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1.
Perception ; : 3010066241248120, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38706200

RESUMO

Knowing where the body is in space requires reference to a stored model of the size and shape of body parts, termed the body model. This study sought to investigate the characteristics of the implicit body model of the trunk by assessing the position sense of midline and lateral body landmarks. Sixty-nine healthy participants localised midline and lateral body landmarks on their thorax, waist and hips, with perceived positions of these landmarks compared to actual positions. This study demonstrates evidence of a significant distortion of the implicit body model of the trunk, presenting as a squatter trunk, wider at the waist and hips. A significant difference was found between perceived and actual location in the horizontal (x) and vertical (y) directions for the majority of trunk landmarks. Evidence of a rightward bias was noted in the perception of six of the nine body landmarks in the horizontal (x) direction, including all midline levels. In the vertical (y) direction, a substantial inferior bias was evident at the thorax and waist. The implicit body model of the trunk is shown to be distorted, with the lumbar spine (waist-to-hip region) held to be shorter and wider than reality.

3.
Atten Percept Psychophys ; 86(3): 1008-1021, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38332382

RESUMO

Localizing tactile stimulation is an important capability for everyday function and may be impaired in people with persistent pain. This study sought to provide a detailed description of lumbar spine tactile localization accuracy in healthy individuals. Sixty-nine healthy participants estimated where they were touched at nine different points, labelled in a 3 × 3 grid over the lumbar spine. Mislocalization between the perceived and actual stimulus was calculated in horizontal (x) and vertical (y) directions, and a derived hypotenuse (c) mislocalization was calculated to represent the direct distance between perceived and actual points. In the horizontal direction, midline sites had the smallest mislocalization. Participants exhibited greater mislocalization for left- and right-sided sites, perceiving sites more laterally than they actually were. For all vertical values, stimulated sites were perceived lower than reality. A greater inaccuracy was observed in the vertical direction. This study measured tactile localization for the low back utilizing a novel testing method. The large inaccuracies point to a possible distortion in the underlying perceptual maps informing the superficial schema; however, further testing comparing this novel method with an established tactile localization task, such as the point-to-point method, is suggested to confirm these findings.


Assuntos
Percepção do Tato , Humanos , Masculino , Feminino , Adulto , Percepção do Tato/fisiologia , Adulto Jovem , Tato/fisiologia , Percepção Espacial/fisiologia , Adolescente , Vértebras Lombares/fisiologia , Região Lombossacral
4.
Phys Chem Chem Phys ; 24(28): 17116-17120, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35791889

RESUMO

A good oxygen reduction reaction (ORR) catalyst should be stable and active under electrochemical reaction conditions. Niobium pentaoxide (Nb2O5) is known to be stable under ORR conditions. However it has a large band gap, which makes conductivity a challenge during the reaction. In this work, we aim to understand if surface modification of the 110 facet of niobium pentaoxide with transition metal doping has any effect on its ORR activity and conductivity. While the problem of conductivity in the case of transition metal oxides (TMOs) can be partially rectified by transition metal doping, it has negligible influence on the ORR activity of the doped systems.

5.
J Am Board Fam Med ; 35(1): 96-101, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35039415

RESUMO

BACKGROUND: Molecular tests (ie, real-time polymerase chain reaction [RT-PCR]) and antigen tests are used to detect SARS-CoV-2. RT-PCR tests are generally considered to be the standard for clinical diagnosis of SARS-CoV-2 due to accuracy and reliability but can take longer to return results than antigen tests. Our aim was to examine if point-of-care (POC) testing for SARS-CoV-2 infection would provide a flexible resource to help achieve workplace safety. We compared test results and time-to-test results between a POC RT-PCR test and a send-out PCR test in a program implemented in summer 2020. RESULTS: POC testing shortened the time to results to 110 minutes in the POC setting from the 754 minutes for send-out tests. The specificity of POC RT-PCR single POC testing was 98.7% compared with send-out RT-PCR testing and was confirmed at 99.8% in a validation analysis. The sensitivity of the POC testing was 100% compared with send-out RT-PCR, although in a validation analysis, sensitivity appeared as 0% because only the 12 positive or indeterminate samples on the first analysis were retested and the majority were false-positives that were correctly ruled out. CONCLUSIONS: POC testing for SARS-CoV-2 with RT-PCR technology is possible at reduced time compared with send-out PCR testing.


Assuntos
COVID-19 , SARS-CoV-2 , Teste para COVID-19 , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Local de Trabalho
6.
Adv Health Care Manag ; 202021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34779184

RESUMO

Purpose: While COVID-19 has upended lives, it has also catalyzed innovation with potential to advance health delivery. Yet, we know little about how the delivery system, and primary care in particular, has responded and how this has impacted vulnerable patients. We aimed to understand the impact of COVID-19 on primary care practice sites and their vulnerable patients and to identify explanations for variation. Approach: We developed and administered a survey to practice managers and physician leaders from 173 primary care practice sites, October-November 2020. We report and graphically depict results from univariate analysis and examine potential explanations for variation in practices' process innovations in response to COVID-19 by assessing bivariate relationships between seven dependent variables and four independent variables. Findings: Among 96 (55.5%) respondents, primary care practice sites on average took more safety (8.5 of 12) than financial (2.5 of 17) precautions in response to COVID-19. Practice sites varied in their efforts to protect patients with vulnerabilities, providing care initially postponed, and experience with virtual visits. Financial risk, practice size, practitioner age, and emergency preparedness explained variation in primary care practices' process innovations. Many practice sites plan to sustain virtual visits, dependent mostly on patient and provider preference and continued reimbursement. Value: While findings indicate rapid and substantial innovation, conditions must enable primary care practice sites to build on and sustain innovations, to support care for vulnerable populations, including those with multiple chronic conditions and socio-economic barriers to health, and to prepare primary care for future emergencies.


Assuntos
COVID-19 , Humanos , Atenção Primária à Saúde , SARS-CoV-2 , Inquéritos e Questionários , Populações Vulneráveis
7.
Lancet Digit Health ; 3(2): e115-e123, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33358138

RESUMO

Ambient intelligence is increasingly finding applications in health-care settings, such as helping to ensure clinician and patient safety by monitoring staff compliance with clinical best practices or relieving staff of burdensome documentation tasks. Ambient intelligence involves using contactless sensors and contact-based wearable devices embedded in health-care settings to collect data (eg, imaging data of physical spaces, audio data, or body temperature), coupled with machine learning algorithms to efficiently and effectively interpret these data. Despite the promise of ambient intelligence to improve quality of care, the continuous collection of large amounts of sensor data in health-care settings presents ethical challenges, particularly in terms of privacy, data management, bias and fairness, and informed consent. Navigating these ethical issues is crucial not only for the success of individual uses, but for acceptance of the field as a whole.


Assuntos
Inteligência Ambiental , Temas Bioéticos , Gerenciamento de Dados/ética , Assistência ao Paciente/ética , Telemedicina/ética , Telemetria/ética , Algoritmos , Coleta de Dados , Tecnologia Digital , Documentação/métodos , Pessoal de Saúde , Humanos , Consentimento Livre e Esclarecido , Aprendizado de Máquina , Assistência ao Paciente/métodos , Segurança do Paciente , Guias de Prática Clínica como Assunto , Privacidade , Qualidade da Assistência à Saúde , Telemedicina/métodos , Telemetria/métodos , Dispositivos Eletrônicos Vestíveis
8.
BMC Musculoskelet Disord ; 20(1): 70, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744620

RESUMO

BACKGROUND: Preclinical osteoarthritis models where damage occurs spontaneously may better reflect the initiation and development of human osteoarthritis. The aim was to assess the commercial pig as a model of spontaneous osteoarthritis development by examining pain-associated behaviour, joint cartilage integrity, as well as the use of porcine cartilage explants and isolated chondrocytes and osteoblasts for ex vivo and in vitro studies. METHODS: Female pigs (Large white x Landrace x Duroc) were examined at different ages from 6 weeks to 3-4 years old. Lameness was assessed as a marker of pain-associated behaviour. Femorotibial joint cartilage integrity was determined by chondropathy scoring and histological staining of proteoglycan. IL-6 production and proteoglycan degradation was assessed in cartilage explants and primary porcine chondrocytes by ELISA and DMMB assay. Primary porcine osteoblasts from damaged and non-damaged joints, as determined by chondropathy scoring, were assessed for mineralisation, proliferative and mitochondrial function as a marker of metabolic capacity. RESULTS: Pigs aged 80 weeks and older exhibited lameness. Osteoarthritic lesions in femoral condyle and tibial plateau cartilage were apparent from 40 weeks and increased in severity with age up to 3-4 years old. Cartilage from damaged joints exhibited proteoglycan loss, which positively correlated with chondropathy score. Stimulation of porcine cartilage explants and primary chondrocytes with either IL-1ß or visfatin induced IL-6 production and proteoglycan degradation. Primary porcine osteoblasts from damaged joints exhibited reduced proliferative, mineralisation, and metabolic capacity. CONCLUSION: In conclusion, the commercial pig represents an alternative model of spontaneous osteoarthritis and an excellent source of tissue for in vitro and ex vivo studies.


Assuntos
Cartilagem Articular , Condrócitos , Articulações , Osteoartrite , Osteoblastos , Animais , Comportamento Animal , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Cartilagem Articular/fisiopatologia , Proliferação de Células , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Condrogênese , Modelos Animais de Doenças , Progressão da Doença , Feminino , Interleucina-6/metabolismo , Articulações/metabolismo , Articulações/patologia , Articulações/fisiopatologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/fisiopatologia , Osteoartrite/psicologia , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteogênese , Proteoglicanas/metabolismo , Proteólise , Índice de Gravidade de Doença , Sus scrofa , Fatores de Tempo
9.
Biotech Histochem ; 94(1): 36-41, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30070929

RESUMO

Marker amplification is a powerful technique for visualizing immunohistochemically deposited markers that otherwise would be invisible. Amplification usually is achieved with physical developers, which are solutions that contain a source of silver(I) plus a reducing agent. When the marker is present in extremely small quantities, prolonged incubation in the developer is required and unwanted background staining in the form of type III argyrophilia becomes problematic. Suppression of type III argyrophilia can be achieved by metal-catalyzed oxidation using the copper/H2O2 system, which normally is applied immediately prior to amplification. Because there is no reason, in principle, why metal-catalyzed oxidation should not be employed at earlier stages in the immunohistochemical staining procedure, we investigated whether earlier oxidation might confer any advantages over the traditional methodology. Immunocolloidal gold combined with two light insensitive physical developers was chosen as the model system, because visualization by light microscopy requires extended periods in the developers. Moreover, the system does not suffer from problems concerning endogenous enzyme- or non-enzyme-catalyzed marker deposition. Applying metal-catalyzed oxidation at each stage of the immunohistochemical procedure revealed that the technique could be employed successfully prior to staining, but not following the primary or secondary antibodies. In the latter cases, specific immunolocalization was lost entirely and only generalized nonspecific staining was seen. A limited investigation into the mechanism of metal-catalyzed oxidation of aldehyde fixed tissue sections suggested that it involved the formation of aldehyde groups. We suggest that the application of metal-catalyzed oxidation prior to immunohistochemical staining would have the advantages of both suppressing type III argyrophilia and inhibiting unwanted endogenous peroxidase activity. We also suggest that metal-catalyzed oxidation might reduce the affinity of tissue for other transition metals, such as copper, whose potential for improving marker amplification techniques has been demonstrated previously in dot-blot model systems.


Assuntos
Anticorpos/química , Antígenos/química , Cobre/química , Imuno-Histoquímica/métodos , Coloração e Rotulagem/métodos , Catálise , Peróxido de Hidrogênio , Oxirredução , Prata/química
10.
Syst Rev ; 6(1): 259, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29258596

RESUMO

BACKGROUND: Social relationships, which are contingent on access to social networks, promote engagement in social activities and provide access to social support. These social factors have been shown to positively impact health outcomes. In the current systematic review, we offer a comprehensive overview of the impact of social activities, social networks and social support on the cognitive functioning of healthy older adults (50+) and examine the differential effects of aspects of social relationships on various cognitive domains. METHODS: We followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines, and collated data from randomised controlled trials (RCTs), genetic and observational studies. Independent variables of interest included subjective measures of social activities, social networks, and social support, and composite measures of social relationships (CMSR). The primary outcome of interest was cognitive function divided into domains of episodic memory, semantic memory, overall memory ability, working memory, verbal fluency, reasoning, attention, processing speed, visuospatial abilities, overall executive functioning and global cognition. RESULTS: Thirty-nine studies were included in the review; three RCTs, 34 observational studies, and two genetic studies. Evidence suggests a relationship between (1) social activity and global cognition and overall executive functioning, working memory, visuospatial abilities and processing speed but not episodic memory, verbal fluency, reasoning or attention; (2) social networks and global cognition but not episodic memory, attention or processing speed; (3) social support and global cognition and episodic memory but not attention or processing speed; and (4) CMSR and episodic memory and verbal fluency but not global cognition. CONCLUSIONS: The results support prior conclusions that there is an association between social relationships and cognitive function but the exact nature of this association remains unclear. Implications of the findings are discussed and suggestions for future research provided. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2012: CRD42012003248 .


Assuntos
Cognição , Relações Interpessoais , Participação Social/psicologia , Apoio Social , Função Executiva , Humanos , Memória
11.
BMC Geriatr ; 17(1): 121, 2017 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-28592236

RESUMO

BACKGROUND: There is increasing demand for formal government funded home help services to support community-dwelling older people in Ireland, yet limited information exists on the health profiles of this group, especially regarding frailty. Our aim was to profile a large cohort of adults in receipt of low level home help and to determine the prevalence of frailty. METHODS: A total 1312 older adults, (≥ 65 years) in receipt of low level home help (< 5 h per week) were reviewed by community nurses and frailty was assessed using the Clinical Frailty Scale (CFS) in this cross-sectional study. Characteristics of the group were compared between males and females and prevalence of frailty was reported according to gender and principal care. Associations between frailty and a number of variables were explored using bivariate and regression analysis. RESULTS: The cohort of low level home-help users was a mean age of 82.1 (SD 7.3) years, predominantly female (70.6%) and over half (69.2%) lived alone. The prevalence of frailty in this population was 41.5%, with subjects primarily considered mildly (23.2%) or moderately frail (14.5%) by the CFS. A further 38.4% were classed as vulnerable. The degree of frailty did not differ significantly across the younger categories aged 65-84 years. However, in the oldest age groups, namely 90-94 and >95 years, moderate frailty was significantly higher relative to the younger groups (21% and 34%, p < 0.05, p < 0.01 respectively). Home help hours significantly correlated with frailty (rs = 0.371, p < 0.001) and functional dependency (rs = 0.609, p < 0.001), but only weakly with age (rs = 0.101, p = 0.034). Based on regression analysis, determinants of frailty included greater dependency (Barthel score), higher home help hours, non-self-caring and communication difficulty, all of which significantly contributed to the model, with a r squared value of 0.508. CONCLUSION: A high prevalence of frailty (41.5%) was documented in this population which associated with higher home help utilisation. Frailty was associated with greater functional dependency, but not strongly with chronological age, until after 90 years. These findings highlight opportunities for developing intervention strategies targeted at ageing in place among home help users.


Assuntos
Idoso Fragilizado , Fragilidade/epidemiologia , Fragilidade/terapia , Serviços de Assistência Domiciliar/tendências , Vida Independente/tendências , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Estudos Transversais , Feminino , Fragilidade/diagnóstico , Humanos , Irlanda/epidemiologia , Masculino , Prevalência
12.
PLoS One ; 11(7): e0158990, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27433936

RESUMO

Naturally occurring canine osteoarthritis represents a welfare issue for affected dogs (Canis familiaris), but is also considered very similar to human osteoarthritis and has therefore been proposed as a model of disease in humans. Central sensitisation is recognized in human osteoarthritis sufferers but identification in dogs is challenging. Electromyographic measurement of responses to nociceptive stimulation represents a potential means of investigating alterations in central nociceptive processing, and has been evaluated in conscious experimental dogs, but is likely to be aversive. Development of a suitable anaesthetic protocol in experimental dogs, which facilitated electrophysiological nociceptive withdrawal reflex assessment, may increase the acceptability of using the technique in owned dogs with naturally occurring osteoarthritis. Seven purpose bred male hound dogs underwent electromyographic recording sessions in each of three states: acepromazine sedation, alfaxalone sedation, and alfaxalone anaesthesia. Electromyographic responses to escalating mechanical and electrical, and repeated electrical, stimuli were recorded. Subsequently the integral of both early and late rectified responses was calculated. Natural logarithms of the integral values were analysed within and between the three states using multi level modeling. Alfaxalone increased nociceptive thresholds and decreased the magnitude of recorded responses, but characteristics of increasing responses with increasing stimulus magnitude were preserved. Behavioural signs of anxiety were noted in two out of seven dogs during recordings in the acepromazine sedated state. There were few significant differences in response magnitude or nociceptive threshold between the two alfaxalone states. Following acepromazine premedication, induction of anaesthesia with 1-2 mg kg-1 alfaxalone, followed by a continuous rate infusion in the range 0.075-0.1 mg kg-1 min-1 produced suitable conditions to enable assessment of spinal nociceptive processing in dogs, without subjecting them to potentially aversive experiences. This methodology may be appropriate for obtaining electrophysiological nociceptive withdrawal reflex data in client-owned dogs with naturally occurring osteoarthritis.


Assuntos
Anestesia/métodos , Anestésicos/administração & dosagem , Osteoartrite/diagnóstico , Dor/diagnóstico , Pregnanodionas/administração & dosagem , Animais , Estado de Consciência/efeitos dos fármacos , Cães , Fenômenos Eletrofisiológicos , Masculino , Osteoartrite/fisiopatologia , Osteoartrite/veterinária , Dor/tratamento farmacológico , Dor/veterinária , Reflexo/efeitos dos fármacos
13.
Work ; 53(2): 399-408, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26519010

RESUMO

BACKGROUND: Disability from mental health (MH) symptoms impairs workers' functioning. Most of what is known about the MH of workers relates to their experiences after intervention or work absence. OBJECTIVE: To profile the clinical symptoms, self-reported absenteeism and presenteeism and treatment response of workers with MH symptoms at the point of accessing MH care and compare the characteristics of patients referred with or without problems related to work. METHODS: Analysis of 11 years of patient data collected in a Shared Mental Health Care (SMHC) clinic referred within a primary care setting in Ontario, Canada. Multiple regression with MH disorders was used to predict absenteeism and presenteeism. Absenteeism and presenteeism were assessed using the 12-item self-administered version of the WHO-DAS 2. Symptom profiles were assessed with the Patient Health Questionnaire (PHQ). RESULTS: Some psychiatric disorders (depression, somatization, anxiety) contributed more to predicting absenteeism and presenteeism than others. Patients referred with work-related problems differed from the general SMHC population in terms of sex and type and number of symptoms. Treatment response was good in both groups after a mean of three treatment visits. CONCLUSIONS: Patients with work-related mental health complaints formed a distinct clinical group that benefitted equally from the intervention(s) provided by SMHC.


Assuntos
Absenteísmo , Pessoas Mentalmente Doentes , Presenteísmo/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ontário , Atenção Primária à Saúde , Encaminhamento e Consulta , Inquéritos e Questionários
14.
Br J Clin Pharmacol ; 80(5): 965-78, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25923821

RESUMO

Arthritis is the commonest cause of disabling chronic pain, and both osteoarthritis (OA) and rheumatoid arthritis (RA) remain major burdens on both individuals and society. Peripheral release of calcitonin gene-related peptide (CGRP) contributes to the vasodilation of acute neurogenic inflammation. Contributions of CGRP to the pain and inflammation of chronic arthritis, however, are only recently being elucidated. Animal models of arthritis are revealing the molecular and pathophysiological events that accompany and lead to progression of both arthritis and pain. Peripheral actions of CGRP in the joint might contribute to both inflammation and joint afferent sensitization. CGRP and its specific receptors are expressed in joint afferents and up-regulated following arthritis induction. Peripheral CGRP release results in activation of synovial vascular cells, through which acute vasodilatation is followed by endothelial cell proliferation and angiogenesis, key features of chronic inflammation. Local administration of CGRP to the knee also increases mechanosensitivity of joint afferents, mimicking peripheral sensitization seen in arthritic joints. Increased mechanosensitivity in OA knees and pain behaviour can be reduced by peripherally acting CGRP receptor antagonists. Effects of CGRP pathway blockade on arthritic joint afferents, but not in normal joints, suggest contributions to sensitization rather than normal joint nociception. CGRP therefore might make key contributions to the transition from normal to persistent synovitis, and the progression from nociception to sensitization. Targeting CGRP or its receptors within joint tissues to prevent these undesirable transitions during early arthritis, or suppress them in established disease, might prevent persistent inflammation and relieve arthritis pain.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Inflamação/fisiopatologia , Articulações/fisiopatologia , Dor/fisiopatologia , Animais , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Modelos Animais de Doenças , Células Endoteliais/fisiologia , Humanos , Inflamação/metabolismo , Articulações/metabolismo , Modelos Biológicos , Neovascularização Patológica/fisiopatologia , Dor/metabolismo
15.
Nucleic Acids Res ; 43(Database issue): D737-42, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25392405

RESUMO

The non-human primate reference transcriptome resource (NHPRTR, available online at http://nhprtr.org/) aims to generate comprehensive RNA-seq data from a wide variety of non-human primates (NHPs), from lemurs to hominids. In the 2012 Phase I of the NHPRTR project, 19 billion fragments or 3.8 terabases of transcriptome sequences were collected from pools of ∼ 20 tissues in 15 species and subspecies. Here we describe a major expansion of NHPRTR by adding 10.1 billion fragments of tissue-specific RNA-seq data. For this effort, we selected 11 of the original 15 NHP species and subspecies and constructed total RNA libraries for the same ∼ 15 tissues in each. The sequence quality is such that 88% of the reads align to human reference sequences, allowing us to compute the full list of expression abundance across all tissues for each species, using the reads mapped to human genes. This update also includes improved transcript annotations derived from RNA-seq data for rhesus and cynomolgus macaques, two of the most commonly used NHP models and additional RNA-seq data compiled from related projects. Together, these comprehensive reference transcriptomes from multiple primates serve as a valuable community resource for genome annotation, gene dynamics and comparative functional analysis.


Assuntos
Bases de Dados Genéticas , Perfilação da Expressão Gênica , Primatas/genética , Análise de Sequência de RNA , Animais , Internet , Macaca , Anotação de Sequência Molecular , Especificidade de Órgãos , Padrões de Referência , Alinhamento de Sequência/normas
16.
BMC Genomics ; 15: 1161, 2014 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-25534508

RESUMO

BACKGROUND: The recent emergence of a novel coronavirus in the Middle East (designated MERS-CoV) is a reminder of the zoonotic and pathogenic potential of emerging coronaviruses in humans. Clinical features of Middle East respiratory syndrome (MERS) include atypical pneumonia and progressive respiratory failure that is highly reminiscent of severe acute respiratory syndrome (SARS) caused by SARS-CoV. The host response is a key component of highly pathogenic respiratory virus infection. Here, we computationally analyzed gene expression changes in a human airway epithelial cell line infected with two genetically distinct MERS-CoV strains obtained from human patients, MERS-CoV SA 1 and MERS-CoV Eng 1. RESULTS: Using topological techniques, including persistence homology and filtered clustering, we performed a comparative transcriptional analysis of human Calu-3 cell host responses to the different MERS-CoV strains, with MERS-CoV Eng 1 inducing early kinetic changes, between 3 and 12 hours post infection, compared to MERS-CoV SA 1. Robust transcriptional changes distinguished the two MERS-CoV strains predominantly at the late time points. Combining statistical analysis of infection and cytokine-stimulated Calu-3 transcriptomics, we identified differential innate responses, including up-regulation of extracellular remodeling genes following MERS-CoV Eng 1 infection and differential pro-inflammatory responses. CONCLUSIONS: Through our genomics-based approach, we found topological differences in the kinetics and magnitude of the host response to MERS-CoV SA 1 and MERS-CoV Eng 1, with differential expression of innate immune and pro-inflammatory responsive genes as a result of IFN, TNF and IL-1α signaling. Predicted activation for STAT3 mediating gene expression relevant for epithelial cell-to-cell adherens and junction signaling in MERS-CoV Eng 1 infection suggest that these transcriptional differences may be the result of amino acid differences in viral proteins known to modulate innate immunity during MERS-CoV infection.


Assuntos
Citocinas/farmacologia , Perfilação da Expressão Gênica , Genômica , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Linhagem Celular , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Fator de Transcrição STAT3/metabolismo , Fatores de Tempo
17.
Nat Biotechnol ; 32(12): 1250-5, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25402615

RESUMO

The domestic ferret (Mustela putorius furo) is an important animal model for multiple human respiratory diseases. It is considered the 'gold standard' for modeling human influenza virus infection and transmission. Here we describe the 2.41 Gb draft genome assembly of the domestic ferret, constituting 2.28 Gb of sequence plus gaps. We annotated 19,910 protein-coding genes on this assembly using RNA-seq data from 21 ferret tissues. We characterized the ferret host response to two influenza virus infections by RNA-seq analysis of 42 ferret samples from influenza time-course data and showed distinct signatures in ferret trachea and lung tissues specific to 1918 or 2009 human pandemic influenza virus infections. Using microarray data from 16 ferret samples reflecting cystic fibrosis disease progression, we showed that transcriptional changes in the CFTR-knockout ferret lung reflect pathways of early disease that cannot be readily studied in human infants with cystic fibrosis disease.


Assuntos
Furões/genética , Genoma , Influenza Humana/genética , Análise de Sequência de DNA , Animais , Sequência de Bases , Mapeamento Cromossômico , Modelos Animais de Doenças , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Influenza Humana/transmissão , Influenza Humana/virologia , Anotação de Sequência Molecular , Dados de Sequência Molecular , Orthomyxoviridae/genética , Orthomyxoviridae/patogenicidade
18.
Science ; 346(6212): 987-91, 2014 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-25359852

RESUMO

Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation nor death from shock, thus restricting pathogenesis studies to nonhuman primates. Here we show that mice from the Collaborative Cross panel of recombinant inbred mice exhibit distinct disease phenotypes after mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, probably mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever.


Assuntos
Modelos Animais de Doenças , Predisposição Genética para Doença , Doença pelo Vírus Ebola/genética , Doença pelo Vírus Ebola/imunologia , Interações Hospedeiro-Patógeno/genética , Camundongos , Receptor TIE-2/genética , Alelos , Animais , Coagulação Sanguínea/genética , Permeabilidade Capilar/genética , Endotélio Vascular/fisiopatologia , Doença pelo Vírus Ebola/sangue , Fígado/irrigação sanguínea , Fígado/metabolismo , Fígado/patologia , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/genética
19.
Arthritis Rheumatol ; 66(8): 2188-200, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24719311

RESUMO

OBJECTIVE: To investigate the role of the sensory neuropeptide calcitonin gene-related peptide (CGRP) in peripheral sensitization in experimental models of osteoarthritis (OA) pain. METHODS: Experimental knee OA was induced in rats by intraarticular injection of monosodium iodoacetate (MIA) or by transection of the medial meniscus (MMT). Single-unit recordings of joint-innervating nociceptors were obtained in MIA- and saline-treated rats following administration of CGRP or the CGRP receptor antagonist CGRP 8-37. Effects of CGRP 8-37 were also examined in rats that underwent MMT and sham operations. Protein and messenger RNA (mRNA) levels of CGRP receptor components in the L3-L4 dorsal root ganglion (DRG) were investigated following MIA treatment. RESULTS: In both the MIA and MMT groups, the mechanical sensitivity of joint nociceptors was enhanced compared to that in the control groups. Exogenous CGRP increased mechanical sensitivity in a greater proportion of joint nociceptors in the MIA-treated rats than in the saline-treated rats. Local blockade of endogenous CGRP by CGRP 8-37 reversed both the MIA- and MMT-induced enhancement of joint nociceptor responses. Joint afferent cell bodies coexpressed the receptor for CGRP, called the calcitonin-like receptor (CLR), and the intracellular accessory CGRP receptor component protein. MIA treatment increased the levels of mRNA for CLR in the L3-L4 DRG and the levels of CLR protein in medium and large joint afferent neurons. CONCLUSION: Our findings provide new and compelling evidence implicating a role of CGRP in peripheral sensitization in experimental OA. Our novel finding of CGRP-mediated control of joint nociceptor mechanosensitivity suggests that the CGRP receptor system may be an important target for the modulation of pain during OA. CGRP receptor antagonists recently developed for migraine pain should be investigated for their efficacy against pain in OA.


Assuntos
Osteoartrite/fisiopatologia , Dor/etiologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Animais , Artrite Experimental , Modelos Animais de Doenças , Masculino , Fenômenos Mecânicos , Osteoartrite/complicações , Ratos , Ratos Sprague-Dawley
20.
mBio ; 5(1): e01102-13, 2014 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-24496798

RESUMO

UNLABELLED: A novel avian-origin H7N9 influenza A virus (IAV) emerged in China in 2013, causing mild to lethal human respiratory infections. H7N9 originated with multiple reassortment events between avian viruses and carries genetic markers of human adaptation. Determining whether H7N9 induces a host response closer to that with human or avian IAV is important in order to better characterize this emerging virus. Here we compared the human lung epithelial cell response to infection with A/Anhui/01/13 (H7N9) or highly pathogenic avian-origin H5N1, H7N7, or human seasonal H3N2 IAV. The transcriptomic response to H7N9 was highly specific to this strain but was more similar to the response to human H3N2 than to that to other avian IAVs. H7N9 and H3N2 both elicited responses related to eicosanoid signaling and chromatin modification, whereas H7N9 specifically induced genes regulating the cell cycle and transcription. Among avian IAVs, the response to H7N9 was closest to that elicited by H5N1 virus. Host responses common to H7N9 and the other avian viruses included the lack of induction of the antigen presentation pathway and reduced proinflammatory cytokine induction compared to that with H3N2. Repression of these responses could have an important impact on the immunogenicity and virulence of H7N9 in humans. Finally, using a genome-based drug repurposing approach, we identified several drugs predicted to regulate the host response to H7N9 that may act as potential antivirals, including several kinase inhibitors, as well as FDA-approved drugs, such as troglitazone and minocycline. Importantly, we validated that minocycline inhibited H7N9 replication in vitro, suggesting that our computational approach holds promise for identifying novel antivirals. IMPORTANCE: Whether H7N9 will be the next pandemic influenza virus or will persist and sporadically infect humans from its avian reservoir, similar to H5N1, is not known yet. High-throughput profiling of the host response to infection allows rapid characterization of virus-host interactions and generates many hypotheses that will accelerate understanding and responsiveness to this potential threat. We show that the cellular response to H7N9 virus is closer to that induced by H3N2 than to that induced by H5N1, reflecting the potential of this new virus for adaptation to humans. Importantly, dissecting the host response to H7N9 may guide host-directed antiviral development.


Assuntos
Células Epiteliais/virologia , Interações Hospedeiro-Patógeno , Subtipo H7N9 do Vírus da Influenza A/genética , Transcriptoma , Antivirais/farmacologia , Linhagem Celular , Perfilação da Expressão Gênica , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Virus da Influenza A Subtipo H5N1/genética , Vírus da Influenza A Subtipo H7N7/genética , Minociclina , Replicação Viral/efeitos dos fármacos
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