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The evolution of nerve growth factor inhibition in clinical medicine
Nerve growth factor (NGF) is a neurotrophin that activates nociceptive neurons to transmit pain signals from the peripheral to the central nervous system and that exerts its effects on neurons by signalling through tyrosine kinase receptors. Antibodies that inhibit the function of NGF and small molecule inhibitors of NGF receptors have been developed and tested in clinical studies to evaluate the efficacy of NGF inhibition as a form of analgesia in chronic pain states including osteoarthritis and chronic low back pain. Clinical studies in individuals with painful knee and hip osteoarthritis have revealed that NGF inhibitors substantially reduce joint pain and improve function compared with NSAIDs for a duration of up to 8 weeks. However, the higher tested doses of NGF inhibitors also increased the risk of rapidly progressive osteoarthritis in a small percentage of those treated. This Review recaps the biology of NGF and the studies that have been performed to evaluate the efficacy of NGF inhibition for chronic musculoskeletal pain states. The adverse events associated with NGF inhibition and the current state of knowledge about the mechanisms involved in rapidly progressive osteoarthritis are also discussed and future studies proposed to improve understanding of this rare but serious adverse event.Nerve growth factor has been investigated as a therapeutic target for osteoarthritis and chronic low back pain, yet worries over adverse effects have stalled drug development. This Review provides an update on the current status of nerve growth factor inhibitors.
Journal Article
Longitudinal effects of gender minority stressors on substance use and related risk and protective factors among gender minority adolescents
Gender minority (GM) adolescents, who have a different gender identity than their sex assigned at birth, may use substances as a coping strategy in response to GM-related stressors. This study examined longitudinal effects of gender minority stressors on substance use in GM adolescents, and related risk factors (internalized transphobia, depressive symptoms, anxious symptoms) and protective factors (resilience, gender-related pride, family functioning, social support, gender-related community connectedness).
Participants were 30 GM adolescents, ages 13-17 years, from the U.S. community-based longitudinal Trans Teen and Family Narratives Project. Participants completed an online survey every 6 months across 2 years (5 waves; data collected 2015-2019).
Exposure to gender minority stressors was associated with higher odds of alcohol use. Across models, internalized transphobia (risk factor), resilience (protective factor), and gender-related pride (protective factor) were the most significant mediators of associations between gender minority stressors and substance use. Family functioning and social support (protective factors) significantly moderated the association between gender minority stressors and alcohol use, such that family functioning and social support were protective for alcohol use at lower levels of gender minority stress, but not at higher levels.
Results suggest that GM adolescents engage in substance use as a coping strategy in response to gender minority stressors. A number of hypothesized risk and protective factors mediated or moderated these associations. Future interventions with GM adolescents should focus efforts on addressing internalized transphobia as a risk factor and strengthening resilience, gender-related pride, and family functioning as protective factors for substance use.
Journal Article
Review of Equine Piroplasmosis
Equine piroplasmosis is caused by one of 2 erythrocytic parasites Babesia caballi or Theileria equi. Although the genus of the latter remains controversial, the most recent designation, Theileria, is utilized in this review. Shared pathogenesis includes tick‐borne transmission and erythrolysis leading to anemia as the primary clinical outcome. Although both parasites are able to persist indefinitely in their equid hosts, thus far, only B. caballi transmits across tick generations. Pathogenesis further diverges after transmission to equids in that B. caballi immediately infects erythrocytes, whereas T. equi infects peripheral blood mononuclear cells. The recent re‐emergence of T. equi in the United States has increased awareness of these tick‐borne pathogens, especially in terms of diagnosis and control. This review focuses in part on factors leading to the re‐emergence of infection and disease of these globally important pathogens.
Journal Article
Dysregulated metabolism of the late herpes simplex virus 1 transcriptome through the vhs-VP22 axis uncouples virus cytopathic effect and virus production
Herpes simplex virus 1 (HSV1) expresses its genes in a classical cascade culminating in the production of large amounts of structural proteins to facilitate virus assembly. HSV1 lacking the virus protein VP22 (Δ22) exhibits late translational shutoff, a phenotype that has been attributed to the unrestrained activity of the virion host shutoff (vhs) protein, a virus-encoded endoribonuclease which induces mRNA degradation during infection. We have previously shown that vhs is also involved in regulating the nuclear-cytoplasmic compartmentalisation of the virus transcriptome, and in the absence of VP22 a number of virus transcripts are sequestered in the nucleus late in infection. Here we show that despite expressing minimal amounts of structural proteins and failing to plaque on human fibroblasts, the strain 17 Δ22 virus replicates and spreads as efficiently as Wt virus, but without causing cytopathic effect (CPE). Nonetheless, CPE-causing virus spontaneously appeared on Δ22-infected human fibroblasts, and four viruses isolated in this way had all acquired point mutations in vhs which rescued late protein translation. However, unlike a virus deleted for vhs, these viruses still induced the degradation of both cellular and viral mRNA suggesting that vhs mutation in the absence of VP22 is necessary to overcome a more complex disturbance in mRNA metabolism than mRNA degradation alone. The ultimate outcome of secondary mutations in vhs is therefore the rescue of virus-induced CPE caused by late protein synthesis, and while there is a clear selective pressure on HSV1 to mutate vhs for optimal production of late structural proteins, the purpose of this is over and above that of virus production.
Journal Article
Families with more than one trans person: Investments and divestments in cisnormativity
Objective To examine how having more than one trans person in a family facilitates investments in or divestments from cisnormativity. Background While there is now a robust body of literature on trans people's experiences with cisgender family members and vice versa, largely missing has been a focus on families where more than one person in the family is trans. Method This paper focuses on a subsample of 10 families from a large international qualitative longitudinal study conducted across six countries, focused on trans young people and their families. The paper draws on interviews conducted in 2022 and 2023 with families in which more than one family member was trans. Transcribed interviews were analyzed thematically. Results The themes developed indicate that while for some families having multiple trans family members may mean that some cisgender family members invest further in cisnormativity, for other family members the existence of multiple trans family members may encourage divestments from cisnormativity, to the benefit of trans young people. Specifically, themes focus on multiple trans family members highlighting cisnormativity, and conversely, multiple trans family members indicating likelihood of support and offering a safe haven. Implications The paper concludes by emphasizing that while encouraging divestments from cisnormativity should not be the work of trans people, it is nonetheless important that research continues to investigate the experiences of families in which more than one person is trans.
Journal Article
Referrals for physical therapy for osteoarthritis during the COVID-19 pandemic: A retrospective analysis
Osteoarthritis (OA) is a leading cause of musculoskeletal pain and disability among Americans. Physical therapy (PT) is recommended per the 2019 ACR /Arthritis Foundation Guideline for Treatment of OA of the Hand, Hip, and Knee. During COVID-19, access to healthcare has been altered in a variety of clinical settings, with the pandemic creating delays in healthcare, with an unknown impact on access to PT care for OA. We sought to determine whether referrals to PT for OA were reduced in 2020 during the COVID-19 pandemic compared to 2019. A retrospective analysis was done of 3586 PT referrals placed by the University of California, Davis for 206 OA ICD-10 codes from January to November 2019 and from January to November 2020. The numbers of PT referrals per month of each year were compared using both descriptive statistics and Poisson Regression analysis. A total of 1972 PT referrals for OA were placed from January to November 2019. Only 1614 referrals for OA were placed from January to November 2020, representing a significant decrease (p = 0.001). Month-by-month analysis of 2020 compared to 2019 revealed statistically significant drops in PT referrals for OA in April (p = 0.001), May (p = 0.001), and August (p = 0.001). These findings reveal a significant reduction in the number of referrals for PT for OA placed in 2020 during the first year of the COVID-19 pandemic. These reductions were particularly evident in the months following state-mandated actions and closures. Factors associated with this outcome may include decreased access to primary care providers, perceptions of PT availability by health care providers, decreased mobility limiting access to both clinic and PT appointments, and/or willingness to engage in PT by patients during the pandemic.
Journal Article
Impact of COVID-19 pandemic on pharmacologic treatment of patients newly diagnosed with osteoporosis
This study determined whether initiation of pharmacologic treatment was delayed for newly diagnosed osteoporosis patients during the COVID-19 pandemic. 1,189 patients [greater than or equal to]50 years with newly diagnosed osteoporosis using dual-energy x-ray absorptiometry (DXA) screening at a single academic institution were included. Patients with previous osteoporosis were excluded. Patients diagnosed between March 1, 2018-January 31, 2020 (pre-pandemic cohort, n = 576) were compared to those diagnosed between March 1, 2020-January 31, 2022 (pandemic cohort, n = 613). Age, sex, race, ethnicity, ordering providers (primary vs specialty), and pharmacological agents were evaluated. Primary outcomes included proportion of patients prescribed therapy within 3 and 6-months of diagnosis, and mean time from diagnosis to treatment initiation. The pre-pandemic cohort had more White patients (74.3 vs 68.4%, p = .02) and no differences between remaining demographic variables. Only 40.5% of newly diagnosed patients initiated pharmacologic therapy within 6 months. Patients treated at 3-months (31.8 vs 35.4%, p = 0.19) and 6-months (37.8 vs 42.9, p = 0.08) were comparable between cohorts (47.2 vs 50.2% p = 0.30). Mean time from diagnosis to treatment initiation was similar (46 vs 45 days, p = 0.72). There were no treatment differences based on gender, race, or ethnicity or between ordering providers (65.1 vs 57.4% primary care, p = 0.08). Bisphosphonates were most often prescribed in both cohorts (89% vs 82.1%). This is the first study assessing COVID-19's impact on pharmacologic treatment of newly diagnosed osteoporosis. 40.5% of newly diagnosed patients were treated pharmacologically within six months of diagnosis, and the pandemic did not significantly affect treatment rates.
Journal Article
Next generation sequencing of viral RNA genomes
Background
With the advent of Next Generation Sequencing (NGS) technologies, the ability to generate large amounts of sequence data has revolutionized the genomics field. Most RNA viruses have relatively small genomes in comparison to other organisms and as such, would appear to be an obvious success story for the use of NGS technologies. However, due to the relatively low abundance of viral RNA in relation to host RNA, RNA viruses have proved relatively difficult to sequence using NGS technologies. Here we detail a simple, robust methodology, without the use of ultra-centrifugation, filtration or viral enrichment protocols, to prepare RNA from diagnostic clinical tissue samples, cell monolayers and tissue culture supernatant, for subsequent sequencing on the Roche 454 platform.
Results
As representative RNA viruses, full genome sequence was successfully obtained from known lyssaviruses belonging to recognized species and a novel lyssavirus species using these protocols and assembling the reads using
de novo
algorithms. Furthermore, genome sequences were generated from considerably less than 200 ng RNA, indicating that manufacturers’ minimum template guidance is conservative. In addition to obtaining genome consensus sequence, a high proportion of SNPs (Single Nucleotide Polymorphisms) were identified in the majority of samples analyzed.
Conclusions
The approaches reported clearly facilitate successful full genome lyssavirus sequencing and can be universally applied to discovering and obtaining consensus genome sequences of RNA viruses from a variety of sources.
Journal Article
Chromium Selectively Accumulates in the Rat Hippocampus after 90 Days of Exposure to Cr(VI) in Drinking Water and Induces Age- and Sex-Dependent Metal Dyshomeostasis
Hexavalent chromium (Cr[VI]) is a widespread environmental pollutant in air and water that is primarily attributed to industrial pollution. The current maximum contaminant levels (MCLs) for drinking water from the World Health Organization and the U.S. Environmental Protection Agency (0.05 and 0.1 mg/L, respectively) were set based on contact dermatitis and warrant further toxicological investigation. While Cr(VI) is neurotoxic and accumulates in the brain, most animal studies only report whole-brain Cr, leaving large knowledge gaps. Few studies consider differences between ages or sexes, and fewer consider essential metal dyshomeostasis. We sought to investigate where Cr accumulates in the brain, considering sex and age differences, following a 90-day drinking water exposure to current MCLs. Here, we report Cr levels in six brain regions of rats exposed to drinking water Cr(VI). We observed Cr only accumulated in the hippocampus, and only in older females. We further assessed changes to essential metals in the hippocampus, observing opposite effects across sexes and between young rats compared to older rats. In sum, our data indicate drinking water Cr(VI) selectively targeted the hippocampus, with geriatric females accumulating the most Cr, and induced significant essential metal dyshomeostasis even in tissues lacking evident Cr accumulation.
Journal Article