Aging and Replicative Senescence Have Related Effects on Human Stem and Progenitor Cells

The regenerative potential diminishes with age and this has been ascribed to functional impairments of adult stem cells. Cells in culture undergo senescence after a certain number of cell divisions whereby the cells enlarge and finally stop proliferation. This observation of replicative senescence has been extrapolated to somatic stem cells in vivo and might reflect the aging process of the whole organism. In this study we have analyzed the effect of aging on gene expression profiles of human mesenchymal stromal cells (MSC) and human hematopoietic progenitor cells (HPC). MSC were isolated from bone marrow of donors between 21 and 92 years old. 67 genes were age-induced and 60 were age-repressed. HPC were isolated from cord blood or from mobilized peripheral blood of donors between 27 and 73 years and 432 genes were age-induced and 495 were age-repressed. The overlap of age-associated differential gene expression in HPC and MSC was moderate. However, it was striking that several age-related gene expression changes in both MSC and HPC were also differentially expressed upon replicative senescence of MSC in vitro. Especially genes involved in genomic integrity and regulation of transcription were age-repressed. Although telomerase activity and telomere length varied in HPC particularly from older donors, an age-dependent decline was not significant arguing against telomere exhaustion as being causal for the aging phenotype. These studies have demonstrated that aging causes gene expression changes in human MSC and HPC that vary between the two different cell types. Changes upon aging of MSC and HPC are related to those of replicative senescence of MSC in vitro and this indicates that our stem and progenitor cells undergo a similar process also in vivo

Synchronous malignant B-cell lymphoma and gastric tubular adenocarcinoma associated with paraneoplastic cutaneous vasculitis: hypereosinophilic syndrome with mixed cryoglobulinemia is an important sign of paraneoplastic syndrome

Gastric adenocarcinoma developing concomitantly with a lymphoma is rare. Furthermore, B-cell lymphoma, originating from lymph nodes, with eosinophilia is extremely rare. We report here a case with a synchronous diffuse large B-cell lymphoma (DLBCL) and an early adenocarcinoma of the stomach. In addition, this case seemed to be associated with paraneoplastic cutaneous vasculitis caused by hypereosinophilic syndrome (HES) with mixed cryoglobulinemia (MC). Many neoplastic diseases that affect internal organs display cutaneous manifestations, which may be the presenting signs and symptoms of the underlying malignancy. In particular, the association between cutaneous vasculitis and malignancy has been widely reviewed, and recently neoplasms have been suggested to produce antigens and the resultant immune complex formations, activating the serum complement, thus cause paraneoplastic vasculitis. In this case, severe eosinophilia and cryoglobulinemia with low complements were observed in a laboratory test. A biopsy specimen from a skin lesion revealed leukocytoclastic vasculitis with severe perivascular infiltration of eosinophils. The cutaneous vasuculitis was considered to be a manifestation of HES with MC, although there were no etiological factors of HES and MC. Therefore, the vasculitis seems to be a symptom of paraneoplastic syndrome in this case. Our finding suggests that the potential presence of malignancies should be kept in mind as a possible underlying disorder especially in the presence of HES with MC; this possibility is interesting also as regards at least part of the pathogenesis for paraneplastic syndrome

Cell Cycle- and Cancer-Associated Gene Networks Activated by Dsg2: Evidence of Cystatin A Deregulation and a Potential Role in Cell-Cell Adhesion

This work was supported by grants from the National Institutes of Health (Mahoney, R01AR056067; Riobo, RO1 GM088256). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Reproducibility of telomere length assessment: an international collaborative study

BACKGROUND: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories. METHODS: We instigated an international collaborative study of telomere length assessment: 10 different laboratories, employing 3 different techniques [Southern blotting, single telomere length analysis (STELA) and real-time quantitative PCR (qPCR)] performed two rounds of fully blinded measurements on 10 human DNA samples per round to enable unbiased assessment of intra- and inter-batch variation between laboratories and techniques. RESULTS: Absolute results from different laboratories differed widely and could thus not be compared directly, but rankings of relative telomere lengths were highly correlated (correlation coefficients of 0.63-0.99). Intra-technique correlations were similar for Southern blotting and qPCR and were stronger than inter-technique ones. However, inter-laboratory coefficients of variation (CVs) averaged about 10% for Southern blotting and STELA and more than 20% for qPCR. This difference was compensated for by a higher dynamic range for the qPCR method as shown by equal variance after z-scoring. Technical variation per laboratory, measured as median of intra- and inter-batch CVs, ranged from 1.4% to 9.5%, with differences between laboratories only marginally significant (P = 0.06). Gel-based and PCR-based techniques were not different in accuracy. CONCLUSIONS: Intra- and inter-laboratory technical variation severely limits the usefulness of data pooling and excludes sharing of reference ranges between laboratories. We propose to establish a common set of physical telomere length standards to improve comparability of telomere length estimates between laboratories

Association between loop diuretic dose changes and outcomes in chronic heart failure: observations from the ESC-EORP Heart Failure Long-Term Registry

[Abstract] Aims. Guidelines recommend down-titration of loop diuretics (LD) once euvolaemia is achieved. In outpatients with heart failure (HF), we investigated LD dose changes in daily cardiology practice, agreement with guideline recommendations, predictors of successful LD down-titration and association between dose changes and outcomes. Methods and results. We included 8130 HF patients from the ESC-EORP Heart Failure Long-Term Registry. Among patients who had dose decreased, successful decrease was defined as the decrease not followed by death, HF hospitalization, New York Heart Association class deterioration, or subsequent increase in LD dose. Mean age was 66±13 years, 71% men, 62% HF with reduced ejection fraction, 19% HF with mid-range ejection fraction, 19% HF with preserved ejection fraction. Median [interquartile range (IQR)] LD dose was 40 (25–80) mg. LD dose was increased in 16%, decreased in 8.3% and unchanged in 76%. Median (IQR) follow-up was 372 (363–419) days. Diuretic dose increase (vs. no change) was associated with HF death [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.12–2.08; P = 0.008] and nominally with cardiovascular death (HR 1.25, 95% CI 0.96–1.63; P = 0.103). Decrease of diuretic dose (vs. no change) was associated with nominally lower HF (HR 0.59, 95% CI 0.33–1.07; P = 0.083) and cardiovascular mortality (HR 0.62 95% CI 0.38–1.00; P = 0.052). Among patients who had LD dose decreased, systolic blood pressure [odds ratio (OR) 1.11 per 10 mmHg increase, 95% CI 1.01–1.22; P = 0.032], and absence of (i) sleep apnoea (OR 0.24, 95% CI 0.09–0.69; P = 0.008), (ii) peripheral congestion (OR 0.48, 95% CI 0.29–0.80; P = 0.005), and (iii) moderate/severe mitral regurgitation (OR 0.57, 95% CI 0.37–0.87; P = 0.008) were independently associated with successful decrease. Conclusion. Diuretic dose was unchanged in 76% and decreased in 8.3% of outpatients with chronic HF. LD dose increase was associated with worse outcomes, while the LD dose decrease group showed a trend for better outcomes compared with the no-change group. Higher systolic blood pressure, and absence of (i) sleep apnoea, (ii) peripheral congestion, and (iii) moderate/severe mitral regurgitation were independently associated with successful dose decrease

Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P\ua0 64 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P\ua0=\ua00.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P\ua075 years. Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF 6445%

Meat Feeding Restricts Rapid Cold Hardening Response and Increases Thermal Activity Thresholds of Adult Blow Flies, Calliphora vicina (Diptera: Calliphoridae)

Virtually all temperate insects survive the winter by entering a physiological state of reduced metabolic activity termed diapause. However, there is increasing evidence that climate change is disrupting the diapause response resulting in non-diapause life stages encountering periods of winter cold. This is a significant problem for adult life stages in particular, as they must remain mobile, periodically feed, and potentially initiate reproductive development at a time when resources should be diverted to enhance stress tolerance. Here we present the first evidence of protein/meat feeding restricting rapid cold hardening (RCH) ability and increasing low temperature activity thresholds. No RCH response was noted in adult female blow flies (Calliphora vicina Robineau-Desvoidy) fed a sugar, water and liver (SWL) diet, while a strong RCH response was seen in females fed a diet of sugar and water (SW) only. The RCH response in SW flies was induced at temperatures as high as 10°C, but was strongest following 3h at 0°C. The CTmin (loss of coordinated movement) and chill coma (final appendage twitch) temperature of SWL females (-0.3 ± 0.5°C and -4.9 ± 0.5°C, respectively) was significantly higher than for SW females (-3.2 ± 0.8°C and -8.5 ± 0.6°C). We confirmed this was not directly the result of altered extracellular K+, as activity thresholds of alanine-fed adults were not significantly different from SW flies. Instead we suggest the loss of cold tolerance is more likely the result of diverting resource allocation to egg development. Between 2009 and 2013 winter air temperatures in Birmingham, UK, fell below the CTmin of SW and SWL flies on 63 and 195 days, respectively, suggesting differential exposure to chill injury depending on whether adults had access to meat or not. We conclude that disruption of diapause could significantly impact on winter survival through loss of synchrony in the timing of active feeding and reproductive development with favourable temperature conditions