ADAPTATION AND SENSITIZATION TO PROTEOTOXIC STRESS

Although severe stress can elicit toxicity, mild stress often elicits adaptations. Here we review the literature on stress-induced adaptations versus stress sensitization in models of neurodegenerative diseases. We also describe our recent findings that chronic proteotoxic stress can elicit adaptations if the dose is low but that high-dose proteotoxic stress sensitizes cells to subsequent challenges. In these experiments, long-term, low-dose proteasome inhibition elicited protection in a superoxide dismutase-dependent manner. In contrast, acute, high-dose proteotoxic stress sensitized cells to subsequent proteotoxic challenges by eliciting catastrophic loss of glutathione. However, even in the latter model of synergistic toxicity, several defensive proteins were upregulated by severe proteotoxicity. This led us to wonder whether high-dose proteotoxic stress can elicit protection against subsequent challenges in astrocytes, a cell type well known for their resilience. In support of this new hypothesis, we found that the astrocytes that survived severe proteotoxicity became harder to kill. The adaptive mechanism was glutathione dependent. If these findings can be generalized to the human brain, similar endogenous adaptations may help explain why neurodegenerative diseases are so delayed in appearance and so slow to progress. In contrast, sensitization to severe stress may explain why defenses eventually collapse in vulnerable neurons

Understanding methods of wound debridement

Autolytic debridement describes the body's natural method of wound-bed cleansing, helping it to prepare the wound bed for healing. In acute wounds, autolytic debridement occurs automatically and often does not require intervention, as during the inflammatory stage of a wound, neutrophils and macrophages digest and removes devitalised tissue, cell debris and contaminants, clearing the wound of any cellular barriers to healing. In chronic wounds, by contrast, healing is often delayed, frequently because of inadequate debridement. The autolytic process becomes overwhelmed by high levels of endotoxins released from damaged tissue (Broadus, 2013). Therefore wound debridement becomes an integral part of chronic-wound management and practitioners involved in wound care must be fully competent at wound-bed assessment and have an awareness of the options available for debridement. This article will review wound-bed assessment, highlighting variations in devitalised tissue, and explore options available for wound debridement, taking into consideration patients’ pain and quality of life

Obituary: In Memory of Michael Jonathan Zigmond, Ph.D., September 1, 1941–August 28, 2023

Producción CientíficaNo abstract availabl

A Systematic Review of Psychometric Properties of Health-Related Quality-of-Life and Symptom Instruments in Adult Acute Leukemia Survivors

Acute leukemia represents 4% of cancer cases in the United States (US) annually. There are over 302,000 people living with acute and chronic leukemia in the US. Treatment has been shown to have both positive and negative effects on health-related quality of life (HRQOL)

Quality of life domains among non-Hodgkin lymphoma survivors: an integrative literature review

Survival rates of individuals with non-Hodgkin lymphoma (NHL) have increased in the past several years, as has the prevalence of older adults who are managing late and long-term effects of the disease and its treatment. In this integrative review, the state of the science for determining the quality of life (QOL) among NHL survivors is outlined. An online search of Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, and the Cochrane Library databases was conducted using the following Keywords: non-Hodgkin lymphoma, health-related quality of life, quality of life, and impact of cancer. Eighteen studies published between 2000 and 2010 are reviewed. Of these, 17 were descriptive, cross-sectional designs, and one was a systematic review. The studies included participants of varying ages and years post-diagnosis as reported in several countries. Importantly, many used one or more QOL measures as outcome variables. Future research is needed on older and minority cancer populations and should include longitudinal and interventional studies

Autolysis: mechanisms of action in the removal of devitalised tissue

Chronic wounds affect millions of people worldwide. In the UK alone, the cost of their treatment is estimated to be between £4.5bn and £5.1bn. The implementation of wound-bed preparation strategies remove the barriers to healing and wound debridement is a key component in preparing the wound bed for wound progression. This article aims to review one of the several debridement methods available to clinicians: autolytic debridement. Autolysis (i.e. autolytic debridement) uses the body's own enzymatic mechanisms to remove devitalised tissue in order to remove the barriers to healing. This review aims to provide clinicians working in wound care with a better understanding of the mechanisms and implications of autolytic debridement

Why Do Cancer Patients Die in the Emergency Department?: An Analysis of 283 Deaths in NC EDs

Emergency department (ED) visits are made by cancer patients for symptom management, treatment effects, oncologic emergencies, or end of life care. While most patients prefer to die at home, many die in health care institutions. The purpose of this study is to describe visit characteristics of cancer patients who died in the ED and their most common chief complaints using 2008 ED visit data from the North Carolina Disease Event Tracking and Epidemiologic Collection Tool (NC DETECT). Of the 37,760 cancer-related ED visits, 283 resulted in death. For lung cancer patients, 104 died in the ED with 70.9% dying on their first ED visit. Research on factors precipitating ED visits by cancer patients is needed to address end of life care needs

PathwayBooster:a tool to support the curation of metabolic pathways

BACKGROUND: Despite several recent advances in the automated generation of draft metabolic reconstructions, the manual curation of these networks to produce high quality genome-scale metabolic models remains a labour-intensive and challenging task. RESULTS: We present PathwayBooster, an open-source software tool to support the manual comparison and curation of metabolic models. It combines gene annotations from GenBank files and other sources with information retrieved from the metabolic databases BRENDA and KEGG to produce a set of pathway diagrams and reports summarising the evidence for the presence of a reaction in a given organism’s metabolic network. By comparing multiple sources of evidence within a common framework, PathwayBooster assists the curator in the identification of likely false positive (misannotated enzyme) and false negative (pathway hole) reactions. Reaction evidence may be taken from alternative annotations of the same genome and/or a set of closely related organisms. CONCLUSIONS: By integrating and visualising evidence from multiple sources, PathwayBooster reduces the manual effort required in the curation of a metabolic model. The software is available online at http://www.theosysbio.bio.ic.ac.uk/resources/pathwaybooster/. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12859-014-0447-2) contains supplementary material, which is available to authorized users

Cytotoxicity models of Huntington's disease and relevance of hormetic mechanisms: A critical assessment of experimental approaches and strategies.

Abstract This paper assesses in vivo cytotoxicity models of Huntington's disease (HD). Nearly 150 agents were found to be moderately to highly effective in mitigating the pathological sequelae of cytotoxic induction of HD features in multiple rodent models. Typically, rodents are treated with a prospective HD-protective agent before, during, or after the application of a chemical or transgenic process for inducing histopathological and behavioral symptoms of HD. Although transgenic and knockout rodent models (1) display relatively high construct and face validity, and (2) are ever more routinely employed to mimic genetic-to-phenotypic expression of HD features, toxicant models are also often employed, and have served as valuable test beds for the elucidation of biochemical processes and discovery of therapeutic targets in HD. Literature searches of the toxicant HD rodent models yielded nearly 150 agents that were moderately to highly effective in mitigating pathological sequelae in multiple mouse and rat HD models. Experimental models, study designs, and exposure protocols (e.g., pre- and post-conditioning) used in testing these agents were assessed, including dosing strategies, endpoints, and dose-response features. Hormetic-like biphasic dose responses, chemoprotective mechanisms, and the translational relevance of the preclinical studies and their therapeutic implications are critically analyzed in the present report. Notably, not one of the 150 agents that successfully delayed onset and progression of HD in the experimental models has been successfully translated to the treatment of humans in a clinical setting. Potential reasons for these translational failures are (1) the inadequacy of dose-response analyses and subsequent lack of useful dosing data; (2) effective rodent doses that are too high for safe human application; (3) key differences between the experimental models and humans in pharmacokinetic/pharmacodynamic features, ages and routes of agent administration; (4) lack of robust pharmacokinetic, mechanistic or systematic approaches to probe novel treatment strategies; and (5) inadequacies of the chemically induced HD model in rats to mimic accurately the complex genetic and developmental origin and progression of HD in humans. These deficiencies need to be urgently addressed if pharmaceutical agents for the treatment of HD are going to be successfully developed in experimental models and translated with fidelity to the clinic