Pathophysiology of NAFLD and NASH in Experimental Models: The Role of Food Intake Regulating Peptides.

Obesity, diabetes, insulin resistance, sedentary lifestyle, and Western diet are the key factors underlying non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases in developed countries. In many cases, NAFLD further progresses to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and to hepatocellular carcinoma. The hepatic lipotoxicity and non-liver factors, such as adipose tissue inflammation and gastrointestinal imbalances were linked to evolution of NAFLD. Nowadays, the degree of adipose tissue inflammation was shown to directly correlate with the severity of NAFLD. Consumption of higher caloric intake is increasingly emerging as a fuel of metabolic inflammation not only in obesity-related disorders but also NAFLD. However, multiple causes of NAFLD are the reason why the mechanisms of NAFLD progression to NASH are still not well understood. In this review, we explore the role of food intake regulating peptides in NAFLD and NASH mouse models. Leptin, an anorexigenic peptide, is involved in hepatic metabolism, and has an effect on NAFLD experimental models. Glucagon-like peptide-1 (GLP-1), another anorexigenic peptide, and GLP-1 receptor agonists (GLP-1R), represent potential therapeutic agents to prevent NAFLD progression to NASH. On the other hand, the deletion of ghrelin, an orexigenic peptide, prevents age-associated hepatic steatosis in mice. Because of the increasing incidence of NAFLD and NASH worldwide, the selection of appropriate animal models is important to clarify aspects of pathogenesis and progression in this field.

[The lifestyle of Pilsner University female students and its effect on vaginal mycosis]. / Zivotní styl plzenských vysokoskolacek a jeho vliv na mykotická onemocnení.

BACKGROUND: Up to now, it does not exit whole look at the life quality of the Pilsner female University students, especially in connection with gynecological history. It is reality that in last years the number of gynecological problems among young women increases such as the number of diseases with immunological background. METHOD: We prepared questionnaire with 36 questions directed to life style, gynecological history, partner's life, food and hygienic habits, and nicotinism. RESULTS: 28 female students from the total group of 141 suffered from vaginal mycosis--22 (78.6%) use pills, 6 (21.4%) no hormonal contraception. 17 (60.7%) prefer flyaway cloth and 9 (32.1%) tight cloth. 141 students mentioned various number (0-25) of their sexual partners: 1-3 (79 students) in 15 cases (19%) mycoses, more than 4 partners (49 students) in 13 (26.5%) mycoses appeared. The first menstruation appeared in o 13 years (10-17 years). High incidence of vaginal mycosis was proven in students using only tampons than hygienic towels. CONCLUSION: Vaginal mycosis is affected by many endogenous and exogenous factors. The main factors in pilsner university female students are hormonal contraception, promiscuity and hygienic habits.

Biogenesis of eukaryotic cytochrome c oxidase.

Eukaryotic cytochrome c oxidase (CcO), the terminal component of the mitochondrial electron transport chain is a heterooligomeric complex that belongs to the superfamily of heme-copper containing terminal oxidases. The enzyme, composed of both mitochondrially and nuclear encoded subunits, is embedded in the inner mitochondrial membrane, where it catalyzes the transfer of electrons form reduced cytochrome c to dioxygen, coupling this reaction with vectorial proton pumping across the inner membrane. Due to the complexity of the enzyme, the biogenesis of CcO involves a multiplicity of steps, carried out by a number of highly specific gene products. These include mainly proteins that mediate the delivery and insertion of copper ions, synthesis and incorporation of heme moieties and membrane-insertion and topogenesis of constituent protein subunits. Isolated CcO deficiency represents one of the most frequently recognized causes of respiratory chain defects in humans, associated with severe, often fatal clinical phenotype. Here we review recent advancements in the understanding of this intricate process, with a focus on mammalian enzyme.

Determination of the Middle Cerebral Artery Occlusion Length in Acute Stroke: Contribution of 4D CT Angiography and Importance for Thrombolytic Efficacy Prediction.

PURPOSE: To assess the benefit of 4D-CT angiography (4D-CTA) in determination and precise measurement of middle cerebral artery (MCA) occlusion in comparison to CTA. Possible relationship of measured occlusion lengths with recanalization after intravenous thrombolysis was analysed as a second objective. METHODS: Detailed evaluation of complete MCA occlusions in 80 patients before intravenous thrombolysis using temporal maximum intensity projection (tMIP) dataset, calculated from 4D-CTA and conventional single-phase CTA was performed. Further, manual measurement technique was compared to results of semiautomatic procedure (vessel analysis) as reference. Statistical analysis of correlation between MCA occlusion length and IVT efficacy (24 h recanalization rate according modified Thrombolysis In Myocardial Infarction criteria-mTIMI) was performed. RESULTS: The distal end of occlusion was identified in all patients using tMIP, but only in 48 patients (60%) using CTA. The manual measurement method was not statistically different and well correlated with reference tMIP-vessel analysis. (15.4 vs. 16.3 mm; p = 0.434; r = 97). In measurable occlusions by CTA, no significant difference was proved in manually measured lengths using tMIP and CTA (14.5 vs. 13.3 mm; p = 0.089). Favorable recanalization (mTIMI 2-3) was achieved in 37 patients (47%). Length of occlusion in M1 segment (p = 0.002) and M2 segment involvement (p = 0.017) were proved as independent negative predictors of recanalization. Using receiver operating characteristics analysis, the cutoff length of the M1 segment occlusion for favorable recanalization was found to be 12 mm. CONCLUSION: The feasibility of MCA occlusion assessment using tMIP datasets and benefit over conventional CTA were confirmed. The manual measurement method was proved as feasible and simple with good correlation to reference semiautomatic analysis. The significant correlation of the MCA occlusion length and early recanalization was found. The length of 12 mm was recognized as cut-off length for favorable recanalization.

Biomonitoring of lead exposure in the Czech Republic.

The systematic and long-term efforts to protect the environment may be successful also in the country in the period of transition from centrally planned to free market economies. The basic requirement is to disseminate reliable information on the exposure levels and expected health effects. The need for high quality information underscores the importance of the quality assurance and quality control systems in the context of good laboratory as well as epidemiologic practices. Each monitoring study should be planned in the way facilitating its use for the evaluation of long-term trends. Besides scientific issues, the communication of risks is of crucial importance. According to our experience, only an involvement of formal as well as informal local authorities and co-operation between all relevant stakeholders can ensure the success.

Clinical Heterogeneity, Tissue Distribution, and Intergenerational Segregation of mtDNA Mutation A3243G.

Tissue distribution and segregation and the functional consequences of heteroplasmic mitochondrial DNA mutation A3243G were studied in 30 carriers. The mutation load in hair follicles was higher in 20 patients with a broad spectrum of clinical symptoms than in 10 nonaffected carriers. The onset of the disease negatively correlated with the mutation load in blood and muscle. The activities of respiratory chain complexes in isolated muscle mitochondria did not decrease in all patients and were normal in isolated platelets. Changes in the heteroplasmy level between pairs of mothers and offspring suggest that random genetic drift is the mechanism associated with the intergenerational transmission of the A3243G mutation. In conclusion, detailed clinical investigations and mitochondrial DNA analyses in several tissues are of the highest diagnostic value for the prognosis of the disease in carriers of the A3243G mutation.

[Disorders of mitochondrial energy metabolism in patients with the Kearns-Sayre syndrome]. / Poruchy mitochondriálního energetického metabolizmu u pacientu s Kearns-Sayreovým syndromem.

BACKGROUND: Kearns-Sayre syndrome is a multisystem disorder caused by rearrangements of mitochondrial genome including various deletions and/or duplications. The aim of the study is to analyse the impact of mitochondrial DNA (mtDNA) deletions on the mitochondrial energetic metabolism in five patients with Kearns-Sayre syndrome. METHODS AND RESULTS: The course of the disease is progressive in all patients. All of them have bilateral ptosis and external opthalmoplegia, four have retinitis pigmentosa, three have progressive muscle weakness and three have pacemaker because of complete A-V heart block. One patient underwent renal transplantation at the age of 12 because of a chronic renal failure. Southern blot analysis in muscle tissue revealed large scale heteroplasmic mtDNA deletions (3-7.4 kb) in all patients, the number of mutated copies of mtDNA ranged from 50 to 70%. Spectrophotometric measurements of respiratory chain complexes activities in muscle tissue revealed various combinations of defects of complex III, IV and I + III activities in all patients. Nevertheless, the lactic acidosis was permanently present only in one patient. Ragged-red fibers were found in two patients. CONCLUSIONS: Although the diagnostic of Kearns-Sayre syndrome is based on clinical features, molecular analysis of mtDNA is necessary to confirm the diagnosis. The prognosis of the disease is unfavourable and co-operation between the patient and various specialists is necessary for the treatment, which is currently only symptomatic.

Prevalence of STDs among prostitutes in Czech border areas with Germany in 1997-2001 assessed in project "Jana".

BACKGROUND: The STD problem emerged in the Czech Republic as a result of geopolitical and social and economic changes in the state. Prostitution is concentrated mainly around border areas with Austria and Germany, contributing to the increase in STDs. The Czech-German project "Jana," based on a project umbrella network of the WHO, was organised. OBJECTIVES: To prevent STDs, including HIV/AIDS, and assessment of STD prevalence in the target group. METHODS: Prostitutes working in night clubs and in the streets and roads of three districts in the West Bohemian Region of the Czech Republic bordering on Germany were studied. Interactions included street work, venereology check up, psychology and sociology counselling, psychological preparation on possible treatment, and continuous and regular contact. RESULTS: The number of "love clubs" involved in project "Jana" increased from 46 in 1997 to 72 in 2000. Of 561 street girls registered in the project during 1997-2001, there was one HIV positive, every 11th prostitute had syphilis, and one in 93 women had gonorrhoea, whereas incidence of syphilis in the Czech Republic was 10.2/100000 and that of gonorrhoea 9.5/100000 inhabitants in 2001, 31 women had Chlamydia trachomatis urinary tract and genital infection, and 25 were HBsAg positives. STD frequency revealed in project participants significantly exceeds numbers of STDs in the other inhabitants of the Czech Republic. The majority of prostitutes were foreigners, mostly Ukrainians and Russians. CONCLUSION: The situation in the border areas is alarming. The priority must be to concentrate efforts on prevention of spread of venereal diseases in borders of economically disparate states.

Novel mutations in a boy with dihydrolipoamide dehydrogenase deficiency.

BACKGROUND: Dihydrolipoamide dehydrogenase (DLD) deficiency is a rare cause of primary lactic acidosis in infancy. MATERIAL AND METHODS: This article presents the results of biochemical and molecular analyses and metabolic response to treatment procedures in a 10-week old boy presenting with vomiting, progressive hypotonia, lactic acidosis (pH 7.04; BE - 20; B-lactate 6.6 mmol/l, controls <2.1; CSF-lactate 4.8 mmol/l, controls <2.0), increased levels of branched chain amino acids in blood, and increased urinary excretion of branched chain oxo-acids due to DLD deficiency. RESULTS: DLD activity was less than 5% of control values in lymphocytes, muscle mitochondria and fibroblasts. Western blot analysis in muscle tissue showed a decrease in the quantity of DLD protein to 40% in comparison to control. A high-fat, low-protein diet supplemented with MCT oils and sodium dichloroacetate resulted in normalization of lactate, amino acids and organic acids in body fluids, but there was no improvement in psychomotor development. Novel heterozygous mutations were found in the DLD gene: A1081G and G1123A. Both mutations affect the same region of the binding site for FAD. The G1123A mutation, resulting in the substitution of Glu 375 > Lys, breaks down the possible interaction of glutamic acid with neighboring lysine and causes electrostatic and steric repulsion, which is likely to destabilize structure in this part of the protein. In case of the A1081G mutation, resulting in substitution of Met 361 > Val, no important intermolecular interactions are broken and the reason for destabilization of the protein is not as clear. CONCLUSIONS: The prognosis for children with DLD deficiency is unfavorable, although long-term normalization of most metabolites in body fluids may be achieved with the proper diet and the administration of sodium dichloroacetate.