A thematic analysis of patients' and their informal caregivers' gendered experiences in traumatic brain injury.

PURPOSE: Research shows that patients' perceptions of themselves and others, in addition to their understanding of the concept of gender, changes after traumatic brain injury (TBI). Little is known about gendered experiences in TBI and care delivery. This study aims to explore perceptions of gender through life experiences and interactions between adult patients with TBI and their informal caregivers. MATERIALS AND METHODS: Seven patients with mild and moderate-severe TBI and eight informal caregivers were interviewed. Transcripts were coded and analysed according to Braun and Clarke's thematic analysis. The Consolidated Criteria for Reporting Qualitative Research guidelines were followed in reporting results. RESULTS: The participants described a transformation of their understanding and experiences of gender following the TBI event. Three themes were identified: (1) Gender designations of "man" and "woman";( 2) Post-injury performativity of gender; and (3) Gender in giving and receiving care. CONCLUSIONS: The findings emphasize the importance of raising awareness among researchers and practitioners on gender as a transformative process for patients with TBI and informal caregivers after the injury. The diversity of patient-caregiver experiences and critical needs based on gender call for intervention approaches that mitigate gender disparities in giving and receiving care. Implications for RehabilitationHistorically, rehabilitation of persons with traumatic brain injury has targeted physical and cognitive impairments, with little attention to their gendered demands in the lived environment.Gender prevails in the lived experiences of persons with traumatic brain injury, and their informal caregivers, and in giving and receiving quality care.A major challenge for clinicians is identifying harmful gendered roles, norms, and relations and the affective/behavioral problems they produce to alleviate enduring distress and reduce disability.Rehabilitation interventions focusing on flexible and adaptive responses to gendered demands in the lived environment of persons with traumatic brain injury are timely.

Is it prime time for sex and gender considerations in traumatic brain injury? Perspectives of rehabilitation care professionals.

PURPOSE: The purpose of this study was to explore rehabilitation clinicians' understanding of how sex and gender facilitate or hinder care provided to patients with traumatic brain injury (TBI). MATERIALS AND METHODS: Sixteen clinicians from various specialities, attending to patients with TBI from a large rehabilitation hospital in Ontario, Canada, were recruited using purposive sampling. Data was collected through semi-structured interviews and thematic analysis was used to identify reoccurring themes. RESULTS: Three themes that facilitate or hinder care of TBI patients were identified: (1) knowledge and evidence; (2) gender and other aspects of recovery; and (3) family caregiving. Lack of education about the topic and inconsistent scientific evidence limited clinicians' attention to sex and gender topics. Social, financial, and cultural characteristics of patients were considered to be more relevant than their sex and gender. The gendered nature of caregiving and its burden on caregivers' health were acknowledged. CONCLUSIONS: Currently, attention to topics of sex and gender as they may influence patients' recovery is limited. However, clinicians are willing to be educated on these topics to enhance rehabilitation care. Further research on the gendered nature of interactions between patient, clinician, and family caregiver during recovery is warranted.IMPLICATIONS FOR REHABILITATIONSex and gender matter for patients undergoing recovery for their traumatic brain injury; however, clinical attention to this topic is limited.Based on the clinicians' perceptions, resources that address patients' psychosocial vulnerabilities should be prioritized (e.g., unequal access to care, financial status, cultural diversity etc.).Clinicians highlighted that psychosocial vulnerability and patients' life roles, before and after injury, are sex and gender specific.Guidelines about sex and gender influences in traumatic brain injury rehabilitation have the potential to enhance clinical practice.

Adapting two American Decision Aids for Mild Traumatic Brain Injury to the Canadian Context Using the Nominal Group Technique.

BACKGROUND: Decision aids are patient-focused tools that have the potential to reduce the overuse of head computed tomography (CT) scans. OBJECTIVE: The objective of this study was to create a consensus among Canadian mild traumatic brain injury and emergency medicine experts on modifications required to adapt two American decision aids about head CT use for adult and paediatric mild traumatic brain injury to the Canadian context. METHODS: We invited 21 Canadian stakeholders and the two authors of the American decision aids to a Nominal Group Technique consensus meeting to generate suggestions for adapting the decision aids. This method encourages idea generation and sharing between team members. Each idea was discussed and then prioritised using a voting system. We collected data using videotaping, writing material and online collaborative writing tools. The modifications proposed were analysed using a qualitative thematic content analysis. RESULTS: Twenty-one participants took part in the meeting, including researchers and clinician researchers (n = 9; 43%), patient partners (n = 3; 14%) and decision makers (n = 2; 10%). A total of 84 ideas were generated. Participants highlighted the need to clarify the purpose of the decision aids, the nature of the problem being addressed and the target population. The tools require sociocultural adaptations, better identification of their target population, better description of head CT utility, advantages and related risks, modification of the visual and written representation of the risk of brain injury and head CT use, and locally adapted, patient follow-up plans. CONCLUSIONS: This study based on a Nominal Group Technique identified several adaptations for two American decision aids about head CT use for mild traumatic brain injury to support their use in Canada's different healthcare, social, cultural and legal context. These adaptations concerned the target users of the decision aids, the information presented, and how the benefits and risks were communicated in the decision aids. Future steps include prototyping the two adapted decision aids, conducting formative evaluations with actual emergency department patients and clinicians, and measuring the impact of the adapted tools on CT scan use.

A mild traumatic brain injury (also called concussion) can happen when the brain moves around in the skull after an impact to the head. A concussion is not a brain bleed and you cannot see a concussion. Concussions do not show up on a computed tomography (CT) scan. Brain bleeds do. Computed tomography scans are specialised X-ray machines that can detect serious brain injuries. Unfortunately, CT scan use also exposes patients to radiation and a future increased risk of cancer.Shared decision making involves health professionals and patients making decisions together based on the best available evidence, health professionals' experience, and patients' values and preferences. Shared decision making improves appropriate diagnostic test use.Two decision aids created in the USA are available to facilitate shared decision making regarding the use of head CT scans for patients with concussion. These decision aids are not fully adapted for use in Canada because the healthcare, social and legal context is different. Our study brought together patients and experts in the field of concussion and shared decision making to analyse these decision aids and propose adaptations that would increase their acceptance in Canadian emergency departments. We used a technique called the Nominal Group Technique to create a consensus about the most important changes to make to both original decision aids. The main adaptations needed for the Canadian context concerned avoiding information about cost and removing any information that does not change clinical management. This project will help us adapt two decision aids for clinical use in Canada and support appropriate CT scan use for patients with concussion.

An inclusive, online Delphi process for setting targets for best practice implementation for spinal cord injury.

RATIONALE, AIMS, AND OBJECTIVES: The Spinal Cord Injury Knowledge Mobilization Network is a pan-Canadian community of practice composed of seven rehabilitation hospitals. The goal of this network is to utilize implementation science processes to facilitate the adoption of best practice in spinal cord injury (SCI) rehabilitation. In addition to selecting specific practices for implementation, a key aspect of effective implementation is the engagement of stakeholders in decision-making processes. To achieve this, the network utilized a Delphi process to reach consensus on two pressure ulcer prevention and management practices to be implemented in SCI inpatient rehabilitation. A diverse, multidisciplinary panel of clinicians, researchers, sponsoring agency representatives, and persons with SCI participated in this process. METHOD: An online Delphi process was conducted in order to prioritize pressure ulcer prevention and management best practice recommendations and performance indicators for implementation. The process was conducted in six stages: (1) steering committee selection; (2) identification and selection of evidence; (3) participant selection and recruitment; (4) survey development; (5) identification of voting criteria; and (6) five rounds of voting. RESULTS: The Delphi process resulted in the selection of two best practices: (1) comprehensive risk assessment and (2) education for pressure ulcer prevention and management in persons with SCI. CONCLUSIONS: In this Delphi process, a large expert panel achieved consensus on best practice recommendations and associated performance indicators for implementation. This process was undertaken as a first step towards optimization of service delivery and outcomes for persons with SCI across Canada.

The Canadian Traumatic Brain Injury Research Consortium: Epitomizing Collaborative Research in Canada.

Traumatic brain injury (TBI) is the leading cause of death in the first half of life and a chronic disability for Canadians of all ages. Despite the recognized importance of TBI, there is no integrated national strategy for research and best practices in Canada. We therefore created the Canadian TBI Research Consortium (CTRC) to build an ideal model of collaboration between Canadian TBI researchers. Our objectives were to: (1) Create a collaborative Canadian research network, (2) improve patient survival, functional outcome, and health through sustainable and scalable evidence-based practice implementation, (3) strengthen the healthcare system for patients with TBI, (4) provide international leadership and collaboration in TBI research, (5) build stronger links with patients and their representatives to help set the research agenda, and to participate in analysis of its impacts, and (6) support current researchers and prepare the next generation of leaders in TBI research. Building on the highly successful 30-year history of the Canadian Critical Care Trials Group, we developed a highly collaborative research group that integrates the multi-disciplinary network of TBI researchers in Canada. The CTRC conducts multi-center clinically relevant practice changing research. Our research is developed around investigator-led project-based research using a programmatic approach and multiple methodologies. Through strong and sustainable career development and mentorship programs, we train and develop the next generation of TBI researchers. Our group is composed of more than 100 Canadian researchers from coast to coast, most of them funded by the Canadian Institutes of Health Research and other granting agencies. In conclusion, the CTRC prioritizes investigator-led TBI research and broadens the research agenda by integrating researchers from different disciplines in the field of TBI research to optimize delivery of care and improve the health of Canadians with TBI. Our goals are being accomplished across the whole continuum of care by conducting clinically relevant and practice-changing research.

Montreal Accord on Patient-Reported Outcomes (PROs) use series - Paper 3: patient-reported outcomes can facilitate shared decision-making and guide self-management.

BACKGROUND: There is a shift toward making health care patient centered, whereby patients are part of medical decision-making and take responsibility for managing their health. Patient-reported outcomes (PROs) capture the patient voice and can be used to engage patients in medical decision-making. OBJECTIVE: The objective of this paper is to present important factors from patients', clinicians', researchers', and decision-makers' perspectives that influence successful adoption of PROs in clinical practice. Factors recommended in this paper were informed by a patient partner. DISCUSSION: Based on themes arising from the Montreal Accord proceedings, we describe factors that influence the adoption of PROs and how PROs can have a positive effect by enhancing communication and providing opportunities to engage patients, carers, and clinicians in care. Consideration of patient factors (e.g., health literacy), family support and networks (e.g., peer-support networks), technology (e.g., e-health), and health care system factors (e.g., resources to implement PROs) is necessary to ensure PROs are successfully adopted. PRO evaluation plans most likely to succeed over the long term are those incorporating PROs identified by patients as necessary for self-management and that coincide with providers' needs for collaboratively developing treatment plans with patients and families.

The financial burden of prescription drugs for neurological conditions in Canada: Results from the National Population Health Study of Neurological Conditions.

This paper describes the current situation in Canada concerning the availability and use of prescription drugs for neurological conditions. We conducted semi-structured qualitative interviews with health care providers, administrators, community organization representatives, opinion leaders and policy makers. The analysis revealed three primary themes related to the availability of and access to prescription drugs to treat neurological conditions. First, we learned that across Canada there is significant vulnerability and a need for advocacy on behalf of people living with these conditions. Second, we learned that the heightened level of vulnerability and need for advocacy stems in part from the significant differences in the drug coverage available in the different provinces and territories. As a result, there are significant inequities across Canada. Third, we determined that the existing situation is also due to the current approach to health governance (i.e., accountability, transparency). Our study provides evidence for the urgent need for a formal discourse on national pharmacare in Canada, with representatives of neurological conditions having a voice at the table.

Health and Community-Based Services for Individuals with Neurological Conditions.

BACKGROUND: The current study involves a national survey of healthcare providers who offer services for individuals with a variety of neurological conditions. It aims to describe the provision of health and community-based services as well as the admission criteria, waitlist practices, and referral sources of these services. METHODS: An online survey was directed at administrators/managers from publicly funded hospital programs, long-term care homes, and community-based healthcare provider agencies that were believed to be providing information and/or services to patients with a variety of neurological conditions. RESULTS: Approximately 60% (n=254) of respondents reported providing services in either urban/suburban areas or rural/remote areas only, whereas the remaining 40% (n=172) provided services regardless of patient location. A small proportion of respondents reported providing services for individuals with dystonia (28%), Tourette syndrome (17%), and Rett syndrome (13%). There was also a paucity of diverse healthcare professionals across all institutions, but particularly mental healthcare professionals in hospitals. Lastly, the majority of respondents reported numerous exclusion criteria with regard to service provision, including prevalent comorbid conditions. CONCLUSIONS: If the few services provided for these neurological patient populations exclude common comorbidities, it is likely that there will be no other place for these individuals to seek care.

Development of a Chronic Care Model for Neurological Conditions (CCM-NC).

BACKGROUND: Persons with neurological conditions and their families face a number of challenges with the provision of health and community-based services. The purpose of this study was to understand the existing health and community service needs and gaps in care and to use this information to develop a model to specify factors and processes that may improve the quality of care and health and well-being for persons with neurological conditions. METHODS: We conducted semi-structured interviews with health care professionals, community-based non-health care professionals working with individuals with neurological conditions, and policy makers -from the Ministries of Health, Community and Social Services, Transportation and Education- across Canada. We used a purposive sampling and snowballing approach to obtain maximum variation across professions, sector and geography (provinces and territories, rural and urban). Data analysis was an iterative, constant comparative process involving descriptive and interpretive analyses and was initially guided by the components of the Expanded Chronic Care Model. RESULTS: A total of 180 individuals completed the interviews: 39% (n = 70) health care professionals, 47% (n = 85) community-based non-health care professionals, and 14% (n = 25) policy makers. Based on the data we developed the Chronic Care Model for Neurological Conditions (CCM-NC). The major needs/gaps are represented by the following themes: acceptance and openness to neurological conditions, evidence informed policy, investments and funding, supported transitions, caregiver support, and life enhancing resources (education, employment, housing and transportation), knowledge and awareness of neurological conditions and availability and access to health services. The model maintains that intersectoral collaboration across the health system, community and policy components is needed. It recognizes that attitudes, policies, enhanced community integration and health system changes are needed to develop activated patients and families, proactive service delivery teams, a person-centred health system and healthy public policy for persons with neurological conditions. CONCLUSION: The CCM-NC will generate debate and discussion about the actions needed in each of the model components to enable people with neurological conditions to sustain healthier lives. Next steps include validating the model with persons with neurological conditions, in and outside of the Canadian context and developing and evaluating interventions to test the model.

Physicians' attitudes toward medical and ethical challenges for patients in the vegetative state: comparing Canadian and German perspectives in a vignette survey.

BACKGROUND: Physicians treating patients in the vegetative state (VS) must deal with uncertainty in diagnosis and prognosis, as well as ethical issues. We examined whether physicians' attitudes toward medical and ethical challenges vary across two national medical practice settings. METHODS: A comparative survey was conducted among German and Canadian specialty physicians, based on a case vignette about the VS. Similarities and differences of participants' attitudes toward medical and ethical challenges between the two samples were analyzed with non-parametric tests (Mann-Whitney-U-Test). RESULTS: The overall response rate was 13.4%. Eighty percent of all participants correctly applied the diagnostic category of VS with no significant differences between countries. Many of the participants who chose the correct diagnosis of VS attributed capabilities to the patient, particularly the ability to feel pain (70%), touch (51%) and to experience hunger and thirst (35%). A large majority of participants (94%) considered the limitation of life-sustaining treatment (LST) under certain circumstances, but more Canadian participants were in favor of always limiting LST (32% vs. 12%; Chi-square: p < 0.001). Finding long-term care placement was considered more challenging by Canadian participants whereas discontinuing LST was much more challenging for German participants. CONCLUSIONS: Differences were found between two national medical practice settings with respect to physicians' experiences and attitudes about treatment limitation about VS in spite of comparable diagnostic knowledge.

How contextual and relational aspects shape the perspective of healthcare providers on decision making for patients with disorders of consciousness: a qualitative interview study.

Disorders of consciousness (DOC) are a family of related neurological syndromes characterized by deficits of varying degrees of wakefulness (e.g., sleep-wake cycles and arousal) or awareness (e.g., reacting to stimuli, interacting with the environment). Although coma rarely persists for more than a few weeks, some patients remain in a subsequent vegetative state or a minimally conscious state for months or years. Caring for patients with DOC raises ethical questions, but the perspectives of healthcare providers on these questions remain poorly documented. We conducted a qualitative study involving healthcare providers with different backgrounds. Semistructured interviews were used to explore attitudes toward ethical issues. We found that contextual (e.g., time, resource allocation) and relational aspects (e.g., communication process, families) shaped how ethical challenges surfaced and were managed. We call for greater awareness of contextual, institutional and social aspects and focus on these issues in training programs.

Emergency department prediction of post-concussive syndrome following mild traumatic brain injury--an international cross-validation study.

BACKGROUND: Between 20-50% of those suffering a mild traumatic brain injury (MTBI) will suffer symptoms beyond 3 months or post-concussive disorder (PCD). Researchers in Sydney conducted a prospective controlled study which identified that bedside recordings of memory impairment together with recordings of moderate or severe pain could predict those who would suffer PCS with 80% sensitivity and specificity of 76%. PRIMARY OBJECTIVE: This study is a cross-validation study of the Sydney predictive model conducted at Montreal General Hospital, Montreal, Canada. METHODS: One hundred and seven patients were assessed in the Emergency Department following a MTBI and followed up by phone at 3 months. The Rivermead Post-Concussive Questionnaire was the main outcome measure. RESULTS: Regression analysis showed that immediate verbal recall and quantitative recording of headache was able to predict PCD with a sensitivity of 71.4% and a specificity of 63.3%. In the combined MTBI groups from Sydney and Montreal the sensitivity was 70.2% and the specificity was 64.2%. CONCLUSION: This is the first study to compare populations from different countries with diverse language groups using a predictive model for identifying PCD following MTBI. The model may be able to identify an 'at risk' population to whom pre-emptive treatment can be offered.

Observations on the ethical and social aspects of disorders of consciousness.

The care of chronically unconscious patients raises vexing medical, ethical, and social questions concerning diagnosis, prognosis, communication with family members, and decision making, including the withdrawal of life support. We provide updates on major controversies surrounding disorders of consciousness. Issues such as withdrawal of artificial nutrition and hydration - which had been considered "settled" by many in the medical, legal and ethical communities - have resurfaced under the pressure of social groups and religious authorities. Some assumptions about the level of awareness and the prognosis of vegetative state and minimal conscious patients are questioned by advances in clinical care because of insights produced by neuroscience research techniques, particularly functional neuroimaging. Both the clinical and neuroscience dimensions of disorders of consciousness raise complex issues such as resource allocation and high levels of diagnostic inaccuracies (at least, for the vegetative state). We conclude by highlighting areas needing further research and collaboration.

Synergizing expectation and execution for stroke communities of practice innovations.

BACKGROUND: Regional networks have been recognized as an interesting model to support interdisciplinary and inter-organizational interactions that lead to meaningful care improvements. Existing communities of practice within the a regional network, the Montreal Stroke Network (MSN) offers a compelling structure to better manage the exponential growth of knowledge and to support care providers to better manage the complex cases they must deal with in their practices. This research project proposes to examine internal and external factors that influence individual and organisational readiness to adopt national stroke best practices and to assess the impact of an e-collaborative platform in facilitating knowledge translation activities. METHODS: We will develop an e-collaborative platform that will include various social networking and collaborative tools. We propose to create online brainstorming sessions ('jams') around each best practice recommendation. Jam postings will be analysed to identify emergent themes. Syntheses of these analyses will be provided to members to help them identify priority areas for practice change. Discussions will be moderated by clinical leaders, whose role will be to accelerate crystallizing of ideas around 'how to' implement selected best practices. All clinicians (~200) involved in stroke care among the MSN will be asked to participate. Activities during face-to-face meetings and on the e-collaborative platform will be documented. Content analysis of all activities will be performed using an observation grid that will use as outcome indicators key elements of communities of practice and of the knowledge creation cycle developed by Nonaka. Semi-structured interviews will be conducted among users of the e-collaborative platform to collect information on variables of the knowledge-to-action framework. All participants will be asked to complete three questionnaires: the typology questionnaire, which classifies individuals into one of four mutually exclusive categories of information seeking; the e-health state of readiness, which covers ten domains of the readiness to change; and a community of practice evaluation survey. SUMMARY: This project is expected to enhance our understanding of collaborative work across disciplines and organisations in accelerating implementation of best practices along the continuum of care, and how e-technologies influence access, sharing, creation, and application of knowledge.

Advancing the chronic care road map: a contemporary overview.

In an effort to assess and advance the community-based model of chronic care, we reviewed a contemporary spectrum of Canadian chronic disease management and prevention (CDMP) programs with a participatory audience of administrators, academics, professional and non-professional providers and patients. While many questions remain unanswered, several common characteristics of CDMP success were apparent. These included community-based partnerships with aligned goals; inter-professional and non-professional care, including patient self-management; measured and shared information on practices and outcomes; and visible leadership. Principal improvement opportunities identified were the enhanced engagement of all stakeholders; further efficacy evidence for team care; facile information systems, with clear rationales for data selection, access, communication and security; and increased education of, and resource support for, patients and caregivers. Two immediate actions were suggested. One was a broad and continuing communication plan highlighting CDMP issues and opportunities. The other was a standardized survey of team structures, interventions, measurements and communications in ongoing CDMP programs, with a causal analysis of their relation to outcomes. In the longer term, the key needs requiring action were more inter-professional education of health human resources and more practical information systems available to all stakeholders. Things can be better.

ONF trainee awards contribute to capacity building in neurotrauma.

OBJECTIVE: Injury to the brain and spinal cord is one of the most catastrophic and costly occurrences in the Ontario health system. The objective of the present study was to evaluate the impact of past Ontario Neurotrauma Foundation (ONF) studentships and fellowships in terms of capacity building in the neurotrauma field in Ontario. METHOD: An online, cross sectional survey amongst past recipients of studentships and fellowships that terminated prior to July 2005. Explicit data were collected on various aspects of career development including current activity, awards and publications. RESULTS: Thirty-six out of 42 (86%) eligible past trainees responded; 12 (33%) were Masters students, 12 (33%) were PhD students and 12 (33%) were Post-Doctoral students. A majority of the recipients (61%) are currently involved in neurotrauma-related activities (clinical, research and teaching) in more than 20% of their time, with no substantial differences between the degree groups. Half the recipients are currently involved in neurotrauma-related research in more than 20% of their time. The awardees published 1.5 peer-review manuscripts/person-year and received multiple awards. A high majority of our recipients (86%) feel that the ONF award had a substantial impact on their career. CONCLUSIONS: A high proportion of past award recipients remain involved in neurotrauma activities, especially in research. These results may lead to a cautious conclusion of the positive impact of the ONF studentships and fellowships on neurotrauma capacity building. These results should be considered in strategic planning of funding agencies similar to ONF.

Deficits in saccadic eye-movement control in Parkinson's disease.

In contrast to their slowed limb movements, individuals with Parkinson's disease (PD) produce rapid automatic eye movements to sensory stimuli and show an impaired ability to generate voluntary eye movements in cognitive tasks. Eighteen PD patients and 18 matched control volunteers were instructed to look either toward (pro-saccade) or away from (anti-saccade) a peripheral stimulus as soon as it appeared (immediate, gap and overlap conditions) or after a variable delay; or, they made sequential saccades to remembered targets after a variable delay. We found that PD patients made more express saccades (correct saccades in the latency range of 90-140 ms) in the immediate pro-saccade task, more direction errors (automatic pro-saccades) in the immediate anti-saccade task, and were less able to inhibit saccades during the delay period in all delay tasks. PD patients also made more directional and end-point errors in the memory-guided sequential task. Their inability to plan eye movements to remembered target locations suggests that PD patients have a deficit in spatial working memory which, along with their deficit in automatic saccade suppression, is consistent with a disorder of the prefrontal-basal ganglia circuit. Impairment of this pathway may release the automatic saccade system from top-down inhibition and produce deficits in volitional saccade control. Parallel findings across various motor, cognitive and oculomotor tasks suggest a common mechanism underlying a general deficit in automatic response suppression.

Differential activity of the nerve growth factor (NGF) antagonist PD90780 [7-(benzolylamino)-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid] suggests altered NGF-p75NTR interactions in the presence of TrkA.

The neurotrophin nerve growth factor (NGF) binds to two receptor types: the tyrosine kinase receptor TrkA and the common neurotrophin receptor p75(NTR). Although many of the biological effects of NGF (such as neuronal growth and survival) are associated with TrkA activation, p75(NTR) also contributes to these activities by enhancing the action of TrkA when receptors are coexpressed. The NGF antagonist PD90780 [7-(benzolylamino)-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid] interacts with NGF, preventing its binding to p75(NTR). In this study, the actions of this compound are further explored, and it is found that PD90780 is not able to inhibit the binding of either brain-derived neurotrophic factor or neurotrophin-3 to p75(NTR), consistent with the direct interactions of the antagonist with NGF. In addition, we demonstrate that the ability of PD90780 to inhibit NGF-p75(NTR) interactions is lower when receptors are coexpressed, compared with when p75(NTR) is the only neurotrophin receptor expressed. These results suggest that the interaction between NGF and the p75(NTR) receptor is altered when TrkA is coexpressed. This alteration can be exploited in the development of antagonists that will selectively inhibit the pro-apoptotic actions of p75(NTR) when expressed in the absence of TrkA, although having less effect on the pro-survival effects of p75(NTR) mediated by enhanced TrkA activation.

Functional expression of corticotropin-releasing hormone (CRH) receptor 1 in cultured rat microglia.

Corticotropin-releasing hormone (CRH), known as a key regulator of the hypothalamic-pituitary-adrenal axis response to stress, elicits its biological effects by binding to two membrane receptors (CRH-R1 and CRH-R2). The present studies examined the presence of functional expression of CRH receptors in cultured microglia of rat. CRH-R1 mRNA and protein were detected by reverse transcriptase polymerase chain reaction (RT-PCR), western blotting and receptor chemical cross-linking assay in cultured microglia. CRH-R2 mRNA was undetectable by RT-PCR. The radioligand binding analysis using [125I]Tyr-rat/human CRH revealed a high affinity binding site (Kd of 1.2 nm and Bmax of 84 fmol/mg of protein). Competition studies using CRH and related peptides indicated kinetic and pharmacological characteristics consistent with the CRH-R1 receptor subtype. Receptor chemical cross-linking assay demonstrated a single band of CRH receptor with a molecular weight of -77 kDa, which was inhibited in the presence of excess unlabeled rat/human CRH in a dose-dependent manner and inhibited by a CRH receptor antagonist astressin. Functional coupled cAMP production in cultured microglia was stimulated by exogenous addition of CRH and related peptides in a dose-dependent manner and blocked by astressin. Our findings suggest the functional expression of CRH-R1 receptor in rat microglia, indicating an important mechanism of interaction between immune and neuroendocrine systems in brain physiological and pathological conditions.