Biomedical subjects

L Sedová

Publications and source records attributed to L Sedová.

10 recordsLinked to original sources

PubMed2006

Region of rat chromosome 8 determines complex nutrigenetic interactions under conditions of sucrose and cholesterol diets.

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.

Animal Nutritional Physiological Phenomena↗

PubMed2005

A 14-gene region of rat chromosome 8 in SHR-derived polydactylous congenic substrain affects muscle-specific insulin resistance, dyslipidaemia and visceral adiposity.

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.

Adipose Tissue↗

PubMed2004

[Possibilities of surgical treatment of upper cervical spine in patients with rheumatoid arthritis].

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.

Adult↗

PubMed2004

[Nutrition genomics].

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.

Animals↗

PubMed2004

PPARs: molecular targets in the pharmacogenomics era.

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.

Animals↗

PubMed2003

Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis.

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.

Antibodies, Antinuclear↗

PubMed2003

Differential linkage of triglyceride and glucose levels on rat chromosome 4 in two segregating rat populations.

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.

Animals↗

PubMed2003

New apolipoprotein A-V: comparative genomics meets metabolism.

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.

Amino Acid Sequence↗

PubMed2002

Metabolic characterization of insulin resistance syndrome feature loci in three brown Norway-derived congenic strains.

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.

Animals↗

PubMed2000

Rat inbred PD/cub strain as a model of dyslipidemia and insulin resistance.

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.

Adipose Tissue↗