipidemic counterpart, the Brown Norway (BN) rat., Materials & Methods: 5-month-old male rats were fed a high-fat diet for 4 weeks, and the experimental groups received rosiglitazone (0.4 mg/100 g body weight) during the last 2 weeks of high-fat diet feeding. We assessed metabolic and morphometric profiles, oxidative stress parameters and gene expression in white adipose tissue., Results: In many followed parameters, we observed genetic background-specific effects of rosiglitazone administration. The mass and the sensitivity of visceral adipose tissue to insulin-stimulated lipogenesis increased with rosiglitazone treatment only in PD, correlating with a PD-specific significant increase in expression of prostaglandin D2 synthase. The glucose tolerance was enhanced in all strains, although fasting plasma glucose was increased by rosiglitazone in BN and BN.SHR4. Among the markers of lipid peroxidation, we observed the rosiglitazone-driven increase of plasma-conjugated dienes only in BN.SHR4. The genes with genotype-specific expression change included ADAM metallopeptidase domain 7, aquaporin 9, carnitine palmitoyltransferase 1B, caveolin 1, catechol-O-methyl transferase, leptin and prostaglandin D2 synthase 2., Conclusion: Rosiglitazone's effects on lipid deposition and insulin sensitivity of peripheral tissues are largely dependent on the genetic background it acts upon.

The three isotypes of peroxisome proliferator-activated receptors (PPARs) are currently perceived as major regulatory nodes (or hubs) of metabolic pathway networks, linking most prevalent diseases including Type 2 diabetes, obesity, dyslipidemia and atherosclerosis. The integrative functions of PPARs are also reflected in their ecogenetic profile, when the variants underlying pharmacogenetic interactions were also shown to modulate the effect of lifestyle factors. Despite their extensive clinical use, there are many outstanding issues, especially concerning their safety. Critical pharmacogenomic assessment is warranted for the new potent ligands of multiple PPAR isoforms as many have displayed serious side-effects in a limited number of treated subjects. Nevertheless, the advent of genomic, transcriptomic and system biology-level approaches, integrating knowledge from model systems and human biology, should greatly facilitate the transition to individualized PPAR-based therapies.

The importance of early environment, including maternal diet during pregnancy, is suspected to play a major role in pathogenesis of metabolic syndrome and related conditions. One of the proposed mechanisms is a mismatch between the prenatal and postnatal environments, leading to misprogramming of the metabolic and signaling pathways of the developing fetus. We assessed whether the exposure to high-sucrose diet (HSD) alleviates the detrimental effects of sucrose feeding in later life (predictive adaptive hypothesis) in a highly inbred model of metabolic syndrome, the PD/Cub rat. Rat dams were continuously fed either standard or HSD (70% calories as sucrose) starting 1 wk before breeding, throughout pregnancy, at birth, and until weaning of the offspring. After weaning, all male offspring were fed HSD until the age of 20 wk, when detailed metabolic and morphometric profiles were ascertained. The early life exposure to a sucrose-rich diet resulted in distinct responses to longtime postnatal HSD feeding. Offspring of the sucrose-fed mothers displayed higher adiposity and substantial increases in triglyceride liver content together with unfavorable distribution of cholesterol into lipoprotein subfractions. On the other hand, their adiponectin concentrations were significantly higher, and insulin sensitivity of skeletal muscle was enhanced compared with the offspring of standard diet-fed mothers. Triglycerides, free fatty acids, overall glucose tolerance, and the insulin sensitivity of adipose tissue were comparable in both groups. In the genetically identical animals, maternal HSD feeding elicited a variety of subtle effects but did not lead to predictive adaptive protection from most HSD-induced metabolic derangements.

Advanced glycation end-product (AGE) pentosidine has previously been demonstrated in different tissues and body fluids. It was suggested as a novel marker for evaluating the pathologic activity in rheumatoid arthritis (RA). In this study we analyzed the relation between pentosidine and markers of inflammation, cartilage turnover, immune response, and disease status of RA. Using HPLC, we analyzed pentosidine in serum and synovial fluid from 39 patients with RA and in serum from 38 healthy controls. Cartilage oligomeric matrix protein (COMP) and antibodies to CCP (anti-CCP) were measured by ELISA. Clinical disease status was assessed by Disease Activity Score 28 (DAS 28) and functional status by Health Assessment Questionnaire (HAQ). We demonstrated significantly higher serum levels of pentosidine in RA patients in comparison with controls. Pentosidine in serum significantly correlated with pentosidine in synovial fluid. Serum pentosidine levels were associated with erythrocyte sedimentation rate (p<0.03) but not with CRP, COMP, anti-CCP antibodies, DAS 28, or HAQ. In contrast to previous studies, we could not show any correlation of pentosidine levels with inflammatory status, clinical disease activity, markers of immune response, or cartilage breakdown. However, AGEs can be suggested as important players participating in joint destruction rather than markers of disease activity.

We have developed a new, double-congenic rat strain BN-Lx.SHR2, which carries two distinct segments of chromosome 2 introgressed from the spontaneously hypertensive rat strain (SHR) into the genetic background of congenic strain BN-Lx, which was previously shown to express variety of metabolic syndrome features. In 16-wk-old male rats of BN-Lx and BN-Lx.SHR2 strains, we compared their glucose tolerance and triacylglycerol and cholesterol concentrations in 20 lipoprotein subfractions and the lipoprotein particle sizes under conditions of feeding standard and high-sucrose diets. Introgression of two distinct SHR-derived chromosome 2 segments resulted in decreased adiposity together with aggravation of glucose intolerance in the double-congenic strain. The BN-Lx.SHR2 rats were more sensitive to sucrose-induced rise in triacylglycerolemia. Although the total cholesterol concentrations of the two strains were comparable after the standard diet and even lower in BN-Lx.SHR2 after sucrose feeding, detailed analysis revealed that under both dietary conditions, the double-congenic strain had significantly higher cholesterol concentrations in low-density lipoprotein fractions and lower high-density lipoprotein fractions. We established a new inbred model showing dyslipidemia and mild glucose intolerance without obesity, attributable to specific genomic regions. For the first time, the chromosome 2 segments of SHR origin are shown to influence other than blood pressure-related features of metabolic syndrome or to be involved in relevant nutrigenomic interactions.

We have previously established a congenic strain SHR-Lx that carries a differential segment of rat chromosome 8 introgressed from a model of metabolic syndrome--the polydactylous rat strain--on the genomic background of spontaneously hypertensive rat (SHR). We compared the glucose tolerance and lipid profile of adult SHR and SHR-Lx males under conditions of standard diet and diets enriched in sucrose and cholesterol, respectively. While there was no evident difference between the SHR and SHR-Lx on standard diet, the one-week sucrose administration revealed the congenic strain sensitivity to carbohydrate-induced dyslipidemia conferred by the differential segment with only mild derangement of glucose tolerance. On the other hand, the high-cholesterol diet administration for three-weeks resulted in a contrasting pattern as the congenic strain displayed significantly lower concentrations of free fatty acids and improved glucose tolerance compared to SHR. After one-month washout period, the SHR-Lx showed higher insulin, triglyceride and cholesterol concentrations together with diminished insulin sensitivity of visceral adipose tissue. In summary, we have identified a genomic region syntenic to human chromosome 11q23, which determines complex nutrigenetic interactions under conditions of sucrose- and cholesterol-enriched diets.

One of the crucial steps on the way to individualized medicine to treat cardiovascular disease (CVD) is to better understand the identities, roles, extent and at least the major patterns of interaction between influential genomic and environmental factors. It is clear that such a bold goal can hardly be achieved without a major upgrade of our conceptualization of the phenomena studied, taking advantage of recent developments of novel technological and computational tools. Firstly, the search for the genomic components of the most common multifactorial CVDs is no longer restricted to protein-coding genes; truly genome-wide investigations should replace them in both humans and animal models. Secondly, the 'environment' has also undergone semantic expansion, incorporating such remote constituents as developmental plasticity and epigenetics on one side, and socioeconomic status on the other. To elucidate and analyze the resulting complex picture, appropriate statistical models and approaches need to be designed to tackle issues such as population stratification and admixture, multiple testing, and multidimensionality reduction in models involving multiple genes and environmental factors. Eventually, an integrated platform bringing together all of the above will probably be necessary to secure relevant information specific to a particular combination of conditions and settings (age, geo-ethnicity and exposure), which may perhaps become visible only after a step back, through systems (network) biology.

The SHR and the PD/Cub are two established rodent models of human metabolic syndrome. Introgression of a ca 30 cM region of rat chromosome 8 from PD/Cub onto the genetic background of SHR was previously shown to influence several of the metabolic syndrome-related traits along with causing the PLS in the SHR-Lx congenic strain. In the process of identification of the causative alleles, we have produced several congenic sublines. The differential segment of SHR-Lx PD5 congenic substrain [SHR.PD(D8Rat42-D8Arb23)/Cub] spans approximately 1.4 Mb encompassing only 14 genes. When comparing the metabolic, morphometric and gene expression profiles of the SHR-Lx PD5 vs. SHR, the polydactyly and several distinct metabolic features observed in the original SHR-Lx congenic were still manifested, suggesting that the responsible genes were "trapped" within the relatively short differential segment of PD/Cub origin in SHR-Lx PD5. Particularly, the SHR-Lx PD5 displayed substantial reduction of insulin sensitivity confined to skeletal muscle. Among the candidate genes, the promyelocytic leukaemia zinc-finger Plzf (Zbtb16) transcription repressor is most likely responsible for the Lx mutation resulting in PLS and could also be involved in the alteration of metabolic pathways. The sequence analysis of the Plzf gene revealed a SNP leading to a threonine to serine substitution in SHR at aminoacid position 208 (T208S). In summary, we have isolated a 1.4 Mb genomic region syntenic to human chromosome 11q23, which, apart from causing polydactyly-luxate syndrome (PLS), affects total body weight, adiposity, lipid profile, insulin sensitivity of skeletal muscle and related gene expression as shown in the SHR-Lx PD5 congenic substrain.

Objective: Blood pressure (BP) and heart rate (HR) responses to stress are significant predictors of cardiovascular morbidity and mortality. Because obesity is a major risk factor for cardiovascular disease, we examined whether diet-induced obesity alters the BP and HR responses to stress and whether these alterations are associated with augmented cardiovascular morbidity in the rat., Research Methods and Procedures: Adult male spontaneously hypertensive rats were fed either a normal diet or high-fat diet (HFD) for 12 weeks. At weeks 0 and 12, body weight was measured, and BP and HR were recorded by radiotelemetry throughout three consecutive day and night periods and in response to 30-minute immobilization stress. At the end of the 12-week intervention, the rats were sacrificed, and their organs and sera were collected., Results: With the intervention, HFD rats showed a significantly greater increase in body weight (as expected) and circulating leptin and free fatty acid levels compared with normal diet rats. In addition, they showed similar increases in BP and HR elevations during stress but significantly slower BP and HR decreases after stress. These HFD-induced delays in stress recovery were associated with BP and HR elevations during the night (behaviorally active) period and with augmentations in cardiac mass., Discussion: The results of this study indicate that, in spontaneously hypertensive rats, dietary obesity delays cardiovascular recovery from stress, and, in parallel, it promotes the development of nocturnal hypertension as well as cardiac hypertrophy. This suggests that dietary obesity may significantly potentiate the impact of daily stressful experiences on the cardiovascular system.

The recent global increase in prevalence of diseases like obesity, type 2 diabetes and hypertension in westernized societies is unfortunately not paralleled by our full understanding of the causative mechanisms. It is now firmly established that the interacting genetic and environmental (diet, smoking) components together determine the development and severity of the particular condition, which makes detailed dissection of such complex traits even more complicated. In effect, there is an unmet urgent need for molecular targets so we can directly modulate the causative factors and devise effective preventive and therapeutic algorithms. Among the most promising molecular targets for treatment of metabolic syndrome-related conditions identified so far, the group of three lipid-sensors, the peroxisome proliferator-activated receptors (PPARs) clearly stands out. The review focuses on pharmacogenetic aspects of recent developments in PPAR biology.

The importance of nutrition for human health and its influence on the onset and course of many diseases are nowadays considered as proven. Only the recent development of molecular biology and biochemical methods allows the elucidation of the molecular mechanisms of diet constituent actions and their subsequent effect on homeostatic mechanisms in health and disease states. The availability of the draft human genome sequence as well as the genome sequences of model organisms, combined with the functional and integrative genomics approaches of systems biology, bring about the possibility to identify alleles and haplotypes responsible for specific reaction to the dietary challenge in susceptible individuals. Such complex interactions are studied within the newly conceived field, the nutrition genomics (nutrigenomics). Using the tools of highly parallel analyses of transcriptome, proteome and metabolome, the nutrition genomics pursues its ultimate goal, i.e. the individualized diet, respecting not only quantitative and qualitative nutritional needs and the actual health status, but also the genetic predispositions of an individual. This approach should lead to prevention of the onset of such diseases as obesity, hypertension or type 2 diabetes, or enhance the efficiency of their therapy.

Purpose of the Study: Patients with rheumatoid arthritis (RA) often suffer from instability of the upper cervical spine. The most common instability is anterior atlanto-axial subluxation (AAS). Instability may lead to neurologic deficits from spinal cord compression and intractable pain, decreasing quality of life and its length., Material and Methods: This prospective study analyzed different fixation methods and the influence of atlanto-axial and occipito-cervical fusion on clinical and radiological outcome. 41 patients with RA with instability of the upper cervical spine were treated surgically for progressive instability, pain and neurological deficit. Average age of our patients was 52.4 years (21-76 years). At the time of surgery, duration of the disease was in average 18.6 years (2-47 years). Patients had advanced stage of the disease according to Steinbroker, on hands stage 3.7 and feet stage 2.9. Atlanto-axial fixation was done for AAS in 27 (24 Magerl transarticular fixations and Brooks-Jenkins technique in 3 patients). Occipito-cervical fusion was done in 13 patients (3 with Ransford loop and sublaminar wires and 9 with CerviFix). One patient was managed in halo-cast fixation. Spinal fusion was performed in all patients using autologenous bone graft. Patients were evaluated by using Functional Rating Index (FRI), Health Assessment Questionnaire (HAQ) and visual pain analogue scale (VAS) before and after surgery in set intervals, when radiological examination was also performed including dynamic films., Results: Three patients died in the postoperative period (3 weeks, 11 and 18 months). 38 patients remained for follow up, which was in average 28.4 months. Fusion was considered when hardware was intact and patient was satisfied, no motion was detected on dynamic X rays or bony fusion was clearly visible. Fusion was assessed in 40 patients, 32 fused, 8 had fibrous non-union. 3 of these patients had hardware failure. 9 patients had preoperatively verified panus formation peridentally, which resorbed after the surgery. FRI evaluation was done in 40 patients, 30 improved (14 patients by more than 10 points), 6 patients did not change and 4 worsened. The improvement after 3 and 12 months was statistically significant (p < 0.001). Average HAQ score decreased after surgery, but the change was not statistically significant (p > 0.05). Average VAS score decreased significantly after surgery (p < 0.05). There were 5 hardware related complications including one vertebral artery injury. None of these complications required subsequent surgery nor had any influence on good clinical outcome., Discussion: Results of FRI and VAS show the benefit from early indication of surgical stabilization of upper cervical spine in patients with RA. Based on our experience, as well as other authors, fixation of AAS by transarticular screw fixation according to Magerl is the preferred method in the younger patient group. Once destruction of the atlanto-axial joints, lateral subluxation or cranial migration of the dens is present, occipito-cervical fusion using titanium malleable implant (CerviFix) is necessary., Conclusion: Positive clinical outcomes advocate early surgical intervention as described in recent literature. Surgery prevents subsequent neurological damage life quality deterioration and shortening of life expectancy.

Background: Epidemiologic studies suggest that in utero exposure to maternal smoking is associated with elevated blood pressure (BP) later in life. Our aims were: (1) to examine effects of intrauterine exposure to nicotine on BP and hypertension target-organ size in rats; and (2) to investigate whether such effects depend on genetic background, by studying two genetically distinct strains of rats: the spontaneously hypertensive rat (SHR) and the normotensive Brown Norway (BN) rat., Methods: Nicotine or saline was administered to dams via subcutaneous osmotic minipumps throughout gestation. In nine-week-old male offspring, we measured BP and heart rate, assessed the weight of kidneys and heart, and determined fasting levels of glucose, insulin, triglycerides (TG), and cholesterol. We also measured gene expression of the insulin-like growth factor (IGF) system in the liver and kidneys., Results: SHR and BN offspring differed in their response to intrauterine exposure to nicotine. SHR exposed to nicotine (vs. saline) exhibited higher BP (P < 0.02) and serum cholesterol levels (P = 0.01), and lower kidney weight (P < 0.0001). In contrast, BN rats did not demonstrate differences between the nicotine and saline groups in these variables, but the nicotine-exposed BN rats showed a significant up-regulation in the gene expression of IGF-1 in the liver (P < 0.0001) and IGF receptor in the kidney (P = 0.006)., Conclusion: These results suggest that intrauterine exposure to nicotine alters the cardiovascular system depending on the genetic background and, as such, supports the notion that the intrauterine environment interacts with genes in determining an individual's health later in life.

The availability of the human genome sequence and the recently completed draft sequences of two major mammalian model species, the mouse (Mus musculus) and the rat (Rattus norvegicus), allow researchers to apply novel approaches for gene identification and characterization, using methods of comparative and functional genomics. Recently, a new gene coding for apolipoprotein A-V was identified in the vicinity of APOA-I/C-III/A-IV cluster on human chromosome 11q23 by comparative sequencing method. In a relatively short time, compelling evidence accumulated for the substantial role of APOA-V in lipid metabolism. Studies in knock-out and transgenic mice revealed that its expression pattern correlates negatively with triglyceride levels. This observation was verified in human population studies in variety of ethnic and age groups. Several single nucleotide polymorphisms were described and particular SNP alleles and haplotypes in the APO A-V gene region were shown to be associated with dyslipidemia. The discovery and characterization of the APO A-V demonstrates current possibilities of the integrative approaches in biology, boosted by the available bioinformatic tools.

The PD/Cub is a recently established model of the IRS. The BN.SHR4 congenic strain was derived by introgression of the chromosome 4 segment of SHR origin (including the defective Cd36/Fat allele) onto the BN/Cub genetic background. We investigated the linkage of metabolic and morphometric phenotypes (total body weight, OGTT, fasting serum levels of TG, FFA) on chromosome 4 in two separate F2 rat populations: the PD/Cub x BN/Cub and PD/Cub x BN.SHR4 (total N = 243). In the PD/Cub x BN.SHR4 F2s, we found significant linkage for fasting TG levels (LOD = 3.26) and suggestive linkage for fasting glycaemia (LOD = 2.80) in the interval Il-6 - D4Bro1, i.e. the part of chromosome 4 of SHR origin in the BN.SHR4 congenic. However, no linkage for fasting TG concentrations, fasting glycaemia or any other followed parameter was found in the second, PD/Cub x BN/Cub F2. The differential linkage of TG and glucose levels to the centromeric part of rat chromosome 4q in the studied F2s points to the importance of this region for the lipid and carbohydrate metabolism at the specific age (10 months) and diet (standard chow) combination. The Cd36/Fat and Il-6 genes are the preliminary positional candidates for the observed effect.

Studies on genetic determination of the insulin resistance syndrome in rat models revealed several susceptibility loci for features of this complex phenotype, i.e. dyslipidemia, insulin resistance and obesity. We analysed the influence of introgression of the RNO4, RNO20 segments of SHR origin and RNO8 segment of PD/Cub origin (all previously shown to be involved in (dys)regulation of carbohydrate and lipid metabolism) onto the genetic background of a common progenitor, the Brown Norway (BN/Cub) rat. The differential segments were genetically characterized in the BN.PD-D8Rat39/D8Rat35 (BN-Lx, RNO8 congenic), BN.SHR-Il6/Cd36 (BN.SHR4, RNO4 congenic) and BN.PD-D8Rat39/D8Rat3, SHR-D4Mgh2/Cd36,SHR-D20Wox3/D20Mgh5 (BN-Lx 1K, RNO4, 8, 20 triple congenic) strains and their metabolic profiling was performed. After one week of high-sucrose diet, all congenic strains showed substantially higher levels of serum triglycerides and free fatty acids as well as impaired glucose tolerance in comparison with the BN/Cub progenitor strain. The BN-Lx 1K triple congenic strain displayed the most profound dyslipidemia, glucose intolerance and highest increase of triglyceridemia in response to high-sucrose diet overall, though accompanied with the significantly lowest adiposity index. These results further support the role of genes present within the studied chromosomal regions in observed metabolic disturbances. Furthermore, these findings point to the studied loci within the gene-gene and gene-environment interactions involved in pathogenesis of the insulin resistance syndrome. The set of defined congenic strains provides a possibility of assessing individual features of such a complex phenotype.

Genome scan and metabolic profile of the PD/Cub rat inbred strain in comparison with SHR and BN strains is presented. The PD/Cub strain has been bred by brother sister mating for more than 60 generations since 1969. Its highly inbred status has been confirmed by PCR genotyping with more than 170 microsatellite markers. No case of residual heterozygosity has been recorded. Accordingly, the values obtained by the analysis of metabolic phenotypes are homogeneous with low variance. The PD/Cub strain has significantly higher triglyceride levels and epididymal fat weight as compared to both SHR and BN strains. The PD strain also displays the lowest incorporation of 14C-U glucose into the epididymal adipose tissue. The data on glucose metabolism clearly indicate that the PD/Cub strain is insulin resistant. Genetic homogeneity and reproducibility of experimental results qualify the PD/Cub rats as an animal model for analysis of the syndrome X.