One of the characteristic features of cells from patients with ataxia telangiectasia (A-T) is that they are in a state of continuous oxidative stress and exhibit constitutive activation of pathways that normally respond to oxidative damage. In this report, we investigated whether the oxidative stress phenotype of A-T cells might be a reflection of an intrinsic mitochondrial dysfunction. Mitotracker Red staining showed that the structural organization of mitochondria in A-T cells was abnormal compared to wild-type. Moreover, A-T cells harbored a much larger population of mitochondria with decreased membrane potential (DeltaPsi) than control cells. In addition, the basal expression levels of several nuclear DNA-encoded oxidative damage responsive genes whose proteins are targeted to the mitochondria--polymerase gamma, mitochondrial topoisomerase I, peroxiredoxin 3 and manganese superoxide dismutase--are elevated in A-T cells. Consistent with these results, we found that overall mitochondrial respiratory activity was diminished in A-T compared to wild-type cells. Treating A-T cells with the antioxidant, alpha lipoic acid (ALA), restored mitochondrial respiration rates to levels approaching those of wild-type. When wild-type cells were transfected with ATM-targeted siRNA, we observed a small but significant reduction in the respiration rates of mitochondria. Moreover, mitochondria in A-T cells induced to stably express full-length ATM, exhibited respiration rates approaching those of wild-type cells. Taken together, our results provide evidence for an intrinsic mitochondrial dysfunction in A-T cells, and implicate a requirement for ATM in the regulation of mitochondrial function.
Large numbers of genetic disorders are caused by nonsense mutations for which compound-induced readthrough of premature termination codons (PTCs) might be exploited as a potential treatment strategy. We have successfully developed a sensitive and quantitative high-throughput screening (HTS) assay, protein transcription/translation (PTT)–enzyme-linked immunosorbent assay (ELISA), for identifying novel PTC-readthrough compounds using ataxia-telangiectasia (A-T) as a genetic disease model. This HTS PTT-ELISA assay is based on a coupled PTT that uses plasmid templates containing prototypic A-T mutated (ATM) mutations for HTS. The assay is luciferase independent. We screened ∼34,000 compounds and identified 12 low-molecular-mass nonaminoglycosides with potential PTC-readthrough activity. From these, two leading compounds consistently induced functional ATM protein in ATM-deficient cells containing disease-causing nonsense mutations, as demonstrated by direct measurement of ATM protein, restored ATM kinase activity, and colony survival assays for cellular radiosensitivity. The two compounds also demonstrated readthrough activity in mdx mouse myotube cells carrying a nonsense mutation and induced significant amounts of dystrophin protein.
Polyethylene glycol (PEG) is an inert, water soluble polymer, used for decades in pharmaceuticals. Although PEG is considered safe, concerns persist about the potential adverse effects of long-term exposure to PEG-containing therapies, specifically in children, following the introduction of PEGylated recombinant factor products used for the treatment of hemophilia. Given the absence of long-term surveillance data, and to evaluate the potential risk, we estimated PEG exposure in the pediatric population receiving PEGylated therapies with pediatric indications administered intravenously or intramuscularly. We used a range of pediatric weights and doses based on prescribing information (PI) or treatment guidelines. PIs and reporting websites were searched for information about adverse events (AEs). For a child weighing 50 kg on the highest prophylactic dose of a FVIII product, the range of total PEG exposure was 40–21,840 mg/year; for factor IX (FIX) products, the range was 13–1342 mg/year; and for other products, the range was 383–26,743 mg/year, primarily as a derivative excipient. No AE patterns attributable to PEG were found for any of these products, including potential renal, neurological, or hepatic AEs. Our analyses suggest the pediatric population has had substantial exposure to PEG for several decades, with no evidence of adverse consequences.
Background: this study examined the health-related quality of life (HRQoL) and wellbeing of people in the Netherlands who had undergone ostomy surgery. Aims: to assess how an ostomy population perceives their HRQoL and determine key stressors that influence HRQoL in this population. Methods: a cross-sectional survey, including the City of Hope National Medical Center Quality of Life Questionnaire for patients with an ostomy and a Visual Analogue Scale measuring HRQoL, was used to evaluate postsurgical patients. Findings: people with an ostomy in the Netherlands have a generally positive HRQoL, but this may be affected by peristomal skin irritation, experience of leakage on to the peristomal skin and whether their surgery was planned. Conclusions: access to specialist nurse support and products designed to prevent leakage and prevent skin irritation—two key drivers of HRQoL—may be able to maximise an individual's health status throughout their lifelong journey as a person with an ostomy.
Background: irritation to peristomal skin remains one of the most prevalent ostomy-related complications influencing an individual's health status and quality of life. Aims: to assess the impact of damaged peristomal skin on the health utility and quality-adjusted life days (QALD) in an international adult ostomy population. Methods: a cross-sectional survey incorporating the SF-6D preference-based health utility index was developed to assess a random selection of post-surgical patients. Findings: health utility decreased with increasing skin irritation among the three geographic groups. The total mean health utility of normal peristomal skin for the three groups dropped incrementally for mild, moderate, and severe irritation. There were no differences in health utility or QALDs between the three country groups. Conclusion: improvement of peristomal skin health is associated with improvements to QALDs. Clinicians, caregivers and patients have the responsibility to address a critical unmet need in skin health through interventions and products designed to support healthy peristomal skin.
PURPOSE: The aim of this study was to identify themes related to barriers and facilitators to the integration of intermittent catheterization (IC) in the daily lives or persons using the form of bladder evacuation. DESIGN: Descriptive, qualitative study. SUBJECTS AND SETTING: A purposive sample of 25 adults from 5 countries (United States, United Kingdom, Germany, France, and the Netherlands) was assembled. All participants had used IC as their primary method of bladder emptying for at least 1 year and, in that time, had used as least 2 different IC products. METHODS: Guided telephone interviews with each participant were conducted by professional staff fluent in each participant's local language as well as trained in qualitative data collection. Interviews were digitally recorded and subsequently transcribed verbatim into English for analysis. We used ATLAS.ti qualitative analysis software (version 7.5.11) to assist with data organization and identification of major themes. Descriptive statistics (eg, mean, standard deviation, or frequency) were used to characterize the sample in terms of sociodemographic and clinical characteristics as collected during the interview. RESULTS: Analysis revealed 9 main themes around individuals' lived experiences of IC: initial fear, urinary tract infection, pain/discomfort, independence, choice, community, life quality, resilience, and acceptance. DISCUSSION: Our results indicate that IC is perceived as a burden by some, but not all, users. The challenge, and opportunity, is to learn more about what has gone right for those who have adapted and to leverage the clinical, practical, psychological, and social factors that enable individuals to integrate IC into the rhythm of their daily lives.
Intermittent catheterization (IC) has benefits such as helping prevent urinary tract infections; however, there are physiological and psychological risk factors. To what extent this is a health burden is not well known and deserves investigation. The primary objective of this study was to explore emotional effects, social connectivity and quality of life (QoL) associated with IC. A search of peer reviewed literature finds adjustment to life after spinal cord injury impacted by emotional and behavioural
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.