To screen or not to screen for peripheral arterial disease in subjects aged 80 and over in primary health care: a cross-sectional analysis from the BELFRAIL study

<p>Abstract</p> <p>Background</p> <p>Peripheral arterial disease (PAD) is common in older people. An ankle-brachial index (ABI) < 0.9 can be used as an indicator of PAD. Patients with low ABI have increased mortality and a higher risk of serious cardiovascular morbidity. However, because 80% of the patients are asymptomatic, PAD remains unrecognised in a large group of patients. The aims of this study were 1) to examine the prevalence of reduced ABI in subjects aged 80 and over, 2) to determine the diagnostic accuracy of the medical history and clinical examination for reduced ABI and 3) to investigate the difference in functioning and physical activity between patients with and without reduced ABI.</p> <p>Methods</p> <p>A cross-sectional study embedded within the BELFRAIL study. A general practitioner (GP) centre, located in Hoeilaart, Belgium, recruited 239 patients aged 80 or older. Only three criteria for exclusion were used: urgent medical need, palliative situation and known serious dementia. The GP recorded the medical history and performed a clinical examination. The clinical research assistant performed an extensive examination including Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS-15), Activities of Daily Living (ADL), Tinetti test and the LASA Physical Activity Questionnaire (LAPAQ). ABI was measured using an automatic oscillometric appliance.</p> <p>Results</p> <p>In 40% of patients, a reduced ABI was found. Cardiovascular risk factors were unable to identify patients with low ABI. A negative correlation was found between the number of cardiovascular morbidities and ABI. Cardiovascular morbidity had a sensitivity of 65.7% (95% CI 53.4-76.7) and a specificity of 48.6% (95% CI 38.7-58.5). Palpation of the peripheral arteries showed the highest negative predictive value (77.7% (95% CI 71.8-82.9)). The LAPAQ score was significantly lower in the group with reduced ABI.</p> <p>Conclusion</p> <p>The prevalence of PAD is very high in patients aged 80 and over in general practice. The clinical examination, cardiovascular risk factors and the presence of cardiovascular morbidity were not able to identify patients with a low ABI. A screening strategy for PAD by determining ABI could be considered if effective interventions for those aged 80 and over with a low ABI become available through future research.</p

Synergistic Antitumor Effects of Novel HDAC Inhibitors and Paclitaxel In Vitro and In Vivo

Preclinical studies support the therapeutic potential of histone deacetylases inhibitors (HDACi) in combination with taxanes. The efficacy of combination has been mainly ascribed to a cooperative effect on microtubule stabilization following tubulin acetylation. In the present study we investigated the effect of paclitaxel in combination with two novel HDACi, ST2782 or ST3595, able to induce p53 and tubulin hyperacetylation. A synergistic effect of the paclitaxel/ST2782 (or ST3595) combination was found in wild-type p53 ovarian carcinoma cells, but not in a p53 mutant subline, in spite of a marked tubulin acetylation. Such a synergistic interaction was confirmed in additional human solid tumor cell lines harboring wild-type p53 but not in those expressing mutant or null p53. In addition, a synergistic cytotoxic effect was found when ST2782 was combined with the depolymerising agent vinorelbine. In contrast to SAHA, which was substantially less effective in sensitizing cells to paclitaxel-induced apoptosis, ST2782 prevented up-regulation of p21WAF1/Cip1 by paclitaxel, which has a protective role in response to taxanes, and caused p53 down-regulation, acetylation and mitochondrial localization of acetylated p53. The synergistic antitumor effects of the paclitaxel/ST3595 combination were confirmed in two tumor xenograft models. Our results support the relevance of p53 modulation as a major determinant of the synergistic interaction observed between paclitaxel and novel HDACi and emphasize the therapeutic interest of this combination

Viruses Associated with Ovarian Degeneration in Apis mellifera L. Queens

Queen fecundity is a critical issue for the health of honeybee (Apis mellifera L.) colonies, as she is the only reproductive female in the colony and responsible for the constant renewal of the worker bee population. Any factor affecting the queen's fecundity will stagnate colony development, increasing its susceptibility to opportunistic pathogens. We discovered a pathology affecting the ovaries, characterized by a yellow discoloration concentrated in the apex of the ovaries resulting from degenerative lesions in the follicles. In extreme cases, marked by intense discoloration, the majority of the ovarioles were affected and these cases were universally associated with egg-laying deficiencies in the queens. Microscopic examination of the degenerated follicles showed extensive paracrystal lattices of 30 nm icosahedral viral particles. A cDNA library from degenerated ovaries contained a high frequency of deformed wing virus (DWV) and Varroa destructor virus 1 (VDV-1) sequences, two common and closely related honeybee Iflaviruses. These could also be identified by in situ hybridization in various parts of the ovary. A large-scale survey for 10 distinct honeybee viruses showed that DWV and VDV-1 were by far the most prevalent honeybee viruses in queen populations, with distinctly higher prevalence in mated queens (100% and 67%, respectively for DWV and VDV-1) than in virgin queens (37% and 0%, respectively). Since very high viral titres could be recorded in the ovaries and abdomens of both functional and deficient queens, no significant correlation could be made between viral titre and ovarian degeneration or egg-laying deficiency among the wider population of queens. Although our data suggest that DWV and VDV-1 have a role in extreme cases of ovarian degeneration, infection of the ovaries by these viruses does not necessarily result in ovarian degeneration, even at high titres, and additional factors are likely to be involved in this pathology

Validation of the MethylationEPIC BeadChip for fresh-frozen and formalin-fixed paraffin-embedded tumours

Abstract DNA methylation is the most studied epigenetic modification due to its role in regulating gene expression, and its involvement in the pathogenesis of cancer and several diseases upon aberrations in methylation. The method of choice to evaluate genome-wide methylation has been the Illumina HumanMethylation450 BeadChip (450K), but it was recently replaced with the MethylationEPIC BeadChip (EPIC). We therefore sought to validate the EPIC array in comparison to the 450K array for both fresh-frozen (FF) and formalin-fixed paraffin-embedded (FFPE) tumours. We also performed analysis on the EPIC array with paired FF and FFPE samples to adapt to a clinical setting where FFPE is routinely used. Further, we compared two restoration methods, REPLI-g and Infinium, for FFPE-derived DNA on the EPIC array. The Pearson correlation of β values for common probes on the 450K and EPIC array was high for both FF (mean: 0.992) and FFPE (mean: 0.984) samples. The β values generated from the EPIC array for FFPE samples correlated well with the paired FF tumours, but varied between 0.901 and 0.987. We did note that sample pairs with lower correlation had less bimodal density distributions of β values and displayed higher noise in the copy number alteration plots (generated from the methylation array data) in the FFPE sample. Both REPLI-g and the Infinium restoration for FFPE samples performed well on the EPIC array and generated equivalent correlation scores to the paired FF sample