Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence.

Tobacco dependence is a leading cause of preventable disease and death worldwide. Nicotine, the main psychoactive component in tobacco cigarettes, has also been garnering increased popularity in its vaporized form, as derived from e-cigarette devices. Thus, an understanding of the molecular mechanisms underlying nicotine pharmacology and dependence is required to ascertain novel approaches to treat drug dependence. In this chapter, we review the field's current understanding of nicotine's actions in the brain, the neurocircuitry underlying drug dependence, factors that modulate the function of nicotinic acetylcholine receptors, and the role of specific genes in mitigating the vulnerability to develop nicotine dependence. In addition to nicotine's direct actions in the brain, other constituents in nicotine and tobacco products have also been found to alter drug use, and thus, evidence is provided to highlight this issue. Finally, currently available pharmacotherapeutic strategies are discussed, along with an outlook for future therapeutic directions to achieve to the goal of long-term nicotine cessation

Identification of Candida glabrata genes involved in pH modulation and modification of the phagosomal environment in macrophages

notes: PMCID: PMC4006850types: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov'tCandida glabrata currently ranks as the second most frequent cause of invasive candidiasis. Our previous work has shown that C. glabrata is adapted to intracellular survival in macrophages and replicates within non-acidified late endosomal-stage phagosomes. In contrast, heat killed yeasts are found in acidified matured phagosomes. In the present study, we aimed at elucidating the processes leading to inhibition of phagosome acidification and maturation. We show that phagosomes containing viable C. glabrata cells do not fuse with pre-labeled lysosomes and possess low phagosomal hydrolase activity. Inhibition of acidification occurs independent of macrophage type (human/murine), differentiation (M1-/M2-type) or activation status (vitamin D3 stimulation). We observed no differential activation of macrophage MAPK or NFκB signaling cascades downstream of pattern recognition receptors after internalization of viable compared to heat killed yeasts, but Syk activation decayed faster in macrophages containing viable yeasts. Thus, delivery of viable yeasts to non-matured phagosomes is likely not triggered by initial recognition events via MAPK or NFκB signaling, but Syk activation may be involved. Although V-ATPase is abundant in C. glabrata phagosomes, the influence of this proton pump on intracellular survival is low since blocking V-ATPase activity with bafilomycin A1 has no influence on fungal viability. Active pH modulation is one possible fungal strategy to change phagosome pH. In fact, C. glabrata is able to alkalinize its extracellular environment, when growing on amino acids as the sole carbon source in vitro. By screening a C. glabrata mutant library we identified genes important for environmental alkalinization that were further tested for their impact on phagosome pH. We found that the lack of fungal mannosyltransferases resulted in severely reduced alkalinization in vitro and in the delivery of C. glabrata to acidified phagosomes. Therefore, protein mannosylation may play a key role in alterations of phagosomal properties caused by C. glabrata.Deutsche ForschungsgemeinschaftNational Institutes for HealthWellcome TrustBBSR

Contributions of high- and low-quality patches to a metapopulation with stochastic disturbance

© The Author(s), 2010. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Theoretical Ecology 5 (2012): 167-179, doi:10.1007/s12080-010-0106-9.Studies of time-invariant matrix metapopulation models indicate that metapopulation growth rate is usually more sensitive to the vital rates of individuals in high-quality (i.e., good) patches than in low-quality (i.e., bad) patches. This suggests that, given a choice, management efforts should focus on good rather than bad patches. Here, we examine the sensitivity of metapopulation growth rate for a two-patch matrix metapopulation model with and without stochastic disturbance and found cases where managers can more efficiently increase metapopulation growth rate by focusing efforts on the bad patch. In our model, net reproductive rate differs between the two patches so that in the absence of dispersal, one patch is high quality and the other low quality. Disturbance, when present, reduces net reproductive rate with equal frequency and intensity in both patches. The stochastic disturbance model gives qualitatively similar results to the deterministic model. In most cases, metapopulation growth rate was elastic to changes in net reproductive rate of individuals in the good patch than the bad patch. However, when the majority of individuals are located in the bad patch, metapopulation growth rate can be most elastic to net reproductive rate in the bad patch. We expand the model to include two stages and parameterize the patches using data for the softshell clam, Mya arenaria. With a two-stage demographic model, the elasticities of metapopulation growth rate to parameters in the bad patch increase, while elasticities to the same parameters in the good patch decrease. Metapopulation growth rate is most elastic to adult survival in the population of the good patch for all scenarios we examine. If the majority of the metapopulation is located in the bad patch, the elasticity to parameters of that population increase but do not surpass elasticity to parameters in the good patch. This model can be expanded to include additional patches, multiple stages, stochastic dispersal, and complex demography.Financial support was provided by the Woods Hole Oceanographic Institution Academic Programs Office; National Science Foundation grants OCE-0326734, OCE- 0215905, OCE-0349177, DEB-0235692, DEB-0816514, DMS- 0532378, OCE-1031256, and ATM-0428122; and by National Oceanic and Atmospheric Administration National Sea Grant College Program Office, Department of Commerce, under Grant No. NA86RG0075 (Woods Hole Oceanographic Institution Sea Grant Project No. R/0-32), and Grant No. NA16RG2273 (Woods Hole Oceanographic Institution Sea Grant Project No. R/0-35)

Validity and usefulness of members reports of implementation progress in a quality improvement initiative: findings from the Team Check-up Tool (TCT)

<p>Abstract</p> <p>Background</p> <p>Team-based interventions are effective for improving safety and quality of healthcare. However, contextual factors, such as team functioning, leadership, and organizational support, can vary significantly across teams and affect the level of implementation success. Yet, the science for measuring context is immature. The goal of this study is to validate measures from a short instrument tailored to track dynamic context and progress for a team-based quality improvement (QI) intervention.</p> <p>Methods</p> <p>Design: Secondary cross-sectional and longitudinal analysis of data from a clustered randomized controlled trial (RCT) of a team-based quality improvement intervention to reduce central line-associated bloodstream infection (CLABSI) rates in intensive care units (ICUs).</p> <p>Setting: Forty-six ICUs located within 35 faith-based, not-for-profit community hospitals across 12 states in the U.S.</p> <p>Population: Team members participating in an ICU-based QI intervention.</p> <p>Measures: The primary measure is the Team Check-up Tool (TCT), an original instrument that assesses context and progress of a team-based QI intervention. The TCT is administered monthly. Validation measures include CLABSI rate, Team Functioning Survey (TFS) and Practice Environment Scale (PES) from the Nursing Work Index.</p> <p>Analysis: Temporal stability, responsiveness and validity of the TCT.</p> <p>Results</p> <p>We found evidence supporting the temporal stability, construct validity, and responsiveness of TCT measures of intervention activities, perceived group-level behaviors, and barriers to team progress.</p> <p>Conclusions</p> <p>The TCT demonstrates good measurement reliability, validity, and responsiveness. By having more validated measures on implementation context, researchers can more readily conduct rigorous studies to identify contextual variables linked to key intervention and patient outcomes and strengthen the evidence base on successful spread of efficacious team-based interventions. QI teams participating in an intervention should also find data from a validated tool useful for identifying opportunities to improve their own implementation.</p

Organizational culture, team climate and diabetes care in small office-based practices

Contains fulltext : 71456.pdf ( ) (Open Access)BACKGROUND: Redesigning care has been proposed as a lever for improving chronic illness care. Within primary care, diabetes care is the most widespread example of restructured integrated care. Our goal was to assess to what extent important aspects of restructured care such as multidisciplinary teamwork and different types of organizational culture are associated with high quality diabetes care in small office-based general practices. METHODS: We conducted cross-sectional analyses of data from 83 health care professionals involved in diabetes care from 30 primary care practices in the Netherlands, with a total of 752 diabetes mellitus type II patients participating in an improvement study. We used self-reported measures of team climate (Team Climate Inventory) and organizational culture (Competing Values Framework), and measures of quality of diabetes care and clinical patient characteristics from medical records and self-report. We conducted multivariate analyses of the relationship between culture, climate and HbA1c, total cholesterol, systolic blood pressure and a sum score on process indicators for the quality of diabetes care, adjusting for potential patient- and practice level confounders and practice-level clustering. RESULTS: A strong group culture was negatively associated to the quality of diabetes care provided to patients (beta = -0.04; p = 0.04), whereas a more 'balanced culture' was positively associated to diabetes care quality (beta = 5.97; p = 0.03). No associations were found between organizational culture, team climate and clinical patient outcomes. CONCLUSION: Although some significant associations were found between high quality diabetes care in general practice and different organizational cultures, relations were rather marginal. Variation in clinical patient outcomes could not be attributed to organizational culture or teamwork. This study therefore contributes to the discussion about the legitimacy of the widespread idea that aspects of redesigning care such as teamwork and culture can contribute to higher quality of care. Future research should preferably combine quantitative and qualitative methods, focus on possible mediating or moderating factors and explore the use of instruments more sensitive to measure such complex constructs in small office-based practices

Iron chelation therapy in the myelodysplastic syndromes and aplastic anemia: a review of experience in South Korea

Emerging clinical data indicate that transfusion-dependent patients with bone marrow-failure syndromes (BMFS) are at risk of the consequences of iron overload, including progressive damage to hepatic, endocrine, and cardiac organs. Despite the availability of deferoxamine (DFO) in Korea since 1998, data from patients with myelodysplastic syndromes, aplastic anemia, and other BMFS show significant iron overload and damage to the heart and liver. The recent introduction of deferasirox, a once-daily, oral iron chelator, may improve the availability of iron chelation therapy to iron-overloaded patients, and improve compliance in patients who may otherwise find adherence to the DFO regimen difficult