When and How Can Death Be an Adaptation?

The concept of phenoptosis (or programmed organismal death) is problematic with respect to most species (including humans) since it implies that dying of old age is an adaptation, which contradicts the established evolutionary theory. But can dying ever be a strategy to promote fitness? Given recent developments in our understanding of the evolution of altruism, particularly kin and multilevel selection theories, it is timely to revisit the possible existence of adaptive death. Here, we discuss how programmed death could be an adaptive trait under certain conditions found in organisms capable of clonal colonial existence, such as the budding yeast Saccharomyces cerevisiae and, perhaps, the nematode Caenorhabditis elegans. The concept of phenoptosis is only tenable if consistent with the evolutionary theory; this accepted, phenoptosis may only occur under special conditions that do not apply to most animal groups (including mammals)

Does senescence promote fitness in Caenorhabditis elegans by causing death?

A widely appreciated conclusion from evolutionary theory is that senescence (aging) is of no adaptive value to the individual that it afflicts. Yet studies of Caenorhabditis elegans and Saccharomyces cerevisiae are increasingly revealing the presence of processes which actively cause senescence and death, leading some biogerontologists to wonder about the established theory. Here we argue that programmed death that increases fitness could occur in C. elegans and S. cerevisiae, and that this is consistent with the classic evolutionary theory of aging. This is because of the special conditions under which these organisms have evolved, particularly the existence of clonal populations with limited dispersal and, in the case of C. elegans, the brevity of the reproductive period caused by protandrous hermaphroditism. Under these conditions, death-promoting mechanisms could promote worm fitness by enhancing inclusive fitness, or worm colony fitness through group selection. Such altruistic, adaptive death is not expected to evolve in organisms with outbred, dispersed populations (e.g. most vertebrate species). The plausibility of adaptive death in C. elegans is supported by computer modelling studies, and new knowledge about the ecology of this species. To support these arguments we also review the biology of adaptive death, and distinguish three forms: consumer sacrifice, biomass sacrifice and defensive sacrifice

Understanding emotionally relevant situations in primary dental practice. 3. Emerging narratives

Background and aims. Dentists experience considerable occupational stress. Stressful clinical situations can provoke high levels of negative emotions, and situations which are associated with positive emotions tend to be overlooked by practitioners. Reflection regarding difficult situations is encouraged to facilitate learning. Cognitive behavioural therapy (CBT) formulations may be applied to situations appraised both positively and negatively. Analysis and interpretation of the dentist's coping behaviour and the consequent outcomes facilitate learning and reflection upon individual interactions with patients. Method. Twenty primary care dental practitioners in the greater Lincoln area participated in a semi-structured interview which explored their stressful and positive clinical experiences. Some of the episodes were analysed to create CBT formulations. Results and discussion. CBT formulations are presented and the learning points highlighted by this structured presentation are discussed. In particular, it is suggested that this structured reconstruction of events, which highlights dentists' emotions, responses and the transactional effects of coping responses, might well facilitate objective reflective learning either individually or as part of peer to peer support. It should facilitate dentists' emotional processing of events and may thus contribute to stress reduction. Conclusion. CBT formulations of positive and negative dental scenarios may be constructed. It is proposed that this is a useful technique to foster reflection and learning in clinical situations and should lead to improved communication skills and shared decision-making, resulting in fewer complaints and thereby reduced stress. It should also improve dentists' emotional processing

How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited

APC Activation Restores Functional CD4+CD25+ Regulatory T Cells in NOD Mice that Can Prevent Diabetes Development

BACKGROUND: Defects in APC and regulatory cells are associated with diabetes development in NOD mice. We have shown previously that NOD APC are not effective at stimulating CD4(+)CD25(+) regulatory cell function in vitro. We hypothesize that failure of NOD APC to properly activate CD4(+)CD25(+) regulatory cells in vivo could compromise their ability to control pathogenic cells, and activation of NOD APC could restore this defect, thereby preventing disease. METHODOLOGY/PRINCIPAL FINDINGS: To test these hypotheses, we used the well-documented ability of complete Freund's adjuvant (CFA), an APC activator, to prevent disease in NOD mice. Phenotype and function of CD4(+)CD25(+) regulatory cells from untreated and CFA-treated NOD mice were determined by FACS, and in vitro and in vivo assays. APC from these mice were also evaluated for their ability to activate regulatory cells in vitro. We have found that sick NOD CD4(+)CD25(+) cells expressed Foxp3 at the same percentages, but decreased levels per cell, compared to young NOD or non-NOD controls. Treatment with CFA increased Foxp3 expression in NOD cells, and also increased the percentages of CD4(+)CD25(+)Foxp3(+) cells infiltrating the pancreas compared to untreated NOD mice. Moreover, CD4(+)CD25(+) cells from pancreatic LN of CFA-treated, but not untreated, NOD mice transferred protection from diabetes. Finally, APC isolated from CFA-treated mice increased Foxp3 and granzyme B expression as well as regulatory function by NOD CD4(+)CD25(+) cells in vitro compared to APC from untreated NOD mice. CONCLUSIONS/SIGNIFICANCE: These data suggest that regulatory T cell function and ability to control pathogenic cells can be enhanced in NOD mice by activating NOD APC

Intensity modulated radiotherapy (IMRT) in patients with carcinomas of the paranasal sinuses: clinical benefit for complex shaped target volumes

INTRODUCTION: The aim of the study was to evaluate the clinical outcome of intensity modulated radiotherapy (IMRT) in 46 patients with paranasal sinus tumors with special respect to treatment-related toxicity. PATIENTS AND METHODS: We treated 46 patients with histologically proven tumors of the paranasal sinuses with IMRT. Histological classification included squamous cell carcinoma in 6, adenocarcinoma in 8, adenoidcystic carcinoma in 20 and melanoma in 8 patients, respectively. Six patients had been treated with RT during initial therapy after primary diagnosis, and IMRT was performed for the treatment of tumor progression as re-irradiation. RESULTS: Overall survival rates were 96% at 1 year, 90% at 3 years. Calculated from the initiation of IMRT as primary radiotherapy, survival rates at 1 and 3 years were 95% and 80%. In six patients IMRT was performed as re-irradiation, and survival rate calculated from re-irradiation was 63% at 1 year. Local control rates were 85% at 1, 81% at 2 and 49% at 3 years after primary RT and 50% at 1 year after re-irradiation. Distant metastases-free survival in patients treated with IMRT as primary RT was 83% after 1 and 64% after 3 years. For patients treated as primary irradiation with IMRT, the distant control rate was 83% at 1 year and 0% at 2 years. No severe radiation-induced side-effects could be observed. CONCLUSION: IMRT for tumors of the paranasal sinuses is associated with very good tumor control rates. Treatment-related acute and long-term toxicity can be minimized as compared to historical results with conventional RT

Replication and Virus-Induced Transcriptome of HAdV-5 in Normal Host Cells versus Cancer Cells - Differences of Relevance for Adenoviral Oncolysis

Adenoviruses (Ads), especially HAdV-5, have been genetically equipped with tumor-restricted replication potential to enable applications in oncolytic cancer therapy. Such oncolytic adenoviruses have been well tolerated in cancer patients, but their anti-tumor efficacy needs to be enhanced. In this regard, it should be considered that cancer cells, dependent on their tissue of origin, can differ substantially from the normal host cells to which Ads are adapted by complex virus-host interactions. Consequently, viral replication efficiency, a key determinant of oncolytic activity, might be suboptimal in cancer cells. Therefore, we have analyzed both the replication kinetics of HAdV-5 and the virus-induced transcriptome in human bronchial epithelial cells (HBEC) in comparison to cancer cells. This is the first report on genome-wide expression profiling of Ads in their native host cells. We found that E1A expression and onset of viral genome replication are most rapid in HBEC and considerably delayed in melanoma cells. In squamous cell lung carcinoma cells, we observed intermediate HAdV-5 replication kinetics. Infectious particle production, viral spread and lytic activity of HAdV-5 were attenuated in melanoma cells versus HBEC. Expression profiling at the onset of viral genome replication revealed that HAdV-5 induced the strongest changes in the cellular transcriptome in HBEC, followed by lung cancer and melanoma cells. We identified prominent regulation of genes involved in cell cycle and DNA metabolism, replication and packaging in HBEC, which is in accord with the necessity to induce S phase for viral replication. Strikingly, in melanoma cells HAdV-5 triggered opposing regulation of said genes and, in contrast to lung cancer cells, no weak S phase induction was detected when using the E2F promoter as reporter. Our results provide a rationale for improving oncolytic adenoviruses either by adaptation of viral infection to target tumor cells or by modulating tumor cell functions to better support viral replication

Assessment of the health of Americans: the average health-related quality of life and its inequality across individuals and groups

BACKGROUND: The assessment of population health has traditionally relied on the population's average health measured by mortality related indicators. Researchers have increasingly recognized the importance of including information on health inequality and health-related quality of life (HRQL) in the assessment of population health. The objective of this study is to assess the health of Americans in the 1990s by describing the average HRQL and its inequality across individuals and groups. METHODS: This study uses the 1990 and 1995 National Health Interview Survey from the United States. The measure of HRQL is the Health and Activity Limitation Index (HALex). The measure of health inequality across individuals is the Gini coefficient. This study provides confidence intervals (CI) for the Gini coefficient by a bootstrap method. To describe health inequality by group, this study decomposes the overall Gini coefficient into the between-group, within-group, and overlap Gini coefficient using race (White, Black, and other) as an example. This study looks at how much contribution the overlap Gini coefficient makes to the overall Gini coefficient, in addition to the absolute mean differences between groups. RESULTS: The average HALex was the same in 1990 (0.87, 95% CI: 0.87, 0.88) and 1995 (0.87, 95% CI: 0.86, 0.87). The Gini coefficient for the HALex distribution across individuals was greater in 1995 (0.097, 95% CI: 0.096, 0.099) than 1990 (0.092, 95% CI: 0.091, 0.094). Differences in the average HALex between all racial groups were the same in 1995 as 1990. The contribution of the overlap to the overall Gini coefficient was greater in 1995 than in 1990 by 2.4%. In both years, inequality between racial groups accounted only for 4–5% of overall inequality. CONCLUSION: The average HRQL of Americans was the same in 1990 and 1995, but inequality in HRQL across individuals was greater in 1995 than 1990. Inequality in HRQL by race was smaller in 1995 than 1990 because race had smaller effect on the way health was distributed in 1995 than 1990. Analysis of the average HRQL and its inequality provides information on the health of a population invisible in the traditional analysis of population health

Describing the impact of health research: a Research Impact Framework

BACKGROUND: Researchers are increasingly required to describe the impact of their work, e.g. in grant proposals, project reports, press releases and research assessment exercises. Specialised impact assessment studies can be difficult to replicate and may require resources and skills not available to individual researchers. Researchers are often hard-pressed to identify and describe research impacts and ad hoc accounts do not facilitate comparison across time or projects. METHODS: The Research Impact Framework was developed by identifying potential areas of health research impact from the research impact assessment literature and based on research assessment criteria, for example, as set out by the UK Research Assessment Exercise panels. A prototype of the framework was used to guide an analysis of the impact of selected research projects at the London School of Hygiene and Tropical Medicine. Additional areas of impact were identified in the process and researchers also provided feedback on which descriptive categories they thought were useful and valid vis-à-vis the nature and impact of their work. RESULTS: We identified four broad areas of impact: I. Research-related impacts; II. Policy impacts; III. Service impacts: health and intersectoral and IV. Societal impacts. Within each of these areas, further descriptive categories were identified. For example, the nature of research impact on policy can be described using the following categorisation, put forward by Weiss: Instrumental use where research findings drive policy-making; Mobilisation of support where research provides support for policy proposals; Conceptual use where research influences the concepts and language of policy deliberations and Redefining/wider influence where research leads to rethinking and changing established practices and beliefs. CONCLUSION: Researchers, while initially sceptical, found that the Research Impact Framework provided prompts and descriptive categories that helped them systematically identify a range of specific and verifiable impacts related to their work (compared to ad hoc approaches they had previously used). The framework could also help researchers think through implementation strategies and identify unintended or harmful effects. The standardised structure of the framework facilitates comparison of research impacts across projects and time, which is useful from analytical, management and assessment perspectives