[Association of renal function, telomere length and markers of chronic inflammation for patients without chronic kidney and cardiovascular diseases].

Most of people over 60 years of age have decreased renal function and the velocity of glomerular filtration rate reduction varies greatly. Presumably, one of the probable mechanisms of accelerated decline of renal function may be a shortening of telomere length due to chronic inflammation. The main purpose of research was to appreciate the association of renal function, leukocytes telomeres length and markers of chronic inflammation in patients without chronic kidney disease and cardiovascular disease. 253 patients without chronic kidney diseases and cardiovascular diseases were included in the study. The average age of patients was 51,5±13,3 years. There were 172 women and 81 men. 55 patients had hypertension of 1-2 degree, 46 patients had normal renal function, 207 had mild failure of kidney function. Albuminuria was < 30 mg/day in all patients. Multivariate linear regression analysis revealed statistically significant correlation between albuminuria level and telomere length (p=0,023), C reactive protein (p=0,047) and fibrinogen (p=0,001). Glomerular filtration rate, urea and creatinine were not associated with telomere length and markers of inflammation but were correlated well with age, p < 0,001. CONCLUSIONS: Albuminuria is mainly associated with chronic inflammation and telomere length (from all studied indices of renal function). Albuminuria may be regarded as a marker of replicative cell senescence and a therapeutic target for the prevention of renal function reduction.

[The age-related changes of the heart rate variability measurements: the role of the inflammation, oxidative stress and telomeres biology].

The autonomic and central nervous system, a number of humoral and reflex effects regulate the heart rate. The main role in the heart rate regulation belongs to the autonomic nervous system. A common method for studying the autonomic influences on the heart rate is the analysis of heart rate variability (HRV), which allows to evaluate the neuro-vegetative status of the organism, determine its adaptive capacity, to evaluate the level of stress and the degree of tension of regulatory systems. An age-related decrease of HRV measurements in healthy people reflects the weakening of the autonomic regulation of cardiac activity. The most pronounced changes are found in patients older than 60 years. The HRV depression is preceded by hemodynamic and metabolic disorders is associated with high cardiovascular risk and is a predictor of life-threatening arrhythmias and sudden death in the elderly.The reasons for HRV changes with age stay unclear. In the light of modern ideas about the mechanisms of aging, several complementary theories proposed. Telomere shortening, the role of oxidative stress and inflammation as possible mechanisms of age-related changes in the autonomic regulation of the heart rhythm, will be discussed in this article.

[Age-related Changes of Left Ventricular Diastolic Function, NT-proBNP Level and Their Association With Leukocyte Telomere Length].

UNLABELLED: With advancing age the left ventricle (LV) undergoes structural and functional changes, thereby creating the substrate for the development of diseases. One possible mechanism of the ageing of the heart is cellular senescence. Leukocyte telomere length (LTL) is a marker of replicative ageing. The purpose of this study was to evaluate the diastolic function of LV and level of NT-proBNP in people of different ages free of cardiovascular diseases and to assess their relationship with LTL. Our data showed that old age is associated with diastolic dysfunction and increase in the levels of NT-proBNP. The group of older subjects had lower values of E/A (0.96 ± 0.036 vs 1.27 ± 0.03, p < 0.001), Em/Am (0.9 ± 0.035 vs 1.5 ± 0.066) and higher values of IVRT (81 ± 1.56 vs 70 ± 1.23 MS, p < 0.001), DT (198 ± 3.98 vs 175 ± 2.82 MS, p < 0.001), that reflected impairment of LV relaxation. NT-proBNP level was higher in the elderly (100.82 ± 7.1 vs 48.47 ± 6.7 ωg/ml, p < 0.01), but it did not correlate with LTL. The most sensitive to the age parameters of LV diastolic function (E/A and Em/Am ratio) were positively and independently of age associated with LTL (p < 0.001). Older individuals with shorter LTL had significantly lower values of E/A ratio. CONCLUSION: Telomere length appears to be a biomarker of myocardium ageing.

[Age-related Changes of Left Ventricular Diastolic Function, NT-proBNP Level and Their Association with Leukocyte Telomere Length].

With advancing age the left ventricle (LV) undergoes structural and functional changes, thereby creating the substrate for the development of diseases. One possible mechanism of the ageing of the heart is cellular senescence. Leukocyte telomere length (LTL) is a marker of replicative ageing. The purpose of this study was to evaluate the diastolic function of LV and level of NT-proBNP in people of different ages free of cardiovascular diseases and to assess their relationship with LTL. Our data showed that old age is associated with diastolic dysfunction and increase in the levels of NT-proBNP. The group of older subjects had lower values of E/A (0.96+/-0.036 vs 1.27+/-0.03, p<0.001), Em/Am (0.9+/-0.035 vs 1.5+/-0.066) and higher values of IVRT (81+/-1.56 vs 70+/-1.23 s, p<0.001), DT (198+/-3.98 vs 175+/-2.82 s, p<0.001), that reflected impairment of LV relaxation. NT-proBNP level was higher in the elderly (100.82+/-7.1 vs 48.47+/-6.7 g/ml, p<0.01), but it did not correlate with LTL. The most sensitive to the age parameters of LV diastolic function (E/A and Em/Am ratio) were positively and independently of age associated with LTL (p<0.001). Older individuals with shorter LTL had significantly lower values of E/A ratio. CONCLUSION: Telomere length appears to be a biomarker of myocardium ageing.

[The renin-angiotensin-aldosterone system and vascular aging].

In this paper we discuss the role of renin-angiotensin-aldosterone system in development of morphological and functional changes in the vascular aging as well as, possibility of its correction by using different groups of drugs.

[Antimicrobial factors of hemolymph and excretion of larvae Lucilia sericata (meigen) (diptera, calliphoridae)].

The present study deals with molecular nature and peculiarities of functioning of two main protective systems of larvae Lucilia sericata--the antimicrobial compounds of hemolymph and of the excretion released by feeding larvae into environmental. There are identified a number of inducible antibacterial peptides including defensins (3844, 4062, and 4117 Da), P-peptide (3043 Da), and four new polypeptides (3235, 3702, 3746, and 3768 Da) In hemolymph of the larvae submitted to bacterial infestation, by the chromatomasspectrometry methods. The excretion of larvae Lucilia sericata contains peptides analogous or identical to hemolymph antibacterial peptides (diptericins: 8882 Da and 9025 Da), high molecular compounds of peptide nature (6466 Da, 6633 Da, 5772 Da, 8631 Da, etc.) differing from the known hemolymph components and low molecular compounds (130-700 Da). Spectrum of excretion bactericidal activity includes various groups of bacterial including the most actual pathogen from medical point of view--the meticillin-resistant Staphylococcus aureus, unlike the hemolymph that does not have antistaphylococcal activity. The excretion components suppressing growth and development of this staphylococcus are represented by substances of the low molecular nature (from 160 to 1020 Da). The performed studies characterize the strategies used by "surgical maggots" for protection from pathogens and for suppression of microbial competitors and allow better understanding of molecular mechanisms of larval therapy of purulent infectious diseases. These studies in perspective can serve the basis for creation of the principally new drugs for struggle with usual and antibiotics-resistant bacterial infections.

[A familial case of severe hemorrhagic fever with renal syndrome].

The authors describe two lethal outcomes of severe hemorrhagic fever with renal syndrome in spouses aged 50 and 44. A detailed description of clinical symptoms, the results of laboratory and instrumental tests, and possible mechanisms of contamination is given. Cross-sectional photographs of kidneys and hypophyseal hemorrhage, as well as radiograms of renal arteries and right pulmonary blood vessels after post-mortem filling with radiopaque mass are presented.

Rates of Jewish ancestral mutations in BRCA1 and BRCA2 in borderline ovarian tumors.

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are known to be associated with an increased risk of breast and epithelial ovarian cancers. Two specific mutations, 185delAG-BRCA1 and 6174delT-BRCA2, have been detected in a substantial proportion (20%-60%) of unselected Ashkenazi Jewish patients--i.e., Jewish patients of Eastern/Northern European descent--with invasive ovarian cancer and in a measurable proportion (2%) of the general Ashkenazi Jewish population. However, uncertainty exists concerning the heritable basis of borderline ovarian tumors and whether these tumors represent an early form of ultimately invasive disease. To gain insight into these issues, we determined the rates of 185delAG-BRCA1 and 6174delT-BRCA2 mutations in patients with borderline ovarian tumors. METHODS: Analysis of 185delAG-BRCA1 and 6174delT-BRCA2 germline mutations was performed by use of a heteroduplex formation assay in samples from 46 consecutive patients with borderline ovarian tumors and 59 consecutive patients with invasive epithelial ovarian cancers. Forty-eight samples were also analyzed by restriction enzyme analysis for the presence of the 5382insC-BRCA1 mutation, a mutation detected in 2.2% of Ashkenazi Jewish patients with breast, but not ovarian, cancer. RESULTS: One (2.2%) of the 46 patient with borderline tumors was identified as a carrier of the 185delAG-BRCA1 mutation, and no patients were found to carry the 6174delT-BRCA2 mutation. Nineteen (32%) of the 59 patients with invasive ovarian cancer were found to carry one of these two mutations; 17 carried 185delAG-BRCA1 and two carried 6174delT-BRCA2 (chi2 test with continuity correction, P = .00028). None of the patients analyzed for 5382insC-BRCA1 were found to carry the mutation. In one high-risk family that included 185delAG-BRCA1 carriers, a single patient with stage IIIc borderline ovarian tumor did not carry the mutation. CONCLUSIONS: Invasive epithelial and borderline ovarian tumors appear to differ in their genetic predisposition and in the molecular mechanisms underlying their genesis.

Mutational analyses of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast and ovarian cancer.

In Ashkenazi (East European) Jews, three predominant mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) account for the majority of germline mutations in high-risk breast and/or ovarian cancer families. Among non-Ashkenazi Jews, the 185delAG, Tyr978Ter, and a handful of "private" mutations have been reported anecdotally within both genes. In this study we attempted to determine the spectrum of BRCA1 and BRCA2 mutations in high-risk Jewish individuals, non-carriers of any of the predominant Jewish mutations. We employed multiplex PCR and denaturing gradient gel electrophoresis (DGGE) analysis for BRCA2, and combined denaturing high performance liquid chromatography (DHPLC) and protein truncation test (PTT) for BRCA1, complemented by DNA sequencing. We screened 47 high-risk Jewish individuals, 26 Ashkenazis, and 21 non-Ashkenazis. Overall, 13 sequence alterations in BRCA1 and eight in BRCA2 were detected: nine neutral polymorphisms and 12 missense mutations, including five novel ones. The novel missense mutations did not co-segregate with disease in BRCA1 and were detected at rates of 6.25% to 52.5% in the general population for BRCA2. Our findings suggest that except for the predominant mutations in BRCA1 and BRCA2 in Jewish individuals, there are only a handful of pathogenic mutations within these genes. It may imply novel genes may underlie inherited susceptibility to breast/ovarian cancer in Jewish individuals.

Could the 185delAG BRCA1 mutation be an ancient Jewish mutation?

A predominant mutation within the BRCA1 predisposition gene, 185delAG, has been detected in about 1% of the Ashkenazi population, considered a high-risk group for breast and ovarian cancers. We examined 639 unrelated healthy Jews of Iraqi extraction, a presumed low-risk group, for the existence of this mutation. Three individuals were identified as 185delAG mutation carriers, and haplotype analysis of the Iraqi mutation carriers revealed that 2 of the Iraqis shared a common haplotype with 6 Ashkenazi mutation carriers, and 1 had a haplotype which differed by a single marker. This study suggests that the BRCA1 185delAG mutation also occurs in populations considered at low-risk for breast and ovarian cancers, and that it might have occurred prior to the dispersion of the Jewish people in the Diaspora, at least at the time of Christ.

[Experience at Sheba Hospital in oncogenetic counseling and genetic testing of women with a high risk for breast and ovarian cancer].

There is inherited predisposition to breast and ovarian cancer in 5-10% of all women with these diseases. Germline mutations in BRCA1 and BRCA2 presumably account for most of the genetically susceptible individuals. We summarize 2 years of experience in counseling and testing for inherited predisposition to these cancers. 597 women (from 320 families) have been evaluated since August 1995. 242 were evaluated for inherited predisposition to breast and ovarian cancer. One-third had clear-cut evidence of familial background. 74 families were of Ashkenazi origin; the age range of breast cancer was 30-35, of ovarian cancer 40-45. In 80% of families other cancers were also noted in first degree family members, including lung, colon, and prostate cancer and leukemia. Genetic testing revealed that 45% of affected and 25% of unaffected women were carriers of a mutation in BRCA1 or BRCA2: 67/90 185delAG (BRCA1), 12/90 6174delT (BRCA2), and 4/90 of 5382insC (BRCA1). In addition, a novel mutation in exon 11 of BRCA1 was detected, carried by 7/90 women. The experience gained in oncogenetic counseling and genetic testing for inherited cancer predisposition will eventually enable determining an optimal, rational therapeutic regimen in carriers of mutations.

[Phenylalanine-4-hydroxylase and tyrosine aminotransferase activities in rat liver tissue under different vitamin E content in the organism]. / Fenilalanin-4-gidroksilaznaia i tirozinaminotransferaznaia aktivnosti v tkani pecheni krys pri razlichnoi obespechennosti organizma vitaminom E.

Enzymic activity of tyrosine aminotransferase is unchanged in subcellular fractions of the liver tissue of control, E-hypovitaminotic rats and of the same animals subjected to a single vitamin E administration. Enzymic activity of phenyl alanine-4-hydroxylase in the supernatant fraction determined in the incubation medium without biopterin in animals with E-hypovitaminosis is 39% lower than in the control rats. The coefficient of phenyl alanine-4-hydroxylase activation with biopterin in vitro in E-hypovitaminotic animals is thrice as high as that in the control rats. A single vitamin E administration produces a 1.8-fold decrease in the activation coefficient. The data obtained give reason to suggest the possible influence to vitamin E on the biopterin level in the liver.

[Effect of alpha-tocopherol on relations between RNA and ubiquinone biosynthesis in rat liver]. / Vzaimosviaz' izmenenii biosinteza RNK i ubikhinona v pecheni krys pod vozdeistviem alpha-tokoferola.

The animals were kept on the low-protein diet deprived of vitamin E. Addition of the latter to the diet fed to a noticeable increase in the intensity of the biosynthesis of total and nuclear RNA of the rat liver. alpha-Tocopherol had a clearly marked stimulant effect on the synthesis of RNA and ubiquinone as shown by in vitro experiments under 30-minute preincubation of the liver from rats with E-hypovitaminosis. Meanwhile actinomycin D was found to inhibit these processes. Under preincubation with actinomycin D or concurrent introduction of the antibiotic with alpha-tocopherol the effect of the latter does no get realized. Unlike alpha-tocopherol, ionol and other synthetic antioxidants proved ineffective. It is assumed that the stimulant effect of vitamin E on the biosynthesis of ubiquinone in the liver of rats with E-hypovitaminosis is related to the increased intensity of the RNA synthesis and differs from the antioxidant one as regards the type. It is also assumed that the action of alpha-tocopherol on the RNA synthesis is effected at the transcriptional level.

[Glutathione peroxidase and glutathione reductase activity in rat liver following administration of vitamin E and methionine]. / Hlutationperoksydazna ta hlutationreduktazna aktyvnosti v tkanyni pechinky shchuriv pry vvedenni vitaminu E i metioninu

A single introduction of vitamin E and D,L-methionine to rats kept on the vivarium ration or their addition to protein-free diet separately does not affect the glutathionperoxidase and glutathionreductase activities in the liver. A simultaneus introdyction of the vitamin and methionine causes an increase in the glutathionperoxidase activity, without changing the glutathionreductase activity. Vitamin E prevents from increasing the glutathionperoxidase and glutathionreductase activities due to selenium. Propyl gallate produces no such effect.

[Glutathione peroxidase and glutathione reductase activity in the rat liver after the administration of sodium selenite]. / Hlutationperoksydazna ta hlutationreduktazna aktyvnist' pechinky shchruiv pislia vvedennia selenitu natriiu

Sodium selenite 24h after its single administration to rats causes an increase in the activity of glutathione peroxidase and glutathione reductase in the liver tissue. 6 h after the selenium administration the enzymes activity does not differ from the control. Doses of 0.15, 0.3, 0.5 and 1 mg of selenium per 1 kg of the animal weight were investigated. 0.3 mg proved to be the least effective dose. An increase in the enzyme activity after administering 0.5 mg of selenium is retained for 6 days and 14 days after it does not differ from the control. The liver relative weight 24 h after administration of 0.5 mg of selenium per 1 kg of animal weight proved to be higher but three days later it did not differ from the control. After administering selenium in a dose of 1 mg/kg the liver relative weight was higher for 6 days. Actinomycin D administered in a dose of 0.5 mg/kg simultaneously with selenite prevents the rise in the enzyme activity and relative weight of the liver caused only by a single injection of selenium in the same dose.

[The role of vitamin E in the biosynthesis of ubiquinone (Q) and ubichromenol (QC) in rat liver]. / Izuchenie roli vitamina E v biosinteze ubikhinona (Q) i ubikhromenola (QC) v pecheni krys.

Some peculiarities of ubiquinone (Q) biosynthesis in the livers of vitamin E-deficient rats induced in vitro by alpha-tocopherol and S-adenosylmethionine (SAM) were investigated. When [C3H3]SAM was used as a precursor, alpha-tocopherol added to the sample induced a marked elevation of the content of Q concomitantly with a drastic increase (2.82-fold) of specific radioactivity of Q in the liver as compared to control. Under identical conditions with 2-14C sodium acetate as precursor, exogenous alpha-tocopherol increased the content (by 31.4%) and specific radioactivity (by 65.2%) of Q in experimental samples, whereas the corresponding parameters of ubichromenol (QC) were essentially unchanged. SAM added to the incubation medium caused a marked increase in the content and specific radioactivity of both Q and QC as compared to control. Similar, and even more conspicuous changes were observed after combined administration of alpha-tocopherol and SAM. The role of vitamin E in the activation of methylation reactions at terminal steps of Q and QC biosynthesis in rat liver is discussed.

Induction of atypical prostatic hyperplasia in rats by sympathomimetic stimulation.

BACKGROUND: Prostatic innervation may participate in its homeostasis and growth. alpha-Adrenergic inhibition alleviates clinical symptoms in benign prostatic hyperplasia. However, the prostatic effect of adrenergic agonists has not been investigated. This study deals with the prostatic effect of subchronic sympathomimetic stimulation. METHODS: Male rats received daily subcutaneous injections of the alpha-adrenergic agonist phenylephrine, 1, 10, or 20 mg/kg per day, the beta-adrenergic agonist isoproterenol, 1, 2.5 or 5 mg/kg per day, or saline, for 30 days, and the prostates were removed for histopathological examination. RESULTS: Phenylephrine induced atypical prostatic hyperplasia, characterized by piling-up with papillary and cribriform patterns, and budding-out of epithelial cells. It decreased prostatic secretions and total weight. Similar results were observed in orchidectomized rats receiving exogenous testosterone supplementation. Isoproterenol had no prostatic morphological effect. CONCLUSIONS: These results raise the possibility that sympathetic stimuli play a role in normal and aberrant growth and differentiation of prostatic epithelium, and suggests neurostimulants-treated animals as a model to study the etiology and development of prostatic hyperplasia.

The 185delAG BRCA1 mutation originated before the dispersion of Jews in the diaspora and is not limited to Ashkenazim.

The 185delAG mutation in BRCA1 is detected in Ashkenazi Jews both in familial breast and ovarian cancer and in the general population. All tested Ashkenazi mutation carriers share the same allelic pattern at the BRCA1 locus. Our previous study showed that this 'Ashkenazi' mutation also occurs in Iraqi Jews with a similar allelic pattern. We extended our analysis to other non-Ashkenazi subsets: 354 of Moroccan origin, 200 Yemenites and 150 Iranian Jews. Heteroduplex analysis complemented by direct DNA sequencing of abnormally migrating bands were employed. Four of Moroccan origin (1. 1%) and none of the Yemenites or Iranians was a carrier of the 185delAG mutation. BRCA1 allelic patterns were determined for four of these individuals and for 12 additional non-Ashkenazi 185delAG mutation carriers who had breast/ovarian cancer. Six non-Ashkenazi individuals shared the common 'Ashkenazi haplotype', four had a closely related pattern, and the rest ( n = 6) displayed a distinct BRCA1 allelic pattern. We conclude that the 185delAG BRCA1 mutation occurs in some non-Ashkenazi populations at rates comparable with that of Ashkenazim. The majority of Jewish 185delAG mutation carriers have a common allelic pattern, supporting the founder effect notion, but dating the mutation's origin to an earlier date than currently estimated. However, the different allelic pattern at the BRCA1 locus even in some Jewish mutation carriers, might suggest that the mutation arose independently.

An identical novel mutation in BRCA1 and a common haplotype in familial ovarian cancer in non-Ashkenazi Jews.

Unique germline mutations in BRCA1 and BRCA2 account for inherited predisposition to breast and ovarian cancer in high-risk families. In Jewish high-risk individuals of Ashkenazi (east European) descent, three predominant mutations, 185delAG and 5382insC (BRCA1) and 6174delT (BRCA2), seem to account for a substantial portion of germline mutations, and two of these mutations (185delAG and 6174delT) are also found at about 1% each in the general Jewish-Ashkenazi population. We identified a novel BRCA1 mutation in two Jewish-non-Ashkenazi families with ovarian cancer: a thymidine to guanidine alteration at position 3053, resulting in substitution of tyrosine at codon 1017 for a stop codon (Tyr1017Ter). The mutation was first detected by protein truncation test (PTT) and confirmed by sequencing and a modified restriction digest assay. Allelotyping of mutation carriers using intragenic BRCA1 markers revealed that the haplotype was identical in these seemingly unrelated families. No mutation carrier was found among 118 unselected Jewish individuals of Iranian origin. Our findings suggest that this novel mutation should be incorporated into the panel of mutations analysed in high-risk families of the appropriate ethnic background, and that the repertoire of BRCA1 mutations in Jewish high-risk families may be limited, regardless of ethnic origin.