Skylab 4 visual observations project report

The Skylab 4 Visual Observations Project was undertaken to determine the ways in which man can contribute to future earth-orbital observational programs. The premission training consisted of 17 hours of lectures by scientists representing 16 disciplines and provided the crewmen information on observational and photographic procedures and the scientific significance of this information. During the Skylab 4 mission, more than 850 observations and 2000 photographs with the 70-millimeter Hasselblad and 35-millimeter Nikon cameras were obtained for many investigative areas. Preliminary results of the project indicate that man can obtain new and unique information to support satellite earth-survey programs because of his inherent capability to make selective observations, to integrate the information, and to record the data by describing and photographing the observational sites

Video-based Assessments of Colonoscopy Inspection Quality Correlate with Quality Metrics and Highlight Areas for Improvement

Background & Aims Adenoma detection rate (ADR) and serrated polyp detection rate (SDR) vary significantly among colonoscopists. Colonoscopy inspection quality (CIQ) is the quality with which a colonoscopist inspects for polyps and may explain some of this variation. We aimed to determine the relationship between CIQ and historical ADRs and SDRs in a cohort of colonoscopists and assess whether there is variation in CIQ components (fold examination, cleaning, and luminal distension) among colonoscopists with similar ADRs and SDRs. Methods We conducted a prospective observational study to assess CIQ among 17 high-volume colonoscopists at an academic medical center. Over 6 weeks, we video-recorded >28 colonoscopies per colonoscopist and randomly selected 7 colonoscopies per colonoscopist for evaluation. Six raters graded CIQ using an established scale, with a maximum whole colon score of 75. Results We evaluated 119 colonoscopies. The median whole-colon CIQ score was 50.1/75. Whole-colon CIQ score (r=0.71; P<.01) and component scores (fold examination r=0.74; cleaning r=0.67; distension r=0.77; all P<.01) correlated with ADR. Proximal colon CIQ score (r=0.67; P<.01) and component scores (fold examination r=0.71; cleaning r=0.62; distension r=0.65; all P<.05) correlated with SDR. CIQ component scores differed significantly between colonoscopists with similar ADRs and SDRs for most of the CIQ skills. Conclusion In a prospective observational study, we found CIQ and CIQ components to correlate with ADR and SDR. Colonoscopists with similar ADRs and SDRs differ in their performance of the 3 CIQ components—specific, actionable feedback might improve colonoscopy technique

Perturbation with Intrabodies Reveals That Calpain Cleavage Is Required for Degradation of Huntingtin Exon 1

Background: Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD), is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD. Methodology/Principal Findings: We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx-1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1-mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA) 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 in vitro yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V_L12.3, turnover of soluble mHDx-1 in living cells is blocked. Conclusions/Significance: These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications

Pain in Multiple System Atrophy a Systematic Review and Meta-Analysis

Background: Individuals with multiple system atrophy (MSA) often complain about pain, nonetheless this remains a poorly investigated non-motor feature of MSA. Objectives: Here, we aimed at assessing the prevalence, characteristics, and risk factors for pain in individuals with MSA. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines, we systematically screened the PubMED, Cochrane, and Web of Science databases for papers published in English until September 30, 2022, combining the following keywords: “pain,” “multiple system atrophy,” “MSA,” “olivopontocerebellar atrophy,” “OPCA,” “striatonigral degeneration,” “SND,” “Shy Drager,” and “atypical parkinsonism.”. Results: The search identified 700 records. Sixteen studies provided information on pain prevalence in cohorts of MSA individuals and were included in a qualitative assessment based on the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. Thirteen studies (11 cross-sectional, two longitudinal) scored ≥14 points on QUADAS assessment and were included in a quantitative analysis, pooling data from 1236 MSA individuals. The resulting pooled prevalence of pain in MSA was 67% (95% confidence intervals [CI] = 57%–75%), and significantly higher in individuals with MSA of parkinsonian rather than cerebellar type (76% [95% CI = 63%–87%] vs. 45% [95% CI = 33%–57%], P = 0.001). Pain assessment tools and collected information were highly heterogeneous across studies. Two studies reported pain treatment strategies and found that only every second person with MSA complaining about pain had received targeted treatment. Conclusions: We found that pain is a frequent, but still under-recognized and undertreated feature of MSA. Further research is needed to improve pain detection and treatment in MSA

Reversible Induction of Phantom Auditory Sensations through Simulated Unilateral Hearing Loss

Tinnitus, a phantom auditory sensation, is associated with hearing loss in most cases, but it is unclear if hearing loss causes tinnitus. Phantom auditory sensations can be induced in normal hearing listeners when they experience severe auditory deprivation such as confinement in an anechoic chamber, which can be regarded as somewhat analogous to a profound bilateral hearing loss. As this condition is relatively uncommon among tinnitus patients, induction of phantom sounds by a lesser degree of auditory deprivation could advance our understanding of the mechanisms of tinnitus. In this study, we therefore investigated the reporting of phantom sounds after continuous use of an earplug. 18 healthy volunteers with normal hearing wore a silicone earplug continuously in one ear for 7 days. The attenuation provided by the earplugs simulated a mild high-frequency hearing loss, mean attenuation increased from <10 dB at 0.25 kHz to >30 dB at 3 and 4 kHz. 14 out of 18 participants reported phantom sounds during earplug use. 11 participants presented with stable phantom sounds on day 7 and underwent tinnitus spectrum characterization with the earplug still in place. The spectra showed that the phantom sounds were perceived predominantly as high-pitched, corresponding to the frequency range most affected by the earplug. In all cases, the auditory phantom disappeared when the earplug was removed, indicating a causal relation between auditory deprivation and phantom sounds. This relation matches the predictions of our computational model of tinnitus development, which proposes a possible mechanism by which a stabilization of neuronal activity through homeostatic plasticity in the central auditory system could lead to the development of a neuronal correlate of tinnitus when auditory nerve activity is reduced due to the earplug

Bilateral Dorsal Cochlear Nucleus Lesions Prevent Acoustic-Trauma Induced Tinnitus in an Animal Model

Animal experiments suggest that chronic tinnitus (“ringing in the ears”) may result from processes that overcompensate for lost afferent input. Abnormally elevated spontaneous neural activity has been found in the dorsal cochlear nucleus (DCN) of animals with psychophysical evidence of tinnitus. However, it has also been reported that DCN ablation fails to reduce established tinnitus. Since other auditory areas have been implicated in tinnitus, the role of the DCN is unresolved. The apparently conflicting electrophysiological and lesion data can be reconciled if the DCN serves as a necessary trigger zone rather than a chronic generator of tinnitus. The present experiment used lesion procedures identical to those that failed to decrease pre-existing tinnitus. The exception was that lesions were done prior to tinnitus induction. Young adult rats were trained and tested using a psychophysical procedure shown to detect tinnitus. Tinnitus was induced by a single unilateral high-level noise exposure. Consistent with the trigger hypothesis, bilateral dorsal DCN lesions made before high-level noise exposure prevented the development of tinnitus. A protective effect stemming from disruption of the afferent pathway could not explain the outcome because unilateral lesions ipsilateral to the noise exposure did not prevent tinnitus and unilateral lesions contralateral to the noise exposure actually exacerbated the tinnitus. The DCN trigger mechanism may involve plastic circuits that, through loss of inhibition, or upregulation of excitation, increase spontaneous neural output to rostral areas such as the inferior colliculus. The increased drive could produce persistent pathological changes in the rostral areas, such as high-frequency bursting and decreased interspike variance, that comprise the chronic tinnitus signal

IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species

Antibody dynamics and spontaneous viral clearance in patients with acute hepatitis C infection in Rio de Janeiro, Brazil

Submitted by Sandra Infurna ([email protected]) on 2017-01-18T10:31:05Z No. of bitstreams: 1 clara_yoshida_etal_IOC_2011.pdf: 146042 bytes, checksum: 8ec889224534b76d755828a99d0660c2 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2017-01-18T10:59:52Z (GMT) No. of bitstreams: 1 clara_yoshida_etal_IOC_2011.pdf: 146042 bytes, checksum: 8ec889224534b76d755828a99d0660c2 (MD5)Made available in DSpace on 2017-01-18T10:59:52Z (GMT). No. of bitstreams: 1 clara_yoshida_etal_IOC_2011.pdf: 146042 bytes, checksum: 8ec889224534b76d755828a99d0660c2 (MD5) Previous issue date: 2011Innsbruck Medical University. Department of Medical Statistics, Informatics and Health Economics. Innsbruck, Austria.Harvard Medical School. Boston, MA, USA / Massachussets General Hospital. Division of Infectious Diseases. Boston, MA, USA.Harvard Medical School. Boston, MA, USA / Massachussets General Hospital. Gastrointestinal Unit. Boston, MA, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hepatites Virais. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hepatites Virais. Rio de Janeiro, RJ. Brasil.Laboratório Central de Saúde Pública Noel Nutels. Divisão de Hepatites. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hepatites Virais. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hepatites Virais. Rio de Janeiro, RJ. Brasil / Universidade Federal do Estado do Rio de Janeiro. Hospital Universitário Gaffrée Guinle. Unidade de Hepatologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Desenvolvimento Tecnológico em Virologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hepatites Virais. Rio de Janeiro, RJ. Brasil.Universitätsklinikum Eppendorf. Medizinische Klinik I. Hamburg, Germany.Fondation Merieux. Emerging Pathogens Laboratory. Lyon, France.University of Innsbruck. Institute of Statistics. Innsbruck, Austria.National Institute on Aging. Gerontology Research Center. Baltimore, USA.Innsbruck Medical University. Department of Medical Statistics, Informatics and Health Economics. Innsbruck, Austria.Innsbruck Medical University. Department of Medical Statistics, Informatics and Health Economics. Innsbruck, Austria.Innsbruck Medical University. Department of Medical Statistics, Informatics and Health Economics. Innsbruck, Austria.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hepatites Virais. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hepatites Virais. Rio de Janeiro, RJ. Brasil.Background: The anti-HCV antibody response has not been well characterized during the early phase of HCV infection and little is known about its relationship to the clinical course during this period. Methods: We analyzed serial anti-HCV antibodies longitudinally obtained from a prospective cohort of 65 patients with acute HCV infection by using a microparticle enzyme immunoassay AxSYM HCV 3.0 (Abbott Diagnostics) during the first 12 months from HCV acquisition in Rio de Janeiro, Brazil. Spontaneous viral clearance (SVC) was defined as undetectable HCV RNA in serum, in the absence of treatment, for three consecutive HCV PCR tests within 12-months of follow-up. Results: Baseline antibody values were similar among patient groups with self-limiting HCV evolution (n = 34) and persistent viremia (n = 31) [median (interquartile range) signal/cut-off ratio (s/co) 78.7 (60.7-93.8) vs. 93.9 (67.8- 111.9), p = 0.26]. During 12-months follow-up, patients with acute spontaneous resolving HCV infection showed significantly lower serial antibody response in comparison to individuals progressing to chronic infection [median (interquartile range) s/co 62.7 (35.2-85.0) vs. 98.4 (70.4-127.4), p < 0.0001]. In addition, patients with self-limiting HCV evolution exhibited an expeditious, sharp decline of serial antibody values after SVC in comparison to those measured before SVC [median (interquartile range) s/co 56.0 (25.4-79.3) vs. 79.4 (66.3-103.0), p < 0.0001]. Conclusion: Our findings indicate a rapid short-term decline of antibody values in patients with acute spontaneous resolving HCV infection