Enhanced cholesterol efflux promotion in well-trained soccer players

It is widely accepted that aerobic physical activity is associated with a less atherogenic lipid and lipoprotein profile and, consequently, with a reduced cardiovascular risk. Both cross-sectional studies and prospective-interventional trials show that the most frequent modification observed consists of a slight but significant increase in high-density lipoprotein cholesterol (HDL-C) levels. Nevertheless, only few studies made an attempt to elucidate if this quantitative modification was accompanied by an improvement in any of HDL antiatherogenic functions. The purpose of this study was to evaluate the main steps of reverse cholesterol transport, the best known antiatherogenic function performed by HDL, in a group of well-trained soccer players (n = 35) in comparison to sedentary controls (n = 15). Average HDL-C levels were 12.5% higher in the sportsmen, in large part because of greater HDL2-C concentration. No statistically significant differences were observed in the other lipid- and lipoprotein-related parameters. The capacity to promote cholesterol efflux from Fu5AH cells was significantly higher in the soccer players than in the control individuals (20.5% +/- 0.4% v 15.9% +/- 1.2%, respectively, P < .001). However, lecithin:cholesterol acyltransferase (LCAT; 2.6 +/- 0.9 v 1.4 +/- 0.3%/mL.h, respectively) and cholesteryl ester transfer protein (CETP; 69.5 +/- 8.3 v 62.7 +/- 14.8%/mL.h, respectively) activities did not reach statistically significant difference between both groups. Correlation analysis showed that cholesterol efflux induced by serum samples was directly related to HDL-C (r = 0.59, P < .001), HDL2-C (r = 0.37, P < .01), and lipoprotein (Lp)A-I (r = 0.44, P < .05). On the other hand, negative correlations were observed with waist/hip ratio (r = -0.36, P < .05), low-density lipoprotein cholesterol (LDL-C; r = -0.33, P < .05), apolipoprotein B (apo B; r = -0.42, P < .05), and LpA-I;A-II (r = -0.51, P < .005). In conclusion, the well-known cardioprotective benefit of regular exercise could be based, at least in part, on a less atherogenic lipid and lipoprotein profile and an enhanced cellular cholesterol efflux.     

Apolipoprotein A-V gene polymorphisms in subjects with metabolic syndrome.

BACKGROUND: Genetic variation at the apolipoprotein A-V locus, recently discovered proximal to the APOA1/C3/A4 gene cluster, is associated with elevated triglyceride concentrations, a risk factor for atherosclerosis. METHODS: The goal of our study was to determine the association of two apolipoprotein A-V (APOA5) gene polymorphisms in a group of urban Romanian subjects with the prevalence of the metabolic syndrome. For this purpose, we assayed -1.131T>C and c.56C>G polymorphisms for 279 subjects divided into three groups: a control group, a metabolic syndrome group and a cardiovascular disease group. Then we correlated the minor allele frequencies with body mass index and biochemical parameters. RESULTS: We obtained higher frequency for -1.131C compared to c.56G alleles, both mainly distributed in overweight subjects. Body mass index and triglyceride levels were higher in -1.131C allele carriers in metabolic syndrome patients, but were not significantly different in c.56G carriers compared to those with the native gene. Metabolic syndrome -1.131C homozygotes presented lower high-density lipoprotein cholesterol and higher glucose levels compared to subjects with the native gene. Total cholesterol, low-density lipoprotein cholesterol and insulin were not different between -1.131C or c.56G allele carriers and those with the native gene. CONCLUSIONS: Our results demonstrate an independent risk for -1.131T>C APOA5 gene polymorphisms in the development of metabolic syndrome.     

Distinct structural TCR repertoires in naturally occurring versus vaccine-induced CD8+ T-cell responses to the tumor-specific antigen NY-ESO-1

Spontaneous immune responses to the cancer testis antigen NY-ESO-1 are frequently found in cancer patients bearing antigen-expressing tumors. In HLA-A2-expressing patients, naturally elicited NY-ESO-1-specific, tumor-reactive cytotoxic T lymphocytes (CTLs) are mostly directed against an immunodominant epitope corresponding to peptide NY-ESO-1 157-165. NY-ESO-1-specific CTLs can also be induced by synthetic peptide vaccines, but they are heterogeneous in terms of functional avidity and tumor reactivity. The authors investigated the structural bases of this phenomenon by analyzing the TCR features of natural and vaccine-induced NY-ESO-1-specific CTLs. The results indicate that CTLs from the two groups exhibit highly structurally conserved but distinct TCR features, suggesting that the synthetic peptides used for vaccination may fail to faithfully mimic the naturally processed antigen. Together, the results of this study underline the strength of TCR molecular monitoring and will be instrumental for the development and monitoring of vaccines aimed at eliciting CTLs with high tumor reactivity.     

Plasma and lung concentrations of ceftazidime administered in continuous infusion to critically ill patients with severe nosocomial pneumonia

Objective To determine the steady-state plasma and epithelial lining fluid (ELF) concentrations of ceftazidime administered in continuous infusion to critically ill patients with severe nosocomial pneumonia.Design Prospective, open-label study.Setting An intensive care unit and research ward in a university hospital.Patients A total of 15 adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation were enrolled.Interventions All subjects received a 30 min intravenous infusion of 2 g ceftazidime followed by a continuous infusion of 4 g over 24 h. The concentrations of ceftazidime in plasma and ELF were determined at steady-state after 2 days of therapy by high performance liquid chromatography.Measurements and main results The mean ±SD steady-state plasma and ELF concentrations of 4 g ceftazidime in continuous infusion were 39.6±15.2 µg/mL and 8.2±4.8 µg/mL, respectively, showing a mean ±SD percentage penetration of ceftazidime into ELF of 20.6±8.9%.Conclusion The administration of 4 g ceftazidime in continuous infusion in critically ill patients with severe nosocomial pneumonia provides concentrations in excess of the minimal inhibitory concentration of many susceptible organisms over the course of therapy both in serum and ELF. However, for some pathogens such as P. aeruginosa, higher doses of ceftazidime should be administered, or another agent should be used in combination.     

Thymic selection generates a large T cell pool recognizing a self-peptide in humans

The low frequency of self-peptide-specific T cells in the human preimmune repertoire has so far precluded their direct evaluation. Here, we report an unexpected high frequency of T cells specific for the self-antigen Melan-A/MART-1 in CD8 single-positive thymocytes from human histocompatibility leukocyte antigen-A2 healthy individuals, which is maintained in the peripheral blood of newborns and adults. Postthymic replicative history of Melan-A/MART-1-specific CD8 T cells was independently assessed by quantifying T cell receptor excision circles and telomere length ex vivo. We provide direct evidence that the large T cell pool specific for the self-antigen Melan-A/MART-1 is mostly generated by thymic output of a high number of precursors. This represents the only known naive self-peptide-specific T cell repertoire directly accessible in humans.     

ERCC1 as a risk stratifier in platinum-based chemotherapy for nonsmall-cell lung cancer

PURPOSE OF REVIEW: Cisplatin-based chemotherapy remains the treatment of choice in advanced nonsmall-cell lung cancer. The development of predictive biomarkers able to identify lung-cancer patients who are most likely to benefit from cisplatin-based chemotherapy would be a powerful tool. Many reports have explored the role of ERCC1 expression in the repair mechanism of cisplatin-induced DNA adducts in cancer cells. RECENT FINDINGS: Using immunohistochemistry in resected tumors, the International Adjuvant Lung Cancer Trial showed that high ERCC1 protein expression was associated with improved survival in patients who did not receive chemotherapy. In contrast, the benefit of adjuvant cisplatin-based chemotherapy was more profound in patients with low ERCC1 expression. Other investigators studying mRNA expression in tumor biopsies from patients treated with cisplatin and gemcitabine showed that patients with low ERCC1 mRNA expression have a longer median survival compared to those with high expression. SUMMARY: High ERCC1 expression is predictive of resistance to platinum-based therapy. Thus, there is solid evidence to support ERCC1 as a useful marker of clinical resistance to platinum-based chemotherapy in the adjuvant setting of nonsmall-cell lung cancer. Meanwhile, optimization of methodology and standardization of technical procedures seem necessary before larger prospective studies can address the same question.     

Self-management and behaviour modification in COPD

There is new evidence from recent studies that disease-specific self-management improves health status and reduces hospital admissions in COPD patients. It is critical to implement health education programs in the continuum of care aimed at behaviour modification. Studies in COPD have shown that self-management increases knowledge and skills the patients require to treat their own illness. It is also essential to be more effective in improving patients' confidence in their ability to follow a self-care regimen, for example, by augmenting self-efficacy. Self-efficacy plays a part in determining which activities or situations an individual will perform or avoid. Results from a recent qualitative study suggested that a continuum self-management program helps COPD patients to perform given self-health behaviours. COPD patients have perceived barriers and factors (disease-related skills), which will hinder or facilitate lifestyle modification. To be successful, self-management does require a multifaceted approach that incorporates not only teaching various disease contents but also implementing strategies to change behaviour in patients. Further research is needed to develop strategies on how to intervene and facilitate behaviour modification in chronic disease and as such the relevance for the implementation of self-management programs in COPD.     

Real-time PCR assay of individual human immunodeficiency virus type 1 variants in coinfected human lymphoid tissues

In the course of infection, human immunodeficiency virus type 1 (HIV-1) mutates, diverging into a "swarm" of viral quasispecies, and the predominance of CCR5- or CXCR4-utilizing quasispecies is strongly associated with the pattern of disease progression. Quantification of CCR5- and CXCR4-utilizing viruses in viral swarms is important in the investigation of the mechanisms of this phenomenon. Here, we report on a new real-time PCR-based methodology for the evaluation of replication of individual CCR5- and CXCR4-utilizing variants. The assay is highly reproducible, with a coefficient of variation of <3%, and it accurately estimates the numbers of virus-specific RNA copies even when their difference in the mixture is 2 orders of magnitude. We demonstrate that replications of CCR5- and CXCR4-utilizing variants can be evaluated and distinguished in experimentally coinfected human lymphoid tissue. The assay we developed may facilitate study of the mechanisms of the R5-to-X4 switch in viral swarms in human tissues infected with HIV-1.