The feasibility of a cognitive behavioural therapy group for men with mild/moderate cognitive impairment

Memory aid groups have often been used as a method for teaching mnemonic strategies to older adults in early stages of dementia. This study describes the use of CBT to address unhelpful memory-related beliefs in three older men with mild/moderate dementia and associated low mood or anxiety. The members were able to participate and engage in the sessions, and changes in behaviour, cognition and affect were monitored over the course of a 7 week group intervention. Recommendations are made for further research

Telomere-based proliferative lifespan barriers in Werner-syndrome fibroblasts involve both p53-dependent and p53-independent mechanisms

Werner-syndrome fibroblasts have a reduced in vitro life span before entering replicative senescence. Although this has been thought to be causal in the accelerated ageing of this disease, controversy remains as to whether Werner syndrome is showing the acceleration of a normal cellular ageing mechanism or the occurrence of a novel Werner-syndrome-specific process. Here, we analyse the signalling pathways responsible for senescence in Werner-syndrome fibroblasts. Cultured Werner-syndrome (AG05229) fibroblasts senesced after approximately 20 population doublings with most of the cells having a 2N content of DNA. This was associated with hypophosphorylated pRb and high levels of p16(Ink4a) and p21(Waf1). Senescent AG05229 cells re-entered the cell cycle following microinjection of a p53-neutralizing antibody. Similarly, production of the human papilloma virus 16 E6 oncoprotein in presenescent AG05229 cells resulted in senescence being bypassed and extended cellular life span. Werner-syndrome fibroblasts expressing E6 did not proliferate indefinitely but reached a second proliferative lifespan barrier, termed M(int), that could be bypassed by forced production of telomerase in post-M1 E6-producing cells. The conclusions from these studies are that: (1) replicative senescence in Werner-syndrome fibroblasts is a telomere-induced p53-dependent event; and (2) the intermediate lifespan barrier M(int) is also a telomere-induced event, although it appears to be independent of p53. Werner-syndrome fibroblasts resemble normal human fibroblasts for both these proliferative lifespan barriers, with the strong similarity between the signalling pathway linking telomeres to cell-cycle arrest in Werner-syndrome and normal fibroblasts providing further support for the defect in Werner syndrome causing the acceleration of a normal ageing mechanism

Cube law, condition factor and weight-length relationships: history, meta-analysis and recommendations

This study presents a historical review, a meta-analysis, and recommendations for users about weight–length relationships, condition factors and relative weight equations. The historical review traces the developments of the respective concepts. The meta-analysis explores 3929 weight–length relationships of the type W = aLb for 1773 species of fishes. It shows that 82% of the variance in a plot of log a over b can be explained by allometric versus isometric growth patterns and by different body shapes of the respective species. Across species median b = 3.03 is significantly larger than 3.0, thus indicating a tendency towards slightly positive-allometric growth (increase in relative body thickness or plumpness) in most fishes. The expected range of 2.5 < b < 3.5 is confirmed. Mean estimates of b outside this range are often based on only one or two weight–length relationships per species. However, true cases of strong allometric growth do exist and three examples are given. Within species, a plot of log a vs b can be used to detect outliers in weight–length relationships. An equation to calculate mean condition factors from weight–length relationships is given as Kmean = 100aLb−3. Relative weight Wrm = 100W/(amLbm) can be used for comparing the condition of individuals across populations, where am is the geometric mean of a and bm is the mean of b across all available weight–length relationships for a given species. Twelve recommendations for proper use and presentation of weight–length relationships, condition factors and relative weight are given

Investigating the role of c-Jun N-terminal kinases in the proliferation of Werner syndrome fibroblasts using diaminopyridine inhibitors

Fibroblasts derived from the progeroid Werner syndrome show reduced replicative lifespan and a "stressed" morphology, both alleviated using the MAP kinase inhibitor SB203580. However, interpretation of these data is problematical because although SB203580 has the stress-activated kinases p38 and JNK1/2 as its preferred targets, it does show relatively low overall kinase selectivity. Several lines of data support a role for both p38 and JNK1/2 activation in the control of cellular proliferation and also the pathology of diseases of ageing, including type II diabetes, diseases to which Werner Syndrome individuals are prone, thus making the use of JNK inhibitors attractive as possible therapeutics. We have thus tested the effects of the widely used JNK inhibitor SP600125 on the proliferation and morphology of WS cells. In addition we synthesised and tested two recently described aminopyridine based inhibitors. SP600125 treatment resulted in the cessation of proliferation of WS cells and resulted in a senescent-like cellular phenotype that does not appear to be related to the inhibition of JNK1/2. In contrast, use of the more selective aminopyridine CMPD 6o at concentrations that fully inhibit JNK1/2 had a positive effect on cellular proliferation of immortalised WS cells, but no effect on the replicative lifespan of primary WS fibroblasts. In addition, CMPD 6o corrected the stressed WS cellular morphology. The aminopyridine CMPD 6r, however, had little effect on WS cells. CMDP 6o was also found to be a weak inhibitor of MK2, which may partially explain its effects on WS cells, since MK2 is known to be involved in regulating cellular morphology via HSP27 phosphorylation, and is thought to play a role in cell cycle arrest. These data suggest that total JNK1/2 activity does not play a substantial role in the proliferation control in WS cells

Small molecule targeting of the p38/Mk2 stress signaling pathways to improve cancer treatment

Purpose: Although a long-term goal of cancer therapy always has been the development of agents that selectively destroy cancer cells, more recent trends have been to seek secondary agents that sensitize cancer cells to existing treatment regimens. In this regard, the present study explored the possibility of using small molecule inhibitors of p38MAPK/MK2 stress signaling pathways as potential agents to enhance the sensitivity of cancer cells with abrogated G1 checkpoint to the DNA damaging agent etoposide by specifically targeting the DNA damage-induced G2 cell cycle checkpoint. Methods: We have applied CCK8 and FACS-based viability assays and cell cycle analysis to investigate the effect of small molecules SB203580 and MK2.III on the sensitivity of small cell lung cancer cells (SCLC) that lack the G1 checkpoint to the DNA damaging agent Etoposide when used in combination. We have also assessed the effectiveness of combination chemotherapy on tumor xenograft suppression with etoposide and MK2.III in immunosuppressed mice. In addition, additional CCK8 cell viability analysis of the MDA-MB-231 breast cancer cell line, and SW620, and SW480 colorectal cancer cell lines was performed. Results: Results suggest that etoposide produces a profound effect on the cell cycle profile of cells in a manner that is consistent with the degree of cell viability that is seen using the viable cell assay. Results of the co-treatment experiments revealed that the p38/MK2 kinase inhibitors SB203580 and MK2.III both enhanced the DNA-damaging effects of etoposide on NCI-H69 cell viability in vitro. Results revealed that in vivo MK2.III was able to act as a chemosensitizer when used in combination with etoposide making NCI-H69 lung cancer cells sensitive to chemotherapeutic drug by 45% compared to single usage of the drug. We also report that MK2.III sensitizes metastatic cell lines SW-620 and MDA-MB-231 to etoposide but does not increase the sensitivity of non-metastasizing SW-480 colorectal cells to DNA damaging agent in vitro. Conclusion: Findings reported in this study provide evidence that specific inhibitors of MK2 may indeed improve overall cancer therapy; however, their effectiveness depends on cell types

Challenges in constraining anthropogenic aerosol effects on cloud radiative forcing using present-day spatiotemporal variability

This is the final version. Available from National Academy of Sciences via the DOI in this recordA large number of processes are involved in the chain from emissions of aerosol precursor gases and primary particles to impacts on cloud radiative forcing. Those processes are manifest in a number of relationships that can be expressed as factors dlnX/dlnY driving aerosol effects on cloud radiative forcing. These factors include the relationships between cloud condensation nuclei (CCN) concentration and emissions, droplet number and CCN concentration, cloud fraction and droplet number, cloud optical depth and droplet number, and cloud radiative forcing and cloud optical depth. The relationship between cloud optical depth and droplet number can be further decomposed into the sum of two terms involving the relationship of droplet effective radius and cloud liquid water path with droplet number. These relationships can be constrained using observations of recent spatial and temporal variability of these quantities. However, we are most interested in the radiative forcing since the preindustrial era. Because few relevant measurements are available from that era, relationships from recent variability have been assumed to be applicable to the preindustrial to present-day change. Our analysis of Aerosol Comparisons between Observations and Models (AeroCom) model simulations suggests that estimates of relationships from recent variability are poor constraints on relationships from anthropogenic change for some terms, with even the sign of some relationships differing in many regions. Proxies connecting recent spatial/temporal variability to anthropogenic change, or sustained measurements in regions where emissions have changed, are needed to constrain estimates of anthropogenic aerosol impacts on cloud radiative forcing.The Pacific Northwest National Laboratory (PNNL) is operated for the Department of Energy (DOE) by Battelle Memorial Institute under Contract DE-AC06-76RLO 1830. Work at PNNL was supported by the US DOE Decadal and Regional Climate Prediction using Earth System Models program and by the US DOE Earth System Modeling program. Work of M.W. and S.Z. performed at Nanjing University was supported by the One Thousand Young Talent Program, Jiangsu Province Specially-Appointed Professor Grant, and the National Natural Science Foundation of China (41575073). A portion of this research was performed using PNNL Institutional Computing resources. The ECHAM6-HAM model was developed by a consortium composed of ETH Zurich, Max Planck Institut für Meteorologie, Forschungszentrum Jülich, University of Oxford, the Finnish Meteorological Institute, and the Leibniz Institute for Tropospheric Research, and is managed by the Center for Climate Systems Modeling (C2SM) at ETH Zurich. D.N. acknowledges support by the Austrian Science Fund (J 3402-N29, Erwin Schrödinger Fellowship Abroad). C2SM at ETH Zurich is acknowledged for providing technical and scientific support. This work was also supported by a grant from the Swiss National Supercomputing Centre under Project ID s431. D.G.P. and P.S. acknowledge support from the United Kingdom (UK) Natural Environment Research Council Grant NE/I020148/1. P.S. and Z.K. acknowledge funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007–2013) ERC project ACCLAIM (Grant Agreement FP7-280025). The development of modal version of the GLObal Model of Aerosol Processes (GLOMAP-mode) within Hadley Center Global Environmental Mode (HadGEM) is part of the United Kingdom Chemistry and Aerosols (UKCA) project, which is supported by both National Environmental Research Council (NERC) and the Joint Department of Energy & Climate Change/Department for Environment, Food & Rural Affairs Meteorology Office Hadley Centre Climate Programme. We acknowledge use of the Met Office and NERC MONSooN high performance computing system, a collaborative facility supplied under the Joint Weather and Climate Research Programme, a strategic partnership between the Met Office and the NERC. Simulations by SPRINTARS were executed with the supercomputer system SX-9/ACE of the National Institute for Environmental Studies, Japan. SPRINTARS is partly supported by the Environment Research and Technology Development Fund (S-12-3) of the Ministry of the Environment, Japan and Japan Society for the Promotion of Science KAKENHI Grants-in-Aid for Scientific Research 15H01728 and 15K12190. Computing resources for CAM5-MG2 simulations were provided by the Climate Simulation Laboratory at National Center for Atmospheric Research (NCAR) Computational and Information Systems Laboratory. NCAR is sponsored by the US National Science Foundation

Homophily and Contagion Are Generically Confounded in Observational Social Network Studies

We consider processes on social networks that can potentially involve three factors: homophily, or the formation of social ties due to matching individual traits; social contagion, also known as social influence; and the causal effect of an individual's covariates on their behavior or other measurable responses. We show that, generically, all of these are confounded with each other. Distinguishing them from one another requires strong assumptions on the parametrization of the social process or on the adequacy of the covariates used (or both). In particular we demonstrate, with simple examples, that asymmetries in regression coefficients cannot identify causal effects, and that very simple models of imitation (a form of social contagion) can produce substantial correlations between an individual's enduring traits and their choices, even when there is no intrinsic affinity between them. We also suggest some possible constructive responses to these results.Comment: 27 pages, 9 figures. V2: Revised in response to referees. V3: Ditt

Maternal deaths in Pakistan : intersection of gender, class and social exclusion.

Background: A key aim of countries with high maternal mortality rates is to increase availability of competent maternal health care during pregnancy and childbirth. Yet, despite significant investment, countries with the highest burdens have not reduced their rates to the expected levels. We argue, taking Pakistan as a case study, that improving physical availability of services is necessary but not sufficient for reducing maternal mortality because gender inequities interact with caste and poverty to socially exclude certain groups of women from health services that are otherwise physically available. Methods: Using a critical ethnographic approach, two case studies of women who died during childbirth were pieced together from information gathered during the first six months of fieldwork in a village in Northern Punjab, Pakistan. Findings: Shida did not receive the necessary medical care because her heavily indebted family could not afford it. Zainab, a victim of domestic violence, did not receive any medical care because her martial family could not afford it, nor did they think she deserved it. Both women belonged to lower caste households, which are materially poor households and socially constructed as inferior. Conclusions: The stories of Shida and Zainab illustrate how a rigidly structured caste hierarchy, the gendered devaluing of females, and the reinforced lack of control that many impoverished women experience conspire to keep women from lifesaving health services that are physically available and should be at their disposal