The Grizzly, September 23, 1983

Security Measures Enacted • Rape Suspect Arrested • Union Welcomes Director • President\u27s Corner • Letters to the Editor • What to do With Your First $10,000 • Art Exhibit Opens • French Professor Earns Doctorate • Bloodmobile is Back • The New Invasion • Some People Never Give Up • Math, Science Teachers Needed • Ursinus Welcomes New Faculty • Calling All Diabetics: Wanna be a Guinea Pig? • New Look Bears Score Grid Upset • Field Hockey Off to Fine Start • Seniors Anchor U.C. Soccer • Sports Profilehttps://digitalcommons.ursinus.edu/grizzlynews/1101/thumbnail.jp

The Grizzly, November 4, 1983

Got a Career? • Convocation Set • Visser Conducts Forum • Ursinus Awaits Celebration • Letters to the Editor: Grenada • Forums Finally Finish • Sixteenth-Century Play to Finish • Sports Medicine - It\u27s Where It\u27s At! • College With a Difference? • Reformation Discussed • Creedence Revived • What is Treaty of Paris? • Japanese Exchange Program Offered • Grizzlies Pull Off Stunning Victory • UC Soccer Awaits ECAC Play • X-Country Caps \u2783 Seasonhttps://digitalcommons.ursinus.edu/grizzlynews/1106/thumbnail.jp

Activation of liver X receptors inhibits experimental fibrosis by interfering with interleukin-6 release from macrophages

Objectives: To investigate the role of liver X receptors (LXRs) in experimental skin fibrosis and evaluate their potential as novel antifibrotic targets. Methods: We studied the role of LXRs in bleomycin-induced skin fibrosis, in the model of sclerodermatous graft-versus-host disease (sclGvHD) and in tight skin-1 (Tsk-1) mice, reflecting different subtypes of fibrotic disease. We examined both LXR isoforms using LXRα-, LXRβ- and LXR-α/β-double-knockout mice. Finally, we investigated the effects of LXRs on fibroblasts and macrophages to establish the antifibrotic mode of action of LXRs. Results: LXR activation by the agonist T0901317 had antifibrotic effects in bleomycin-induced skin fibrosis, in the sclGvHD model and in Tsk-1 mice. The antifibrotic activity of LXRs was particularly prominent in the inflammation-driven bleomycin and sclGvHD models. LXRα-, LXRβ- and LXRα/β-double-knockout mice showed a similar response to bleomycin as wildtype animals. Low levels of the LXR target gene ABCA-1 in the skin of bleomycin-challenged and control mice suggested a low baseline activation of the antifibrotic LXR signalling, which, however, could be specifically activated by T0901317. Fibroblasts were not the direct target cells of LXRs agonists, but LXR activation inhibited fibrosis by interfering with infiltration of macrophages and their release of the pro-fibrotic interleukin-6. Conclusions: We identified LXRs as novel targets for antifibrotic therapies, a yet unknown aspect of these nuclear receptors. Our data suggest that LXR activation might be particularly effective in patients with inflammatory disease subtypes. Activation of LXRs interfered with the release of interleukin-6 from macrophages and, thus, inhibited fibroblast activation and collagen release

Novel mutation of the PRNP gene of a clinical CJD case

BACKGROUND: Transmissible spongiform encephalopathies (TSEs), a group of neurodegenerative diseases, are thought to be caused by an abnormal isoform of a naturally occurring protein known as cellular prion protein, PrP(C). The abnormal form of prion protein, PrP(Sc )accumulates in the brain of affected individuals. Both isoforms are encoded by the same prion protein gene (PRNP), and the structural changes occur post-translationally. Certain mutations in the PRNP gene result in genetic TSEs or increased susceptibility to TSEs. CASE PRESENTATION: A 70 year old woman was admitted to the hospital with severe confusion and inability to walk. Relatives recognized memory loss, gait and behavioral disturbances over a six month period prior to hospitalization. Neurological examination revealed Creutzfeldt-Jakob disease (CJD) related symptoms such as incontinence, Babinski sign and myoclonus. EEG showed periodic sharp waves typical of sporadic CJD and cerebrospinal fluid analysis (CSF) was positive for the presence of the 14-3-3-protein. As the disease progressed the patient developed akinetic mutism and died in the tenth month after onset of the disease symptoms. Unfortunately, no autopsy material was available. PRNP sequencing showed the occurrence of a point mutation on one allele at codon 193, which is altered from ACC, coding for a threonine, to ATC, encoding an isoleucine (T193I). CONCLUSION: Here we report a novel mutation of the PRNP gene found in an elderly female patient resulting in heterozygosity for isoleucine and threonine at codon 193, in which normally homozygosity for threonine is expected (T193). The patient presented typical clinical symptoms of CJD. EEG findings and the presence of the 14-3-3 protein in the CSF, contributed to CJD diagnosis, allowing the classification of this case as a probable CJD according to the World Health Organization (WHO) accepted criteria

Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis

Background and objectives: Fibrosis is a major socioeconomic burden, but effective antifibrotic therapies are not available in the clinical routine. There is growing evidence for a central role of Wnt signalling in fibrotic diseases such as systemic sclerosis, and we therefore evaluated the translational potential of pharmacological Wnt inhibition in experimental dermal fibrosis. Methods: We examined the antifibrotic effects of PKF118-310 and ICG-001, two novel inhibitors of downstream canonical Wnt signalling, in the models of prevention and treatment of bleomycin-induced dermal fibrosis as well as in experimental dermal fibrosis induced by adenoviral overexpression of a constitutively active transforming growth factor (TGF)-β receptor I. Results: PKF118-310 and ICG-001 were well tolerated throughout all experiments. Both therapeutic approaches showed antifibrotic effects in preventing and reversing bleomycin-induced dermal fibrosis as measured by skin thickness, hydroxyproline content and myofibroblast counts. PKF118-310 and ICG-001 were effective in inhibiting TGF-β receptor I-driven fibrosis as assessed by the same outcome measures. Conclusions: Blockade of canonical Wnt signalling by PKF118-310 and ICG-001 showed antifibrotic effects in different models of skin fibrosis. Both therapies were well tolerated. Although further experimental evidence for efficacy and tolerability is necessary, inhibition of canonical Wnt signalling is a promising treatment approach for fibrosis

Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study

Background: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms. Methods: We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. Findings: Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10-15; heterozygous model p=1·01 × 10-135), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10-9), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10-10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. Interpretation: We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders. Funding: Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust

Chronic Viral Infection and Primary Central Nervous System Malignancy

Primary central nervous system (CNS) tumors cause significant morbidity and mortality in both adults and children. While some of the genetic and molecular mechanisms of neuro-oncogenesis are known, much less is known about possible epigenetic contributions to disease pathophysiology. Over the last several decades, chronic viral infections have been associated with a number of human malignancies. In primary CNS malignancies, two families of viruses, namely polyomavirus and herpesvirus, have been detected with varied frequencies in a number of pediatric and adult histological tumor subtypes. However, establishing a link between chronic viral infection and primary CNS malignancy has been an area of considerable controversy, due in part to variations in detection frequencies and methodologies used among researchers. Since a latent viral neurotropism can be seen with a variety of viruses and a widespread seropositivity exists among the population, it has been difficult to establish an association between viral infection and CNS malignancy based on epidemiology alone. While direct evidence of a role of viruses in neuro-oncogenesis in humans is lacking, a more plausible hypothesis of neuro-oncomodulation has been proposed. The overall goals of this review are to summarize the many human investigations that have studied viral infection in primary CNS tumors, discuss potential neuro-oncomodulatory mechanisms of viral-associated CNS disease and propose future research directions to establish a more firm association between chronic viral infections and primary CNS malignancies

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http://archive.org/details/experimentalinve00zerrNAN

Variation in Response to Artificial Selection for Light Sensitivity in Guppies (\u3ci\u3ePoecilia reticulate\u3c/i\u3e)

We performed artificial selection on the visual system in guppies (Poecilia reticulate), using the optomotor reaction threshold as the selection criterion. Two lines were selected for increased sensitivity to blue light, two were selected for increased sensitivity to red light, and two were unselected controls. There was significant response to selection in all four selected lines and significant heritability for sensitivity. An examination of the spectral sensitivity function showed that the form of the response differed between the red and blue lines and among the red lines. Such divergence is likely because there are many different mechanisms allowing response to selection for spectral sensitivity. Diverse mechanisms allow a divergent response by different populations to the same selective pressures. Such a mechanism can promote diversity in vision and visual signals, and any multicomponent system where different components can respond to the same selective regime

Health Care Service Utilization Among Anxious and Nonanxious Youth

Background: Anxiety disorders are the most common mental health problem, impacting 15% to 20% of youth at any given time. Despite high prevalence, little is known about the type of health care services utilized by anxious youth, impeding public health efforts to improve access to and quality of care. To address this need, the current study will directly compare service utilization in a large sample of anxious and nonanxious youth patients enrolled within Mental Health Research Network (MHRN). Methods: Preliminary analyses were conducted using a sample of 17,929 youths (ages 4 to 17 years) from Kaiser Permanente Northwest (KPNW). Anxiety diagnoses were derived from ICD-9 codes and service use from procedure codes during 2013–2014. Analyses were completed using a match-control design, in which anxious youth were matched with their nonanxious peers using sociodemographic indices. Results: Results from the KPNW site showed that anxious youth were significantly more likely to receive care than nonanxious matched controls in pediatrics (odds ratio [OR]: 2.28; P \u3c 0.001), family medicine (OR: 1.36; P \u3c 0.001), emergency departments (OR: 2.23; P \u3c 0.001), and urgent care (OR: 1.66; P \u3c 0.001). Anxious youth also were more likely to receive services in specialty care settings such as outpatient mental health (OR: 17.34; P \u3c 0.001), inpatient mental health (OR: 16.56; P \u3c 0.001), neurology (OR: 3.71; P \u3c 0.001) and cardiology (OR: 2.85; P \u3c 0.001). Overall, anxious youths in this insured sample were high utilizers of services, including increased use of high-cost services. Conclusion: Final analyses will integrate data from an additional three MHRN sites using innovative statistical methods designed to pool and analyze de-identified services data across multiple sites. The present study will be one of the first to examine health services use for a large and diverse sample of anxious youth across several different health care settings and systems. Findings from this study will provide unique and critical information about the availability and type of care currently utilized by anxious youth. Results may be useful in guiding efforts to most efficiently intervene with this widely prevalent and highly impairing condition