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Importance: African American men experience greater prostate cancer incidence and mortality than White men. Growing literature supports associations of neighborhood disadvantage, which disproportionately affects African American men, with aggressive prostate cancer; chronic stress and downstream biological impacts (eg, increased inflammation) may contribute to these associations. Objective: To examine whether several neighborhood disadvantage metrics are associated with prostate tumor RNA expression of stress-related genes. Design, Setting, and Participants: This cross-sectional study leveraged prostate tumor transcriptomic data for African American and White men with prostate cancer who received radical prostatectomy at the University of Maryland Medical Center between August 1992 and January 2021. Data were analyzed from May 2023 to April 2024. Exposures: Using addresses at diagnosis, 2 neighborhood deprivation metrics (Area Deprivation Index [ADI] and validated bayesian Neighborhood Deprivation Index) as well as the Racial Isolation Index (RI) and historical redlining were applied to participants' addresses. Self-reported race was determined using electronic medical records. Main Outcomes and Measures: A total of 105 stress-related genes were evaluated with each neighborhood metric using linear regression, adjusting for race, age, and year of surgery. Genes in the Conserved Transcriptional Response to Adversity (CTRA) and stress-related signaling genes were included. Results: A total of 218 men (168 [77%] African American, 50 [23%] White) with a median (IQR) age of 58 (53-63) years were included. African American participants experienced greater neighborhood disadvantage than White participants (median [IQR] ADI, 115 [100-130] vs 92 [83-104]; median [IQR] RI, 0.68 [0.34-0.87] vs 0.11 [0.06-0.14]). ADI was positively associated with expression for 11 genes; HTR6 (serotonin pathway) remained significant after multiple-comparison adjustment (ß = 0.003; SE, 0.001; P < .001; Benjamini-Hochberg q value = .01). Several genes, including HTR6, were associated with multiple metrics. We observed higher expression of 5 proinflammatory genes in the CTRA with greater neighborhood disadvantage (eg, CXCL8 and ADI, ß = 0.008; SE, 0.003; P = .01; q value = .21). Conclusions and Relevance: In this cross-sectional study, the expression of several stress-related genes in prostate tumors was higher among men residing in disadvantaged neighborhoods. This study is one of the first to suggest associations of neighborhood disadvantage with prostate tumor RNA expression. Additional research is needed in larger studies to replicate findings and further investigate interrelationships of neighborhood factors, tumor biology, and aggressive prostate cancer to inform interventions to reduce disparities.
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Negro ou Afro-Americano , Neoplasias da Próstata , Brancos , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Negro ou Afro-Americano/estatística & dados numéricos , Negro ou Afro-Americano/genética , Estudos Transversais , Maryland/epidemiologia , Características da Vizinhança , Prostatectomia/estatística & dados numéricos , Neoplasias da Próstata/genética , Neoplasias da Próstata/cirurgia , Características de Residência/estatística & dados numéricos , Estresse Psicológico/genética , Brancos/genética , Brancos/estatística & dados numéricosRESUMO
BACKGROUND: Many adverse events are identified as nursing-sensitive indicators (NSIs) and have evidence-based care bundles known to reduce risk of occurrence. Kamishibai cards are a tool from the manufacturing industry used for practice auditing and improvements. Use of Kamishibai cards is believed to be common in the healthcare setting, but true evidence-based guidelines do not yet exist to guide their implementation. AIMS: The aim of this integrative review was to identify best practices around the implementation of Kamishibai cards in the healthcare setting for improvement in NSI-associated outcomes. METHODS: Eleven nurses at three facilities worked through the evidence using the Johns Hopkins Evidence-Based Practice Model. RESULTS: Ten articles were included for this review. Broad themes included direct observation with non-punitive and timely feedback, clearly visualized results, use of evidence-based care bundles, pre-implementation education, and both leadership and frontline-staff involvement. All facilities showed improvement in NSI-associated outcomes after the implementation of K-cards. LINKING ACTION TO ACTION: In health care, K-cards can be implemented and designed with additional focus on the bundles of care they are intended to audit and staff support, but further evidence would better define guidelines around implementation.
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Prática Clínica Baseada em Evidências , Humanos , Prática Clínica Baseada em Evidências/métodosRESUMO
BACKGROUND: Evidence-based practice is at the forefront of providing quality patient care by using the best available evidence and clinical expertise, while also considering patient needs and preferences for clinical decisions. However, evidence-based practice may not be consistently used even when the evidence supports the therapy. The purpose of this study was to assess the factors associated with the use of evidence-based practice among respiratory therapy faculty teaching in a large community college system and post-professional students enrolled in a university-based, respiratory therapy baccalaureate degree-advancement program. METHODS: A non-probability, descriptive survey research design was used to develop and administer an online questionnaire. RESULTS: All respondents demonstrated sufficient knowledge and understanding of introductory concepts of evidence-based practice but knowledge of specific components of the evidence-based practice process was not as strong. Self-efficacy in knowledge and the use of evidence-based practice among faculty and degree-advancement students varied. Faculty and students rated their self-efficacy high in assessing patients' needs, values, and treatment preferences but ratings were lower for using the PICO (patient/population/problem, intervention, comparison, outcome) technique and interpreting common statistical tests. Students viewed their previous evidence-based practice learning experiences more favorably compared with faculty (P = .008). Faculty and students searched and read the research literature more often compared with critically appraising and using the research literature. Logistic regression analysis indicated no statistically significant relationship of knowledge, self-efficacy, and learning experiences to the use of evidence-based practice among respiratory therapy students, Χ 2 (4, N = 54) = 7.73; P = .10. CONCLUSIONS: Analysis of the results suggested that respiratory therapy faculty and students were knowledgeable and confident with regard to evidence-based practice but their use of evidence-based practice in clinical decisions was limited. Although the evidence-based practice knowledge, self-efficacy, and learning experiences had minimal influence on the use of evidence-based practice, the results of the study provide a foundation for future research.
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Competência Clínica , Prática Clínica Baseada em Evidências , Conhecimentos, Atitudes e Prática em Saúde , Terapia Respiratória , Autoeficácia , Humanos , Terapia Respiratória/educação , Inquéritos e Questionários , Masculino , Feminino , Adulto , Competência Clínica/estatística & dados numéricos , Docentes/psicologiaRESUMO
Chronic pain often alternates between transient remission and relapse of severe pain. While most research on chronic pain has focused on mechanisms maintaining pain, there is a critical unmet need to understand what prevents pain from re-emerging in those who recover from acute pain. We found that interleukin (IL)-10, a pain resolving cytokine, is persistently produced by resident macrophages in the spinal meninges during remission from pain. IL-10 upregulated expression and analgesic activity of δ-opioid receptor (δOR) in the dorsal root ganglion. Genetic or pharmacological inhibition of IL-10 signaling or δOR triggered relapse to pain in both sexes. These data challenge the widespread assumption that remission of pain is simply a return to the naïve state before pain was induced. Instead, our findings strongly suggest a novel concept that: remission is a state of lasting pain vulnerability that results from a long-lasting neuroimmune interactions in the nociceptive system.
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Type 1 diabetes (T1D) is characterized by hyperphagia, hyperglycemia and activation of the hypothalamic-pituitary-adrenal (HPA) axis. We have reported previously that daily leptin injections help to alleviate these symptoms. Therefore, we hypothesized that leptin gene therapy could help to normalize the neuroendocrine dysfunction seen in T1D. Adult male Sprague Dawley rats were injected i.v. with a lentiviral vector containing the leptin gene or green fluorescent protein. Ten days later, they were injected with the vehicle or streptozotocin (STZ). HPA function was assessed by measuring norepinephrine (NE) levels in the paraventricular nucleus (PVN) and serum corticosterone (CS). Treatment with the leptin lentiviral vector (Lepvv) increased leptin and insulin levels in non-diabetic rats, but not in diabetic animals. There was a significant reduction in blood glucose levels in diabetic rats due to Lepvv treatment. Both NE levels in the PVN and serum CS were reduced in diabetic rats treated with Lepvv. Results from this study provide evidence that leptin gene therapy in STZ-induced diabetic rats was able to partially normalize some of the neuroendocrine abnormalities, but studies with higher doses of the Lepvv are needed to develop this into a viable option for treating T1D.
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Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Vetores Genéticos/administração & dosagem , Leptina/genética , Animais , Corticosterona/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animais de Doenças , Terapia Genética , Injeções Intravenosas , Lentivirus/genética , Masculino , Norepinefrina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: With a large incarcerated patient population in the United States, there is a unique potential for clinical learning for undergraduate nursing students with this population. METHOD: The Virginia Commonwealth University (VCU) School of Nursing and VCU Health System have created a unique partnership in which baccalaureate nursing students complete their first clinical rotation on VCU Health System's Secure Care Unit (SCU). At the conclusion of their semester, baccalaureate students assigned to the SCU for the fundamentals clinical were asked to provide feedback on their experiences. RESULTS: Both challenges and positive outcomes were identified by students who completed their first clinical rotation providing care to this unique population. CONCLUSION: The formation of this relationship between the VCU School of Nursing and the VCU Health System's SCU is helping to meet patient, student, and clinical unit needs and also making a positive impact on the stakeholders involved. [J Nurs Educ. 2021;60(8):470-471.].
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Bacharelado em Enfermagem , Estudantes de Enfermagem , Atenção à Saúde , Humanos , Aprendizagem , Estados Unidos , UniversidadesRESUMO
Nursing students must gain experience collaborating with other members of the health-care team. Simulation can provide intra- and interprofessional collaboration experience; however, there can be barriers such as scheduling difficulties. We evaluated multi-patient, standardized patient simulations using telehealth as a strategy to provide baccalaureate nursing students with opportunities to learn and practice intra- and interprofessional collaboration. Forty-four final-semester nursing students participated. Student groups rotated to the simulation laboratory over 12 weeks to participate in two simulations that used telehealth to enable them to communicate patient concerns to other clinicians: a nurse practitioner, respiratory therapists, and social workers. Self-reported collaborative competencies and amount of collaboration in the clinical setting were measured at the start and end of the semester. Satisfaction and self-confidence were measured immediately after each simulation. For collaborative competencies, there was a statistically significant improvement in all item, subscale, and overall scale mean scores. Amount of clinical collaboration significantly improved, with the amount who indicated they never reported a patient concern to another professional decreasing from 39.5% to 6.8%. Findings also revealed a high level of student satisfaction and self-confidence following the simulations. Using telehealth to collaborate during simulations is a promising strategy to prepare nursing students for practice by improving collaborative competencies and encouraging more collaboration in the clinical setting.
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Estudantes de Enfermagem , Telemedicina , Humanos , Relações Interprofissionais , Equipe de Assistência ao Paciente , Simulação de PacienteRESUMO
Increasing evidence suggests a role of epigenetic mechanisms at chromosome 8q24, an important cancer genetic susceptibility region, in prostate cancer. We investigated whether MYC DNA methylation at 8q24 (six CpG sites from exon 3 to the 3' UTR) in prostate tumor was associated with tumor aggressiveness (based on Gleason score, GS), and we incorporated RNA expression data to investigate the function. We accessed radical prostatectomy tissue for 50 Caucasian and 50 African American prostate cancer patients at the University of Maryland Medical Center, selecting an equal number of GS 6 and GS 7 cases per group. MYC DNA methylation was lower in tumor than paired normal prostate tissue for all six CpG sites (median difference: -14.74 to -0.20 percentage points), and we observed similar results for two nearby sites in The Cancer Genome Atlas (p < 0.0001). We observed significantly lower methylation for more aggressive (GS 7) than less aggressive (GS 6) tumors for three exon 3 sites (for CpG 212 (chr8:128753145), GS 6 median = 89.7%; GS 7 median = 85.8%; p-value = 9.4 × 10-4). MYC DNA methylation was not associated with MYC expression, but was inversely associated with PRNCR1 expression after multiple comparison adjustment (q-value = 0.04). Findings suggest that prostate tumor MYC exon 3 hypomethylation is associated with increased aggressiveness.
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Biomarcadores Tumorais/genética , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Estudos de Coortes , Ilhas de CpG/genética , Metilação de DNA , Epigênese Genética , Éxons/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , RNA Longo não Codificante/genéticaRESUMO
BACKGROUND: Nurse faculty must utilize teaching strategies that promote student achievement of essential competencies, and simulation can provide experiential learning to help prepare students for professional practice. PURPOSE: The purpose of this phenomenological qualitative study was to explore baccalaureate nursing students' experiences with multi-patient, standardized patient simulations that used telehealth to provide opportunities to learn and practice intra- and interprofessional collaboration. Student perceptions of their ability to utilize lessons from the simulations in clinical practice were also examined. METHODS: Focus group interviews were conducted with 27 final-semester baccalaureate nursing students after they had participated in two telehealth-enhanced simulations. RESULTS: Analysis revealed five themes: Anxiety due to lack of experience, Improved clinical reasoning, Real world practice, How to communicate effectively, and Application to clinical practice. CONCLUSION: The use of telehealth helped overcome barriers to implementing collaborative simulations and provided students with experiential learning that addressed essential competencies for safe and effective professional nursing practice.
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Bacharelado em Enfermagem , Estudantes de Enfermagem , Telemedicina , Competência Clínica , Humanos , Simulação de Paciente , Aprendizagem Baseada em ProblemasRESUMO
Ventilator graphic monitoring is common in ICUs. The graphic information provides clinicians with immediate clues regarding patient-ventilator interaction and ventilator function. These display tools are aimed at reducing complications associated with mechanical ventilation, such as patient-ventilator asynchrony. It is also useful to assess respiratory mechanics in mechanically ventilated patients using both scalar and plot displays on the ventilator. Additional information can be gained by observing secondary ventilator measures including stress index, inflection points, and work of breathing. Ventilator graphics impact mechanical ventilation management through optimizing effectiveness of patient care and enhancing promptness of clinician response. Despite being a valuable asset in providing high-quality patient care, many bedside clinicians do not have a thorough understanding of ventilator graphics. Mastery of ventilator graphics interpretation is key in managing patients who are receiving ventilatory support.
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Mecânica Respiratória , Ventiladores Mecânicos , Humanos , Unidades de Terapia Intensiva , Monitorização Fisiológica , Respiração Artificial , Fenômenos Fisiológicos RespiratóriosRESUMO
OBJECTIVE: To assess the effect of healthy or unhealthy food brands on consumer ratings of a food's perceived healthfulness, caloric content, and estimated price. METHODS: Using a crossover design, 35 adults aged 18-25 years scored a variety of healthy and unhealthy foods paired with "healthy" or "unhealthy" brands or with no brand present, on their healthfulness, caloric content, and estimated price. For each outcome measure, ANOVA was used to evaluate the effect of brand condition on healthy and unhealthy foods. RESULTS: Pairing an unhealthy food with a "healthy brand" led to increased ratings of healthfulness (P < .001), decreased estimates of caloric content (P < .001), and increased price (P < .001). Pairing a healthy food with an "unhealthy brand" led to decreased ratings of healthfulness (P < .001), increased estimates of caloric content (P < .001), and decreased price (P < .001). CONCLUSIONS AND IMPLICATIONS: These findings extend previous research showing that brands may influence perceptions of food products. Future studies are needed to understand the implications of pairing healthy foods with "unhealthy brands" on actual food intake.
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Preferências Alimentares/psicologia , Alimentos/classificação , Marketing , Adolescente , Adulto , Estudos Cross-Over , Dieta Saudável , Indústria Alimentícia , Humanos , Valor Nutritivo , Adulto JovemRESUMO
Type I Diabetes (T1D) is associated with reduced leptin levels and increased stress axis activity marked by elevations in norepinephrine (NE) levels in the paraventricular nucleus (PVN) of the hypothalamus. We hypothesized that leptin suppresses stress axis activity in T1D through central and peripheral mechanisms. In the first experiment, adult male Sprague Dawley rats were implanted with a cannula in the PVN and randomly divided into a non-diabetic group treated with vehicle (nâ¯=â¯6) and a diabetic group treated with streptozotocin (nâ¯=â¯13). Food intake and water intake was measured for 14â¯days. On the last day, a subset of diabetic rats were treated with 500⯵g of leptin i.p. Rats were subjected to push-pull perfusion of the PVN and hourly blood sampling for 5â¯h. In the next experiment, diabetic rats were treated either with an alpha-2 adrenergic agonist, clonidine (CLON), or a beta adrenergic agonist isoproterenol (ISO), to reverse the effects of leptin. Rats were subjected to push pull perfusion and hourly blood sampling. In experiment 1, T1D increased food intake, water intake, NE release in the PVN and circulating CS levels. Leptin treatment decreased NE release modestly but produced a robust reduction in corticosterone (CS) levels. In experiment 2, CLON but not ISO was able to reverse the effect of leptin on NE levels in the PVN, however, both agonists were capable of blocking leptin's effects on circulating CS. These results suggest that in diabetic rats, the sensitivity of the hypothalamus to beta adrenergic agonists is altered, while the adrenals remain sensitive to both alpha and beta adrenergic agonists.
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Leptina/metabolismo , Norepinefrina/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Agonistas Adrenérgicos/metabolismo , Agonistas alfa-Adrenérgicos/metabolismo , Animais , Clonidina/farmacologia , Corticosterona/análise , Corticosterona/sangue , Diabetes Mellitus Experimental/fisiopatologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Isoproterenol/farmacologia , Leptina/fisiologia , Masculino , Norepinefrina/fisiologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Polymodal thermo- and mechanosensitive two-pore domain potassium (K2P) channels of the TREK subfamily generate 'leak' currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses. These dimeric voltage-gated ion channel (VGIC) superfamily members have a unique topology comprising two pore-forming regions per subunit. In contrast to other potassium channels, K2P channels use a selectivity filter 'C-type' gate as the principal gating site. Despite recent advances, poor pharmacological profiles of K2P channels limit mechanistic and biological studies. Here we describe a class of small-molecule TREK activators that directly stimulate the C-type gate by acting as molecular wedges that restrict interdomain interface movement behind the selectivity filter. Structures of K2P2.1 (also known as TREK-1) alone and with two selective K2P2.1 (TREK-1) and K2P10.1 (TREK-2) activators-an N-aryl-sulfonamide, ML335, and a thiophene-carboxamide, ML402-define a cryptic binding pocket unlike other ion channel small-molecule binding sites and, together with functional studies, identify a cation-π interaction that controls selectivity. Together, our data reveal a druggable K2P site that stabilizes the C-type gate 'leak mode' and provide direct evidence for K2P selectivity filter gating.
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Canais de Potássio de Domínios Poros em Tandem/agonistas , Canais de Potássio de Domínios Poros em Tandem/química , Animais , Ácido Araquidônico/química , Ácido Araquidônico/metabolismo , Ácido Araquidônico/farmacologia , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Células HEK293 , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Lipídeos , Camundongos , Modelos Moleculares , Pichia , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Conformação Proteica/efeitos dos fármacos , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Tiofenos/química , Tiofenos/metabolismo , Tiofenos/farmacologia , Xenopus laevisRESUMO
Objective. To assess the impact of an advanced cardiac life support (ACLS) simulation on pharmacy student confidence and knowledge. Design. Third-year pharmacy students participated in a simulation experience that consisted of team roles training, high-fidelity ACLS simulations, and debriefing. Students completed a pre/postsimulation confidence and knowledge assessment. Assessment. Overall, student knowledge assessment scores and student confidence scores improved significantly. Student confidence and knowledge changes from baseline were not significantly correlated. Conversely, a significant, weak positive correlation between presimulation studying and both presimulation confidence and presimulation knowledge was discovered. Conclusions. Overall, student confidence and knowledge assessment scores in ACLS significantly improved from baseline; however, student confidence and knowledge were not significantly correlated.
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Suporte Vital Cardíaco Avançado/educação , Estudantes de Farmácia , Adulto , Competência Clínica , Simulação por Computador , Avaliação Educacional , Feminino , Humanos , Conhecimento , Masculino , Manequins , Adulto JovemRESUMO
BACKGROUND: Chronic exposure to estradiol-17ß (E2) in adult female rats increases mean arterial pressure by stimulating superoxide production in the rostral ventrolateral medulla (RVLM). However the mechanisms behind this phenomenon are unknown. We hypothesized that E2 exposure induces the gene expression of cytokines, chemokines and NADPH oxidase (Nox) in the RVLM that promotes superoxide production and aging would exacerbate this effect. METHODS: Young adult (3-4 month old) and middle-aged (6-8 month old) female Sprague Dawley rats were sham-implanted (YS and MS respectively) or implanted s.c. with slow-release E2 pellets (20 ng of E2/day for 90 days; YE and ME respectively). Blood pressure (BP) was measured during the last 3 weeks of exposure in a separate set of rats. At the end of treatment, the animals were sacrificed and RVLM was isolated from the brainstem. PCR array and Quantitative RT-PCR were performed with the tissue to quantify genes associated with hypertension and superoxide production. Superoxide dismutase (SOD) activity was also measured in the RVLM from a different set of animals. RESULTS: E2 exposure increased mean arterial pressure in both YE and ME animals. Inflammatory genes such as interleukin-1ß, interleukin-6 and monocyte chemoattractant protein-1 were significantly up-regulated in the RVLM of ME treated female rats compared to YS rats, but not in YE rats. Endothelin-1 (ET-1) gene was up-regulated in the RVLM of both YE and ME rats that were exposed to E2. Furthermore, chronic E2 treatment increased the mRNA levels of Nox1 and Nox2 genes in the RVLM of YE but not ME animals. SOD activity was reduced in MA animals, compared to young animals. E2 treatment had no significant effect on SOD activity. CONCLUSION: Chronic E2 exposure stimulates the expression of inflammatory genes in older animals and increases the expression of Nox subunits in the RVLM of younger animals. SOD activity was reduced in older animals. This suggests increased superoxide production in younger animals, but reduced superoxide elimination in older animals. On the other hand, E2 exposure stimulates ET-1 expression in both young and aging animals. These findings suggest that hypertension caused by chronic E2 exposure may involve different molecular mediators in young and aging animals, however ET-1 and superoxide could be common mediators for both age groups.
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Envelhecimento , Citocinas/metabolismo , Estradiol/farmacologia , Estrogênios/farmacologia , Expressão Gênica/efeitos dos fármacos , Bulbo/efeitos dos fármacos , Análise de Variância , Animais , Pressão Sanguínea/efeitos dos fármacos , Citocinas/genética , Endotelinas/genética , Endotelinas/metabolismo , Feminino , NADP/genética , NADP/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: No evaluation of sex and race influences on mycophenolic acid (MPA) pharmacokinetics and adverse effects (AEs) during enteric-coated mycophenolate sodium (ECMPS) and tacrolimus immunosuppression are available. The primary objective of this study was to investigate the influence of sex and race on MPA and MPA glucuronide (MPAG) pharmacokinetics in stable renal transplant recipients receiving ECMPS and tacrolimus METHODS: The pharmacokinetics of MPA and MPAG and their associated gastrointestinal AEs were investigated in 67 stable renal transplant recipients: 22 African American males (AAMs), 13 African American females (AAFs), 16 Caucasian males (CMs), and 16 Caucasian females (CFs) receiving ECMPS and tacrolimus. A validated gastrointestinal AE rating included diarrhea, dyspepsia, vomiting, and acid-suppressive therapy was completed. Apparent clearance, clearance normalized to body mass index (BMI), area under the concentration-time curve from time zero to 12 h (AUC12) and dose-normalized AUC12 (AUC*) were determined using a statistical model that incorporated gastrointestinal AE and clinical covariates. RESULTS: Males had more rapid apparent MPA clearance (CMs 13.8 ± 6.27 L/h vs. AAMs 10.2 ± 3.73 L/h) than females (CFs 8.70 ± 3.33 L/h and AAFs 9.71 ± 3.94 L/h; p = 0.014) with a race-sex interaction (p = 0.043). Sex differences were observed in MPA clearance/BMI (p = 0.033) and AUC* (p = 0.033). MPA AUC12 was greater than 60 mg·h/L in 57 % of renal transplant recipients (RTR) with 71 % of patients demonstrating gastrointestinal AEs and a higher score noted in females. In all patients, females exhibited 1.40-fold increased gastrointestinal AE scores compared with males (p = 0.024). Race (p = 0.044) and sex (p = 0.005) differences were evident with greater MPAG AUC12 in AAFs and CFs. CONCLUSION: Sex and race differences were evident, with females having slower MPA clearance, higher MPAG AUC12, and more severe gastrointestinal AEs. These findings suggest sex and race should be considered during MPA immunosuppression.
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Negro ou Afro-Americano , Glucuronídeos/farmacocinética , Transplante de Rim , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacocinética , Tacrolimo/administração & dosagem , População Branca , Adulto , Idoso , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacocinética , Estudos Transversais , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Glucuronídeos/efeitos adversos , Humanos , Imunossupressores/administração & dosagem , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Fatores Sexuais , TransplantadosRESUMO
Mechanical and thermal activation of ion channels is central to touch, thermosensation, and pain. The TRAAK/TREK K(2P) potassium channel subfamily produces background currents that alter neuronal excitability in response to pressure, temperature, signaling lipids, and anesthetics. How such diverse stimuli control channel function is unclear. Here we report structures of K(2P)4.1 (TRAAK) bearing C-type gate-activating mutations that reveal a tilting and straightening of the M4 inner transmembrane helix and a buckling of the M2 transmembrane helix. These conformational changes move M4 in a direction opposite to that in classical potassium channel activation mechanisms and open a passage lateral to the pore that faces the lipid bilayer inner leaflet. Together, our findings uncover a unique aspect of K(2P) modulation, indicate a means for how the K(2P) C-terminal cytoplasmic domain affects the C-type gate which lies â¼40Å away, and suggest how lipids and bilayer inner leaflet deformations may gate the channel.
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Membrana Celular/química , Membrana Celular/metabolismo , Ativação do Canal Iônico/fisiologia , Canais de Potássio/química , Canais de Potássio/metabolismo , Temperatura , Animais , Células Cultivadas , Bicamadas Lipídicas/metabolismo , Mutação , Oócitos , Estimulação Física , Canais de Potássio/genética , Estrutura Secundária de Proteína , Xenopus laevisRESUMO
Use of randomized peptide libraries to evolve molecules with new functions provides a means for developing novel regulators of protein activity. Despite the demonstrated power of such approaches for soluble targets, application of this strategy to membrane systems, such as ion channels, remains challenging. Here, we have combined libraries of a tethered protein scaffold with functional selection in yeast to develop a novel activator of the G-protein-coupled mammalian inwardly rectifying potassium channel Kir3.2 (GIRK2). We show that the novel regulator, denoted N5, increases Kir3.2 (GIRK2) basal activity by inhibiting clearance of the channel from the cellular surface rather than affecting the core biophysical properties of the channel. These studies establish the tethered protein display strategy as a means to create new channel modulators and highlight the power of approaches that couple randomized libraries with direct selections for functional effects. Our results further underscore the possibility for the development of modulators that influence channel function by altering cell surface expression densities rather than by direct action on channel biophysical parameters. The use of tethered library selection strategies coupled with functional selection bypasses the need for a purified target and is likely to be applicable to a range of membrane protein systems.
Assuntos
Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Animais , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Regulação da Expressão Gênica , Ativação do Canal Iônico/efeitos dos fármacos , Ativação do Canal Iônico/genética , Camundongos , Microinjeções , Oócitos , Técnicas de Patch-Clamp , Biblioteca de Peptídeos , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Transporte Proteico , Xenopus laevisRESUMO
BACKGROUND: Medication errors are common upon hospital admission. Clinical pharmacist involvement in medication reconciliation is effective in identifying and rectifying medication errors. However, data is lacking on the economic impact, time requirements, and severity of errors resolved by clinical pharmacists. OBJECTIVE: To determine the incidence of unintended admission medication discrepancies resolved by clinical pharmacists. Secondary objectives were to determine the type of discrepancies, potential severity, proximal cause, and economic impact of this clinical pharmacy program. METHODS: This was a single-center, prospective, observational study conducted at a major teaching medical institution. Following institutional review board approval, data collection was conducted over a 4-week period (August 22, 2011, to September 16, 2011). Descriptive statistical methods were performed for all data analyses. RESULTS: A total of 517 patients involving 5006 medications were included in this study. More than 25% (n = 132) of patients had at least 1 error associated with a medication ordered on hospital admission. Pharmacists resolved a total of 467 admission medication errors (3.5 ± 2.3 errors/patient). The most common type of medication error resolved was medication omission (79.6%). In regard to severity, 46% of medication errors were considered significant or serious. Overall, the mean total time was 44.4 ± 21.8 minutes per medication reconciliation. This clinical pharmacy program was estimated to carry a net present value of $5.7 million over 5 years. CONCLUSION: Clinical pharmacist involvement within a multidisciplinary health care team during the admission medication reconciliation process demonstrated a significant improvement in patient safety and an economic benefit.