RESUMO
PURPOSE: Black birthing parents and their newborns disproportionately experience newborn drug testing for prenatal substance exposure by health care professionals (HCPs), which contributes to Child Protective Services (CPS) reporting, family separation, and termination of parental rights. This qualitative study aims to interrogate dominant power structures by exploring knowledge, attitudes, and experiences of HCPs and CPS professionals regarding the influence of structural racism on inequities in newborn drug testing practices. METHODS: We conducted semistructured interviews with 30 physicians, midwives, nurses, social workers, and CPS professionals guided by an explanatory framework, and conducted inductive, reflexive thematic analysis. RESULTS: We identified 3 primary themes: (1) levels of racism beyond the hospital structure contributed to higher rates of drug testing for Black newborns; (2) inconsistent hospital policies led to racialized application of state law and downstream CPS reporting; and (3) health care professionals knowledge of the benefits and disproportionate harms of CPS reporting on Black families influenced their decision making. CONCLUSION: Health care professionals recognized structural racism as a driver of disproportionate newborn drug testing. Lack of knowledge and skill limitations of HCPs were barriers to dismantling power structures, thus impeding systems-level change. Institutional changes should shift focus from biologic testing and reporting to supporting the mutual needs of birthing parent and child through family-centered substance use treatment. State and federal policy changes are needed to ensure health equity for Black families and eliminate reporting to CPS for prenatal substance exposure when no concern for child abuse and neglect exists.
Assuntos
Negro ou Afro-Americano , Serviços de Proteção Infantil , Triagem Neonatal , Detecção do Abuso de Substâncias , Feminino , Humanos , Recém-Nascido , Gravidez , Atitude do Pessoal de Saúde , Pessoal de Saúde/psicologia , Triagem Neonatal/normas , Pesquisa Qualitativa , Racismo , Detecção do Abuso de Substâncias/normas , Racismo Sistêmico/prevenção & controleRESUMO
The Disrupted in Schizophrenia 1 (DISC1) gene is disrupted by a balanced chromosomal translocation (1; 11) (q42; q14.3) in a Scottish family with a high incidence of major depression, schizophrenia, and bipolar disorder. Subsequent studies provided indications that DISC1 plays a role in brain development. Here, we demonstrate that suppression of DISC1 expression reduces neural progenitor proliferation, leading to premature cell cycle exit and differentiation. Several lines of evidence suggest that DISC1 mediates this function by regulating GSK3beta. First, DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. Importantly, expression of stabilized beta-catenin overrides the impairment of progenitor proliferation caused by DISC1 loss of function. Furthermore, GSK3 inhibitors normalize progenitor proliferation and behavioral defects caused by DISC1 loss of function. Together, these results implicate DISC1 in GSK3beta/beta-catenin signaling pathways and provide a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders.
Assuntos
Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurogênese , Transdução de Sinais , beta Catenina/metabolismo , Células-Tronco Adultas/citologia , Células-Tronco Adultas/metabolismo , Animais , Encéfalo/citologia , Encéfalo/embriologia , Embrião de Mamíferos/metabolismo , Técnicas de Silenciamento de Genes , Glicogênio Sintase Quinase 3 beta , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismoRESUMO
Many patients with opioid use disorders do not receive evidence-based treatment. The COVID-19 pandemic expanded the use of telehealth for prescribing medications for opioid use disorder (OUD). The uptake of telehealth has been variable, and this uneven expansion has created natural experiments to test assumptions and answer key questions about what improves outcomes for patients with OUD. Many current quality of care measures are not patient centered and do not focus on the practical questions that clinicians face. What criteria should be met before prescribing buprenorphine? Are physical exams necessary? Does the frequency and type of drug testing predict clinical outcomes? Are short check-in visits by phone or video better than less frequent in-person visits? Answering these questions can help define the essential components of high-quality care for patients with OUD. Defining the features of high-quality care can help create guardrails that will help protect our patients from potentially exploitive and ineffective care. Telehealth will likely end up being one additional tool to deliver care, but the scientific questions that can be answered during this period of rapid change can help answer some of the fundamental questions about providing high-quality care-and that will help all our patients, no matter how care is delivered.
Assuntos
Buprenorfina , COVID-19 , Transtornos Relacionados ao Uso de Opioides , Telemedicina , Buprenorfina/uso terapêutico , Humanos , Tratamento de Substituição de Opiáceos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , PandemiasRESUMO
Obesity and type 2 diabetes mellitus are risk factors for hypertension, coronary heart disease, cardiac arrhythmias including atrial fibrillation, heart failure and sudden cardiac death. The effects of obesity and diabesity on heart rhythm were investigated in the Zucker diabetic fatty (ZDF) and Zucker fatty (ZF) compared to the Zucker lean (ZL) control rat. In vivo biotelemetry techniques were used to assess the electrocardiogram and other cardiac and metabolic parameters. ZDF rats were characterized by age-dependent elevations in fasting and non-fasting blood glucose, glucose intolerance and weight gain and ZF rats were characterized by smaller elevations in fasting and non-fasting blood glucose and greater weight gain compared to ZL rats. Heart rate (HR) was progressively reduced in ZDF, ZF and ZL rats. At 195 days (6.5 months) of age there were significant differences in HR between ZDF (265 ± 8 bpm, n = 10), ZF (336 ± 9 bpm, n = 10) and ZL (336 ± 10 bpm, n = 10) rats and significant differences in HRV between ZDF (22 ± 1 bpm, n = 10), ZF (27 ± 1 bpm, n = 10) and ZL (31 ± 1 bpm, n = 10) rats. Power spectral analysis revealed no significant (P > 0.05) differences in HRV at low frequencies, reduced HRV at high frequencies and increased sympathovagal balance in ZDF compared to ZF and ZL rats. HR was reduced by ageing and additionally reduced by diabesity in the absence of changes in physical activity and body temperature. Reductions in HRV associated with altered sympathovagal drive might partly underlie disturbed HR in the ZDF rat. Possible explanations for reduced HR and future mechanistic studies are discussed.
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Diabetes Mellitus Tipo 2 , Animais , Insulina , Masculino , Obesidade , RatosRESUMO
Diabetes mellitus (DM) is a major and worsening global health problem, currently affecting over 450 million people and reducing their quality of life. Type 2 diabetes mellitus (T2DM) accounts for more than 90% of DM and the global epidemic of obesity, which largely explains the dramatic increase in the incidence and prevalence of T2DM in the past 20 years. Obesity is a major risk factor for DM which is a major cause of morbidity and mortality in diabetic patients. The electro-mechanical function of the heart is frequently compromised in diabetic patients. The aim of this review is to discuss the pathophysiology of electro-mechanical dysfunction in the diabetic heart and in particular, the Zucker diabetic fatty (ZDF) rat heart, a well-studied model of T2DM and obesity.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/fisiopatologia , Coração/fisiopatologia , Obesidade/fisiopatologia , Animais , Ratos , Ratos ZuckerRESUMO
Mitosis entails global alterations to chromosome structure and nuclear architecture, concomitant with transient silencing of transcription. How cells transmit transcriptional states through mitosis remains incompletely understood. While many nuclear factors dissociate from mitotic chromosomes, the observation that certain nuclear factors and chromatin features remain associated with individual loci during mitosis originated the hypothesis that such mitotically retained molecular signatures could provide transcriptional memory through mitosis. To understand the role of chromatin structure in mitotic memory, we performed the first genome-wide comparison of DNase I sensitivity of chromatin in mitosis and interphase, using a murine erythroblast model. Despite chromosome condensation during mitosis visible by microscopy, the landscape of chromatin accessibility at the macromolecular level is largely unaltered. However, mitotic chromatin accessibility is locally dynamic, with individual loci maintaining none, some, or all of their interphase accessibility. Mitotic reduction in accessibility occurs primarily within narrow, highly DNase hypersensitive sites that frequently coincide with transcription factor binding sites, whereas broader domains of moderate accessibility tend to be more stable. In mitosis, proximal promoters generally maintain their accessibility more strongly, whereas distal regulatory elements tend to lose accessibility. Large domains of DNA hypomethylation mark a subset of promoters that retain accessibility during mitosis and across many cell types in interphase. Erythroid transcription factor GATA1 exerts site-specific changes in interphase accessibility that are most pronounced at distal regulatory elements, but has little influence on mitotic accessibility. We conclude that features of open chromatin are remarkably stable through mitosis, but are modulated at the level of individual genes and regulatory elements.
Assuntos
Montagem e Desmontagem da Cromatina , Cromossomos , Genoma , Mitose/genética , Animais , Sítios de Ligação , Ciclo Celular/genética , Diferenciação Celular/genética , Imunoprecipitação da Cromatina , Biologia Computacional , Metilação de DNA , Desoxirribonuclease I/metabolismo , Células Eritroides/citologia , Células Eritroides/metabolismo , Fator de Transcrição GATA1/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Interfase/genética , Camundongos , Mitose/efeitos dos fármacos , Regiões Promotoras Genéticas , Ligação Proteica , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/metabolismo , Transcrição GênicaRESUMO
Effects of curcumin, a major ingredient of turmeric, were tested on the function of the α7-subunit of the human nicotinic acetylcholine (α7-nACh) receptor expressed in Xenopus oocytes and on nociception in mouse models of tonic and visceral pain. Curcumin caused a significant potentiation of currents induced by acetylcholine (ACh; 100 µM) with an EC50 value of 0.2 µM. The effect of curcumin was not dependent on the activation of G-proteins and protein kinases and did not involve Ca2+-dependent Cl- channels expressed endogenously in oocytes. Importantly, the extent of curcumin potentiation was enhanced significantly by decreasing ACh concentrations. Curcumin did not alter specific binding of [125I]α-bungarotoxin. In addition, curcumin attenuated nociceptive behavior in both tonic and visceral pain models without affecting motor and locomotor activity and without producing tolerance. Pharmacological and genetic approaches revealed that the antinociceptive effect of curcumin was mediated by α7-nACh receptors. Curcumin potentiated the antinociceptive effects of the α7-nACh receptor agonist N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU282987). Collectively, our results indicate that curcumin is a positive allosteric modulator of α7-nACh receptor and reverses nociception in mouse models of tonic and visceral pain.
Assuntos
Curcumina/farmacologia , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Dor/fisiopatologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Curcumina/uso terapêutico , Modelos Animais de Doenças , Feminino , Inflamação/complicações , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Dor/complicações , Receptor Nicotínico de Acetilcolina alfa7/agonistasRESUMO
Measuring electrical activity of neural networks by microelectrode array (MEA) has recently shown promise for screening level assessments of chemical toxicity on network development and function. Important aspects of interneuronal communication can be quantified from a single MEA recording, including individual firing rates, coordinated bursting, and measures of network synchrony, providing rich datasets to evaluate chemical effects. Further, multiple recordings can be made from the same network, including during the formation of these networks in vitro. The ability to perform multiple recording sessions over the in vitro development of network activity may provide further insight into developmental effects of neurotoxicants. In the current study, a recently described MEA-based screen of 86 compounds in primary rat cortical cultures over 12â¯days in vitro was revisited to establish a framework that integrates all available primary measures of electrical activity from MEA recordings into a composite metric for deviation from normal activity (total scalar perturbation). Examining scalar perturbations over time and increasing concentration of compound allowed for definition of critical concentrations or "tipping points" at which the neural networks switched from recovery to non-recovery trajectories for 42 compounds. These tipping point concentrations occurred at predominantly lower concentrations than those causing overt cell viability loss or disrupting individual network parameters, suggesting tipping points may be a more sensitive measure of network functional loss. Comparing tipping points for six compounds with plasma concentrations known to cause developmental neurotoxicity in vivo demonstrated strong concordance and suggests there is potential for using tipping points for chemical prioritization.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Animais , Animais Recém-Nascidos , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Relação Dose-Resposta a Droga , Potenciais da Membrana/efeitos dos fármacos , Microeletrodos , Rede Nervosa/patologia , Neurônios/patologia , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/fisiopatologia , Ratos , Medição de Risco , Fatores de Tempo , Técnicas de Cultura de Tecidos , Testes de Toxicidade/instrumentação , ToxicocinéticaRESUMO
NEW FINDINGS: What is the central question of this study? To investigate haemodynamic dysfunction in the type 2 diabetic Goto-Kakizaki (GK) rat, we measured shortening and Ca2+ transport in ventricular myocytes from epicardial (EPI) and endocardial (ENDO) regions. What is the main finding and its importance? EPI and ENDO GK myocytes displayed similar hypertrophy. Time to peak (TPK) and time to half (THALF) relaxation were prolonged in EPI GK myocytes. TPK Ca2+ transient was prolonged and THALF decay of the Ca2+ transient was shortened in EPI GK myocytes. Amplitude of shortening, Ca2+ transient and sarcoplasmic reticulum Ca2+ were unaltered in EPI and ENDO myocytes from Goto-Kakizaki compared with control rats. We demostrated regional differences in shortening and Ca2+ transport in Goto-Kakizaki rats. ABSTRACT: Diabetic cardiomyopathy is considered to be one of the major diabetes-associated complications, and the pathogenesis of cardiac dysfunction is not well understood. The electromechanical properties of cardiac myocytes vary across the walls of the chambers. The aim of this study was to investigate shortening and Ca2+ transport in epicardial (EPI) and endocardial (ENDO) left ventricular myocytes in the Goto-Kakizaki (GK) type 2 diabetic rat heart. Shortening and intracellular Ca2+ transients were measured by video edge detection and fluorescence photometry. Myocyte surface area was increased in EPI-GK and ENDO-GK compared with control EPI-CON and ENDO-CON myocytes. Time to peak shortening was prolonged in EPI-GK compared with EPI-CON and in ENDO-CON compared with EPI-CON myocytes. Time to half-relaxation of shortening and time to peak Ca2+ transient were prolonged in EPI-GK compared with EPI-CON myocytes. Time to half-decay of the Ca2+ transient was prolonged in EPI-CON compared with EPI-GK and in EPI-CON compared with ENDO-CON myocytes. The amplitude of shortening and the Ca2+ transient were unaltered in EPI-GK and ENDO-GK compared with their respective controls. Sarcoplasmic reticulum Ca2+ and myofilament sensitivity to Ca2+ were unaltered in EPI-GK and ENDO-GK compared with their respective controls. Regional differences in Ca2+ signalling in healthy and diabetic myocytes might account for variation in the dynamics of myocyte shortening. Further studies will be required to clarify the mechanisms underlying regional differences in the time course of shortening and the Ca2+ transient in EPI and ENDO myocytes from diabetic and control hearts.
Assuntos
Cálcio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Animais , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio/fisiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Masculino , Contração Miocárdica/fisiologia , Miofibrilas/metabolismo , Ratos , Retículo Sarcoplasmático/metabolismo , Retículo Sarcoplasmático/fisiologiaRESUMO
Diabetes mellitus is a major global health disorder and, currently, over 450 million people have diabetes with 90% suffering from type 2 diabetes. Left untreated, diabetes may lead to cardiovascular diseases which are a leading cause of death in diabetic patients. Calcium is the trigger and regulator of cardiac muscle contraction and derangement in cellular Ca2+ homeostasis, which can result in heart failure and sudden cardiac death. It is of paramount importance to investigate the regional involvement of Ca2+ in diabetes-induced cardiomyopathy. Therefore, the aim of this study was to investigate the voltage dependence of the Ca2+ transients in endocardial (ENDO) and epicardial (EPI) myocytes from the left ventricle of the Goto-Kakizaki (GK) rats, an experimental model of type 2 diabetes mellitus. Simultaneous measurement of L-type Ca2+ currents and Ca2+ transients was performed by whole-cell patch clamp techniques. GK rats displayed significantly increased heart weight, heart weight/body weight ratio, and non-fasting and fasting blood glucose compared to controls (CON). Although the voltage dependence of L-type Ca2+ current was unaltered, the voltage dependence of the Ca2+ transients was reduced to similar extents in EPI-GK and ENDO-GK compared to EPI-CON and ENDO-CON myocytes. TPK L-type Ca2+ current and Ca2+ transient were unaltered. THALF decay of L-type Ca2+ current was unaltered; however, THALF decay of the Ca2+ transient was shortened in ENDO and EPI myocytes from GK compared to CON rat hearts. In conclusion, the amplitude of L-type Ca2+ current was unaltered; however, the voltage dependence of the Ca2+ transient was reduced to similar extents in EPI and ENDO myocytes from GK rats compared to their respective controls, suggesting the possibility of dysfunctional sarcoplasmic reticulum Ca2+ transport in the GK diabetic rat hearts.
Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Endocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Pericárdio/metabolismo , Animais , Canais de Cálcio Tipo L/metabolismo , Diabetes Mellitus Tipo 2/patologia , Cardiomiopatias Diabéticas/patologia , Endocárdio/patologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Miócitos Cardíacos/patologia , Pericárdio/patologia , RatosRESUMO
In 2016, Clallam County became the first county in Washington State to mandate reporting of fatal and nonfatal opioid overdoses. This reporting improved our understanding of opioid overdoses in the community and allowed us to provide harm reduction and case management services after nonfatal overdoses. By using the Washington State Prescription Monitoring Program, we have been able to notify health care providers when their patients have experienced a fatal or nonfatal opioid overdose to help better guide their prescribing practices.
Assuntos
Overdose de Drogas/epidemiologia , Notificação de Abuso , Entorpecentes/intoxicação , População Rural , Adolescente , Adulto , Confiabilidade dos Dados , Overdose de Drogas/mortalidade , Overdose de Drogas/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/terapia , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Administração em Saúde Pública , Fatores de Risco , Washington/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Physicians often find significant challenges in assessing automobile driving in persons with mild cognitive impairment and mild dementia and deciding when to report to transportation administrators. Care must be taken to balance the safety of patients and other road users with potential negative effects of issuing such reports. OBJECTIVE: The aim of this study was to assess whether a computer-based Driving in Dementia Decision Tool (DD-DT) increased appropriate reporting of patients with mild dementia or mild cognitive impairment to transportation administrators. METHODS: The study used a parallel-group cluster nonblinded randomized controlled trial design to test a multifaceted knowledge translation intervention. The intervention included a computer-based decision support system activated by the physician-user, which provides a recommendation about whether to report patients with mild dementia or mild cognitive impairment to transportation administrators, based on an algorithm derived from earlier work. The intervention also included a mailed educational package and Web-based specialized reporting forms. Specialists and family physicians with expertise in dementia or care of the elderly were stratified by sex and randomized to either use the DD-DT or a control version of the tool that required identical data input as the intervention group, but instead generated a generic reminder about the reporting legislation in Ontario, Canada. The trial ran from September 9, 2014 to January 29, 2016, and the primary outcome was the number of reports made to the transportation administrators concordant with the algorithm. RESULTS: A total of 69 participating physicians were randomized, and 36 of these used the DD-DT; 20 of the 35 randomized to the intervention group used DD-DT with 114 patients, and 16 of the 34 randomized to the control group used it with 103 patients. The proportion of all assessed patients reported to the transportation administrators concordant with recommendation did not differ between the intervention and the control groups (50% vs 49%; Z=-0.19, P=.85). Two variables predicted algorithm-based reporting-caregiver concern (odds ratio [OR]=5.8, 95% CI 2.5-13.6, P<.001) and abnormal clock drawing (OR 6.1, 95% CI 3.1-11.8, P<.001). CONCLUSIONS: On the basis of this quantitative analysis, in-office abnormal clock drawing and expressions of concern about driving from caregivers substantially influenced physicians to report patients with mild dementia or mild cognitive impairment to transportation administrators, but the DD-DT tool itself did not increase such reports among these expert physicians. TRIAL REGISTRATION: ClinicalTrials.gov NCT02036099; https://clinicaltrials.gov/ct2/show/NCT02036099 (Archived by WebCite at http://www.webcitation.org/6zGMF1ky8).
Assuntos
Disfunção Cognitiva/terapia , Tomada de Decisões/ética , Demência/psicologia , Idoso , Condução de Veículo , Computadores , Feminino , Humanos , MasculinoRESUMO
Chemotherapy-induced nausea and vomiting (CINV) remain the most common and devastating side-effects associated with cancer chemotherapy. In recent decades, several lines of research emphasize the importance of 5-hydroxytryptamine3 (5-HT3; serotonin) receptors in the pathogenesis and treatment of CINV. 5-HT3 receptors are members of ligand-gated ion channels that mediate the rapid and transient membrane-depolarizing effect of 5-HT in the central and peripheral nervous system. These receptors play important roles in nausea and vomiting, as well as regulation of peristalsis and pain transmission. The development of antagonists for 5-HT3 receptor dramatically improved the treatment of CINV in cancer patients. In fact, the most common use of 5-HT3 receptor antagonists to date is the treatment of nausea and vomiting. In recent years, there has been an increasing tendency to use natural plant products as important therapeutic entities in the treatment of various diseases. In this article, we examined the results of earlier studies on the actions of natural compounds on the functional properties of 5-HT3 receptors. It is likely that these natural modulators of 5-HT3 receptors can be employed as lead structures for the synthesis of therapeutic agents for treating CINV in future clinical studies.
Assuntos
Náusea/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Vômito/metabolismo , Regulação Alostérica , Antineoplásicos/efeitos adversos , Sítios de Ligação , Canabidiol/farmacologia , Zingiber officinale/química , Humanos , Náusea/induzido quimicamente , Antagonistas do Receptor 5-HT3 de Serotonina/química , Terpenos/farmacologia , Vômito/induzido quimicamenteRESUMO
Microbiota regulate intestinal physiology by modifying host gene expression along the length of the intestine, but the underlying regulatory mechanisms remain unresolved. Transcriptional specificity occurs through interactions between transcription factors (TFs) and cis-regulatory regions (CRRs) characterized by nucleosome-depleted accessible chromatin. We profiled transcriptome and accessible chromatin landscapes in intestinal epithelial cells (IECs) from mice reared in the presence or absence of microbiota. We show that regional differences in gene transcription along the intestinal tract were accompanied by major alterations in chromatin accessibility. Surprisingly, we discovered that microbiota modify host gene transcription in IECs without significantly impacting the accessible chromatin landscape. Instead, microbiota regulation of host gene transcription might be achieved by differential expression of specific TFs and enrichment of their binding sites in nucleosome-depleted CRRs near target genes. Our results suggest that the chromatin landscape in IECs is preprogrammed by the host in a region-specific manner to permit responses to microbiota through binding of open CRRs by specific TFs.
Assuntos
Montagem e Desmontagem da Cromatina , Mucosa Intestinal/metabolismo , Microbiota , Transcrição Gênica , Animais , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , TranscriptomaRESUMO
BACKGROUND: Driving in persons with dementia poses risks that must be counterbalanced with the importance of the care for autonomy and mobility. Physicians often find substantial challenges in the assessment and reporting of driving safety for persons with dementia. This paper describes a driving in dementia decision tool (DD-DT) developed to aid physicians in deciding when to report older drivers with either mild dementia or mild cognitive impairment to local transportation administrators. METHODS: A multi-faceted, computerized decision support tool was developed, using a systematic literature and guideline review, expert opinion from an earlier Delphi study, as well as qualitative interviews and focus groups with physicians, caregivers of former drivers with dementia, and transportation administrators. The tool integrates inputs from the physician-user about the patient's clinical and driving history as well as cognitive findings, and it produces a recommendation for reporting to transportation administrators. This recommendation is translated into a customized reporting form for the transportation authority, if applicable, and additional resources are provided for the patient and caregiver. CONCLUSIONS: An innovative approach was needed to develop the DD-DT. The literature and guideline review confirmed the algorithm derived from the earlier Delphi study, and barriers identified in the qualitative research were incorporated into the design of the tool.
Assuntos
Condução de Veículo/psicologia , Disfunção Cognitiva/diagnóstico , Tomada de Decisões Assistida por Computador , Demência/diagnóstico , Notificação de Abuso , Acidentes de Trânsito/prevenção & controle , Idoso , Canadá , Cuidadores , Humanos , Médicos , Guias de Prática Clínica como AssuntoAssuntos
Redução do Dano , Transtornos Relacionados ao Uso de Substâncias/psicologia , Transtornos Relacionados ao Uso de Substâncias/terapia , Adulto , Buprenorfina/uso terapêutico , Anticoncepção/métodos , Overdose de Drogas/tratamento farmacológico , Overdose de Drogas/psicologia , Feminino , Heroína/efeitos adversos , Humanos , Masculino , Metadona/uso terapêutico , Metanfetamina/efeitos adversos , Naloxona/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/terapia , Gravidez , Qualidade de Vida , Encaminhamento e ConsultaRESUMO
OBJECTIVE: To give FPs an understanding of the "lived experience" of dementia via the words of a person with dementia (PWD)- Faye Forbes, a 64-year-old Anglican priest with Alzheimer disease who provides her perspectives on living with dementia-and to use these thoughts to improve care and outcomes. SOURCES OF INFORMATION: Ovid MEDLINE was searched from January 2005 to February 2015 using subject headings for dementia, caregiver, perspectives, and quality of health care. Articles geared toward FPs were selected. Relevant review articles and original research articles were used when appropriate and if they were applicable to PWDs and their caregivers. MAIN MESSAGE: There are several frameworks that organize the main experiences described by patients and caregivers. We used a review of the qualitative literature to provide the framework to summarize Faye's experience under the following headings: seeking a diagnosis, accessing supports and services, information needs, disease management, and communication and attitudes. CONCLUSION: Physicians should consider these themes when developing a management plan for PWDs. Trying to understand the experiences and perspectives of PWDs and their caregivers is important in providing optimal care.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Cuidadores/psicologia , Serviços de Saúde Mental/normas , Médicos de Família/normas , HumanosRESUMO
DNaseI footprinting is an established assay for identifying transcription factor (TF)-DNA interactions with single base pair resolution. High-throughput DNase-seq assays have recently been used to detect in vivo DNase footprints across the genome. Multiple computational approaches have been developed to identify DNase-seq footprints as predictors of TF binding. However, recent studies have pointed to a substantial cleavage bias of DNase and its negative impact on predictive performance of footprinting. To assess the potential for using DNase-seq to identify individual binding sites, we performed DNase-seq on deproteinized genomic DNA and determined sequence cleavage bias. This allowed us to build bias corrected and TF-specific footprint models. The predictive performance of these models demonstrated that predicted footprints corresponded to high-confidence TF-DNA interactions. DNase-seq footprints were absent under a fraction of ChIP-seq peaks, which we show to be indicative of weaker binding, indirect TF-DNA interactions or possible ChIP artifacts. The modeling approach was also able to detect variation in the consensus motifs that TFs bind to. Finally, cell type specific footprints were detected within DNase hypersensitive sites that are present in multiple cell types, further supporting that footprints can identify changes in TF binding that are not detectable using other strategies.
Assuntos
Pegada de DNA/métodos , Desoxirribonuclease I , Análise de Sequência de DNA/métodos , Fatores de Transcrição/metabolismo , Sítios de Ligação , Cromatina/química , Imunoprecipitação da Cromatina , Humanos , Modelos Genéticos , Motivos de NucleotídeosRESUMO
BACKGROUND/AIMS: The Zucker diabetic fatty (ZDF, FA/FA) rat is a genetic model of type 2 diabetes, characterized by insulin resistance with progressive metabolic syndrome. We have previously demonstrated mitochondrial dysfunction and oxidative stress in the heart, kidneys and pancreas of ZDF rats. However, the precise molecular mechanism of disease progression is not clear. Our aim in the present study was to investigate oxidative stress and mitochondrial dysfunction in the liver and brain of ZDF rats. METHODS: In this study, we have measured mitochondrial oxidative stress, bioenergetics and redox homeostasis in the liver and brain of ZDF rats. RESULTS: Our results showed increased reactive oxygen species (ROS) production in the ZDF rat brain compared to the liver, while nitric oxide (NO) production was markedly increased both in the brain and liver. High levels of lipid and protein peroxidation were also observed in these tissues. Glutathione metabolism and mitochondrial respiratory functions were adversely affected in ZDF rats when compared to Zucker lean (ZL, +/FA) control rats. Reduced ATP synthesis was also observed in the liver and brain of ZDF rats. Western blot analysis confirmed altered expression of cytochrome P450 2E1, iNOS, p-JNK, and IκB-α confirming an increase in oxidative and metabolic stress in ZDF rat tissues. CONCLUSIONS: Our data shows that, like other tissues, ZDF rat liver and brain develop complications associated with redox homeostasis and mitochondrial dysfunction. These results, thus, might have implications in understanding the etiology and pathophysiology of diabesity which in turn, would help in managing the disease associated complications.