Microtubule-Associated Protein Tau in Oligodendrocytes Following Acute Brain Injury

With the growing evidence supporting glia-neuronal signalling it is becoming increasingly apparent that it is crucial to gain an understanding of the mechanisms underlying the degeneration of both neurons and glia to fully understand the pathogenesis of acute and chronic degenerative diseases of the brain. Breakdown of the cytoskeleton is thought to represent a common pathway mediating irreversible neuronal damage in a variety of both acute and chronic neurodegenerative conditions. One of the most well documented alterations to the cytoskeleton, occurring in various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and progressive supranuclear palsy, is the formation of neurofibrillary tangles. The formation of neurofibrillary tangles is thought to involve alterations in the microtubule-associated protein tau, the protein being hyperphosphorylated compared to its normal form. Tau is traditionally believed to be a neuron-specific protein where it is predominantly located within the axonal compartment. Supporting this specific localisation of tau, immunoreactivity was found only within axons in histologically normal rat or human brain tissue throughout the investigations carried out in this thesis. However, the novel finding of this thesis was the presence of tau immunoreactivity within oligodendrocytes in both rat and human brain tissue following acute brain injury. The studies described in this thesis were aimed at characterising the increased tau immunoreactivity present in oligodendrocytes in animal models of acute brain injury, in human post-mortem brain tissue from patients who died following a stroke or head injury and in an oligodendrocyte cell line. In the initial study of the thesis tau-positive oligodendrocytes were present 4 h following glutamate-induced toxicity in the rat. In order to confirm that the induction of tau immunoreactivity in these cells following injury was not a phenomenum characteristic to the rat, human post-mortem brain tissue from acute brain injured patients was examined for the presence of tau-positive oligodendrocytes. Tau-positive oligodendrocytes were detected within areas of tissue, as defined by decreased haematoxylin and eosin staining, affected by brain injury, but not in tissue obtained from control patients who had no previous history of neurological or psychiatric disorders. Tau-positive oligodendrocytes were detected as early as 2 h following head injury, suggesting that this is a rapid response of these cells to acute brain injury. In support of this, the induction of tau immunoreactivity in oligodendrocytes was detected as early as 40 min following the induction of permanent focal cerebral ischaemia in the rat. Glutamate toxicity has been shown to be involved in neuronal degeneration following ischaemic brain injury, and tau-positive oligodendrocytes were detected 4 h following intracortical perfusion of IM monosodium glutamate, both within the resulting cortical lesion and in the white matter immediately underlying this area. This result implicated glutamate in the mechanisms underlying the accumulation of tau in oligodendrocytes following injury. However, the ability of NaCl to induce a similar response in oligodendrocytes suggested that mechanisms other than glutamate toxicity may be involved. Using pure oligodendrocyte cultures exposed to monosodium glutamate or NaCl it was shown that alteration of tau in these cells was a direct effect, not mediated through neuronal degeneration. Taken together the results of these studies indicated that some aspect of the brain injury in vivo other than glutamate receptor activation may be involved in the alteration of tau in oligodendrocytes. In order to investigate further the mechanisms which may be involved in this oligodendrocyte response, the effects of 3 pharmacological agents on the density of tau-positive oligodendrocytes following focal cerebral ischaemia in the rat were determined. Pre-treatment with the spin trap agent alpha-phenyl-tert-butyl-nitrone reduced the number of tau-positive oligodendrocytes by 55% in the subcortical white matter of the ischaemic hemisphere compared to untreated animals at 40 min after middle cerebral artery occlusion. In contrast, pre-treatment with glutamate receptor antagonists dizocilpine or 2,3-dihydroxy-6-nitro-7-sulpfamoyl-benzo(F) quinoxaline, failed to reduce the number of tau-positive oligodendrocytes following 40 min of ischaemia. Thus free radial mediated mechanisms were involved in the induction of tau immunoreactivity in oligodendrocytes following ischaemic brain injury. In both the animal models of brain injury and the human post-mortem brain tissue obtained from patients who died following a stroke or head injury, tau-positive oligodendrocytes were detected with a range of antibodies to different epitopes of the protein. This suggested that there may be increased levels of the full-length protein. (Abstract shortened by ProQuest.)

INTREPID:single- versus multiple-inhaler triple therapy for COPD in usual clinical practice

INTRODUCTION: Real-world trial data comparing single- with multiple-inhaler triple therapy (MITT) in COPD patients are currently lacking. The effectiveness of once-daily single-inhaler fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) and MITT were compared in usual clinical care. METHODS: INTREPID was a multicentre, randomised, open-label, phase IV effectiveness study comparing FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA inhaler with a clinician's choice of any approved non-ELLIPTA MITT in usual COPD clinical practice in five European countries. Primary end-point was proportion of COPD Assessment Test (CAT) responders (≥2-unit decrease in CAT score from baseline) at week 24. Secondary end-points in a subpopulation included change from baseline in forced expiratory volume in 1 s (FEV(1)) and percentage of patients making at least one critical error in inhalation technique at week 24. Safety was also assessed. RESULTS: 3092 patients were included (FF/UMEC/VI n=1545; MITT n=1547). The proportion of CAT responders at week 24 was significantly greater with FF/UMEC/VI versus non-ELLIPTA MITT (OR 1.31, 95% CI 1.13–1.51; p<0.001) and mean change from baseline in FEV(1) was significantly greater with FF/UMEC/VI (77 mL versus 28 mL; treatment difference 50 mL, 95% CI 26–73 mL; p<0.001). The percentage of patients with at least one critical error in inhalation technique was low in both groups (FF/UMEC/VI 6%; non-ELLIPTA MITT 3%). Safety profiles, including incidence of pneumonia serious adverse events, were similar between treatments. CONCLUSIONS: In a usual clinical care setting, treatment with once-daily single-inhaler FF/UMEC/VI resulted in significantly more patients gaining health status improvement and greater lung function improvement versus non-ELLIPTA MITT

Machine learning for determining lateral flow device results for testing of SARS-CoV-2 infection in asymptomatic populations

Rapid antigen tests, in the form of lateral flow devices (LFD) allow testing of a large population for SARS-CoV-2. To reduce the variability seen in device interpretation, we show the design and testing of an AI algorithm based on machine learning. The machine learning (ML) algorithm is trained on a combination of artificially hybridised LFDs and LFD data linked to RT-qPCR result. Participants are recruited from assisted test sites (ATS) and health care workers undertaking self-testing and images analysed using the ML algorithm. A panel of trained clinicians are used to resolve discrepancies. In total, 115,316 images are returned. In the ATS sub study, sensitivity increased from 92.08% to 97.6% and specificity from 99.85% to 99.99%. In the self-read sub-study, sensitivity increased from 16.00% to 100%, and specificity from 99.15% to 99.40%. An ML-based classifier of LFD results outperforms human reads in asymptomatic testing sites and self-reading

Point-of-care Head and Neck Sonography for Clinical Problem-solving: Impact of One-day Training Sessions on Medical Student Education

Introduction The curriculum for medical student education is continuously evolving to emphasize knowledge acquisition with critical problem-solving skills. Medical schools have started to implement curricula to teach point-of-care ultrasound skills. To our knowledge, the expansion into head and neck sonography for medical student education is novel and has never been studied. Our objective was to determine the feasibility of implementing point-of-care head and neck sonography and critical problem-solving instruction for medical student education. Methods This was a cross-sectional study enrolling third-year medical students with minimal prior ultrasound experience. A one-day educational curriculum focusing on the use of head and neck ultrasound for clinical problem-solving was integrated into one of the week-long intersessions. The components of point-of-care ultrasound workshop included asynchronous learning, one-hour didactic lecture, followed by a pre-test assessment, then a one-day hands-on workshop, and finally a post-test assessment administered at the end of the training session. Results A total of 123 subjects participated in this study. Ninety-one percent completed the questionnaire prior to the workshop and 83% completed the post-test questionnaire. The level of comfort with using an ultrasound system significantly increased from 31% to 92%. Additionally, the comfort level in interpreting ultrasound images also significantly increased from 21% to 84%. Eighty-nine percent (95% CI, 86%-97%) had an interest in learning ultrasound and would enroll in an optional ultrasound curriculum if given the opportunity. Knowledge of specific ultrasound applications also increased from 60% (after asynchronous learning and lectures) to 95% (after additional hands-on sonographic training). Conclusion At our institution, we successfully integrated point-of-care head and neck sonography and critical problem-solving instruction for medical student education.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Thiopurine monotherapy is effective in ulcerative colitis but significantly less so in Crohn’s disease: long-term outcomes for 11 928 patients in the UK inflammatory bowel disease bioresource

Objective: Thiopurines are widely used as maintenance therapy in inflammatory bowel disease (IBD) but the evidence base for their use is sparse and their role increasingly questioned. Using the largest series reported to date, we assessed the long-term effectiveness of thiopurines in ulcerative colitis (UC) and Crohn’s disease (CD), including their impact on need for surgery. Design: Outcomes were assessed in 11 928 patients (4968 UC, 6960 CD) in the UK IBD BioResource initiated on thiopurine monotherapy with the intention of maintaining medically induced remission. Effectiveness was assessed retrospectively using patient-level data and a definition that required avoidance of escalation to biological therapy or surgery while on thiopurines. Analyses included overall effectiveness, time-to-event analysis for treatment escalation and comparison of surgery rates in patients tolerant or intolerant of thiopurines. Results: Using 68 132 patient-years of exposure, thiopurine monotherapy appeared effective for the duration of treatment in 2617/4968 (52.7%) patients with UC compared with 2378/6960 (34.2%) patients with CD (p<0.0001). This difference was corroborated in a multivariable analysis: after adjusting for variables including treatment era, thiopurine monotherapy was less effective in CD than UC (OR 0.47, 95% CI 0.43 to 0.51, p<0.0001). Thiopurine intolerance was associated with increased risk of surgery in UC (HR 2.44, p<0.0001); with a more modest impact on need for surgery in CD (HR=1.23, p=0.0015). Conclusion: Thiopurine monotherapy is an effective long-term treatment for UC but significantly less effective in CD

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders