Investigating aprataxin function: roles in DNA single strand break repair and functional cellular effects

Aprataxin protects nuclear and mitochondrial DNA against genotoxic stress, and loss-of-function mutations in the APTX gene cause the autosomal recessive cerebellar ataxia, Ataxia Oculomotor Apraxia 1 (AOA1) in humans. In an effort to extend current understanding of aprataxin function, this thesis examines the roles of aprataxin, especially in response to oxidative damage. Firstly, involvement of aprataxin during the gap-filling as well as the end-processing steps of single strand break repair were demonstrated using an in vitro single strand break repair assay using synthetic DNA substrates, cell-free lysates and/or recombinant proteins. Next, loss-of-function studies were conducted in Aptx-/- mouse embryonic fibroblasts (MEFs) and tissues from adult mice harbouring a toxic gain-of-function mutant form of superoxide dismutase1 (SOD1G93A). Expression of the mutant SOD1G93A enhanced sensitivity to oxidative damage in aprataxin-deleted cells and revealed an accelerated senescence and attenuated somatic growth phenotype. Together these findings suggest that aprataxin function is involved in optimal repair of single strand breaks and is therefore critical in maintaining cell function in situations of elevated oxidative stress

What Does It Take for a Family to Afford to Pay for Health Care?

Addresses how much Californians can afford to pay for health care based on their current insurance premiums and out-of-pocket expenses as well as other basic necessities, such as housing, child care, transportation, food, and taxes

Kansans with Disabilities Speak Out about Employment Opportunities

In 2007, Kansas was awarded a Comprehensive Employment Systems grant from the Centers for Medicare and Medicaid Services (CMS) to further understand and address barriers to employment for Kansans with disabilities. One activity funded by the grant was a series of consumer focus groups to discuss employment. Focus group participants reaffirmed the earlier findings regarding barriers and identified several new ones, which are detailed in the articl

Health Care Behaviors and Decision-Making Processes Among Enrollees In A State High Risk Insurance Pool: Focus Group Findings

Purpose-To better understand the relationship between health insurance coverage and health care behaviors of persons with potentially disabling conditions enrolled in a state high risk insurance pool. Approach or Design-Six focus groups with risk pool enrollees in two sites. Setting-Suburban areas in the state of Kansas. Participants-Forty-two individuals ages 29 to 62 years, all with potentially disabling physical or mental health conditions. Method-Qualitative analysis of focus group transcripts using pile sorting and theme identification. Results-High premiums and deductibles limit participants’ ability to afford basic health services and access to prescription medications despite their middle-class socioeconomic status. Participants report delaying or forgoing needed medical care due to lack of coverage and/or out-of-pocket costs. They employ numerous and potentially dangerous strategies to minimize costs, especially for prescription medications. Some report “saving up” needed procedures until their total costs will exceed that year’s deductible. Conclusion-Individuals in the risk pool were making medical decisions on the basis of cost rather than need. Many shared stories of medical complications as a result of delayed care and most expressed stress related to the difficulty of making decisions about their care and use of prescribed medications. The individual, nongroup insurance market, with its higher out-of-pocket costs, may not meet the needs of people with chronic health conditions.Kansas Health Policy Authority, U.S. Department of Health and Human Services, Centers for Medicare and Medicaid Services (11-P-92389/7-01

Study Protocol: A Randomized Controlled Trial of Patient Navigation-Activation to Reduce Cancer Health Disparities

Abstract Background Cancer health disparities affecting low-income and minority patients are well documented. Root-causes are multifactorial, including diagnostic and treatment delays, social and financial barriers, and poor communication. Patient navigation and communication coaching (activation) are potential interventions to address disparities in cancer treatment. The purpose of this clinical trial is to test the effectiveness of an intervention combining patient navigation and activation to improve cancer treatment. Methods/Design The Rochester Patient Navigation Research Program (PNRP) is a National Cancer Institute-sponsored, patient-level randomized trial (RCT) of patient navigation and activation, targeting newly-diagnosed breast and colorectal cancer patients in Rochester, NY. The goal of the program is to decrease cancer health disparities by addressing barriers to receipt of cancer care and promoting patient self-efficacy. The intervention uses trained, paraprofessional patient navigators recruited from the target community, and a detailed training and supervisory program. Recruited patients are randomly assigned to receive either usual care (except for baseline and follow-up questionnaires and interviews) or intervention. The intervention patients receive tailored assistance from their patient navigators, including phone calls, in-person meetings, and behind-the-scenes coordination of care. A total of 344 patients have been recruited. Outcomes measured at three month intervals include timeliness of care, patient adherence, patient satisfaction, quality of life, self-efficacy, health literacy, and cancer knowledge. Discussion This unique intervention combining patient navigation and patient activation is designed to address the multifactorial problem of cancer health disparities. If successful, this study will affect the design and implementation of patient navigation programs. Trials Registration clinicaltrials.gov identifier NCT00496678http://deepblue.lib.umich.edu/bitstream/2027.42/78254/1/1471-2407-10-551.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78254/2/1471-2407-10-551.pdfPeer Reviewe

Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing

Aprataxin (APTX) deficiency causes progressive cerebellar degeneration, ataxia and oculomotor apraxia in man. Cell free assays and crystal structure studies demonstrate a role for APTX in resolving 5'-adenylated nucleic acid breaks, however, APTX function in vertebrates remains unclear due to the lack of an appropriate model system. Here, we generated a murine model in which a pathogenic mutant of superoxide dismutase 1 (SOD1(G93A)) is expressed in an Aptx-/- mouse strain. We report a delayed population doubling and accelerated senescence in Aptx-/- primary mouse fibroblasts, which is not due to detectable telomere instability or cell cycle deregulation but is associated with a reduction in transcription recovery following oxidative stress. Expression of SOD1(G93A) uncovers a survival defect ex vivo in cultured cells and in vivo in tissues lacking Aptx. The surviving neurons feature numerous and deep nuclear envelope invaginations, a hallmark of cellular stress. Furthermore, they possess an elevated number of high-density nuclear regions and a concomitant increase in histone H3 K9 trimethylation, hallmarks of silenced chromatin. Finally, the accelerated cellular senescence was also observed at the organismal level as shown by down-regulation of insulin-like growth factor 1 (IGF-1), a hallmark of premature ageing. Together, this study demonstrates a protective role of Aptx in vivo and suggests that its loss results in progressive accumulation of DNA breaks in the nervous system, triggering hallmarks of premature ageing, systemically

The FIM® instrument to identify patients at risk of falling in geriatric wards: a 10-year retrospective study

Objectives: the main objective was to evaluate if the admission functional independence measure (FIM®) score could be used to predict the risk of falls in geriatric inpatients. Design: a 10-year retrospective study was performed. Setting: the study was conducted in a 298-bed geriatric teaching hospital in Geneva, Switzerland. Subjects: all patients discharged from the hospital from 1 January 1997 to 31 December 2006 were selected. Main outcome measures: measures used were FIM® scores at admission using the FIM® instrument and number of falls extracted from the institution's fall report forms. Results: during the study period, there were 23,966 hospital stays. A total of 8,254 falls occurred. Of these, 7,995 falls were linked to 4,651 stays. Falls were recorded in 19.4% of hospital stays, with a mean incidence of 7.84 falls per 1,000 patients-days. Although there was a statistically significant relationship between total FIM® score, its subscales, and the risk of falling, the sensitivity, specificity, positive predictive value and negative predictive value obtained with receiver operating characteristic curves were insufficient to permit fall prediction. This might be due in part to a non-linear relationship between FIM® score and fall risk. Conclusion: in this study, the FIM® instrument was found to be unable to predict risk of falls in general geriatric ward

Corrigendum/Erratum to Teens, screens and quarantine; The relationship between adolescent media use and mental health prior to and during COVID-19 [Heliyon 8(7), July 2022 e09898].

[This corrects the article DOI: 10.1016/j.heliyon.2022.e09898.]

A SAGE-based screen for genes expressed in sub-populations of neurons in the mouse dorsal root ganglion

<p>Abstract</p> <p>Background</p> <p>The different sensory modalities temperature, pain, touch and muscle proprioception are carried by somatosensory neurons of the dorsal root ganglia. Study of this system is hampered by the lack of molecular markers for many of these neuronal sub-types. In order to detect genes expressed in sub-populations of somatosensory neurons, gene profiling was carried out on wild-type and TrkA mutant neonatal dorsal root ganglia (DRG) using SAGE (serial analysis of gene expression) methodology. Thermo-nociceptors constitute up to 80 % of the neurons in the DRG. In TrkA mutant DRGs, the nociceptor sub-class of sensory neurons is lost due to absence of nerve growth factor survival signaling through its receptor TrkA. Thus, comparison of wild-type and TrkA mutants allows the identification of transcripts preferentially expressed in the nociceptor or mechano-proprioceptor subclasses, respectively.</p> <p>Results</p> <p>Our comparison revealed 240 genes differentially expressed between the two tissues (P < 0.01). Some of these genes, CGRP, Scn10a are known markers of sensory neuron sub-types. Several potential markers of sub-populations, Dok4, Crip2 and Grik1/GluR5 were further analyzed by quantitative RT-PCR and double labeling with TrkA,-B,-C, c-ret, parvalbumin and isolectin B4, known markers of DRG neuron sub-types. Expression of Grik1/GluR5 was restricted to the isolectin B4+ nociceptive population, while Dok4 and Crip2 had broader expression profiles. Crip2 expression was however excluded from the proprioceptor sub-population.</p> <p>Conclusion</p> <p>We have identified and characterized the detailed expression patterns of three genes in the developing DRG, placing them in the context of the known major neuronal sub-types defined by molecular markers. Further analysis of differentially expressed genes in this tissue promises to extend our knowledge of the molecular diversity of different cell types and forms the basis for understanding their particular functional specificities.</p

Teens, screens and quarantine; the relationship between adolescent media use and mental health prior to and during COVID-19.

This study examines associations between media use and mental health for adolescents prior to and during the COVID-19 pandemic. Using two separate datasets that sampled adolescents (8th, 10th, and 12th graders) in 2018 (n = 31,825) and 2020 (n = 1,523), mental health (hopelessness and happiness), media use (time spent using a variety of media), and personal health habits (sleep) were assessed. Overall, we found that there were significant differences by year in adolescent hopelessness, with adolescents reporting less hopelessness in 2020 (during COVID-19) than in 2018 (pre COVID-19). There were not&nbsp;​practical significant differences in adolescent happiness and loneliness. Adolescents also reported getting more sleep in our 2020 sample than the 2018 sample. Adolescents in 2020 spent significantly more time watching movies and video chatting, but less time texting and on social media than adolescents in 2018. Finally, we found that time spent video chatting and sleep had a different relationship with various aspects of mental health (happiness, hopelessness, or loneliness) in 2018 vs. 2020