A toxicogenomics approach to identify new plausible epigenetic mechanisms of ochratoxin a carcinogenicity in rat.

Ochratoxin A (OTA) is a mycotoxin occurring naturally in a wide range of food commodities. In animals, it has been shown to cause a variety of adverse effects, nephrocarcinogenicity being the most prominent. Because of its high toxic potency and the continuous exposure of the human population, OTA has raised public health concerns. There is significant debate on how to use the rat carcinogenicity data to assess the potential risk to humans. In this context, the question of the mechanism of action of OTA appears of key importance and was studied through the application of a toxicogenomics approach. Male Fischer rats were fed OTA for up to 2 years. Renal tumors were discovered during the last 6 months of the study. The total tumor incidence reached 25% at the end of the study. Gene expression profile was analyzed in groups of animals taken in intervals from 7 days to 12 months. Tissue-specific responses were observed in kidney versus liver. For selected genes, microarray data were confirmed at both mRNA and protein levels. In kidney, several genes known as markers of kidney injury and cell regeneration were significantly modulated by OTA. The expression of genes known to be involved in DNA synthesis and repair, or genes induced as a result of DNA damage, was only marginally modulated. Very little or no effect was found amongst genes associated with apoptosis. Alterations of gene expression indicating effects on calcium homeostasis and a disruption of pathways regulated by the transcription factors hepatocyte nuclear factor 4 alpha (HNF4alpha) and nuclear factor-erythroid 2-related factor 2 (Nrf2) were observed in the kidney but not in the liver. Previous data have suggested that a reduction in HNF4alpha may be associated with nephrocarcinogenicity. Many Nrf2-regulated genes are involved in chemical detoxication and antioxidant defense. The depletion of these genes is likely to impair the defense potential of the cells, resulting in chronic elevation of oxidative stress in the kidney. The inhibition of defense mechanism appears as a highly plausible new mechanism, which could contribute to OTA carcinogenicity.

Metabolic profiling using principal component analysis, discriminant partial least squares, and genetic algorithms.

The aim of this study was to evaluate evolutionary variable selection methods in improving the classification of (1)H nuclear magnetic resonance (NMR) metabonomic profiles, and to identify the metabolites that are responsible for the classification. Human plasma, urine, and saliva from a group of 150 healthy male and female subjects were subjected to (1)H NMR-based metabonomic analysis. The (1)H NMR spectra were analyzed using two pattern recognition methods, principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA), to identify metabolites responsible for gender differences. The use of genetic algorithms (GA) for variable selection methods was found to enhance the classification performance of the PLS-DA models. The loading plots obtained by PCA and PLS-DA were compared and various metabolites were identified that are responsible for the observed separations. These results demonstrated that our approach is capable of identifying the metabolites that are important for the discrimination of classes of individuals of similar physiological conditions.

Correlating the molecular electrostatic potentials of some organic peroxides with their antimalarial activities.

The molecular electrostatic potentials (MEPs) of artemisinin (also known as qinghaosu), yingzhaosu A, and some synthetic analogues have been calculated and studied as a means of distinguishing between high and low antimalarial activity. To facilitate comparison, the dimensionality of the MEP was reduced by Kohonen Neural Network transforms. The reduction revealed that peroxides exhibiting high antimalarial activity are characterized by a continuous strip of negative electric potential surrounding the molecule, whereas peroxides of lesser activity show a broken strip.

Bicyclonucleosides and ring-chain interconversion.

Four types of bicyclonucleosides differing in the easiness of their ring-chain interconversion have been prepared, some exhibited anti-HIV activity and the ratio of their cyclic and open-chain forms could have some bearing on their biological activity.

Correlates of cognitive status of old patients with isolated systolic hypertension: the Syst-Eur Vascular Dementia Project.

OBJECTIVE: To assess cognitive functions and their correlates for a dementia-free cohort of old patients with isolated systolic hypertension. DESIGN: Cross-sectional data from the randomization period of the European Trial in Elderly with Systolic Hypertension (Syst-Eur Vascular Dementia Project). SETTING: Sixteen European countries and Israel. PARTICIPANTS: We studied 2252 patients aged 60-100 years (mean 70). MAIN OUTCOME MEASURES: Mini Mental State Examination (MMSE) and Spearman correlation of MMSE scores to demographic data or blood pressure. RESULTS: The MMSE was successfully completed for 1474 women and 751 men. The baseline blood pressure averaged 173 +/- 10/86 +/- 6 mmHg (means +/- SD). Median age at which education of patients at school had stopped was 15 years. Men and women who consumed alcohol (28%) had median intakes of 8 and 3 g/day, respectively. The median MMSE score was 29 (range 15-30). The maximum score of 30 was attained by 609 (30%) subjects. Fifty-nine (3%) patients had a MMSE score of 23 or less. The MMSE score decreased with advancing age (r = -0.21, P < 0.001). Both for men and for women, it was positively correlated to the level of education (r = 0.30 and r = 0.32, P < 0.001). For women after adjustment for age and the level of education, the score was correlated negatively to systolic blood pressure (r = -0.07, P < 0.05) but positively to intake of alcohol (r = 0.06, P < 0.05). CONCLUSION: In a cohort of elderly patients with isolated systolic hypertension, baseline cognitive function measured in terms of the MMSE score was high, probably due to selective recruitment of patients who were not clinically demented. Blood pressure was a weak contributor to cognitive status compared with age and level of education. Baseline cognitive function of women was negatively and independently correlated to systolic blood pressure.

A QSAR study of the antimalarial activity of some synthetic 1,2,4-trioxanes.

The antimalarial activity of a series of synthetic 1,2,4-trioxanes is correlated with molecular structure by using a pharmacophore search method (CATALYST). The technique is shown to have predictive accuracy and confirms that docking between an active trioxane and the receptor, heme, is the crucial step for drug action.

[The effect of myosin from the human myocardium on quantitative T-lymphocyte values--active rosettes in patients with myocardial infarct and stenocardia]. / Izsledvane na vliianieto na miozin ot choveshki miokard vurkhu kolichestvenite stoinosti na T-limfotsitite--aktivni rozetki pri bolni s infarkt na miokarda i stenokardiia.

The aim of the investigation is to study the influence of human myocardium myosin on the quantitative values of T-lymphocytes examined as active rosettes [correction of rosellae] in patients with ischemic heart disease. The study included 99 patients with ischemic heart disease, 49 of them with myocardial infarction and 50--with stenocardia. The controls were 61 clinically healthy donors. It was established that the active rosettes [correction of rosellae] in the patients with myocardial infarction were significantly less than in the controls (p less than 0.05). A significant inhibiting action of the human myocardium myosin on the active rosettes [correction of rosellae] was manifested (p less than 0.002). This action in the patients with stenocardia was less expressed (p less than 0.05). Myosin from a striated muscle did not exert an inhibiting action (p greater than 0.1). The results prove the participation of human myocardium myosin in the pathogenetic mechanism of T-lymphocytes suppression in patients with ischemic heart disease.

[The cellular immunity indices of patients with a rheumatic heart defect]. / Izsledvane na niakoi pokazateli ot kletuchniia imunitet pri bolni s revmatichen porok na surtseto.

In 29 patients with clinical diagnosis of rheumatic valvular disease the quantitative values of active rosettes and the specific sensitization to human heart myosin were examined. The specific sensitization to human heart myosin was examined by two methods concurrently: method of inhibiting leucocyte migration in agarose and method for direct specific lymphocytolysis with myosin. The results were compared with those of 44 clinically healthy controls. In the patients with rheumatic valvular disease (RVD) the values of the active rosettes are significantly lower (p less than 0.01) than in the healthy controls. With the method of direct specific lymphocytolysis with myosin statistically significant sensibilization of the lymphocytes to myosin was found in the patients with RVD (p less than 0.001). In 5 patients examined before and after operation it was established that 2-4 weeks after a successful correction of the hemodynamics the specific sensibilization of the lymphocytes to myosin was no more present.

The effect of Haversian remodeling on the tensile properties of human cortical bone.

The purpose of this study was to determine the effect of Haversian remodeling on the tensile properties of human cortical bone by testing specimens containing, as far a possible, a single type of bone tissue. Fifty-one specimens were prepared from sixteen fresh tibias, removed at autopsy. Age range was 19-35. Regions were selected so that the specimens would consist almost exclusively of either primary bone or Haversian bone. The ultimate tensile strength, ultimate strain and Young's modulus of elasticity were determined at a loading rate of 0.05 mm s-1. The primary bone specimens were found to have a significantly higher ultimate tensile strength and modulus of elasticity than those formed of Haversian bone.

[Reliability of an echocardiographic evaluation of the left ventricular pumping function in ischemic heart disease]. / Nadezhdnost na ekhokardiografskata otsenka na pompenata funktsiia na liavata kamera pri iskhemichna bolest na surtseto.

Almost simultaneous angiographic and echocardiographic determination of the pump indices of left ventricle was performed to 38 male patients, aged 34 to 58. A special computer was used for the processing of the data. The echocardiographic indices were calculated by three formulae: cube, Forteen and Teiholz . Coefficients of correlation were derived between the two methods, confirming a relatively high reliability of echocardiography in the evaluation of left ventricular pump function, particularly if the calculations were selectively performed according to one of the three formulae, depending on the value of diastolic measure of left ventricle.

[Diagnosis and functional assessment of pulmonary thromboembolism]. / Diagnostika i funtsionalna otsenka na belodrobnata tromboemboliia.

The authors discuss the problems of diagnostics and functional assessment of pulmonary thrombo-embolia. The potentialities of the clinical indices, electrocardiography, X-ray, blood-gas analysis, capnography, right cardiac catheterization and angiopulmography in the diagnostics and assessment of the form of thrombo-embolia of pulmonary artery were revealed in 54 patients with cardiac and pulmonary form of thrombo-embolia. The stage potentialities in that respect of the various health institutions are outlined and the necessity of evacuation of the patients where they would be best attended is stressed upon.

[Comparative evaluation between the impedance method and the Fick method for determining cardiac minute volume]. / Sravnitelna otsenka mezhdu impedans-metoda i metoda na Fik za opredeliane na minutniia surdechen obem.

The authors determined the minute heart volume, according to Fick method with right cardiac catheterization of 20 healthy youths. With the comparison of the results obtained, the differences were within the limits of +/- 10, and in almost half of the examined-- +/- 5%. The relatively small discrepancies in the values obtained, suggest that the impedence-method proves to be a reliable method for bloodless determination of minute heart volume.

[Hemodynamic and phase characteristics of the impedance cardiogram]. / Khemodinamichna i fazova kharakteristika na impedans-kardiogramata.

The authors realized synchronous records of impedance--cardiogram with PCG, ECG and the curves of the pressure within the separate cardio-vascular segments. That enables them to make a phase characteristic of the separate parts of impedance-cardiographic curve, thus establishing that the latter is synchronized with the mechanics of the left ventricle.

[Abdominal manifestations of chronic pyelonephritis]. / Abdominalni proiavi pri khronichniia pielonefrit.

The most frequent abdominal complaints in chronic pyelonephritis are analyzed and one patient is described, who with the exacerbation of the disease manifested the clinical picture of acute abdomen. The involvement of visceral-dermal reflexes with hyperalgesia, muscular defense, vomiting, meteroism and disturbances in intestinal motility imitated the picture of acute abdominal drama, forcing the surgical intervention. The varied abdominal symptomatics in about 20 per cent of the cases with chronic exacerbated pyelonephritis, should be critically assessed by the therapeutists.