Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 14 de 14
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Ann Intern Med ; 176(1): 29-38, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36534976

RESUMEN

BACKGROUND: Older patients with advanced chronic kidney disease (CKD) face difficult decisions about managing kidney failure, frequently experiencing decisional conflict, regret, and treatment misaligned with preferences. OBJECTIVE: To assess whether a decision aid about kidney replacement therapy improved decisional quality compared with usual care. DESIGN: Multicenter, randomized, controlled trial. (ClinicalTrials.gov: NCT03522740). SETTING: 8 outpatient nephrology clinics associated with 4 U.S. centers. PARTICIPANTS: English-fluent patients, 70 years and older with nondialysis CKD stages 4 to 5 recruited from 2018 to 2020. INTERVENTION: DART (Decision-Aid for Renal Therapy) is an interactive, web-based decision aid for older adults with CKD. Both groups received written education about treatments. MEASUREMENTS: Change in the decisional conflict scale (DCS) score from baseline to 3, 6, 12, and 18 months. Secondary outcomes included change in prognostic and treatment knowledge and change in uncertainty. RESULTS: Among 400 participants, 363 were randomly assigned: 180 to usual care, 183 to DART. Decisional quality improved with DART with mean DCS declining compared with control (mean difference, -8.5 [95% CI, -12.0 to -5.0]; P < 0.001), with similar findings at 6 months, attenuating thereafter. At 3 months, knowledge improved with DART versus usual care (mean difference, 7.2 [CI, 3.7 to 10.7]; P < 0.001); similar findings at 6 months were modestly attenuated at 18 months (mean difference, 5.9 [CI, 1.4 to 10.3]; P = 0.010). Treatment preferences changed from 58% "unsure" at baseline to 28%, 20%, 23%, and 14% at 3, 6, 12, and 18 months, respectively, with DART, versus 51% to 38%, 35%, 32%, and 18% with usual care. LIMITATION: Latinx patients were underrepresented. CONCLUSION: DART improved decision quality and clarified treatment preferences among older adults with advanced CKD for 6 months after the DART intervention. PRIMARY FUNDING SOURCE: Patient-Centered Outcomes Research Institute (PCORI).


Asunto(s)
Técnicas de Apoyo para la Decisión , Insuficiencia Renal Crónica , Humanos , Anciano , Insuficiencia Renal Crónica/terapia , Pronóstico , Pacientes , Toma de Decisiones
2.
Am J Kidney Dis ; 80(5): 599-609, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35351579

RESUMEN

RATIONALE & OBJECTIVE: Older adults with advanced chronic kidney disease (CKD) face difficult decisions about dialysis initiation. Although shared decision making (SDM) can help align patient preferences and values with treatment options, the extent to which older patients with CKD experience SDM remains unknown. STUDY DESIGN: A cross-sectional analysis of patient surveys examining decisional readiness, treatment options education, care partner support, and SDM. SETTING & PARTICIPANTS: Adults aged 70 years or older from Boston, Chicago, San Diego, or Portland (Maine) with nondialysis advanced CKD. PREDICTORS: Decisional readiness factors, treatment options education, and care partner support. OUTCOMES: Primary: SDM measured by the 9-item Shared Decision Making Questionnaire (SDM-Q-9) instrument, with higher scores reflecting greater SDM. Exploratory: Factors associated with SDM. ANALYTICAL APPROACH: We used multivariable linear regression models to examine the associations between SDM and predictors, controlling for demographic and health factors. RESULTS: Among 350 participants, mean age was 78 ± 6 years, 58% were male, 13% identified as Black, and 48% had diabetes. Mean SDM-Q-9 score was 52 ± 28. SDM item agreement ranged from 41% of participants agreeing that "my doctor and I selected a treatment option together" to 73% agreeing that "my doctor told me that there are different options for treating my medical condition." In multivariable analysis adjusted for demographic characteristics, lower estimated glomerular filtration rate, and diabetes, being "well informed" and "very well informed" about kidney treatment options, having higher decisional certainty, and attendance at a kidney treatment options class were independently associated with higher SDM-Q-9 scores. LIMITATIONS: The cross-sectional study design limits the ability to make temporal associations between SDM and the predictors. CONCLUSIONS: Many older patients with CKD do not experience SDM when making dialysis decisions, emphasizing the need for greater access to and delivery of education for individuals with advanced CKD.


Asunto(s)
Toma de Decisiones Conjunta , Insuficiencia Renal Crónica , Humanos , Masculino , Anciano , Anciano de 80 o más Años , Femenino , Estudios Transversales , Insuficiencia Renal Crónica/terapia , Toma de Decisiones , Encuestas y Cuestionarios , Participación del Paciente
3.
Environ Res ; 196: 110320, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33098817

RESUMEN

BACKGROUND: Air pollution exposure is ubiquitous with demonstrated effects on morbidity and mortality. A growing literature suggests that prenatal air pollution exposure impacts neurodevelopment. We posit that the Environmental influences on Child Health Outcomes (ECHO) program will provide unique opportunities to fill critical knowledge gaps given the wide spatial and temporal variability of ECHO participants. OBJECTIVES: We briefly describe current methods for air pollution exposure assessment, summarize existing studies of air pollution and neurodevelopment, and synthesize this information as a basis for recommendations, or a blueprint, for evaluating air pollution effects on neurodevelopmental outcomes in ECHO. METHODS: We review peer-reviewed literature on prenatal air pollution exposure and neurodevelopmental outcomes, including autism spectrum disorder, attention deficit hyperactivity disorder, intelligence, general cognition, mood, and imaging measures. ECHO meta-data were compiled and evaluated to assess frequency of neurodevelopmental assessments and prenatal and infancy residential address locations. Cohort recruitment locations and enrollment years were summarized to examine potential spatial and temporal variation present in ECHO. DISCUSSION: While the literature provides compelling evidence that prenatal air pollution affects neurodevelopment, limitations in spatial and temporal exposure variation exist for current published studies. As >90% of the ECHO cohorts have collected a prenatal or infancy address, application of advanced geographic information systems-based models for common air pollutant exposures may be ideal to address limitations of published research. CONCLUSIONS: In ECHO we have the opportunity to pioneer unifying exposure assessment and evaluate effects across multiple periods of development and neurodevelopmental outcomes, setting the standard for evaluation of prenatal air pollution exposures with the goal of improving children's health.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Trastorno del Espectro Autista , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/estadística & datos numéricos , Niño , Salud Infantil , Exposición a Riesgos Ambientales/estadística & datos numéricos , Femenino , Humanos , Inteligencia , Material Particulado/análisis , Embarazo
4.
J Interprof Care ; 35(1): 46-54, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-31928247

RESUMEN

Building on trauma-informed care (TIC), Trauma and Violence-Informed Care (TVIC) aims to minimize re-traumatization for people who have previously experienced violence, support people currently experiencing violence and draw attention to structural violence. Previous research has not explored how health care providers understand TVIC nor studied either TIC or TVIC in primary health care (PHC). This analysis of the perspectives of fourteen PHC staff regarding the impacts of interprofessional TVIC education sessions was conducted as part of a larger study of an intervention to promote equity in PHC. Researchers drew on general clinic observations and observations of TVIC training sessions and analyzed in-depth interviews with PHC staff who took part in TVIC training, using an interpretive description approach. While the impacts varied, all participants described enhancements in their knowledge, awareness and/or confidence in providing care related to trauma and violence. Factors intrinsic to the process of educating staff, including providing staff with data on trauma and violence in the patient population, and supporting interprofessional discussions, influenced how participants understood, integrated, and prioritized TVIC. Importantly, structural, organizational, and personal contexts significantly influenced how participants enacted TVIC in practice. This study contributes knowledge about interprofessional TVIC education and how diverse professionals understand and enact TVIC concepts in PHC, pointing to the role of TVIC in challenging the biomedical paradigm in PHC and the difficulties of using a structural lens in clinical practice.


Asunto(s)
Educación Interprofesional , Relaciones Interprofesionales , Personal de Salud , Humanos , Atención Primaria de Salud , Violencia
5.
AIDS Behav ; 19(10): 1875-87, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26297567

RESUMEN

Though evidence shows that Mobile health (mHealth) interventions can improve adherence and viral load in HIV-positive persons, few have studied the health care providers' (HCP) perspective. We conducted a prospective mixed methods pilot study using the WelTel intervention wherein HIV-positive participants (n = 25) received weekly interactive text messages for 6 months. Text message response rate and topic data were collected to illustrate the HCP experience. The aim of this study is to explore intervention acceptability and feasibility from the HCP perspective through a baseline focus group and end of study interviews with HCP impacted by the intervention. Interview data were thematically coded using the Technology Acceptance Model. HCPs identified that the WelTel intervention engaged patients in building relationships, while organizing and streamlining existing mHealth efforts and dealing with privacy issues. HCPs recognized that although workload would augment initially, intervention benefits were many, and went beyond simply improving HIV viral load.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Actitud del Personal de Salud , Infecciones por VIH/tratamiento farmacológico , Personal de Salud/psicología , Cumplimiento de la Medicación , Envío de Mensajes de Texto , Adulto , Colombia Británica , Teléfono Celular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Relaciones Profesional-Paciente , Estudios Prospectivos , Sistemas Recordatorios , Telemedicina , Carga Viral
6.
BMJ Open ; 14(2): e080740, 2024 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-38326252

RESUMEN

INTRODUCTION: People who are dependent on opioids experience acute pain similar to other individuals. However, treating acute pain in these patients renders unique challenges such as opioid-induced hyperalgesia, opioid tolerance, withdrawal and stigma from healthcare providers. Thus, it is crucial to identify effective strategies for treating acute pain in this population and to highlight gaps in knowledge to create a high standard of care. The main objective of the proposed scoping review is to identify current strategies for treating the acute pain in individuals with opioid dependence or use disorder. METHODS AND ANALYSIS: MEDLINE via the PubMed interface, Embase and Cochrane Central, Web of Science: Conference Proceedings Citation Index and Google Scholar will be searched. Forward and backward citation searching of the final included studies will also be conducted. Two independent reviewers will screen the titles and abstracts of sources, review and assess relevant full-text studies and extract data. Data will be presented in a diagram and will contribute to a qualitative thematic analysis. ETHICS AND DISSEMINATION: Data will be gathered from publicly accessible sources, so ethics approval is not necessary. The results will be disseminated through a peer-reviewed journal and reported at conferences related to addiction medicine. TRIAL REGISTRATION NUMBER: 10.17605/OSF.IO/BG6SJ.


Asunto(s)
Dolor Agudo , Trastornos Relacionados con Opioides , Humanos , Analgésicos Opioides/uso terapéutico , Dolor Agudo/tratamiento farmacológico , Tolerancia a Medicamentos , Revisión por Pares , Proyectos de Investigación , Literatura de Revisión como Asunto
7.
Clin J Am Soc Nephrol ; 17(7): 957-965, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35672037

RESUMEN

BACKGROUND AND OBJECTIVES: Coronavirus disease 2019 (COVID-19) disrupted medical care across health care settings for older patients with advanced CKD. Understanding how shared decision making for kidney treatment decisions was influenced by the uncertainty of an evolving pandemic can provide insights for supporting shared decision making through the current and future public health crises. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed thematic and narrative analyses of semistructured interviews with patients (CKD stages 4 and 5, age 70+), care partners, and clinicians from Boston, Portland (Maine), San Diego, and Chicago from August to December 2020. RESULTS: We interviewed 76 participants (39 patients, 17 care partners, and 20 clinicians). Among patient participants, 13 (33%) patients identified as Black, and seven (18%) had initiated dialysis. Four themes with corresponding subthemes emerged related to treatment decision making and the COVID-19 pandemic: (1) adapting to changed educational and patient engagement practices (patient barriers to care and new opportunities for telemedicine); (2) reconceptualizing vulnerability (clinician awareness of illness severity increased and limited discussions of patient COVID-19 vulnerability); (3) embracing home-based dialysis but not conservative management (openness to home-based modalities and limited discussion of conservative management and advanced care planning); and (4) satisfaction and safety with treatment decisions despite conditions of uncertainty. CONCLUSIONS: Although clinicians perceived greater vulnerability among older patients CKD and more readily encouraged home-based modalities during the COVID-19 pandemic, their discussions of vulnerability, advance care planning, and conservative management remained limited, suggesting areas for improvement. Clinicians reported burnout caused by the pandemic, increased time demands, and workforce limitations, whereas patients remained satisfied with their treatment choices despite uncertainty. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Decision Aid for Renal Therapy (DART), NCT03522740.


Asunto(s)
COVID-19 , Fallo Renal Crónico , Anciano , Toma de Decisiones , Humanos , Riñón , Fallo Renal Crónico/terapia , Pandemias , Investigación Cualitativa , Incertidumbre
8.
JAMA Netw Open ; 4(12): e2137193, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34870680

RESUMEN

Importance: Telehealth has been posited as a cost-effective means for improving access to care for persons with chronic conditions, including kidney disease. Perceptions of telehealth among older patients with chronic illness, their care partners, and clinicians are largely unknown but are critical to successful telehealth use and expansion efforts. Objective: To identify patient, care partner, and nephrologists' perceptions of the patient-centeredness, benefits, drawbacks of telehealth compared to in-person visits. Design, Setting, and Participants: This qualitative study used semistructured interviews conducted from August to December 2020 with purposively sampled patients (aged 70 years or older, chronic kidney disease stages 4 to 5), care partners, and clinicians in Boston, Massachusetts; Chicago, Illinois; Portland, Maine; and San Diego, California. Main Outcomes and Measures: Participants described telehealth experiences, including factors contributing to and impeding engagement, satisfaction, and quality of care. Thematic analysis was used to analyze data. Results: Of 60 interviews, 19 (32%) were with clinicians, 30 (50%) with patients, and 11 (18%) with care partners; 16 clinicians (84%) were nephrologists; 17 patient participants (43%) were non-Hispanic Black, and 38 (67%) were women. Four overarching themes characterized telehealth's benefits and drawbacks for patient-centered care among older, chronically ill adults: inconsistent quality of care, patient experience and engagement, loss of connection and mistrust (eg, challenges discussing bad news), and disparities with accessing telehealth. Although telehealth improved convenience and care partner engagement, participants expressed concerns about clinical effectiveness and limitations of virtual physical examinations and potentially widening disparities in access. Many participants shared concerns about harms to the patient-clinician relationship, limited ability to comfort patients in virtual settings, and reduced patient trust. Conclusions and Relevance: Older patients, care partners, and kidney clinicians (ie, nephrologists and physician assistants) shared divergent views of patient-centered telehealth care, especially its clinical effectiveness, patient experience, access to care, and clinician-patient relationship. Understanding older patients' and kidney clinicians' perceptions of telehealth elucidate barriers that should be addressed to promote high-quality care and telehealth use.


Asunto(s)
Cuidadores/psicología , Fallo Renal Crónico/psicología , Fallo Renal Crónico/terapia , Participación del Paciente/psicología , Prioridad del Paciente/psicología , Anciano , Actitud del Personal de Salud , Comunicación , Toma de Decisiones , Femenino , Humanos , Masculino , Investigación Cualitativa , Telemedicina
9.
J Racial Ethn Health Disparities ; 7(1): 109-116, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31686369

RESUMEN

High stress is a public health issue in the United States (US), that disproportionately affects socially-marginalized group members, including racial and ethnic minorities and those of low socioeconomic status. While city governments have the potential to reduce stress exposure and health disparities through municipal policies, very little is known about factors that are associated with mayor officials' beliefs about stress as a determinant of disparities. This information is important because it can inform the design of interventions to educate city policymakers about evidence related to stress and health disparities. Using data from a 2016 survey of 230 mayor officials (101 mayors, 129 senior staff), multivariable logistic regression was used to determine the extent to which respondents' individual characteristics (e.g., ideology, highest level of education) and the characteristics of their city's population (e.g., percentage of residents non-white) were associated with their identification of stress as a factor that has a "very strong effect" on health disparities. Forty-four percent of respondents identified stress as having a very strong effect on health disparities. In the fully adjusted model, every percentage point increase in the proportion of a respondent's city population that was non-White increased the odds of identifying stress as having a very strong effect on health disparities by 2% [adjusted odds ratio (aOR) = 1.02; 95% CI = 1.00,1.04]. Interventions are needed to increase city policymakers' knowledge about the role of stress in the production of health disparities, which could, in turn, help cultivate political will for city policies that reduce disparities.


Asunto(s)
Actitud Frente a la Salud , Disparidades en el Estado de Salud , Gobierno Local , Grupos Minoritarios/psicología , Competencia Profesional/estadística & datos numéricos , Estrés Psicológico/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Grupos Minoritarios/estadística & datos numéricos , Pobreza/psicología , Pobreza/estadística & datos numéricos , Estados Unidos
10.
Mol Immunol ; 85: 185-195, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28282643

RESUMEN

Thymic cellularity is influenced by a variety of biological and environmental factors, such as age and stress; however, little is known about the molecular genetic mechanisms that regulate this process. Immediate early genes of the Early growth response (Egr) family have critical roles in immune function and response to environmental stress. The transcription factors, Egr1, Egr2 and Egr3, play roles in the thymus and in peripheral T-cell activation. Nab2, which binds Egrs 1, 2, and 3 as a co-regulator of transcription, also regulates peripheral T-cell activation. However, a role for Nab2 in the thymus has not been reported. Using Nab2-deficient (KO) mice we found that male Nab2KO mice have reduced thymus size and decreased numbers of thymocytes, compared with age-matched wildtype (WT) mice. Furthermore, the number of thymocytes in Nab2KO males decreases more rapidly with age. This effect is sex-dependent as female Nab2KO mice show neither reduced thymocyte numbers nor accelerated thymocyte loss with age, compared to female WT littermates. Since stress induces expression of Nab2 and the Egrs, we examined whether loss of Nab2 alters stress-induced decrease in thymic cellularity. Restraint stress induced a significant decrease in thymic cellularity in Nab2KO and WT mice, with significant changes in the thymocyte subset populations only in the Nab2KO mice. Stress reduced the percentage of DP cells by half and increased the percentage of CD4SP and CD8SP cells by roughly three-fold in Nab2KO mice. These findings indicate a requirement for Nab2 in maintaining thymocyte number in male mice with age and in response to stress.


Asunto(s)
Envejecimiento/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Represoras/metabolismo , Estrés Psicológico/metabolismo , Timo/patología , Envejecimiento/inmunología , Envejecimiento/patología , Animales , Femenino , Citometría de Flujo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Neoplasias/inmunología , Proteínas Represoras/inmunología , Restricción Física , Caracteres Sexuales , Estrés Psicológico/inmunología , Estrés Psicológico/patología , Timo/inmunología , Timo/metabolismo
11.
Emotion ; 16(6): 807-14, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27337681

RESUMEN

According to psychological models as well as common intuition, intense positive and negative situations evoke highly distinct emotional expressions. Nevertheless, recent work has shown that when judging isolated faces, the affective valence of winning and losing professional tennis players is hard to differentiate. However, expressions produced by professional athletes during publicly broadcasted sports events may be strategically controlled. To shed light on this matter we examined if ordinary people's spontaneous facial expressions evoked during highly intense situations are diagnostic for the situational valence. In Experiment 1 we compared reactions with highly intense positive situations (surprise soldier reunions) versus highly intense negative situations (terror attacks). In Experiment 2, we turned to children and compared facial reactions with highly positive situations (e.g., a child receiving a surprise trip to Disneyland) versus highly negative situations (e.g., a child discovering her parents ate up all her Halloween candy). The results demonstrate that facial expressions of both adults and children are often not diagnostic for the valence of the situation. These findings demonstrate the ambiguity of extreme facial expressions and highlight the importance of context in everyday emotion perception. (PsycINFO Database Record


Asunto(s)
Emociones/fisiología , Expresión Facial , Adulto , Femenino , Humanos , Masculino , Adulto Joven
12.
Soc Sci Med ; 58(4): 863-77, 2004 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-14672599

RESUMEN

This article addresses the question of whether literacy could be mediating the relationships of schooling to maternal health behavior in populations undergoing demographic transition. Recent studies in which literacy was directly assessed suggest a literacy pathway to demographic change. The literacy skills of 167 urban and rural mothers of school-aged children in Lalitpur District of the Kathmandu Valley of Nepal were assessed by tests of reading comprehension, academic language proficiency, health media skills and health narrative skill, as part of studies in the urban and rural communities that included a maternal interview and ethnographic fieldwork on the contexts of family life, health care and female schooling. Regression analysis of the data indicates the retention of literacy skills in adulthood and their influence on health behavior; ethnographic evidence shows that selective bias in school attainment does not account for the results. Further direct assessment studies are recommended.


Asunto(s)
Escolaridad , Conductas Relacionadas con la Salud , Conocimientos, Actitudes y Práctica en Salud , Conducta Materna/psicología , Madres/educación , Lectura , Sociología Médica , Adulto , Preescolar , Femenino , Conductas Relacionadas con la Salud/etnología , Transición de la Salud , Humanos , Masculino , Conducta Materna/etnología , Nepal , Dinámica Poblacional , Análisis de Regresión , Salud Rural/estadística & datos numéricos , Salud Urbana/estadística & datos numéricos
13.
J Assoc Nurses AIDS Care ; 25(6): 614-25, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24768442

RESUMEN

Patient engagement in care and adherence to medication are critical to achieving the full benefits of antiretroviral therapy (ART) among people with HIV infection. A randomized controlled trial in Kenya, WelTelKenya1, showed that an interactive mobile phone text-messaging intervention can improve adherence and viral load suppression. We conducted a pilot study to adapt the WelTel intervention for HIV-infected clients (n = 25) at an HIV clinic in Vancouver, British Columbia. Between April and June 2012, we recruited five participants from five groups: youth (14-24 years), mature (≥50 years), English as a second language, remote (≥3 hours travel time to clinic), and nonsuppressed (CD4+ T cell count <200 cells/mm(3) and viral load ≥250 copies/mL on two consecutive occasions). Participants described the intervention as a useful way to communicate with health care providers, thus increasing the ability to access services, report side effects, and attend appointments.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Teléfono Celular , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación , Adolescente , Adulto , Actitud Frente a la Salud , Linfocitos T CD4-Positivos , Canadá , Continuidad de la Atención al Paciente , Humanos , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Investigación Cualitativa , Sistemas Recordatorios , Envío de Mensajes de Texto , Adulto Joven
14.
Neuropsychopharmacology ; 37(10): 2285-98, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22692564

RESUMEN

The immediate-early gene early growth response 3 (Egr3) is associated with schizophrenia and expressed at reduced levels in postmortem patients' brains. We have previously reported that Egr3-deficient (Egr3(-/-)) mice display reduced sensitivity to the sedating effects of clozapine compared with wild-type (WT) littermates, paralleling the heightened tolerance of schizophrenia patients to antipsychotic side effects. In this study, we have used a pharmacological dissection approach to identify a neurotransmitter receptor defect in Egr3(-/-) mice that may mediate their resistance to the locomotor suppressive effects of clozapine. We report that this response is specific to second-generation antipsychotic agents (SGAs), as first-generation medications suppress the locomotor activity of Egr3(-/-) and WT mice to a similar degree. Further, in contrast to the leading theory that sedation by clozapine results from anti-histaminergic effects, we show that H1 histamine receptors are not responsible for this effect in C57BL/6 mice. Instead, selective serotonin 2A receptor (5HT(2A)R) antagonists ketanserin and MDL-11939 replicate the effect of SGAs, repressing the activity in WT mice at a dosage that fails to suppress the activity of Egr3(-/-) mice. Radioligand binding revealed nearly 70% reduction in 5HT(2A)R expression in the prefrontal cortex of Egr3(-/-) mice compared with controls. Egr3(-/-) mice also exhibit a decreased head-twitch response to 5HT(2A)R agonist 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI). These findings provide a mechanism to explain the reduced sensitivity of Egr3(-/-) mice to the locomotor suppressive effects of SGAs, and suggest that 5HT(2A)Rs may also contribute to the sedating properties of these medications in humans. Moreover, as the deficit in cortical 5HT(2A)R in Egr3(-/-) mice aligns with numerous studies reporting decreased 5HT(2A)R levels in the brains of schizophrenia patients, and the gene encoding the 5HT(2A)R is itself a leading schizophrenia candidate gene, these findings suggest a potential mechanism by which putative dysfunction in EGR3 in humans may influence risk for schizophrenia.


Asunto(s)
Proteína 3 de la Respuesta de Crecimiento Precoz/deficiencia , Proteína 3 de la Respuesta de Crecimiento Precoz/genética , Hipnóticos y Sedantes/metabolismo , Actividad Motora/efectos de los fármacos , Receptor de Serotonina 5-HT2A/metabolismo , Animales , Clozapina/farmacología , Modelos Animales de Enfermedad , Humanos , Ketanserina , Masculino , Ratones , Ratones Transgénicos , Piperidinas , Esquizofrenia/metabolismo , Agonistas del Receptor de Serotonina 5-HT2 , Antagonistas de la Serotonina/farmacología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA