RESUMO
Objectives: This study aimed to assess the acceptability, value, and perceived barriers of using electronic risk calculators for predicting and communicating the risk of death in community-dwelling older adults. Methods: One focus group and eight interviews were conducted with 16 participants with experience caring for patients or family members at end of life. A prototype mortality risk tool was used to anchor discussions. Data were analysed using a qualitative content analysis approach. Results: Five themes emerged: acceptability, communication, barriers to use, broadening the circle of care, and tool limitations. Participants found the tool helpful for preparation, planning, and providing care, but disagreed on its community availability. Personalized risk estimates were valued for facilitating early goals of care conversations and normalizing discussions about death. However, concerns were raised about the tool's interpretation for individuals with different language, cultural, or educational backgrounds. Conclusions: While electronic risk calculators were found to be acceptable, balancing autonomy with varying preferences for receiving the information and potential need for support is crucial. Innovation: Providing patient-oriented life-expectancy estimates can enhance decisional capacity and facilitate shared decision-making between patients, their families, and healthcare professionals. Further research is needed to explore effective communication of personalized risk tools and additional benefits, harms, and barriers to implementation.
RESUMO
BACKGROUND: Individuals with chronic diseases often search for health information online. The Diabetes Online Community (DOC) is an active community with members who exchange health information; however, few studies have examined health information brokering in the DOC. OBJECTIVE: The aim of this study was to develop and validate the Attitudes Toward Seeking Health Information Online (ATSHIO) scale in a sample of adults with type 1 diabetes (T1D). METHODS: People with T1D were recruited through the DOC, specifically Facebook and Twitter. They were provided with a Qualtrics link to complete the survey. This was a mixed methods study that used thematic analysis along with existing theory and formative research to design the quantitative ATSHIO scale. RESULTS: A total of 166 people with T1D participated in this study. Confirmatory factor analyses determined a 2-factor scale (Trusting and Evaluating Online Health Information in the DOC and Engaging With Online Health Information in the DOC) with good convergent validity and discriminant validity. Correlations were found between social support, online health information-seeking, diabetes distress, and disease management. CONCLUSIONS: The ATSHIO scale can be used to investigate how people with diabetes are using the internet for obtaining health information, which is especially relevant in the age of telehealth and Health 2.0.
RESUMO
Introduction: Cardiovascular diseases (CVDs) have been associated with an increased risk of dementia; yet the evidence is mixed. This review critically appraises and synthesises current evidence exploring associations between dementia risk and CVD and their risk factors, including coronary heart disease, heart failure, atrial fibrillation, hypertension, hyperlipidaemia, and arterial stiffness. Methods: MEDLINE, Embase, PsycINFO, and the Cochrane Database of Systematic Reviews were searched to identify systematic reviews with meta-analyses investigating the association between at least one of the CVDs of interest and dementia risk. The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Systematic Reviews was used to assess methodological quality. Results: Twenty-five meta-analyses published between 2007 and 2021 were included. Studies largely consisted of cohorts from North America and Europe. Findings were variable, with coronary heart disease, heart failure, and atrial fibrillation consistently associated with increased risk for all-cause dementia, but results were inconsistent for Alzheimer's disease. Hypertension was more frequently associated with dementia during mid-life compared to late life. Findings concerning cholesterol were complex, and while results were inconsistent for low-density lipoprotein cholesterol and total cholesterol, there appeared to be no associations between triglycerides and high-density lipoprotein cholesterol. All meta-analyses investigating hypercholesterolaemia showed significant increases in dementia risk. There was a paucity of research on the association between arterial stiffness and dementia risk. Conclusion: Targeted CVD dementia prevention strategies could reduce dementia prevalence. Future research should determine the underpinning mechanisms linking heart and brain health to determine the most effective strategies for dementia risk reduction in CVD populations.
RESUMO
BACKGROUND: Dementia is a major public health priority. Although there is abundant evidence of an association between dementia and poor cardiovascular health, findings have been inconsistent and uncertain in identifying which factors increase dementia risk in those with cardiovascular disease. Indeed, multiple variables including sociodemographic, economic, health, lifestyle and education may indicate who is at higher vs. lower dementia risk and could be used in prediction modelling. Therefore, the aim of this review is to synthesise evidence on the key risk factors for dementia in those with a history of cardiovascular disease. METHODS: This is an overview of reviews protocol, registered on PROSPERO (CRD42021265363). Four electronic databases including MEDLINE, EMBASE, PsycINFO, and the Cochrane Database of Systematic Reviews will be searched. Studies will be included if they are systematic reviews and/or meta-analyses that have investigated the risk of incident dementia (all-cause and subtypes including Alzheimer's disease and vascular dementia) in people with a history of coronary heart disease, heart failure, atrial fibrillation, hypertension, hyperlipidaemia, and vascular stiffness. Study selection will be completed by two independent researchers according to the eligibility criteria, and conflicts resolved by a third reviewer. References will be exported into Covidence for title and abstract sifting, full-text review, and data extraction. Methodological quality will be assessed using the AMSTAR-2 criteria and confidence of evidence will be assessed using the GRADE classification. This overview of reviews will follow PRISMA guidelines. If there is sufficient homogeneity in the data, the results will be pooled, and a meta-analysis conducted to determine the strength of association between each risk factor and incident all-cause dementia and its subtypes for each cardiovascular diagnoses separately. DISCUSSION: We will create a comprehensive summary of the key risk factors linking cardiovascular diseases to risk of incident dementia. This knowledge is essential for informing risk predictive model development as well as the development of risk reduction and prevention strategies.
Assuntos
Doença de Alzheimer , Doenças Cardiovasculares , Demência Vascular , Doença de Alzheimer/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Humanos , Metanálise como Assunto , Literatura de Revisão como Assunto , Fatores de RiscoRESUMO
INTRODUCTION: Hypertrophic submucosal nerves, defined as ≥40 µm in diameter, are considered supportive of a diagnosis of HSCR, but the effect of age on nerve diameter has not been well-studied. We sought to determine the distribution of the largest nerve diameter in ganglionic rectal biopsies and the significance of hypertrophic submucosal nerves in the diagnosis of Hirschsprung disease (HSCR) based on age. METHODS: Rectal biopsies performed in the evaluation of HSCR were retrospectively reviewed from 179 patients (151 ganglionic biopsies, 28 aganglionic biopsies), and the diameter of the largest submucosal nerve was measured. RESULTS: In non-Hirschsprung disease (non-HSCR) biopsies, submucosal nerve diameter increased with age. In patients <1 year, the average diameter was 34.1 ± 11.6 µm but increased to 50.8 ± 17.3 µm after 1 year of age. Submucosal nerves ≥40 µm in diameter were significantly associated with HSCR across all ages [HSCR = 25/28 (89.3%) vs non-HSCR = 59/151 (39.1%), p < 0.0001] and remained significant in patients <1 year of age [HSCR = 22/24 (91.7%) vs non-HSCR = 19/91 (20.9%), p < 0.0001]. CONCLUSIONS: The diameter of submucosal nerves increases with age, and ≥40 µm nerves are common after 1 year of age.
Assuntos
Doença de Hirschsprung , Biópsia , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/patologia , Humanos , Hipertrofia/patologia , Reto/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: Prognostication tools that report personalized mortality risk and survival could improve discussions about end-of-life and advance care planning. We sought to develop and validate a mortality risk model for older adults with diverse care needs in home care using self-reportable information - the Risk Evaluation for Support: Predictions for Elder-Life in the Community Tool (RESPECT). METHODS: Using a derivation cohort that comprised adults living in Ontario, Canada, aged 50 years and older with at least 1 Resident Assessment Instrument for Home Care (RAI-HC) record between Jan. 1, 2007, and Dec. 31, 2012, we developed a mortality risk model. The primary outcome was mortality 6 months after a RAI-HC assessment. We used proportional hazards regression with robust standard errors to account for clustering by the individual. We validated this algorithm for a second cohort of users of home care who were assessed between Jan. 1 and Dec. 31, 2013. We used Kaplan-Meier survival curves to estimate the observed risk of death at 6 months for assessment of calibration and median survival. We constructed 61 risk groups based on incremental increases in the estimated median survival of about 3 weeks among adults at high risk and 3 months among adults at lower risk. RESULTS: The derivation and validation cohorts included 435 009 and 139 388 adults, respectively. We identified a total of 122 823 deaths within 6 months of a RAI-HC assessment in the derivation cohort. The mean predicted 6-month mortality risk was 10.8% (95% confidence interval [CI] 10.7%-10.8%) and ranged from 1.54% (95% CI 1.53%-1.54%) in the lowest to 98.1% (95% CI 98.1%-98.2%) in the highest risk group. Estimated median survival spanned from 28 days (11 to 84 d at the 25th and 75th percentiles) in the highest risk group to over 8 years (1925 to 3420 d) in the lowest risk group. The algorithm had a c-statistic of 0.753 (95% CI 0.750-0.756) in our validation cohort. INTERPRETATION: The RESPECT mortality risk prediction tool that makes use of readily available information can improve the identification of palliative and end-of-life care needs in a diverse older adult population receiving home care.
Assuntos
Planejamento Antecipado de Cuidados , Avaliação Geriátrica/métodos , Medição de Risco/métodos , Assistência Terminal , Idoso , Morte , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: While most individuals wish to die at home, the reality is that most will die in hospital. AIM: To determine whether receiving a physician home visit near the end-of-life is associated with lower odds of death in a hospital. DESIGN: Observational retrospective cohort study, examining location of death and health care in the last year of life. SETTING/PARTICIPANTS: Population-level study of Ontarians, a Canadian province with over 13 million residents. All decedents from April 1, 2010 to March 31, 2013 (n = 264,754). RESULTS: More than half of 264,754 decedents died in hospital: 45.7% died in an acute care hospital and 7.7% in complex continuing care. After adjustment for multiple factors-including patient illness, home care services, and days of being at home-receiving at least one physician home visit from a non-palliative care physician was associated with a 47% decreased odds (odds-ratio, 0.53; 95%CI: 0.51-0.55) of dying in a hospital. When a palliative care physician specialist was involved, the overall odds declined by 59% (odds ratio, 0.41; 95%CI: 0.39-0.43). The same model, adjusting for physician home visits, showed that receiving palliative home care was associated with a similar reduction (odds ratio, 0.49; 95%CI: 0.47-0.51). CONCLUSION: Location of death is strongly associated with end-of-life health care in the home. Less than one-third of the population, however, received end-of-life home care or a physician visit in their last year of life, revealing large room for improvement.
Assuntos
Hospitais/estatística & dados numéricos , Visita Domiciliar/estatística & dados numéricos , Assistência Terminal/métodos , Canadá , Estudos de Coortes , Morte , Feminino , Serviços de Assistência Domiciliar/estatística & dados numéricos , Serviços de Assistência Domiciliar/tendências , Cuidados Paliativos na Terminalidade da Vida/tendências , Hospitalização/tendências , Hospitais/tendências , Humanos , Masculino , Razão de Chances , Cuidados Paliativos , Médicos , Qualidade de Vida , Estudos Retrospectivos , Assistência Terminal/tendênciasRESUMO
In the clinical setting, previous studies have shown personalized risk assessment and communication improves risk perception and motivation. We evaluated an online health calculator that estimated and presented six different measures of life expectancy/mortality based on a person's sociodemographic and health behavior profile. Immediately after receiving calculator results, participants were invited to complete an online survey that asked how informative and motivating they found each risk measure, whether they would share their results and whether the calculator provided information they need to make lifestyle changes. Over 80% of the 317 survey respondents found at least one of six healthy living measures highly informative and motivating, but there was moderate heterogeneity regarding which measures respondents found most informative and motivating. Overall, health age was most informative and life expectancy most motivating. Approximately 40% of respondents would share the results with their clinician (44%) or social networks (38%), although the information they would share was often different from what they found informative or motivational. Online personalized risk assessment allows for a more personalized communication compared to historic paper-based risk assessment to maximize knowledge and motivation, and people should be provided a range of risk communication measures that reflect different risk perspectives.
Assuntos
Comportamentos Relacionados com a Saúde , Estilo de Vida Saudável , Expectativa de Vida , Motivação , Inquéritos e Questionários , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/epidemiologia , Dieta , Exercício Físico , Feminino , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores Sexuais , Fumar/epidemiologia , Fatores Socioeconômicos , Adulto JovemRESUMO
Pulmonary arterial hypertension (PAH) has demonstrated multi-serotonin receptor dependent pathologies, characterized by increased tone (5-HT1B receptor) and complex lesions (SERT, 5-HT1B, 5-HT2B receptors) of the pulmonary vasculature together with right ventricular hypertrophy, ischemia and fibrosis (5-HT2B receptor). Selective inhibitors of individual signaling elements - SERT, 5-HT2A, 5HT2B, and combined 5-HT2A/B receptors, have all been tested clinically and failed. Thus, inhibition of tryptophan hydroxylase 1 (TPH1), the rate limiting step in 5-HT synthesis, has been suggested as a more broad, and thereby more effective, mode of 5-HT inhibition. However, selectivity over non-pathogenic enzyme family members, TPH2, phenylalanine hydroxylase, and tyrosine hydroxylase has hampered therapeutic development. Here we describe the site/sequence, biochemical, and biophysical characterization of a novel allosteric site on TPH1 through which selectivity over TPH2 and related aromatic amino acid hydroxylases is achieved. We demonstrate the mechanism of action by which novel compounds selectively inhibit TPH1 using surface plasma resonance and enzyme competition assays with both tryptophan ligand and BH4 co-factor. We demonstrate 15-fold greater potency within a human carcinoid cell line versus the most potent known TPH1/2 non-specific inhibitor. Lastly, we detail a novel canine in vivo system utilized to determine effective biologic inhibition of newly synthesized 5-HT. These findings are the first to demonstrate TPH1-selective inhibition and may pave the way to a truly effective means to reduce pathologic 5-HT and thereby treat complex remodeling diseases such as PAH.
RESUMO
OBJECTIVES: To describe the level of need and divertibility of newly admitted nursing home residents, describe the factors that drive need, and describe the outcomes of residents across different levels of need. DESIGN: Retrospective cohort study. SETTING: A total of 640 publicly funded nursing homes (also known as long-term care facilities) in Ontario, Canada. PARTICIPANTS: All newly admitted residents between January 1, 2010 and March 1, 2012. MEASUREMENTS: We categorized residents into 36 groups based on different levels of (1) cognitive impairment, (2) difficulty in activities of daily living (ADL), (3) difficulty in instrumental ADLs, and (4) whether or not they had a caregiver at home. Residents were then categorized as having low, intermediate, or high needs; applying results from previous "Balance of Care" studies, we also captured the proportion who could have been cost-effectively diverted into the community. We then contrasted the characteristics of residents across the needs and divertible groupings, and compared 4 outcomes among these groups: hospital admissions, emergency department visits, mortality, and return to home. RESULTS: A population-level cohort of 64,105 incident admissions was captured. About two-thirds had great difficulty performing ADLs (65%) and had mild to severe cognitive impairment (66%); over 90% had great difficulty with instrumental ADLs. Just less than 50% of the new admissions were considered to be residents with high care needs (cognitively impaired with great ADL difficulty), while only 4.5% (2880 residents) had low care needs (cognition and ADL intact). Those with dementia (71.0%) and previous stroke (21.5%) were over-represented in the high needs group. Those that cannot be divertible to anywhere else but an institution with 24 hour nursing care comprised 41.3% (n = 26,502) of residents. Only 5.4% (n = 3483), based on community resources available, could potentially be cost-effectively diverted to the community. Those at higher needs experienced higher rates of mortality, higher total cost across all health sectors, and lower rates of return to home. CONCLUSIONS: The majority of those admitted into nursing homes have high levels of need (driven largely by dementia and stroke) and could not have their needs met cost-effectively elsewhere, suggesting that the system is at capacity. Caring for the long-term care needs of the aging population should consider the balance of investments in institution and community settings.
Assuntos
Atividades Cotidianas , Disfunção Cognitiva/diagnóstico , Necessidades e Demandas de Serviços de Saúde/estatística & dados numéricos , Casas de Saúde , Admissão do Paciente/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/epidemiologia , Estudos de Coortes , Feminino , Avaliação Geriátrica/estatística & dados numéricos , Humanos , Masculino , Ontário , Estudos RetrospectivosRESUMO
Sulfur mustard [SM, bis-(2-chloroethyl) sulfide] is a highly reactive bifunctional alkylating agent that has been used as a vesicating agent in warfare scenarios to induce severe lung, skin, and eye injury. SM cutaneous lesions are characterized by both vesication and severe inflammation, but the molecular mechanisms that lead to these signs and symptoms are not well understood. There is a pressing need for effective therapeutics to treat this injury. An understanding of the molecular mechanisms of injury and identification of potential therapeutic targets is necessary for rational therapeutic development. We have applied a high-throughput small interfering RNA (siRNA) screening approach to the problem of SM cutaneous injury in an effort to meet these needs. Our siRNA screening efforts have initially focused on SM-induced inflammation in cutaneous injury since chronic inflammation after exposure appears to play a role in progressive clinical pathology, and intervention may improve clinical outcome. Also, targets that mitigate cellular injury should reduce the inflammatory response. Historical microarray data on this injury were mined for targets and pathways implicated in inflammation, and a siRNA library of 2,017 targets was assembled for screening. Primary screening and library deconvolution were performed using human HaCaT keratinocytes and focused on cell death and inflammatory markers as end points. Using this in vitro approach, we have identified and validated novel targets for the potential treatment of SM-induced cutaneous injury.
Assuntos
Ensaios de Triagem em Larga Escala/métodos , Irritantes/toxicidade , Terapia de Alvo Molecular/métodos , Gás de Mostarda/toxicidade , RNA Interferente Pequeno , Linhagem Celular , Substâncias para a Guerra Química/toxicidade , Dermatite de Contato/etiologia , Humanos , Queratinócitos/efeitos dos fármacos , Pele/efeitos dos fármacosRESUMO
OBJECTIVE: This study aims to assess middle-aged women's needs when making body weight management decisions and to evaluate a knowledge translation tool for addressing their needs. METHODS: A mixed-methods study used an interview-guided theory-based survey of professional women aged 40 to 65 years. The tool summarized evidence to address their needs and enabled women to monitor actions taken. Acceptability and usability were reported descriptively. RESULTS: Sixty female participants had a mean body mass index of 28.0 kg/m(2) (range, 17.0-44.9 kg/m(2)), and half were premenopausal. Common options for losing (82%) or maintaining (18%) weight included increasing physical activity (60%), eating healthier (57%), and getting support (40%). Decision-making involved getting information on options (52%), soliciting others' decisions/advice (20%), and being self-motivated (20%). Preferred information sources included written information (97%), counseling (90%), and social networking websites (43%). Five professionals (dietitian, personal trainer, occupational therapist, and two physicians) had similar responses. Of 53 women sent the tool, 27 provided acceptability feedback. They rated it as good to excellent for information on menopause (96%), body weight changes (85%), and managing body weight (85%). Most would tell others about it (81%). After 4 weeks of use, 25 women reported that the wording made sense (96%) and that the tool had clear instructions (92%) and was easy to use across time (88%). The amount of information was rated as just right (64%), but the tool had limited space for responding (72%). CONCLUSIONS: When making decisions about body weight management, women's needs were "getting information" and "getting support." The knowledge translation tool was acceptable and usable, but further evaluation is required.
Assuntos
Manutenção do Peso Corporal/fisiologia , Tomada de Decisões , Conhecimentos, Atitudes e Prática em Saúde , Menopausa/fisiologia , Pesquisa Translacional Biomédica/métodos , Redução de Peso/fisiologia , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Avaliação das Necessidades , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: To determine the effectiveness of exercise and/or nutrition interventions and to address body weight changes during the menopause transition. METHODS: A systematic review of the literature was conducted using electronic databases, grey literature, and hand searching. Two independent researchers screened for studies using experimental designs to evaluate the impact of exercise and/or nutrition interventions on body weight and/or central weight gain performed during the menopausal transition. Studies were quality appraised using Cochrane risk of bias. Included studies were analyzed descriptively. RESULTS: Of 3,564 unique citations screened, 3 studies were eligible (2 randomized controlled trials, and 1 pre/post study). Study quality ranged from low to high risk of bias. One randomized controlled trial with lower risk of bias concluded that participation in an exercise program combined with dietary interventions might mitigate body adiposity increases, which is normally observed during the menopause transition. The other two studies with higher risk of bias suggested that exercise might attenuate weight loss or weight gain and change abdominal adiposity patterns. CONCLUSIONS: High quality studies evaluating the effectiveness of interventions targeting body weight changes in women during their menopause transition are needed. Evidence from one higher quality study indicates an effective multifaceted intervention for women to minimize changes in body adiposity.
Assuntos
Dieta , Exercício Físico , Comportamentos Relacionados com a Saúde , Estilo de Vida , Menopausa , Obesidade/terapia , Aumento de Peso , Feminino , Humanos , Redução de PesoRESUMO
BACKGROUND: About half of women decrease their regular exercise during middle age. Concurrently, they experience a reduction in basal metabolic rate and loss of lean muscle as they transition to menopause. The combined effects place these women at increased risk for body weight gain and associated co-morbidities. Further research is required to better assess their barriers to regular exercise and to develop more applied knowledge aimed to improve the applicability of clinical interventions aimed at this population. The main aim of this study was to identify enablers and barriers influencing adherence to regular exercise in middle-aged women who exercise. METHODS: An interpretive description qualitative study was conducted using individual interviews. The two key questions were focused on planning to engage in physical activity and succeeding or planning to engage in physical activity and not succeeding. Inductive content analysis was used. RESULTS: Fifty-three women interviewed were aged 40-62 years and experiencing mild to moderate menopausal symptoms. Six broad themes influencing adhering to regular exercise were: routine, intrinsic motivation, biophysical issues, psychosocial commitments, environmental factors, and resources. Common sub-themes were identified as enabling factors: daily structure that incorporated physical activity (broad theme routine), anticipated positive feelings associated with physical activity (intrinsic), and accountability to others (psychosocial). Other common sub-themes identified as barriers were disruptions in daily structure (routine), competing demands (routine) and self-sacrifice (psychosocial). CONCLUSIONS: The most common barrier middle-aged women describe as interfering with adhering to regular exercise was attributable to the demands of this life stage at home and with others. Lack of time and menopausal symptoms were not identified as the common barriers. To support women to adhere to regular exercise, healthcare professionals should consider a narrative approach to assessing barriers and focus on enablers to overcoming identified barriers.
Assuntos
Exercício Físico/psicologia , Cooperação do Paciente/psicologia , Adulto , Atitude Frente a Saúde , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Estilo de Vida , Pessoa de Meia-Idade , Motivação , Pesquisa Qualitativa , Inquéritos e QuestionáriosRESUMO
CONTEXT: Sulfur mustard (SM) is a highly reactive vesicating agent that can induce severe ocular injury. The clinical features of this injury have been well documented, but the molecular basis for this pathology is not well understood. Identification and validation of specific targets is necessary in the effort to develop effective therapeutics for this injury. Currently used rabbit models are not well suited for many molecular studies because the necessary reagents are not widely available. However, these reagents are widely available for the mouse model. OBJECTIVE: Our objective is to develop a mouse model of SM-induced ocular injury suitable for the study of the molecular mechanisms of injury and the evaluation of therapeutics. MATERIALS AND METHODS: Ocular exposure to sulfur mustard vapor was accomplished by using a vapor cup method. Dose response studies were conducted in female BALB/c mice. An exposure dose which produced moderate injury was selected for further study as moderate injury was determined to be amenable to studying the beneficial effects of potential therapeutics. Histopathology and inflammatory markers were evaluated for up to 28 days after exposure, while clinical injury progression was evaluated for 1 year post-exposure. RESULTS: A biphasic ocular injury was observed in mice exposed to SM. Acute phase SM ocular injury in mice was characterized by significant corneal epithelium loss, corneal edema, limbal engorgement, and ocular inflammation. This was followed by a brief recovery phase. A delayed injury phase then ensued in the following weeks to months and was characterized by keratitis, stromal edema, infiltrates, neovascularization, and eventual corneal scarring. DISCUSSION AND CONCLUSIONS: SM-induced ocular injury in mice is consistent with observations of SM-induced ocular injury in humans and rabbit models. However, in the mouse model, the SM ocular injury, a more rapid onset of the delayed injury phase was observed. We have developed an animal model of SM injury that is suitable for studies to elucidate molecular mechanisms of injury and identify potential therapeutic targets.
Assuntos
Substâncias para a Guerra Química/toxicidade , Modelos Animais de Doenças , Traumatismos Oculares/induzido quimicamente , Gás de Mostarda/toxicidade , Animais , Citocinas/metabolismo , Progressão da Doença , Epitélio Corneano/efeitos dos fármacos , Epitélio Corneano/patologia , Epitélio Corneano/fisiologia , Traumatismos Oculares/metabolismo , Traumatismos Oculares/patologia , Feminino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Fisiológica , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
RATIONALE: Whether idiopathic, familial, or secondary to another disease, pulmonary arterial hypertension (PAH) is characterized by increased vascular tone, neointimal hyperplasia, medial hypertrophy, and adventitial fibrosis. Imatinib, a potent receptor tyrosine kinase inhibitor, reverses pulmonary remodeling in animal models of PAH and improves hemodynamics and exercise capacity in selected patients with PAH. OBJECTIVES: Here we use both imatinib and knockout animals to determine the relationship between platelet-derived growth factor receptor (PDGFR) and serotonin signaling and investigate the PAH pathologies each mediates. METHODS: We investigated the effects of imatinib (100 mg/kg) on hemodynamics, vascular remodeling, and downstream molecular signatures in the chronic hypoxia/SU5416 murine model of PAH. MEASUREMENTS AND MAIN RESULTS: Treatment with imatinib reduced all measures of PAH pathology observed in hypoxia/SU5416 mice. In addition, 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase 1 (Tph1) expression were reduced compared with the normoxia/SU5416 control group. Imatinib attenuated hypoxia-induced increases in Tph1 expression in pulmonary endothelial cells in vitro via inhibition of the PDGFR-ß pathway. To better understand the consequences of this novel mode of action for imatinib, we examined the development of PAH after hypoxic/SU5416 exposure in Tph1-deficient mice (Tph1(-/-)). The extensive changes in pulmonary vascular remodeling and hemodynamics in response to hypoxia/SU5416 were attenuated in Tph1(-/-) mice and further decreased after imatinib treatment. However, imatinib did not significantly further impact collagen deposition and collagen 3a1 expression in hypoxic Tph1(-/-) mice. Post hoc subgroup analysis suggests that patients with PAH with greater hemodynamic impairment showed significantly reduced 5-HT plasma levels after imatinib treatment compared with placebo. CONCLUSIONS: We report a novel mode of action for imatinib, demonstrating TPH1 down-regulation via inhibition of PDGFR-ß signaling. Our data reveal interplay between PDGF and 5-HT pathways within PAH, demonstrating TPH1-dependent imatinib efficacy in collagen-mediated mechanisms of fibrosis.
Assuntos
Hipertensão Pulmonar/fisiopatologia , Piperazinas/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Triptofano Hidroxilase/metabolismo , Animais , Benzamidas , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Hipóxia/complicações , Mesilato de Imatinib , Indóis/farmacologia , Camundongos , Camundongos Knockout , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Serotonina/metabolismoRESUMO
Mutations in the gene for the transforming growth factor (TGF)-beta superfamily receptor, bone morphogenetic protein receptor II, underlie heritable forms of pulmonary arterial hypertension (PAH). Aberrant signaling via TGF-beta receptor I/activin receptor-like kinase 5 may be important for both the development and progression of PAH. We investigated the therapeutic potential of a well-characterized and potent activin receptor-like kinase 5 inhibitor, SB525334 [6-(2-tert-butyl-5-{6-methyl-pyridin-2-yl}-1H-imidazol-4-yl)-quinoxaline] for the treatment of PAH. In this study, we demonstrate that pulmonary artery smooth muscle cells from patients with familial forms of idiopathic PAH exhibit heightened sensitivity to TGF-beta1 in vitro, which can be attenuated after the administration of SB525334. We further demonstrate that SB525334 significantly reverses pulmonary arterial pressure and inhibits right ventricular hypertrophy in a rat model of PAH. Immunohistochemical studies confirmed a significant reduction in pulmonary arteriole muscularization induced by monocrotaline (used experimentally to induce PAH) after treatment of rats with SB525334. Collectively, these data are consistent with a role for the activin receptor-like kinase 5 in the progression of idiopathic PAH and imply that strategies to inhibit activin receptor-like kinase 5 signaling may have therapeutic benefit.