The effect of colesevelam treatment on bile acid and lipid metabolism and glycemic control in healthy men.

The treatment of hypercholesterolemia with bile acid (BA) sequestrants results in upregulation of BA synthesis through the classical pathway initiated by cholesterol 7alpha-hydroxylase (CYP7A1). To characterize the detailed dynamics of serum lipid and BA concentrations and the BA synthesis rate in response to treatment with BA sequestrants and to determine whether the -203A/C promoter polymorphism of the CYP7A1 encoding gene (CYP7A1) affects such a response, this pilot study was carried out in healthy men (8 homozygous for the -203A allele and 8 homozygous for the -203C allele of CYP7A1). The subjects were treated for 28 days with colesevelam and blood was drawn for analysis before and on days 1, 3, 7, 14 and 28 of treatment. The response of lipids, BA, fibroblast growth factor-19 (FGF19) and 7alpha-hydroxy-4-cholesten-3-one (C4) to colesevelam did not differ between carriers of -203A and -203C alleles; their data were then aggregated for further analysis. Colesevelam treatment caused immediate suppression of FGF19 concentration and a fivefold increase in CYP7A1 activity, as assessed from C4 concentration, followed by a 17 % decrease in LDL-cholesterol. Although total plasma BA concentrations were not affected, the ratio of cholic acid/total BA rose from 0.25+/-0.10 to 0.44+/-0.16 during treatment at the expense of decreases in chenodeoxycholic and deoxycholic acid.

The effect of heme oxygenase on ganglioside redistribution within hepatocytes in experimental estrogen-induced cholestasis.

Cholestasis is characterized by the elevation of serum total bile acids (TBA), which leads to the production of both free radicals and oxidative stress. Although they do not share the same mechanisms, membrane glycosphingolipids (GSL) and the antioxidant enzyme heme oxygenase-1 (HMOX1) both act against the pro-oxidative effect of TBA. The aim of the study was to assess the role of HMOX on GSL redistribution and composition within hepatocytes in the rat model of estrogen-induced cholestasis. Compared to the controls, an increase of total gangliosides in the liver homogenates of the cholestatic group (P=0.001) was detected; further, it paralleled along with the activation of their biosynthetic b-branch pathway (P<0.01). These effects were partially prevented by HMOX activation. Cholestasis was accompanied by a redistribution of GM1 ganglioside from the cytoplasm to the sinusoids; while HMOX activation led to the retention of GM1 in the cytoplasm (P=0.014). Our study shows that estrogen-induced cholestasis is followed by changes in the synthesis and/or distribution of GSL. These changes are not only triggered by the detergent power of accumulated TBA, but also by their pro-oxidant action. Increases in the antioxidant defenses might represent an important supportive therapeutic measure for patients with cholestatic liver disease.

Regulation of diurnal variation of cholesterol 7alpha-hydroxylase (CYP7A1) activity in healthy subjects.

Cholesterol 7alpha-hydroxylase (CYP7A1), the key regulatory enzyme of bile acid synthesis, displays a pronounced diurnal variation. To better understand the regulation of CYP7A1 activity, three day-long examinations were carried out in 12 healthy men. The concentrations of 7alpha-hydroxycholest-4-en-3-one (C4), a surrogate marker of CYP7A1 activity, bile acids (BA), insulin, glucose, nonesterified fatty acids, triglycerides, and cholesterol were measured in serum in 90-min intervals from 7 AM till 10 PM. To lower and to increase BA concentration during the study, the subjects received cholestyramine and chenodeoxycholic acid (CDCA), respectively, in two examinations. No drug was used in the control examination. There was a pronounced diurnal variation of C4 concentration with a peak around 1 PM in most of the subjects. The area under the curve (AUC) of C4 concentration was five times higher and three times lower when subjects were treated with cholestyramine and CDCA, respectively. No relationship was found between AUC of C4 and AUC of BA concentration, but AUC of C4 correlated positively with that of insulin. Moreover, short-term treatment with cholestyramine resulted in about 10 % suppression of glycemia throughout the day. Our results suggest that insulin is involved in the regulation of diurnal variation of CYP7A1 activity in humans.

Infliximab dependency in children with Crohn's disease.

BACKGROUND: Recently, infliximab dependency has been described. AIM: To assess frequency of ID in 82 consecutive Crohn's disease children treated with infliximab 2000-2006 and to describe clinical and genetic predictors of long-term infliximab response. METHODS: A phenotype model of infliximab dependency was used to assess treatment response: 'immediate outcome' (30 days after infliximab start)--complete/partial/no response. 'Long-term outcome': (i) prolonged response: maintenance of complete/partial response; (ii) infliximab dependency: relapse < or = 90 days after intended infliximab cessation requiring repeated infusions to regain complete/partial response or need of infliximab >12 months to sustain response. Polymorphisms TNF-308 A>G, TNF-857 C>T, Casp9 93 C>T, FasL-844 C>T, LTA 252 C>T and CARD15 (R702W, G908R, 1007fs) were analysed. RESULTS: Ninety-four per cent of children obtained complete/partial response. In long-term outcome, 22% maintained prolonged response, 12% had no response, while 66% became infliximab dependent. Perianal disease and no previous surgery were associated with infliximab dependency (OR 5.34, 95% CI: 1.24-22.55; OR 6.7, 95% CI: 1.67-26.61). No association was found with studied polymorphisms. The cumulative probability of surgery 50 months after starting infliximab was 10% in infliximab dependency, 30% in prolonged responders and 70% in nonresponders (P = 0.0002). CONCLUSIONS: Sixty-six per cent of children became infliximab dependent. Perianal disease and no surgery prior to infliximab were associated with infliximab dependency phenotype.

Influence of VEGF polymorphism on progression of autosomal dominant polycystic kidney disease.

BACKGROUND: Significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). Dysregulation of vascular endothelial growth factor (VEGF) expression in the kidney has been demonstrated in a wide range of renal diseases. The aim of the present study was to assess the influence of the -2578 C/A and the -1154 G/A polymorphisms in the regulatory region of the VEGF gene upon the progression of ADPKD toward end-stage renal disease (ESRD). METHODS: The study was performed on 283 ADPKD patients (145 males, 138 females, mean age 51.7 +/- 10.3 years) who had reached ESRD. Patients were divided into three groups: (1) ESRD development later than in 63 years (slow progressors, n = 47), (2) ESRD development before 45 years (rapid progressors, n = 69), and (3) ESRD development between 45 and 63 years (intermediate progressors, n = 167). Genetically unrelated healthy Czech individuals were analyzed as a control group (n = 311, 153 males, 158 females, mean age 44.6 +/- 9.2 years). DNA samples were genotyped for the -2578 C/A and for the -1154 G/A polymorphisms of the VEGF gene promoter. The serum levels of VEGF were established in 111 healthy Czech individuals from the control group. RESULTS: The VEGF -2578 C/A and -1154 G/A genotype distribution showed no differences among the groups of slow, rapid and intermediate progressors. The age of ESRD with regard to different genotypes was not significantly different in all ADPKD patients. However, the AA genotype of the -2578 C/A polymorphism was associated with a significantly higher age of ESRD than other genotypes in rapid progressors (42.7 vs. 40.5 years, p = 0.01). The CG haplotype was found significantly more frequent in ADPKD rapid progressors than in slow progressors (p = 0.047). Serum levels of VEGF did not significantly differ in the control group, according to different genotypes of both polymorphisms. CONCLUSION: To conclude, AA genotype of the -2578 C/A polymorphism was related to better prognosis of the disease in a limited group of ADPKD patients. Classical genetic recessive and dominant model did not find significant influence of separate VEGF polymorphisms on the progression of ADPKD. Accordingly, CG haplotype was associated with earlier onset of ESRD in ADPKD patients.

Variants of CARD15, TNFA and PTPN22 and susceptibility to Crohn's disease in the Czech population: high frequency of the CARD15 1007fs.

Crohn's disease (CD) has been shown to be associated with the variants in the CARD15 gene as well as in other genes involved in the immune response. The frequencies of the variants profoundly differ among populations and so does the associated risk. We examined the associations of variants in the CARD15, TNFA and PTPN22 genes with pediatric-onset and adult-onset CD in the Czech population. Genotype, phenotype and allelic frequencies were compared between 345 patients with CD (136 pediatric-onset and 209 adult-onset patients) and 501 unrelated healthy controls. At least one minor allele of the CARD15 gene was carried by 46% patients and only 21% control subjects (OR = 3.2, 95% CI 2.4-4.4). In a multiple logistic regression model, the strongest association with CD was found for the 1007fs variant (OR = 4.6, 95% CI 3.0-7.0), followed by p.G908R (OR = 2.9, 95% CI 1.5-5.7) and p.R702W (OR = 1.7, 95% CI 1.0-2.9), while no independent association was found for the remaining variants in the CARD15 gene (p.268S, p.955I and p.289S), for the p.R620W variant in the PTPN22 gene or for the g.-308G>A variant in the TNFA gene. The age at CD onset was strongly modified by positivity for the 1007fs allele: it was present in 42% pediatric-onset and only 25% adult-onset patients. In conclusion, we report a high frequency of the minor allele of the CARD15 1007fs polymorphism in the Czech population and a strong effect of this allele on the age at disease onset.

[Relation between alcohol intake and some metabolic and cardiovascular risk factors in healthy men]. / Vztah mezi dietním príjmem alkoholu a nekterymi metabolickými a kardiovaskulárními rizikovými faktory u zdravých muzu.

BACKGROUND: Czech Republic belongs to countries with worldwide highest alcohol per capita intake. Although mild intake of alcohol may exhibit protective effects, its abuse is associated with true deleterious consequences for the whole organism. The aim of our study was to assess relation between alcohol intake and several metabolic and cardiovascular risk factors. METHODS AND RESULTS: In the group of clinically healthy men (n=102, mean age 39.1 +/- 10.8 years) complete clinical examination, biochemical work-up and weekly dietary profile assessment were performed. Data were compared using standard statistical tests and linear regression analyses. Participants were divided into 4 groups according to the regular weekly alcohol intake (group 0: <70 g; group 1: 70-210 g: group 2: 211-420 g; group 3: >420 g alcohol/week). We found close relation between alcohol intake and several risk factors for cardiovascular diseases and metabolic syndrome such as WHR, BMI, total caloric intake, blood pressure, serum lipids, or iron metabolites and markers of oxidative stress (AGEs, AOPP). CONCLUSIONS: This study proves an important relationship between alcohol intake and risk factors for cardiovascular diseases or metabolic syndrome. Subjects abusing alcohol thus seem not to be only at higher risk for alcohol-mediated liver damage, but also for the cardiovascular and common metabolic diseases.

[Nuclear factor kappa B in the treatment of inflammatory and tumor diseases]. / Nukleární faktor kappa B v lécbe zánetlivých a nádorových onemocnení.

Since its discovery in 1986 nuclear factor kappa B attracted attention of scientists all over the world. Intensive research has proved its indisputable role in pathogenesis of particularly inflammatory and tumor diseases and revealed many possibilities in the modulation of its function. For some of the modulators distinct therapeutic effects have been proved in in vitro and in vivo studies or even in the clinical trials, some of them are still to be tested. One may expect wide use of different inhibitors or modulators of nuclear factor kappa B in various indications, which will markedly enhance the therapeutic effect.

[Gilbert's syndrome--myths and reality]. / Gilbertuv syndrom--mýty a realita.

Gilbert's syndrome is defined as a hereditary, mild, chronic, unconjugated hyperbilirubinemia occurring in the absence of overt hemolysis or any other evidence of liver disease. It is caused by a mutation of the specific UDP glucuronosyl transferase conjugating bilirubin with glucuronic acid resulting in a reduced activity of this enzyme. Gilbert's syndrome is considered as a rather benign disorder without necessity of any therapeutic intervention. It is therefore crucial to establish a correct diagnosis and differentiate this syndrome from serious disorders of the liver tissue. In recent years strong antioxidant effects of bilirubin were demonstrated in numerous studies and the protective role of hyperbilirubinemia in the pathogenesis of various oxidative stress-mediated diseases was suggested. Gilbert's syndrome and its relationship to associated disorders such as hemolysis, pigment cholelithiasis, neonatal jaundice, schizophrenia and drug interactions are also being discussed.