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1.
Artigo em Inglês | MEDLINE | ID: mdl-34619016

RESUMO

A 33-year-old Hispanic male with a history of recent orchiectomy for suspected testicular cancer presented to the emergency department with worsening exertional chest pain and dyspnea in the setting of a 2-month history of diffuse myalgias and symmetric polyarthralgias.

2.
Dev Biol ; 481: 75-94, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34597675

RESUMO

While the epithelial cell cortex displays profound asymmetries in protein distribution and morphology along the apico-basal axis, the extent to which the cytoplasm is similarly polarized within epithelial cells remains relatively unexplored. We show that cytoplasmic organelles within C. elegans embryonic intestinal cells develop extensive apico-basal polarity at the time they establish cortical asymmetry. Nuclei and conventional endosomes, including early endosomes, late endosomes, and lysosomes, become polarized apically. Lysosome-related gut granules, yolk platelets, and lipid droplets become basally enriched. Removal of par-3 activity does not disrupt organelle positioning, indicating that cytoplasmic apico-basal asymmetry is independent of the PAR polarity pathway. Blocking the apical migration of nuclei leads to the apical positioning of gut granules and yolk platelets, whereas the asymmetric localization of conventional endosomes and lipid droplets is unaltered. This suggests that nuclear positioning organizes some, but not all, cytoplasmic asymmetries in this cell type. We show that gut granules become apically enriched when WHT-2 and WHT-7 function is disrupted, identifying a novel role for ABCG transporters in gut granule positioning during epithelial polarization. Analysis of WHT-2 and WHT-7 ATPase mutants is consistent with a WHT-2/WHT-7 heterodimer acting as a transporter in gut granule positioning. In wht-2(-) mutants, the polarized distribution of other organelles is not altered and gut granules do not take on characteristics of conventional endosomes that could have explained their apical mispositioning. During epithelial polarization wht-2(-) gut granules exhibit a loss of the Rab32/38 family member GLO-1 and ectopic expression of GLO-1 is sufficient to rescue the basal positioning of wht-2(-) and wht-7(-) gut granules. Furthermore, depletion of GLO-1 causes the mislocalization of the endolysosomal RAB-7 to gut granules and RAB-7 drives the apical mispositioning of gut granules when GLO-1, WHT-2, or WHT-7 function is disrupted. We suggest that ABC transporters residing on gut granules can regulate Rab dynamics to control organelle positioning during epithelial polarization.

3.
Cell Syst ; 12(8): 780-794.e7, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34139154

RESUMO

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.


Assuntos
Biomarcadores/análise , COVID-19/patologia , Progressão da Doença , Proteoma/fisiologia , Fatores Etários , Contagem de Células Sanguíneas , Gasometria , Ativação Enzimática , Humanos , Inflamação/patologia , Aprendizado de Máquina , Prognóstico , Proteômica , SARS-CoV-2/imunologia
4.
Brain Commun ; 3(2): fcab114, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34136812

RESUMO

Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in pre-symptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia was in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerized tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology, we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice.

5.
J Interprof Care ; : 1-8, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33906566

RESUMO

Information sharing, a component of patient and family engagement (PFE), is an important process that may contribute to intensive care unit (ICU) quality of care. Yet, virtually no studies explore how the process of information sharing unfolds in the ICU from the interprofessional team and family member perspectives. To better understand the process of information sharing, we conducted ethnographic fieldwork in a 20-bed medical ICU, focusing on behaviors and interactions of the interprofessional team and family members (May 2016 - October 2016). We completed 17.5 observation hours, 6 shadowing sessions, and 12 semi-structured interviews with 17 total participants. We used thematic content analysis and iterative inductive coding to identify three themes about the information sharing process: 1) family factors (health literacy and past experience with the ICU environment) influence information sharing; 2) clinicians strategies can support engagement in the process of information sharing (assessing families' need for information, understanding a families' hope, using rounds as an opportunity for information sharing); 3) the process of information sharing allows for trust building between families and the ICU team. Our findings suggest that information sharing is a crucial process that may serve as a catalyst for effective patient and family engagement in the ICU.

6.
Sci Rep ; 11(1): 8456, 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33875684

RESUMO

Encasing an OLED between two planar metallic electrodes creates a Fabry-Pérot microcavity, resulting in significant narrowing of the emission bandwidth. The emission from such microcavity OLEDs depends on the overlap of the resonant cavity modes and the comparatively broadband electroluminescence spectrum of the organic molecular emitter. Varying the thickness of the microcavity changes the mode structure, resulting in a controlled change in the peak emission wavelength. Employing a silicon wafer substrate with high thermal conductivity to dissipate excess heat in thicker cavities allows cavity thicknesses from 100 to 350 nm to be driven at high current densities. Three resonant modes, the fundamental and first two higher harmonics, are characterized, resulting in tunable emission peaks throughout the visible range with increasingly narrow bandwidth in the higher modes. Angle resolved electroluminescence spectroscopy reveals the outcoupling of the TE and TM waveguide modes which blue-shift with respect to the normal emission at higher angles. Simultaneous stimulation of two resonant modes can produce dual peaks in the violet and red, resulting in purple emission. These microcavity-based OLEDs employ a single green molecular emitter and can be tuned to span the entire color gamut, including both the monochromatic visible range and the purple line.

7.
Materials (Basel) ; 14(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806446

RESUMO

Conjugated donor-acceptor molecules with intramolecular charge transfer absorption are employed for single-component organic solar cells. Among the five types of donor-acceptor molecules, the strong push-pull structure of DTDCPB resulted in solar cells with high JSC, an internal quantum efficiency exceeding 20%, and high VOC exceeding 1 V with little photon energy loss around 0.7 eV. The exciton binding energy (EBE), which is a key factor in enhancing the photocurrent in the single-component device, was determined by quantum chemical calculation. The relationship between the photoexcited state and the device performance suggests that the strong internal charge transfer is effective for reducing the EBE. Furthermore, molecular packing in the film is shown to influence photogeneration in the film bulk.

8.
Nat Biotechnol ; 39(7): 846-854, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33767396

RESUMO

Accurate quantification of the proteome remains challenging for large sample series and longitudinal experiments. We report a data-independent acquisition method, Scanning SWATH, that accelerates mass spectrometric (MS) duty cycles, yielding quantitative proteomes in combination with short gradients and high-flow (800 µl min-1) chromatography. Exploiting a continuous movement of the precursor isolation window to assign precursor masses to tandem mass spectrometry (MS/MS) fragment traces, Scanning SWATH increases precursor identifications by ~70% compared to conventional data-independent acquisition (DIA) methods on 0.5-5-min chromatographic gradients. We demonstrate the application of ultra-fast proteomics in drug mode-of-action screening and plasma proteomics. Scanning SWATH proteomes capture the mode of action of fungistatic azoles and statins. Moreover, we confirm 43 and identify 11 new plasma proteome biomarkers of COVID-19 severity, advancing patient classification and biomarker discovery. Thus, our results demonstrate a substantial acceleration and increased depth in fast proteomic experiments that facilitate proteomic drug screens and clinical studies.


Assuntos
Proteômica/métodos , Espectrometria de Massas em Tandem , Arabidopsis/metabolismo , Biomarcadores/metabolismo , COVID-19/sangue , COVID-19/diagnóstico , Linhagem Celular , Humanos , Peptídeos/análise , Proteoma/análise , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Índice de Gravidade de Doença
9.
BMJ Open ; 11(3): e045120, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674378

RESUMO

OBJECTIVES: Lung ultrasound (LUS) is a portable, low-cost respiratory imaging tool but is challenged by user dependence and lack of diagnostic specificity. It is unknown whether the advantages of LUS implementation could be paired with deep learning (DL) techniques to match or exceed human-level, diagnostic specificity among similar appearing, pathological LUS images. DESIGN: A convolutional neural network (CNN) was trained on LUS images with B lines of different aetiologies. CNN diagnostic performance, as validated using a 10% data holdback set, was compared with surveyed LUS-competent physicians. SETTING: Two tertiary Canadian hospitals. PARTICIPANTS: 612 LUS videos (121 381 frames) of B lines from 243 distinct patients with either (1) COVID-19 (COVID), non-COVID acute respiratory distress syndrome (NCOVID) or (3) hydrostatic pulmonary edema (HPE). RESULTS: The trained CNN performance on the independent dataset showed an ability to discriminate between COVID (area under the receiver operating characteristic curve (AUC) 1.0), NCOVID (AUC 0.934) and HPE (AUC 1.0) pathologies. This was significantly better than physician ability (AUCs of 0.697, 0.704, 0.967 for the COVID, NCOVID and HPE classes, respectively), p<0.01. CONCLUSIONS: A DL model can distinguish similar appearing LUS pathology, including COVID-19, that cannot be distinguished by humans. The performance gap between humans and the model suggests that subvisible biomarkers within ultrasound images could exist and multicentre research is merited.


Assuntos
COVID-19/diagnóstico por imagem , Aprendizado Profundo , Pulmão/diagnóstico por imagem , Redes Neurais de Computação , Edema Pulmonar/diagnóstico por imagem , Síndrome do Desconforto Respiratório/diagnóstico por imagem , Canadá , Diagnóstico Diferencial , Humanos
10.
Exp Neurol ; 338: 113607, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33460644

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of cancer treatment, often associated with degeneration of sensory axons or their terminal regions. Presence of the slow Wallerian degeneration protein (WLDS), or genetic deletion of sterile alpha and TIR motif containing protein 1 (SARM1), which strongly protect axons from degeneration after injury or axonal transport block, alleviate pain in several CIPN models. However, oxaliplatin can cause an acute pain response, suggesting a different mechanism of pain generation. Here, we tested whether the presence of WLDS or absence of SARM1 protects against acute oxaliplatin-induced pain in mice after a single oxaliplatin injection. In BL/6 and WldS mice, oxaliplatin induced significant mechanical and cold hypersensitivities which were absent in Sarm1-/- mice. Despite the presence of hypersensitivity there was no significant loss of intraepidermal nerve fibers (IENFs) in the footpads of any mice after oxaliplatin treatment, suggesting that early stages of pain hypersensitivity could be independent of axon degeneration. To identify other changes that could underlie the pain response, RNA sequencing was carried out in DRGs from treated and control mice of each genotype. Sarm1-/- mice had fewer gene expression changes than either BL/6 or WldS mice. This is consistent with the pain measurements in demonstrating that Sarm1-/- DRGs remain relatively unchanged after oxaliplatin treatment, unlike those in BL/6 and WldS mice. Changes in levels of four transcripts - Alas2, Hba-a1, Hba-a2, and Tfrc - correlated with oxaliplatin-induced pain, or absence thereof, across the three genotypes. Our findings suggest that targeting SARM1 could be a viable therapeutic approach to prevent oxaliplatin-induced acute neuropathic pain.


Assuntos
Antineoplásicos/toxicidade , Proteínas do Domínio Armadillo/metabolismo , Proteínas do Citoesqueleto/metabolismo , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Oxaliplatina/toxicidade , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
11.
PLoS One ; 16(1): e0244275, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33406116

RESUMO

PURPOSE: Studies have evaluated the application of perfusion MR for predicting survival in patients with astrocytic brain tumors, but few of them statistically adjust their results to reflect the impact of the variability of treatment administered in the patients. Our aim was to analyze the association between the perfusion values and overall survival time, with adjustment for various clinical factors, including initial treatments and follow-up treatments. MATERIALS AND METHODS: This study consisted of 51 patients with astrocytic brain tumors who underwent perfusion-weighted MRI with MultiHance® at a dose of 0.1 mmol/kg prior to initial surgery. We measured the mean rCBV, the 5% & 10% maximum rCBV, and the variation of rCBV in the tumors. Comparisons were made between patients with and without 2-year survival using two-sample t-test or Wilcoxon rank-sum test for the continuous data, or chi-square and Fisher exact tests for categorical data. The multivariate cox-proportional hazard regression was fit to evaluate the association between rCBV and overall survival time, with adjustment for clinical factors. RESULTS: Patients who survived less than 2 years after diagnosis had a higher mean and maximum rCBV and a larger variation of rCBV. After adjusting for clinical factors including therapeutic measures, we found no significant association of overall survival time within 2 years with any of these rCBV values. CONCLUSIONS: Although patients who survived less than 2 years had a higher mean and maximum rCBV and a larger variation of rCBV, rCBV itself may not be used independently for predicting 2-year survival of patients with astrocytic brain tumors.


Assuntos
Astrocitoma/mortalidade , Neoplasias Encefálicas/mortalidade , Angiografia por Ressonância Magnética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/uso terapêutico , Astrocitoma/diagnóstico por imagem , Astrocitoma/tratamento farmacológico , Astrocitoma/patologia , Mapeamento Encefálico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Bases de Dados Factuais , Humanos , Estimativa de Kaplan-Meier , Masculino , Meglumina/análogos & derivados , Meglumina/química , Pessoa de Meia-Idade , Compostos Organometálicos/química , Estudos Retrospectivos , Temozolomida/uso terapêutico , Adulto Jovem
12.
Heliyon ; 7(1): e05843, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33474507

RESUMO

Positive psychology has attracted extensive interests from educators, researchers, and organizations. Many would recognize the work of Martin Seligman (e.g., Seligman, 2010) and Mihaly Csikszentmihalyi (e.g.,Csíkszentmihályi, 2014b). In its summarized form, positive psychology is concerned with a person's state of flourishing, his/her perceived sense of resilience and inner virtues, and a desire to have positive outlooks in life. Positive psychology is significant, forming the basis for other research inquiries - for example, the advancement of the theory of optimization (Fraillon, 2004; Phan, Ngu and Yeung, 2019b). Considering this evidence, we develop and offer an alternative theoretical model for discussion, which we termed as 'holistic psychology'. Holistic psychology, the main focus of this theoretical-conceptual article, is significant for its emphasis on the existence of life experiences, which may exist on a continuous spectrum without distinction between negativity and positivity. This testament, we contend, reflects the importance of inclusiveness and that one could consider maladaptive and negative life experiences (e.g., school disengagement) as sources of vitality, motivating and governing a person to seek for improvement, resulting in a state of flourishing. Our conceptualization in this sense is philosophical, grounded in the main premise of optimization (Fraillon, 2004; Phan et al., 2019b) in which we propose a key tenet for consideration - namely, the 'transformation' of negative life experiences into a source of 'energy' (i.e., denoted as E) for subsequent enactment. In detail for discussion, our proposed model of holistic psychology consists of four major stages: (i) personal reflection, (ii) the sub-process of transformation, (iii) enactment of energy, and (iv) arousal and sustaining an improved state of functioning.

13.
Lancet Neurol ; 20(1): 49-59, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33212063

RESUMO

BACKGROUND: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. METHODS: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. FINDINGS: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. INTERPRETATION: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran. FUNDING: Alnylam Pharmaceuticals.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Avaliação de Resultados em Cuidados de Saúde , Polineuropatias/tratamento farmacológico , Pré-Albumina/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia , Adulto , Idoso , Neuropatias Amiloides Familiares/complicações , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Polineuropatias/etiologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/efeitos adversos , Índice de Gravidade de Doença
14.
J Neurotrauma ; 38(5): 573-581, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33096965

RESUMO

This study is to examine the effects of a 12-session moderate intensity-interval-training program with blood flow restriction (BFR) and body cooling (BC) on people who have had persistent post-concussive symptoms (PPCS) for <1 year. A single-blind randomized controlled trial of interval-training exercise with BFR and BC was conducted. Twenty-five adults with PPCS were assigned to the experimental group (n = 14) or the control group (n = 11). Both groups rode a recumbent elliptical machine for 21 min at moderate intensity (65% predicted maximum heart rate) twice a week for 6 weeks, but only the experimental group received BFR and BC while riding. The variances of overall PPCS scale scores and their sub-domain scores for individuals during the 6-week intervention and 6-week follow-up period were calculated. During the intervention, the fluctuation of overall symptom severity, severity in the cognitive domain and severity in the mood domain were significantly less in the experimental group (p = 0.03; p = 0.02; p = 0.02). During the follow-up period, the number of symptoms remained more stable in the experimental group (p = 0.02), and a trend toward less fluctuation of symptom severity (p = 0.05) was also observed. The reduced number of symptoms in the cognitive and sleep domains remained more stable in the experimental group following the intervention (p = 0.007; p = 0.02). The severity of mood and sleep symptoms also remained more stable during the follow-up period in the experimental group (p = 0.04). More stable recovery was found in individuals who exercised using BFR and BC than in those who underwent exercise without BFR and BC. Moderate intensity-interval-training exercise with BFR and BC alleviated post-concussive symptoms in people who have had PPCS <1 year.

15.
Transl Psychiatry ; 10(1): 377, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33149110

RESUMO

Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43Q331K mouse, an ALS-FTD model with a human-equivalent mutation (TDP-43Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS-FTD patients. The TDP-43Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS-FTD.


Assuntos
Esclerose Amiotrófica Lateral , Apatia , Demência Frontotemporal , Idoso , Esclerose Amiotrófica Lateral/genética , Animais , Proteínas de Ligação a DNA/genética , Demência Frontotemporal/genética , Humanos , Masculino , Camundongos , Mutação
16.
J Am Coll Emerg Physicians Open ; 1(2): 124-131, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33000024

RESUMO

Background: Artificial intelligence (AI) is increasingly a part of daily life and offers great possibilities to enrich health care. Imaging applications of AI have been mostly developed by large, well-funded companies and currently are inaccessible to the comparatively small market of point-of-care ultrasound (POCUS) programs. Given this absence of commercial solutions, we sought to create and test a do-it-yourself (DIY) deep learning algorithm to classify ultrasound images to enhance the quality assurance work-flow for POCUS programs. Methods: We created a convolutional neural network using publicly available software tools and pre-existing convolutional neural network architecture. The convolutional neural network was subsequently trained using ultrasound images from seven ultrasound exam types: pelvis, heart, lung, abdomen, musculoskeletal, ocular, and central vascular access from 189 publicly available POCUS videos. Approximately 121,000 individual images were extracted from the videos, 80% were used for model training and 10% each for cross validation and testing. We then tested the algorithm for accuracy against a set of 160 randomly extracted ultrasound frames from ultrasound videos not previously used for training and that were performed on different ultrasound equipment. Three POCUS experts blindly categorized the 160 random images, and results were compared to the convolutional neural network algorithm. Descriptive statistics and Krippendorff alpha reliability estimates were calculated. Results: The cross validation of the convolutional neural network approached 99% for accuracy. The algorithm accurately classified 98% of the test ultrasound images. In the new POCUS program simulation phase, the algorithm accurately classified 70% of 160 new images for moderate correlation with the ground truth, α = 0.64. The three blinded POCUS experts correctly classified 93%, 94%, and 98% of the images, respectively. There was excellent agreement among the experts with α = 0.87. Agreement between experts and algorithm was good with α = 0.74. The most common error was misclassifying musculoskeletal images for both the algorithm (40%) and POCUS experts (40.6%). The algorithm took 7 minutes 45 seconds to review and classify the new 160 images. The 3 expert reviewers took 27, 32, and 45 minutes to classify the images, respectively. Conclusions: Our algorithm accurately classified 98% of new images, by body scan area, related to its training pool, simulating POCUS program workflow. Performance was diminished with exam images from an unrelated image pool and ultrasound equipment, suggesting additional images and convolutional neural network training are necessary for fine tuning when using across different POCUS programs. The algorithm showed theoretical potential to improve workflow for POCUS program directors, if fully implemented. The implications of our DIY AI for POCUS are scalable and further work to maximize the collaboration between AI and POCUS programs is warranted.

17.
Free Radic Biol Med ; 161: 115-124, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33049334

RESUMO

Lanthionine synthase C-like protein-1 (LanCL1) is a glutathione (GSH)-binding protein of uncertain function, widely expressed in mammalian cells. Recent data suggests that LanCL1 has glutathione S-transferase (GST)-like activity, while other reports claim that LanCL1 suppresses mitogen-activated kinase (MAPK) phosphorylation. In the present study, recombinant human LanCL1 had less than 10% the specific activity of GST. When CRISPR-Cas9 was used to stably ablate LanCL1 from HeLa cells, the resulting line was sensitized to H2O2 toxicity. [GSH], [GSSG], [GSH]/[GSSG] and GST activity were unaltered by LanCL1 knockout but glutathione reductase and glutathione peroxidase activities were significantly elevated. LanCL1-KO cells did not differ in basal or H2O2-induced p38-MAPK, ERK p42/p44 or JNK phosphorylation; however, MAPK-targeted transcription factor regulators c-Jun and IκBα were significantly decreased. Because c-Jun and IκBα levels are ubiquitin regulated, experiments addressed the hypothesis that LanCL1 affects ubiquitination dynamics. In the presence of the 26S proteasome inhibitor bortezomib, ubiquitinated proteins accumulated faster in LanCL1-KO cells, suggesting that LanCL1 positively regulates deubiquitination. The activity of ubiquitin C-terminal hydrolase (UCH), a major deubiquitinase (DUB) subclass, was significantly decreased in LanCL1-KO cells while protein levels of A20/TNFAIP3, USP9X and USP10 DUBs were significantly reduced. UCH activity in HeLa cell lysates was lost upon treatment with H2O2 and significantly recovered by addition of recombinant LanCL1 plus GSH. Taken together these data suggest that LanCL1 likely does not act as a GST-like enzyme in vivo, but rather modulates ubiquitin-dependent cell signaling pathways through positive regulation of redox-sensitive DUBs.


Assuntos
Enzimas Desubiquitinantes , Peróxido de Hidrogênio , Animais , Células HeLa , Humanos , Hidroliases , Complexos Multienzimáticos , Oxirredução , Receptores Acoplados a Proteínas G/metabolismo , Ubiquitina Tiolesterase
18.
Clin Biomech (Bristol, Avon) ; 80: 105133, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32777685

RESUMO

BACKGROUND: Overground lower-limb robotic exoskeletons are assistive devices used to facilitate ambulation and gait rehabilitation. Our understanding of how closely they resemble comfortable and slow walking is limited. This information is important to maximise the effects of gait rehabilitation. The aim was to compare the 3D gait parameters of able-bodied individuals walking with and without an exoskeleton at two speeds (self-selected comfortable vs. slow, speed-matched to the exoskeleton) to understand how the user's body moved within the device. METHODS: Eight healthy, able-bodied individuals walked along a 12-m walkway with and without the exoskeleton. Three-dimensional whole-body kinematics inside the device were captured. Temporal-spatial parameters and sagittal joint kinematics were determined for normal and exoskeleton walking. One-way repeated measures ANOVAs and statistical parametric mapping were used to compare the three walking conditions (P < .05). FINDINGS: The walking speeds of the slow (0.44[0.03] m/s) and exoskeleton (0.41[0.03] m/s) conditions were significantly slower than the comfortable walking speed (1.54[0.07] m/s). However, time in swing was significantly greater (P < .001, d = -3.64) and double support was correspondingly lower (P < .001, d = 3.72) during exoskeleton gait than slow walking, more closely resembling comfortable speed walking. Ankle and knee angles were significantly reduced in the slow and exoskeleton conditions. Angles were also significantly different for the upper body. INTERPRETATION: Although the slow condition was speed-matched to exoskeleton gait, the stance:swing ratio of exoskeleton stepping more closely resembled comfortable gait than slow gait. The altered upper body kinematics suggested that overground exoskeletons may provide a training environment that would also benefit balance training.


Assuntos
Exoesqueleto Energizado , Marcha , Fenômenos Mecânicos , Robótica , Velocidade de Caminhada , Adulto , Fenômenos Biomecânicos , Feminino , Humanos , Masculino
19.
Cell Syst ; 11(1): 11-24.e4, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32619549

RESUMO

The COVID-19 pandemic is an unprecedented global challenge, and point-of-care diagnostic classifiers are urgently required. Here, we present a platform for ultra-high-throughput serum and plasma proteomics that builds on ISO13485 standardization to facilitate simple implementation in regulated clinical laboratories. Our low-cost workflow handles up to 180 samples per day, enables high precision quantification, and reduces batch effects for large-scale and longitudinal studies. We use our platform on samples collected from a cohort of early hospitalized cases of the SARS-CoV-2 pandemic and identify 27 potential biomarkers that are differentially expressed depending on the WHO severity grade of COVID-19. They include complement factors, the coagulation system, inflammation modulators, and pro-inflammatory factors upstream and downstream of interleukin 6. All protocols and software for implementing our approach are freely available. In total, this work supports the development of routine proteomic assays to aid clinical decision making and generate hypotheses about potential COVID-19 therapeutic targets.


Assuntos
Proteínas Sanguíneas/metabolismo , Infecções por Coronavirus/sangue , Pneumonia Viral/sangue , Proteômica/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/isolamento & purificação , Biomarcadores/sangue , Proteínas Sanguíneas/análise , COVID-19 , Infecções por Coronavirus/classificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias/classificação , Pneumonia Viral/classificação , Pneumonia Viral/patologia , Pneumonia Viral/virologia , SARS-CoV-2 , Adulto Jovem
20.
Sci Rep ; 10(1): 9474, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528044

RESUMO

BACKGROUND: Incidental findings are a well-known complication of imaging studies done for both diagnostic and research purposes. Little is known about the rates and types of incidental findings found on brain MRI in patients with HIV infection, who may be at risk for HIV-Associated Neurocognitive Disorders (HAND). METHODS: The parent study included 108 adults with HIV infection and 125 demographically-matched uninfected controls who completed MRI and neuropsychological testing. Incidental findings were classified by the study team as vascular, neoplastic, congenital, other neurologic, or non-neurologic. Categorical measures were compared using Pearson chi-square tests; continuous measures were compared using t-tests. RESULTS: Among participants with HIV infection, 36/108 (33%) had incidental findings compared to 33/125 (26%) controls (p = 0.248). Rates of incidental findings were significantly correlated with increasing age in both participants with HIV infection (p = 0.013) and controls (p = 0.022). We found no correlation between presence of incidental findings and sex or race/ethnicity among either cohort, and no correlation with CD4 count or HAND status for the HIV-infected cohort. CONCLUSIONS: Incidental findings were common in both participants with HIV infection and controls, at higher rates than previously reported in healthy populations. There was no significant difference in prevalence between the groups.


Assuntos
Encéfalo/patologia , Infecções por HIV/complicações , Infecções por HIV/patologia , Adulto , Idoso , Encéfalo/virologia , Contagem de Linfócito CD4/métodos , Estudos de Coortes , Feminino , Infecções por HIV/virologia , Humanos , Achados Incidentais , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Adulto Jovem
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