99 research outputs found
Ribavirin in the treatment of chronic hepatitis C unresponsive to alfa interferon
For the 30-50% of patients with chronic hepatitis C who do not respond to alpha-interferon therapy there is no alternative treatment. Some previously untreated patients have shown a biochemical response to ribavirin, but the antiviral effects of this substance on alpha-interferon-resistant cases is largely unknown. Twelve patients with chronic hepatitis C who had not responded to a 6-12 month course of alpha-interferon were included in this study. Oral ribavirin was administered at a dose of 16 mg/kg per day for 6 or 9 months. Aminotransferase levels had not significantly changed during interferon therapy but decreased significantly during ribavirin treatment (mean alanine aminotransferase at baseline, 102 +/- 18 IU/l vs. 55 +/- 14 IU/l at 6 months; P = 0.0001). Aminotransferase levels became normal in 6 cases (50%), significantly decreased in 3 patients (25%), and did not significantly change in the remaining 3 cases (25%). All patients with normalized aminotransferase values relapsed after ribavirin was discontinued and aminotransferase activity returned to pretreatment levels. Before therapy serum hepatitis C virus RNA was detected by polymerase chain reaction in 10 cases. None of them had cleared viral RNA when tested following 3, 6 and 9 months of ribavirin therapy. Side-effects were mild and reversible. In conclusion, about half of the patients with chronic hepatitis C who are unresponsive to alpha-interferon show a clear-cut biochemical response after 6-9 months of ribavirin administration. However, ribavirin does not clear circulating hepatitis C virus RNA and relapses occur after withdrawal.
Interaction among sex, aging, and epigenetic processes concerning visceral fat, insulin resistance, and dyslipidaemia
The distribution of adipose tissue is influenced by gender and by age, shifting from
subcutaneous to visceral depots with longevity, increasing the development of several
aging-related diseases and manifestations such as obesity, metabolic syndrome, and
insulin resistance. Epigenetics might have an important role in aging processes.
The aim of this research was to investigate the interactions between aging and
epigenetic processes and the role of visceral adipose tissue, insulin resistance, and
dyslipidaemia. Two different study samples of 366 and 269 adult participants were
analyzed. Anthropometric, biochemical (including the triglycerides-glucose (TyG) index),
and blood pressure measurements were assessed following standardized methods.
Body composition measurements by Dual-energy X-ray absorptiometry (DXA) were
also performed for the second sample. Methylation data were assessed by Infinium
Human Methylation BeadChip (Illumina) in peripheral white blood cells. Epigenetic age
acceleration was calculated using the methods DNAmAge (AgeAcc) and GrimAge
(AgeAccGrim). Age acceleration (AgeAccGrim) showed better correlations than AgeAcc
with most of the measured variables (waist circumference, glucose, HOMA-IR,
HDL-cholesterol, triglycerides, and TyG index) for the first sample. In the second sample,
all the previous correlations were confirmed, except for HOMA-IR. In addition, many of
the anthropometrical measurements assessed by DXA and C-reactive protein (CRP) were
also statistically associated with AgeAccGrim. Associations separated by sex showed
statistically significant correlations between AgeAccGrim and HDL-cholesterol or CRP in
women, whereas, in men, the association was with visceral adipose tissue mass DXA,
triglycerides and TyG index. Linear regression models (model 1 included visceral adipose
tissue mass DXA and TyG index and model 2 included HDL-cholesterol and CRP) showed
a significant association for men concerning visceral adipose tissue mass DXA and TyG
index, while HDL-cholesterol and CRP were associated in women. Moreover, structural
equation modeling showed that the TyG index was mediating the majority of the visceral adipose tissue mass action on age acceleration. Collectively, these findings showed that
there are different mechanisms affecting epigenetic age acceleration depending on sex.
The identified relationships between epigenetic age acceleration and disease markers
will contribute to the understanding of the development of age-related diseases
Prediction of the response of chronic hepatitis C to interferon alfa: a statistical analysis of pretreatment variables
Pretreatment variables that could predict the response of chronic hepatitis C to interferon alfa treatment have not been fully assessed. Eighteen baseline variables were evaluated in a series of 100 consecutive patients treated with a 12 month course of interferon alfa. For the purposes of this study, response was defined as the return to normal of aminotransferase activities before the third month of treatment. Seventy per cent of the patients responded to treatment. Six variables were associated with an increased likelihood of response assessed by univariate analysis. With stepwise multiple regression analysis assessment, however, only three variables remained independently predictive of response: low gamma glutamyltransferase (gamma GT) activities (p 0.66 mu kat/l (n = 45) (p = 0.048). Response was attained in 75% of non-obese patients (n = 80), compared with only 50% of obese patients (n = 20) (p = 0.03). Finally, 80% of patients without cirrhosis (n = 76) responded, while among those with cirrhosis (n = 24) the response rate was only 37% (p 40 years old, and with gamma GT activities >0.66 mu kat/l responded to interferon alfa (p<0.001). Those findings may be useful when evaluating interferon alfa trials and it is suggested that this treatment should be applied early in the course of chronic hepatitis C
Interaction between an adcy3 genetic variant and two weight-lowering diets affecting body fatness and body composition outcomes depending on macronutrient distribution: a randomized trial
The adenylate cyclase 3 (ADCY3) gene is involved in the regulation of several metabolic
processes including the development and function of adipose tissue. The effects of the ADCY3
rs10182181 genetic variant on changes in body composition depending on the macronutrient
distribution intake after 16 weeks of the dietary intervention were tested. The ADCY3 genetic
variant was genotyped in 147 overweight or obese subjects, who were randomly assigned to one
of the two diets varying in macronutrient content: a moderately-high-protein diet and a low-fat
diet. Anthropometric and body composition measurements (DEXA scan) were recorded. Significant
interactions between the ADCY3 genotype and dietary intervention on changes in weight, waist
circumference, and body composition were found after adjustment for covariates. Thus, in the
moderately-high-protein diet group, the G allele was associated with a lower decrease of fat mass,
trunk and android fat, and a greater decrease in lean mass. Conversely, in the low-fat diet group
carrying the G allele was associated with a greater decrease in trunk, android, gynoid, and visceral
fat. Subjects carrying the G allele of the rs10182181 polymorphism may benefit more in terms of
weight loss and improvement of body composition measurements when undertaking a hypocaloric
low-fat diet as compared to a moderately-high-protein diet
Specific and general HLA-DR binding motifs: comparison of algorithms
Using panels of peptides well characterized for their ability to bind to HLA DR1, DRB1*1101, or DRB1*0401 molecules, algorithms were deduced to predict binding to these molecules. These algorithms consist of blocks of 8 amino acids containing an amino acid anchor (Tyr, Phe, Trp, Leu, Ile, or Val) at position i and different amino acid combinations at positions i+2 to i+7 depending on the class II molecule. The sensitivity (% of correctly predicted binder peptides) and specificity (% of correctly predicted non-binder peptides) of these algorithms, were tested against different independent panels of peptides and compared to other algorithms reported in the literature. Similarly, using a panel of 232 peptides able to bind to one or more HLA molecules as well as 43 non-binder peptides, we deduced a general motif for the prediction of binding to HLA-DR molecules. The sensitivity and specificity of this general motif was dependent on the threshold score used for the predictions. For a score of 0.1, the sensitivity and specificity were 84.7% and 69.8%, respectively. This motif was validated against several panels of binder and non-binder peptides reported in the literature, as well as against 35, 15-mer peptides from hepatitis C virus core protein, that were synthesized and tested in a binding assay against a panel of 19 HLA-DR molecules. The sensitivities and specificities against these panels of peptides were similar to those attained against the panels used to deduce the algorithm. These results show that comparison of binder and non-binder peptides, as well as correcting for the relative abundance of amino acids in proteins, is a useful approach to deduce performing algorithms to predict binding to HLA molecules
Detection of anti-hepatitis C virus antibodies by ELISA using synthetic peptides
A novel ELISA assay for the detection of anti-hepatitis C virus antibodies in the sera of infected individuals is described. This assay is based on a mixture of three 15-amino acid synthetic peptides encompassing regions of core and NS4 proteins of hepatitis C virus. Comparison with other available ELISA assays based on recombinant polypeptides shows that, short synthetic peptides have the advantage over some larger recombinant peptides by giving higher specificity without loss of sensitivity
DNA methylation in genes of longevityâregulating pathways: association with obesity and metabolic complications
Aging is the main risk factor for most chronic diseases. Epigenetic mechanisms, such as DNA methylation
(DNAm) plays a pivotal role in the regulation of physiological responses that can vary along lifespan. The aim of
this research was to analyze the association between leukocyte DNAm in genes involved in longevity and the
occurrence of obesity and related metabolic alterations in an adult population. Subjects from the MENA cohort
(n=474) were categorized according to age () and the presence of metabolic alterations: increased
waist circumference, hypercholesterolemia, insulin resistance, and metabolic syndrome. The methylation levels
of 58 CpG sites located at genes involved in longevityâregulating pathways were strongly correlated (FDRâ
adjusted< 0.0001) with BMI. Fifteen of them were differentially methylated (p<0.05) between younger and
older subjects that exhibited at least one metabolic alteration. Six of these CpG sites, located at MTOR
(cg08862778), ULK1 (cg07199894), ADCY6 (cg11658986), IGF1R (cg01284192), CREB5 (cg11301281), and RELA
(cg08128650), were common to the metabolic traits, and CREB5, RELA, and ULK1 were statistically associated
with age. In summary, leukocyte DNAm levels of several CpG sites located at genes involved in longevityâ
regulating pathways were associated with obesity and metabolic syndrome traits, suggesting a role of DNAm in
agingârelated metabolic alterations
Epigenetic modifications as outcomes of exercise interventions related to specific metabolic alterations: a systematic review
Background: Chronic diseases arise as a consequence of an unhealthy lifestyle primarily characterized by physical inactivity and unbalanced diets. Regular physical activity can improve health, and there is consistent evidence that these improvements may be the result of epigenetic modifications. Objective: To identify epigenetic modificationsas outcomes of exercise interventions related to specific metabolic alterations. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) methodology for manuscript research and preparation was followed using PubMed and EBSCO databases for literature review. Out of 2,638 articles identified, only 34 articles met the inclusion criteria. Results: The sections of the review were organized by metabolic alterations in which studies were grouped according to healthy, diseased, and trained individuals. Resistance exercise in humans induced epigenetic changes in pathways associated with energy metabolism and insulin sensitivity, contributing to healthy skeletal muscle. Endurance exercise also caused modifications in biomarkers associated to metabolic alterations through changes in DNA methylation and the expression of specific miRNAs. However, both resistance and endurance exercise are necessary to obtain a better physiological adaptation and a combination of both seems to be needed to properly tackle the increasing prevalence of non-communicable pathologies. Conclusion: Given the heterogeneity and complexity of the existing literature, it is currently not possible to propose a specific recommendation about the type, intensity, or duration of exercise that could be beneficial for different subsets of the population (healthy, diseased, and/or trained). Nevertheless, this review highlights the importance of exercise for health and shows the need to perform more research in this emerging area to identify epigenetic biomarkers that could serve as indicators of exercise adaptations
Immunogenicity of variable regions of hepatitis C virus proteins: selection and modification of peptide epitopes to assess hepatitis C virus genotypes by ELISA
The immunogenicity of variable regions of hepatitis C virus (HCV) proteins was studied by ELISA by using 543 synthetic peptides from 120 variable regions and 90 sera from HCV-infected patients. Some regions from certain genotypes were less immunogenic, or even non-immunogenic, compared with their equivalents in other genotypes. However, the mean recognition of all peptides from genotypes 1a, 1b and 3 by sera infected with genotypes 1a, 1b and 3, respectively, showed no significant differences, suggesting a similar overall immunogenicity of variable regions from these genotypes. Proteins NS4a, NS4b and NS5a were found to be the most immunogenic. Recognition of individual peptides by the sera of infected patients showed that the humoral response against HCV is patient-dependent. The work shows that 15-mer peptides may encompass several B-cell epitopes. These epitopes may lie in slightly different positions in different genotypes. Thirty-one percent of the 543 peptides were recognized by some of the 35 healthy donors. This may be a reflection of the large number of antigens to which they had been exposed, but it may also reflect a strategy of HCV to respond to immune pressure. After selection and modification, a set of 40 peptides was used to assess genotypes 1a, 1b, 1, 2 and 3 in the sera of HCV-infected patients, with sensitivities of 34.1, 48.5, 68.8, 58.3 and 48.9% and specificities of 100, 99.1, 97.1, 99.5 and 99%, respectively. The overall sensitivity and specificity for the assessment of genotypes 1, 2 and 3 were 64 and 98%, respectively
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