RESUMO
Objective: This analysis explored the association of treatment adherence with beliefs about medication, patient demographic and disease characteristics and medication types in rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS) to develop adherence prediction models. Methods: The population was a subset from ALIGN, a multicountry, cross-sectional, self-administered survey study in adult patients (n=7328) with six immune-mediated inflammatory diseases who were routinely receiving systemic therapy. Instruments included Beliefs about Medicines Questionnaire (BMQ) and 4-item Morisky Medication Adherence Scale (MMAS-4©), which was used to define adherence. Results: A total of 3390 rheumatological patients were analysed (RA, n=1943; PsA, n=635; AS, n=812). Based on the strongest significant associations, the adherence prediction models included type of treatment, age, race (RA and AS) or disease duration (PsA) and medication beliefs (RA and PsA, BMQ-General Harm score; AS, BMQ-Specific Concerns score). The models had cross-validated areas under the receiver operating characteristic curve of 0.637 (RA), 0.641 (PsA) and 0.724 (AS). Predicted probabilities of full adherence (MMAS-4©=4) ranged from 5% to 96%. Adherence was highest for tumour necrosis factor inhibitors versus other treatments, older patients and those with low treatment harm beliefs or concerns. Adherence was higher in white patients with RA and AS and in patients with PsA with duration of disease <9 years. Conclusions: For the first time, simple medication adherence prediction models for patients with RA, PsA and AS are available, which may help identify patients at high risk of non-adherence to systemic therapies. Trial registration number: ACTRN12612000977875.
Assuntos
Artrite Psoriásica/epidemiologia , Artrite Psoriásica/terapia , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/terapia , Adesão à Medicação/estatística & dados numéricos , Espondilite Anquilosante/epidemiologia , Espondilite Anquilosante/terapia , Adulto , Idoso , Antirreumáticos/uso terapêutico , Estudos Transversais , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Prognóstico , Vigilância em Saúde Pública , Autorrelato , Inquéritos e QuestionáriosRESUMO
The non-integrin 37/67-kDa laminin receptor (LAMR1) is a complex protein with diverse functions. LAMR1 is widely expressed in epithelial cells and recently it was reported on neutrophils and a subset of activated T cells. Ligation of LAMR1 on peripheral blood mononuclear cells (PBMC) downregulated LPS-induced TNFα production, suggesting immune functions. However, its expression on primary monocytes remain unknown. Interestingly, LAMR1 mRNA is downregulated in PBMC of patients with early rheumatoid arthritis (RA), and low gene expression is an independent predictor of poor response to anti-TNFα treatment, suggesting a role in RA pathogenesis. We found LAMR1 was constitutively expressed on all peripheral blood monocytes and a subset of B cells from healthy individuals and patients with RA and it was abundantly present in synovial tissue of patients with RA. On monocytes and synovial tissue lower levels of LAMR1 expression tended to correlate with increased disease activity scores. In vitro treatment of monocytes with IFNγ or IL-10 up-regulated surface LAMR1 in healthy individuals and patients with RA with greater effects observed in healthy individuals. Importantly, treatment with IFNγ significantly increased specific binding of monocytes to laminin-1. TNFα and IL-1ß caused marginal downregulation of LAMR1 in patients but effects in controls were variable. Taken together, constitutively expressed LAMR1 on monocytes is differentially regulated by pro-inflammatory and immune-regulatory cytokines suggesting LAMR1 may regulate the threshold and amplitude of their activation and migration. Decreased levels in patients with RA may indicate loss of this potentially critical homeostatic regulation thereby contributing to the excessive inflammation.
Assuntos
Artrite Reumatoide/imunologia , Subpopulações de Linfócitos B/imunologia , Leucócitos Mononucleares/imunologia , Receptores de Laminina/sangue , Proteínas Ribossômicas/sangue , Líquido Sinovial/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Subpopulações de Linfócitos B/patologia , Citocinas/imunologia , Feminino , Humanos , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
AIM: To understand the patient experience of being admitted to hospital with acute low back pain (LBP), with a view to developing suggestions for care and LBP management guidelines. METHOD: Interpretive phenomenological analysis (IPA) was adopted to examine semi-structured interviews from patients admitted to hospital with acute LBP. Sampling continued until thematic saturation was reached (n = 14). Data were analyzed using the Framework Method, so that data from multiple participants could be systematically summarized, compared, and analyzed. RESULTS: Four themes were identified: pain and helplessness, desire for validation, interactions with healthcare teams, and a return to pre-morbid identity and roles. Patients' initial presentation to hospital was characterized by severe pain, disability and difficulty in communicating their illness experience. Patients expected doctors to investigate for an underlying cause of the back pain. To recover, they were required to navigate a system they did not understand, interacting with healthcare workers who seemed to operate independently rather than as a team. Patients viewed medical treatment as a means of returning to pre-morbid activities of daily living, roles and relationships. Using these themes, a model of the inpatient journey was developed. CONCLUSION: We have described new patient insights which highlight how the hospital environment adds unique challenges to managing acute LBP. Several suggestions for acute LBP management guidelines are made: developing lay summaries for patients, including methods for communicating the team structure and roles to patients, and ensuring all members of treating teams are educated to ensure guidelines are consistently implemented.
Assuntos
Dor Aguda/psicologia , Prestação Integrada de Cuidados de Saúde , Dor Lombar/psicologia , Admissão do Paciente , Satisfação do Paciente , Dor Aguda/diagnóstico , Dor Aguda/fisiopatologia , Dor Aguda/terapia , Adaptação Psicológica , Adulto , Idoso , Idoso de 80 Anos ou mais , Atitude do Pessoal de Saúde , Comunicação , Efeitos Psicossociais da Doença , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Entrevistas como Assunto , Dor Lombar/diagnóstico , Dor Lombar/fisiopatologia , Dor Lombar/terapia , Masculino , Pessoa de Meia-Idade , Percepção da Dor , Limiar da Dor , Equipe de Assistência ao Paciente , Relações Profissional-Paciente , Pesquisa Qualitativa , Recuperação de Função Fisiológica , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: Gout is increasing despite effective therapies to lower serum urate concentrations to 0.36 mmol/L or less, which, if sustained, significantly reduces acute attacks of gout. Adherence to urate-lowering therapy (ULT) is poor, with rates of less than 50% 1 year after initiation of ULT. Attempts to increase adherence in gout patients have been disappointing. We aim to evaluate the effectiveness of use of a personal, self-management, 'smartphone' application (app) to achieve target serum urate concentrations in people with gout. We hypothesise that personalised feedback of serum urate concentrations will improve adherence to ULT. METHODS AND ANALYSIS: Setting and designPrimary care. A prospective, cluster randomised (by general practitioner (GP) practices), controlled trial. PARTICIPANTS: GP practices will be randomised to either intervention or control clusters with their patients allocated to the same cluster. INTERVENTION: The intervention group will have access to the Healthy.me app tailored for the self-management of gout. The control group patients will have access to the same app modified to remove all functions except the Gout Attack Diary. PRIMARY AND SECONDARY OUTCOMES: The proportion of patients whose serum urate concentrations are less than or equal to 0.36 mmol/L after 6 months. Secondary outcomes will be proportions of patients achieving target urate concentrations at 12 months, ULT adherence rates, serum urate concentrations at 6 and 12 months, rates of attacks of gout, quality of life estimations and process and economic evaluations. The study is designed to detect a ≥30% improvement in the intervention group above the expected 50% achievement of target serum urate at 6 months in the control group: power 0.80, significance level 0.05, assumed 'dropout' rate 20%. ETHICS AND DISSEMINATION: This study has been approved by the University of New South Wales Human Research Ethics Committee. Study findings will be disseminated in international conferences and peer-reviewed journal. TRIAL REGISTRATION NUMBER: ACTRN12616000455460.
Assuntos
Gota/terapia , Internet , Projetos de Pesquisa , Autogestão/métodos , Alopurinol/uso terapêutico , Supressores da Gota/uso terapêutico , Humanos , Cooperação do Paciente , Estudos Prospectivos , Qualidade de Vida , Ácido Úrico/sangueRESUMO
PURPOSE: The medical education community is rapidly accepting the use of entrustable professional activities (EPAs) as a means of assessing residents. Stakeholder engagement is advised in developing EPAs, but no studies have investigated the role of patient input. In this qualitative study, the authors investigated what patient input may add to designing a patient-centered EPA. METHOD: The authors chose "management of acute low back pain (LBP)" as a common, important clinical task on which to base the patient-centered EPA. In 2015, 14 patients who presented to a teaching hospital with acute LBP participated in semistructured interviews exploring their illness experience and expectations of doctors. Clinicians representing multiple disciplines participated in a focus group. The authors used the Framework Method to analyze data, identifying and developing themes, similarities, and differences between patient and clinician input. They used the findings to develop the EPA. Through an iterative procedure of data review and tracking data sources, they determined how patient and clinician input informed each EPA descriptor. RESULTS: Drawing from their firsthand experience of LBP, patients described unique expectations of trainees which directly informed EPA descriptors. For example, the authors primarily used patients' detailed descriptions of desirable and observable trainee behaviors to inform the required attitudes descriptor. CONCLUSIONS: Patients can provide unique contributions, complementary to those of clinicians, to EPAs. Consultations with patients led to the development of a patient-centered EPA, which aligned best clinical practice with patient expectations. Educators seeking to apply patient-centered care to EPA development could adopt a similar approach.
Assuntos
Competência Clínica/normas , Educação de Pós-Graduação em Medicina/normas , Internato e Residência/normas , Dor Lombar/terapia , Participação do Paciente , Assistência Centrada no Paciente/normas , Competência Profissional/normas , Adulto , Avaliação Educacional/métodos , Feminino , Grupos Focais , Humanos , Masculino , Satisfação do Paciente , Avaliação de Programas e Projetos de Saúde , Estudantes de Medicina , Estados Unidos , Adulto JovemRESUMO
The constitutive heparin+ (HP) mast cells (MCs) in mice express mouse MC protease (mMCP)-5 and carboxypeptidase A (mMC-CPA). The amino acid sequence of mMCP-5 is most similar to that of human chymase-1, as are the nucleotide sequences of their genes and transcripts. Using a homologous recombination approach, a C57BL/6 mouse line was created that possessed a disrupted mMCP-5 gene. The resulting mice were fertile and had no obvious developmental abnormality. Lack of mMCP-5 protein did not alter the granulation of the IL-3/IL-9-dependent mMCP-2+ MCs in the jejunal mucosa of Trichinella spiralis-infected mice. In contrast, the constitutive HP+ MCs in the tongues of mMCP-5-null mice were poorly granulated and lacked mMC-CPA protein. Bone marrow-derived MCs were readily developed from the transgenic mice using IL-3. Although these MCs contained high levels of mMC-CPA mRNA, they also lacked the latter exopeptidase. mMCP-5 protein is therefore needed to target translated mMC-CPA to the secretory granule along with HP-containing serglycin proteoglycans. Alternately, mMCP-5 is needed to protect mMC-CPA from autolysis in the cell's granules. Fibronectin was identified as a target of mMCP-5, and the exocytosis of mMCP-5 from the MCs in the mouse's peritoneal cavity resulted in the expression of metalloproteinase protease-9, which has been implicated in arthritis. In support of the latter finding, experimental arthritis was markedly reduced in mMCP-5-null mice relative to wild-type mice in two disease models.
Assuntos
Artrite Experimental/patologia , Quimases/efeitos adversos , Mastócitos/enzimologia , Animais , Artrite Experimental/enzimologia , Artrite Experimental/etiologia , Carboxipeptidases A/análise , Carboxipeptidases A/deficiência , Carboxipeptidases A/metabolismo , Quimases/deficiência , Quimases/fisiologia , Humanos , Mastócitos/metabolismo , Mastócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Vesículas Secretórias/metabolismoRESUMO
Pneumococcal disease, caused by the bacterium Streptococcus pneumoniae, is a major burden to global health. Although the World Health Organisation (WHO) strongly recommends the inclusion of pneumococcal conjugate vaccines in national immunisation programmes (NIP's) worldwide, this has not occurred in many countries in the WHO South East Asia and Western Pacific regions - particularly longstanding middle-income countries. It is widely accepted that carriage of S. pneumoniae is a precursor to developing any pneumococcal disease. The reduction in pneumococcal disease from vaccine serotypes (VT) following widespread implementation of the pneumococcal conjugate vaccine (PCV) is believed to be through the direct immunogenic protective effect of immunised individuals as well as indirectly through herd immunity diminishing the incidence of disease in nonimmunised individuals. In Malaysia, pneumococcal disease is not included in national surveillance programmes and although PCVs have been licensed, they have not been included in the NIP. Hence, the vaccine is only available privately and the majority of the population is not able to afford it. There is an urgent need to develop surveillance programmes in Malaysia to include pneumococcal serotype data from carriage and invasive disease so that it may help guide national vaccine policy prior to a decision being taken on the inclusion of PCVs in the NIP.
Assuntos
Portador Sadio , Infecções Pneumocócicas/epidemiologia , Streptococcus pneumoniae/classificação , Sudeste Asiático , Humanos , Malásia , Vacinas Pneumocócicas , Prevalência , SorogrupoRESUMO
BACKGROUND: We hypothesised that vertebroplasty provides effective analgesia for patients with poorly controlled pain and osteoporotic spinal fractures of less than 6 weeks' duration. The effectiveness of vertebroplasty, using an adequate vertebral fill technique, in fractures of less than 6 weeks' duration has not been specifically assessed by previously published masked trials. METHODS: This was a multicentre, randomised, double-blind, placebo-controlled trial of vertebroplasty in four hospitals in Sydney, Australia. We recruited patients with one or two osteoporotic vertebral fractures of less than 6 weeks' duration and Numeric Rated Scale (NRS) back pain greater than or equal to 7 out of 10. We used an automated telephone randomisation service provided by the National Health and Medical Research Council to assign patients (1:1; stratified according to age, degree of vertebral compression, trauma, corticosteroid use, and hospital) to either vertebroplasty or placebo, immediately before the procedure. Patients received conscious sedation. Vertebroplasty was done with the adequate vertebral fill technique and the placebo procedure with simulated vertebroplasty. Follow-up was for 6 months. Outcome assessors and patients were masked to treatment allocation. The primary outcome was the proportion of patients with NRS pain below 4 out of 10 at 14 days post-intervention in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01482793. FINDINGS: Between Nov 4, 2011, and Dec 5, 2014, 120 patients were enrolled. 61 patients were randomly assigned to vertebroplasty and 59 to placebo. 24 (44%) patients in the vertebroplasty group and 12 (21%) in the control group had an NRS pain score below 4 out of 10 at 14 days (between-group difference 23 percentage points, 95% CI 6-39; p=0·011). Three patients in each group died from causes judged unrelated to the procedure. There were two serious adverse events in each group, related to the procedure (vertebroplasty group) and the fracture (control group). INTERPRETATION: Vertebroplasty is superior to placebo intervention for pain reduction in patients with acute osteoporotic spinal fractures of less than 6 weeks' in duration. These findings will allow patients with acute painful fractures to have an additional means of pain management that is known to be effective. FUNDING: Education grant from CareFusion Corporation.
Assuntos
Método Duplo-Cego , Fraturas por Osteoporose , Fraturas por Compressão , Humanos , Medição da Dor , Resultado do Tratamento , VertebroplastiaRESUMO
Mast cells (MCs) participate in diseases such as systemic mastocytosis (SM) and allergic conditions. Less well understood is the role of MCs in non-allergic inflammatory disorders like rheumatoid arthritis (RA). Studying definitive roles for MCs in human diseases has been hampered by the lack of a well-accepted biomarker for monitoring in vivo MC activation. This study aimed to investigate the utility of urinary tetranor PGDM (T-PGDM) as a biomarker of in vivo MC activation in patients with SM, and apply this biomarker to assess MC involvement in relation to RA disease activity. A prospective, cross-sectional cohort study was conducted to measure a major urinary metabolite of prostaglandin D2, T-PGDM. Urine samples were collected from patients with RA (n = 60), SM (n = 17) and healthy normal controls (n = 16) and T-PGDM excretion was determined by enzyme immunoassay as nanograms per milligram of urinary creatinine (ng/mg Cr). Mean urinary T-PGDM excretion was significantly higher (p < 0.01) in patients with SM compared to controls (37.2 vs. 11.5 ng/mg Cr) with 65% of SM patients showing elevated levels. One third of patients with RA had elevated T-PGDM excretion, and the mean level in the RA group (20.0 ng/mg Cr) was significantly higher than controls (p < 0.01). Medications inhibiting cyclooxygenase reduced T-PGDM excretion. Urinary T-PGDM excretion appears promising as a biomarker of in vivo MC activity and elevated levels in 33% of patients with RA provides evidence of MC activation in this disease.
RESUMO
Consultants regularly need to decide whether a trainee can be entrusted to perform a clinical activity independently. 'Entrustable professional activities' (EPA) provide a framework for justifying and better utilising supervisor entrustment decisions for trainee feedback and assessment in the workplace. Since being proposed by Olle ten Cate in 2005, EPA are emerging as an integral part of many international medical curricula, and are being considered by the Royal Australasian College of Physicians in the current review of physician training. EPA are defined as tasks or responsibilities that can be entrusted to a trainee once sufficient competence is reached to allow for unsupervised practice. An example might be to entrust a trainee to 'Initiate and co-ordinate care of the palliative patient' with only off-site or indirect supervision. Rather than attempting to measure directly each of the many separate competencies required to undertake such a complex task, EPA direct the trainee and supervisor's attention to the trainee's performance in a limited number of selected, representative, important day-to-day activities. EPA-based assessment is gaining momentum, amongst significant concerns regarding feasibility of implementation. While the optimal process for designing and implementing EPA remains to be determined, it is an assessment strategy where the over-arching goal of optimal patient care remains in clear sight. This review explores the central role of trust in medical training, the case for EPA and potential barriers to implementing EPA-based assessment.
Assuntos
Competência Clínica/normas , Educação Médica/normas , Médicos , Confiança , Desempenho Profissional/educação , Educação Médica/métodos , HumanosRESUMO
BACKGROUND: The UNSW Australia Medicine program explicitly structures peer learning in program wide mixing of students where students from two adjoining cohorts complete the same course together, including all learning activities and assessment. The purpose of this evaluation is to explore the student experience of peer learning and determine benefits and concerns for junior and senior students. METHODS: All medical students at UNSW Australia in 2012 (n = 1608) were invited to complete the Peer Learning Questionnaire consisting of 26 fixed-response items and 2 open-ended items exploring vertical integration and near-peer teaching. Assessment data from vertically integrated and non-vertically integrated courses were compared for the period 2011-2013. RESULTS: We received valid responses from 20 % of medical students (n = 328). Eighty percent of respondents were positive about their experience of vertical integration. Year 1 students reported that second year students provided guidance and reassurance (87.8 %), whilst year 2 students reported that the senior role helped them to improve their own understanding, communication and confidence (84 %). Vertical integration had little effect on examination performance and failure rates. CONCLUSIONS: This evaluation demonstrates that vertical integration of students who are one year apart and completing the same course leads to positive outcomes for the student experience of learning. Students benefit through deeper learning and the development of leadership qualities within teams. These results are relevant not only for medical education, but also for other professional higher education programs.
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Medicina Clínica/educação , Educação de Graduação em Medicina/métodos , Avaliação Educacional , Grupo Associado , Aprendizagem Baseada em Problemas/organização & administração , Inquéritos e Questionários , Competência Clínica , Currículo , Feminino , Humanos , Masculino , New South Wales , Satisfação Pessoal , Avaliação de Programas e Projetos de Saúde , Faculdades de Medicina/organização & administração , Estudantes de Medicina/estatística & dados numéricos , Adulto JovemRESUMO
The ideal immune response is rapid, proportionate and effective. Crucially, it must also be finite. An inflammatory response which is disproportionate or lasts too long risks injury to the host; chronic un-regulated inflammation in autoimmune diseases is one example of this. Thus, mechanisms to regulate and ultimately terminate immune responses are central to a healthy immune system. Despite extensive knowledge of what drives immune responses, our understanding of mechanisms of immune termination remains relatively sparse. It is clear that such processes are more complex than a one-dimensional homeostatic balance. Recent discoveries have revealed ever more nuanced mechanisms of signal termination, such as intrinsically self-limiting signals, multiple inhibitory mechanisms acting in tandem and activating proteins behaving differently in a variety of contexts. This review will summarise some important mechanisms, including termination by immunoreceptor tyrosine-based inhibitory motifs (ITIM), inhibition by soluble antagonists, receptor endocytosis or ubiquitination, and auto-inhibition by newly synthesised intracellular inhibitory molecules. Several recent discoveries showing immunoreceptor tyrosine-based activation motifs transducing inhibitory signals, ITIM mediating activating responses and the possible roles of immunoreceptor tyrosine-based switch motifs will also be explored.
Assuntos
Endocitose/imunologia , Sistema Imunitário/fisiologia , Motivo de Inibição do Imunorreceptor Baseado em Tirosina/imunologia , Ubiquitinação/imunologia , Animais , Humanos , Transdução de SinaisRESUMO
BACKGROUND: This paper is an evaluation of an integrated selection process utilising previous academic achievement [Universities Admission Index (UAI)], a skills test [Undergraduate Medicine and Health Sciences Admission Test (UMAT)], and a structured interview, introduced (in its entirety) in 2004 as part of curriculum reform of the undergraduate Medicine Program at the University of New South Wales (UNSW), Australia. Demographic measures of gender, country of birth, educational background and rurality are considered. METHOD: Admission scores and program outcomes of 318 students enrolled in 2004 and 2005 were studied. Regression analyses were undertaken to determine whether selection scores predicted overall, knowledge-based and clinical-based learning outcomes after controlling for demographics. RESULTS: UAI attained the highest values in predicting overall and knowledge-based outcomes. The communication dimension of the interview achieved similar predictive values as UAI for clinical-based outcomes, although predictive values were relatively low. The UMAT did not predict any performance outcome. Female gender, European/European-derived country of birth and non-rurality were significant predictors independent of UAI scores. CONCLUSION: Results indicate promising validity for an integrated selection process introduced for the Medicine Program at UNSW, with UAI and interview predictive of learning outcomes. Although not predictive, UMAT may have other useful roles in an integrated selection process. Further longitudinal research is proposed to monitor and improve the validity of the integrated student selection process.
Assuntos
Critérios de Admissão Escolar , Faculdades de Medicina/normas , Adolescente , Adulto , Teste de Admissão Acadêmica , Escolaridade , Feminino , Humanos , Masculino , New South Wales , Reprodutibilidade dos Testes , Critérios de Admissão Escolar/estatística & dados numéricos , Faculdades de Medicina/organização & administração , Adulto JovemRESUMO
BACKGROUND: This study evaluates the impact of a new 'Preparation for Internship' (PRINT) course, which was developed to facilitate the transition of University of New South Wales (UNSW) medical graduates from Medical School to Internship. METHODS: During a period of major curricular reform, the 2007 (old program) and 2009 (new program) cohorts of UNSW final year students completed the Clinical Capability Questionnaire (CCQ) prior to and after undertaking the PRINT course. Clinical supervisors' ratings and self-ratings of UNSW 2009 medical graduates were obtained from the Hospital-based Prevocational Progress Review Form. RESULTS: Prior to PRINT, students from both cohorts perceived they had good clinical skills, with lower ratings for capability in procedural skills, operational management, and administrative tasks. After completing PRINT, students from both cohorts perceived significant improvement in their capability in procedural skills, operational management, and administrative tasks. Although PRINT also improved student-perceived capability in confidence, interpersonal skills and collaboration in both cohorts, curriculum reform to a new outcomes-based program was far more influential in improving self-perceptions in these facets of preparedness for hospital practice than PRINT. CONCLUSIONS: The PRINT course was most effective in improving students' perceptions of their capability in procedural skills, operational management and administrative tasks, indicating that student-to-intern transition courses should be clinically orientated, address relevant skills, use experiential learning, and focus on practical tasks. Other aspects that are important in preparation of medical students for hospital practice cannot be addressed in a PRINT course, but major improvements are achievable by program-wide curriculum reform.
Assuntos
Educação de Graduação em Medicina , Internato e Residência , Competência Clínica , Currículo , Avaliação Educacional , New South Wales , Avaliação de Programas e Projetos de Saúde , Faculdades de Medicina , Inquéritos e QuestionáriosAssuntos
Articulação do Tornozelo/microbiologia , Antirreumáticos/efeitos adversos , Artrite Infecciosa/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Histoplasmose/diagnóstico , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Idoso , Antirreumáticos/uso terapêutico , Artrite Infecciosa/etiologia , Artrite Infecciosa/imunologia , Artrite Reumatoide/complicações , Austrália , Histoplasmose/etiologia , Histoplasmose/imunologia , Humanos , Imunossupressores/uso terapêutico , Laos , Masculino , ViagemRESUMO
The S1A serine proteases function in many key biological processes such as development, immunity, and blood coagulation. S1A proteases contain a highly conserved disulfide bond (Cys(191)-Cys(220) in chymotrypsin numbering) that links two ß-loop structures that define the rim of the active site pocket. Mast cell ßII-tryptase is a S1A protease that is associated with pathological inflammation. In this study, we have found that the conserved disulfide bond (Cys(220)-Cys(248) in ßII-tryptase) exists in oxidized and reduced states in the enzyme stored and secreted by mast cells. The disulfide bond has a standard redox potential of -301 mV and is stoichiometrically reduced by the inflammatory mediator, thioredoxin, with a rate constant of 350 m(-1) s(-1). The oxidized and reduced enzymes have different substrate specificity and catalytic efficiency for hydrolysis of both small and macromolecular substrates. These observations indicate that ßII-tryptase activity is post-translationally regulated by an allosteric disulfide bond. It is likely that other S1A serine proteases are similarly regulated.
Assuntos
Cisteína/química , Mastócitos/enzimologia , Oxirredução , Triptases/química , Regulação Alostérica , Animais , Sítios de Ligação , Catálise , Domínio Catalítico , Linhagem Celular Tumoral , Cisteína/metabolismo , Dissulfetos/química , Dissulfetos/metabolismo , Humanos , Mastócitos/metabolismo , Camundongos , Relação Estrutura-Atividade , Especificidade por Substrato , Triptases/metabolismoRESUMO
Mouse mast cell protease (mMCP)-6-null C57BL/6 mice lost less aggrecan proteoglycan from the extracellular matrix of their articular cartilage during inflammatory arthritis than wild-type (WT) C57BL/6 mice, suggesting that this mast cell (MC)-specific mouse tryptase plays prominent roles in articular cartilage catabolism. We used ex vivo mouse femoral head explants to determine how mMCP-6 and its human ortholog hTryptase-ß mediate aggrecanolysis. Exposure of the explants to recombinant hTryptase-ß, recombinant mMCP-6, or lysates harvested from WT mouse peritoneal MCs (PMCs) significantly increased the levels of enzymatically active matrix metalloproteinases (MMP) in cartilage and significantly induced aggrecan loss into the conditioned media, relative to replicate explants exposed to medium alone or lysates collected from mMCP-6-null PMCs. Treatment of cartilage explants with tetramer-forming tryptases generated aggrecan fragments that contained C-terminal DIPEN and N-terminal FFGVG neoepitopes, consistent with MMP-dependent aggrecanolysis. In support of these data, hTryptase-ß was unable to induce aggrecan release from the femoral head explants obtained from Chloe mice that resist MMP cleavage at the DIPEN↓FFGVG site in the interglobular domain of aggrecan. In addition, the abilities of mMCP-6-containing lysates from WT PMCs to induce aggrecanolysis were prevented by inhibitors of MMP-3 and MMP-13. Finally, recombinant hTryptase-ß was able to activate latent pro-MMP-3 and pro-MMP-13 in vitro. The accumulated data suggest that human and mouse tetramer-forming tryptases are MMP convertases that mediate cartilage damage and the proteolytic loss of aggrecan proteoglycans in arthritis, in part, by activating the zymogen forms of MMP-3 and MMP-13, which are constitutively present in articular cartilage.
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Agrecanas/metabolismo , Cartilagem Articular/metabolismo , Mastócitos/imunologia , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Animais , Artrite/metabolismo , Células Cultivadas , Precursores Enzimáticos/metabolismo , Matriz Extracelular/metabolismo , Inflamação , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Triptases/deficiência , Triptases/genética , Triptases/metabolismoRESUMO
OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that significantly impairs patients' quality of life and can be life threatening. This study aimed to describe the experiences and perspectives of adults living with SLE. METHODS: We conducted a systematic review and thematic synthesis of qualitative studies that explored the experiences of adults living with SLE. We searched MEDLINE, Embase, PsycINFO, CINAHL (to November week 1, 2012), Google Scholar, a thesis database, and reference lists of relevant articles. RESULTS: Forty-six studies involving 1,385 participants were included. Five themes were identified: restricted lifestyle(including subthemes of pervasive pain, debilitating fatigue, mental deterioration, disruptive episodic symptoms, and postponing parenthood), disrupted identity (gaining diagnostic closure, prognostic uncertainty, being a burden, hopelessness, heightened self-consciousness, fearing rejection, and guilt and punishment), societal stigma and indifference(illness trivialization, socially ostracized, and averse to differential treatment), gaining resilience (optimism, control and empowerment, being informed and involved, and valuing mutual understanding), and treatment adherence (preserving health, rapport with clinicians, negotiating medication regimens, and financial burden). CONCLUSION: SLE has a severe and pervasive impact on patients' self-esteem and independence. Their physical and social functioning is limited and they feel anxious about their future. Patients perceive that SLE is trivialized, misunderstood,and stigmatized by their family, friends, and physicians, which intensifies their sense of isolation. Educational, psychosocial, and self-care interventions are needed to promote mental resilience, positive coping strategies, self-advocacy, and capacities for social participation, and thereby to achieve better treatment and health outcomes in patients with SLE.