The non-alcoholic fraction of beer increases stromal cell derived factor 1 and the number of circulating endothelial progenitor cells in high cardiovascular risk subjects: A randomized clinical trial

Rationale

Moderate alcohol consumption is associated with a decrease in cardiovascular risk, but fermented beverages seem to confer greater cardiovascular protection due to their polyphenolic content. Circulating endothelial progenitor cells (EPC) are bone-marrow-derived stem cells with the ability to repair and maintain endothelial integrity and function and are considered as a surrogate marker of vascular function and cumulative cardiovascular risk. Nevertheless, no study has been carried out on the effects of moderate beer consumption on the number of circulating EPC in high cardiovascular risk patients.

Objective

To compare the effects of moderate consumption of beer, non-alcoholic beer and gin on the number of circulating EPC and EPC-mobilizing factors.

Methods

In this crossover trial, 33 men at high cardiovascular risk were randomized to receive beer (30 g alcohol/d), the equivalent amount of polyphenols in the form of non-alcoholic beer, or gin (30 g alcohol/d) for 4 weeks. Diet and physical exercise were carefully monitored.

Results

The number of circulating EPC and EPC-mobilizing factors were determined at baseline and after each intervention. After the beer and non-alcoholic beer interventions, the number of circulating EPC significantly increased by 8 and 5 units, respectively, while no significant differences were observed after the gin period. In correlation, stromal cell derived factor 1 increased significantly after the non-alcoholic and the beer interventions.

Conclusions

The non-alcoholic fraction of beer increases the number of circulating EPC in peripheral blood from high cardiovascular risk subjects.

Clinical trial registration

http://www.controlled-trials.com/ISRCTN95345245 ISRCTN95345245     

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIB binding to the cell surface

CCR5 and CXCR4, the respective cell surface coreceptors of R5 and X4 HIV-1 strains, both form heterodimers with CD4, the principal HIV-1 receptor. Using several resonance energy transfer techniques, we determined that CD4, CXCR4, and CCR5 formed heterotrimers, and that CCR5 coexpression altered the conformation of both CXCR4/CXCR4 homodimers and CD4/CXCR4 heterodimers. As a result, binding of the HIV-1 envelope protein gp120_IIIB to the CD4/CXCR4/CCR5 heterooligomer was negligible, and the gp120-induced cytoskeletal rearrangements necessary for HIV-1 entry were prevented. CCR5 reduced HIV-1 envelope-induced CD4/CXCR4-mediated cell-cell fusion. In nucleofected Jurkat CD4 cells and primary human CD4⁺ T cells, CCR5 expression led to a reduction in X4 HIV-1 infectivity. These findings can help to understand why X4 HIV-1 strains infection affect T-cell types differently during AIDS development and indicate that receptor oligomerization might be a target for previously unidentified therapeutic approaches for AIDS intervention.For HIV-1 to enter a target cell, the viral envelope glycoprotein gp120 must interact with a set of cell surface molecules that include the primary receptor, CD4 (1), and a chemokine receptor (CCR5 or CXCR4) that acts as a coreceptor (2, 3). These molecules form CD4/chemokine receptor complexes, as deduced from coprecipitation data for CXCR4 or CCR5 with CD4 (4–8).Most HIV-1 variants isolated from newly infected individuals use CCR5 and CD4 to enter host cells; these M-tropic R5 strains are predominant in acute and asymptomatic phases of HIV infection. CD4⁺ T helper type 1 (Th1) cells, which express high CCR5 levels (9, 10), are implicated in maintaining asymptomatic status (11, 12). The “viral shift” from R5 to T-tropic X4 HIV-1 strains correlates with AIDS progression (13, 14). X4 strains infect mainly CD4⁺ Th2 cells, which express little CCR5 and whose CXCR4 levels resemble those of Th1 cells (15, 16), which suggests that cell susceptibility to HIV-1 infection depends on the CD4/coreceptor ratio and on receptor levels during cell activation and/or differentiation (17). CXCR4 and CCR5 are present as homodimers and heterodimers at the plasma membrane (18–20). In addition, gp120-mediated CD4/CXCR4 and CD4/CCR5 association and clustering is reported (21–23). Nonetheless, little is known of how CCR5 expression influences the CD4/CXCR4 interaction, or of the molecular basis that underlies the differences in X4 strains infection relative to CCR5 levels at the cell surface.Here, we identify CD4/CXCR4/CCR5 oligomers at the cell membrane, even in the absence of ligands. CCR5 expression in these complexes modifies the heterodimeric CD4/CXCR4 conformation and blocks gp120_IIIB binding, without altering binding of the CXCR4 ligand CXCL12 and its subsequent signaling. gp120_IIIB-triggered LIMK1 activation, cofilin dephosphorylation, and the actin cytoskeleton rearrangement necessary for cell-cell fusion were impeded in CD4/CXCR4/CCR5-expressing cells. The data obtained using recombinant gp120_IIIB glycoprotein were confirmed by experiments showing that X4 HIV-1 infection of Jurkat and primary T cells is regulated by CCR5 expression.     

Potential involvement of GRIN2B encoding the NMDA receptor subunit NR2B in the spectrum of Alzheimer’s disease

Increasing evidence links dysregulation of NR2B-containing N-methyl-d-aspartate receptor remodelling and trafficking to Alzheimer’s disease (AD). This theme offers the possibility that the GRIN2B gene, encoding this selective NR2B subunit, represents a potential molecular modulating factor for this disease. Based on this hypothesis, we carried out a mutation scanning of exons and flanking regions of GRIN2B in a well-characterized cohort of AD patients, recruited from Southern Italy. A “de novo” p.K1293R mutation, affecting a highly conserved residue of the protein in the C-terminal domain, was observed for the first time in a woman with familial AD, as the only genetic alteration of relevance. Moreover, an association study between the other detected sequence variants and AD was performed. In particular, the study was focused on five identified single nucleotide polymorphisms: rs7301328, rs1805482, rs3026160, rs1806191 and rs1806201, highlighting a significant contribution from the GRIN2B rs1806201 T allele towards disease susceptibility [adjusted odds ratio (OR) = 1.92, 95% confidence interval (CI) 1.40–2.63, p < 0.001, after correction for sex, age, and APOE ε4 genotype]. This was confirmed by haplotype analysis that identified a specific haplotype, carrying the rs1806201 T allele (CCCTC), over-represented in patients versus controls (adjusted OR = 6.03; p < 0.0001). Although the pathogenic role of the GRIN2B-K1293R mutation in AD is not clear, our data advocate that genetic variability in the GRIN2B gene, involved in synaptic functioning, might provide valuable insights into disease pathogenesis, continuing to attract significant attention in biomedical research on its genetic and functional role.     

The EORTC QLQ-C15-PAL questionnaire: validation study for Spanish bone metastases patients

Purpose

Quality of life (QL) is a key outcome for advanced disease cancer patients. The European Organization for Research and Treatment of Cancer (EORTC) has developed the QLQ-C15-PAL questionnaire, a short version of the QLQ-C30 for palliative care. The aim of the present study is to validate the QLQ-C15-PAL for use with Spanish patients with bone metastasis.

Methods

For this study, we used a consecutive sample of stage IV cancer patients with bone metastases who started radiotherapy with palliative intention. Two assessments were proposed for each patient: one on the first day of treatment and one a month after the end of the radiotherapy sessions. Psychometric evaluation of the structure, reliability, and validity was undertaken.

Results

One hundred and sixteen patients completed the first questionnaire and seventy five completed the second. Multitrait scaling analysis showed that all items met the standards for convergent validity, and all except the fatigue scale met the standards for divergent validity. Cronbach’s coefficient met the 0.7 alpha criterion on all scales except pain (second assessment). Most QLQ-C15-PAL areas had low-to-moderate correlations with the other areas. Significant differences appeared in the comparisons between groups with regard to: patients who died before the second assessment (six areas); patients receiving chemotherapy before starting radiotherapy in the two assessments (three and four areas, respectively); the performance status in the two assessments (nine and eight areas); and the number of RT sessions received (four). Quality of life was better in the second assessment in nine areas.

Conclusion

The QLQ-C15-PAL is a reliable and valid instrument when applied to a sample of Spanish patients. These results are in line with those of other validation studies.     

The Spanish version of the Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) is valid for use in the general population

Purpose

Mental well-being has aroused interest in Europe as an indicator of population health. The Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) was developed in the United Kingdom showing good face validity and has been previously adapted into Spanish. The aim of this study is to assess the validity and reliability of the Spanish version of WEMWBS in the general population.

Methods

Cross-sectional home face-to-face interview survey with computer-assisted personal interviewing was administered with the 2011 Catalan Health Interview Survey Wave 3, which is representative of the non-institutionalized general population of Catalonia, Spain. A total of 1,900 participants 15+ years of age were interviewed. The Spanish version of WEMWBS was administered together with socioeconomic and health-related variables, with a hypothesized level of association.

Results

Similar to the original, confirmatory factor analysis fits a one-factor model adequately (CFI = 0.974; TLI = 0.970; RMSEA = 0.059; χ ² = 584.82; df = 77; p < .001) and has a high internal consistency (Cronbach’s alpha = 0.930; Guttman’s lambda 2 = 0.932). The WEMWBS discriminated between population groups in all health-related and socioeconomic variables, except in gender (p = 0.119), with a magnitude similar to that hypothesized. Overall, mental well-being was higher for the general population of Catalonia (average and whole distribution) than that for Scotland general population.

Conclusions

The Spanish version of WEMWBS showed good psychometric properties similar to the UK original scale. Whether better mental well-being in Catalonia is due to methodological or substantive cultural, social, or environmental factors should be further researched.     

In vitro batch cultures of gut microbiota from healthy and ulcerative colitis (UC) subjects suggest that sulphate-reducing bacteria levels are raised in UC and by a protein-rich diet

Imbalances in gut microbiota composition during ulcerative colitis (UC) indicate a role for the microbiota in propagating the disorder. Such effects were investigated using in vitro batch cultures (with/without mucin, peptone or starch) inoculated with faecal slurries from healthy or UC patients; the growth of five bacterial groups was monitored along with short-chain fatty acid (SCFA) production. Healthy cultures gave two-fold higher growth and SCFA levels with up to ten-fold higher butyrate production. Starch gave the highest growth and SCFA production (particularly butyrate), indicating starch-enhanced saccharolytic activity. Sulphate-reducing bacteria (SRB) were the predominant bacterial group (of five examined) for UC inocula whereas they were the minority group for the healthy inocula. Furthermore, SRB growth was stimulated by peptone presumably due to the presence of sulphur-rich amino acids. The results suggest raised SRB levels in UC, which could contribute to the condition through release of toxic sulphide.