RESUMO
OBJECTIVE: Nonadherence to antidepressants interferes with optimal treatment of late-life depression. This analysis examines clinical and treatment factors predicting medication nonadherence in difficult-to-treat late-life depression. METHODS: Secondary analysis of data from a clinical trial of antidepressant pharmacotherapy for Major Depressive Disorder in 468 adults aged 60+ years. All participants received venlafaxine XR for 12 weeks. Nonremitters were randomized to augmentation with either aripiprazole or placebo for 12 additional weeks. Medication adherence was assessed 14 times over 24 weeks. The analyses examined sociodemographic, clinical, and treatment factors that may predict antidepressant nonadherence during early (weeks 1-6), late (weeks 7-12), and augmentation (weeks 13--24) treatment. RESULTS: Poor cognitive function and early response were predictive of early nonadherence. Poor cognitive function and prior nonadherence were predictive of late nonadherence. Living alone was associated with nonadherence both late and during augmentation treatment. CONCLUSION: Future studies should consider the role of early response and cognitive function to improve antidepressant adherence, particularly among older adults who live alone.
Assuntos
Transtorno Depressivo Maior , Idoso , Antidepressivos/uso terapêutico , Depressão , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Humanos , Adesão à Medicação , Cloridrato de Venlafaxina/uso terapêuticoRESUMO
Nitric oxide (NO) is one of the critical components of the vasculature, regulating key signaling pathways in health. In macrovessels, NO functions to suppress cell inflammation as well as adhesion. In this way, it inhibits thrombosis and promotes blood flow. It also functions to limit vessel constriction and vessel wall remodeling. In microvessels and particularly capillaries, NO, along with growth factors, is important in promoting new vessel formation, a process termed angiogenesis. With age and cardiovascular disease, animal and human studies confirm that NO is dysregulated at multiple levels including decreased production, decreased tissue half-life, and decreased potency. NO has also been implicated in diseases that are related to neurotransmission and cancer although it is likely that these processes involve NO at higher concentrations and from nonvascular cell sources. Conversely, NO and drugs that directly or indirectly increase NO signaling have found clinical applications in both age-related diseases and in younger individuals. This focused review considers recently reported advances being made in the field of NO signaling regulation at several levels including enzymatic production, receptor function, interacting partners, localization of signaling, matrix-cellular and cell-to-cell cross talk, as well as the possible impact these newly described mechanisms have on health and disease.
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Vasos Sanguíneos/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Modelos Cardiovasculares , Neovascularização Fisiológica/fisiologia , Óxido Nítrico/metabolismo , Animais , Velocidade do Fluxo Sanguíneo , HumanosRESUMO
BACKGROUND: Long-QT syndrome (LQTS) may result in syncope, seizures, or sudden cardiac arrest. Although 16 LQTS-susceptibility genes have been discovered, 20% to 25% of LQTS remains genetically elusive. METHODS AND RESULTS: We performed whole-exome sequencing child-parent trio analysis followed by recessive and sporadic inheritance modeling and disease-network candidate analysis gene ranking to identify a novel underlying genetic mechanism for LQTS. Subsequent mutational analysis of the candidate gene was performed with polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing on a cohort of 33 additional unrelated patients with genetically elusive LQTS. After whole-exome sequencing and variant filtration, a homozygous p.D18fs*13 TRDN-encoded triadin frameshift mutation was discovered in a 10-year-old female patient with LQTS with a QTc of 500 milliseconds who experienced recurrent exertion-induced syncope/cardiac arrest beginning at 1 year of age. Subsequent mutational analysis of TRDN revealed either homozygous or compound heterozygous frameshift mutations in 4 of 33 unrelated cases of LQTS (12%). All 5 TRDN-null patients displayed extensive T-wave inversions in precordial leads V1 through V4, with either persistent or transient QT prolongation and severe disease expression of exercise-induced cardiac arrest in early childhood (≤3 years of age) and required aggressive therapy. The overall yield of TRDN mutations was significantly greater in patients ≤10 years of age (5 of 10, 50%) compared with older patients (0 of 24, 0%; P=0.0009). CONCLUSIONS: We identified TRDN as a novel underlying genetic basis for recessively inherited LQTS. All TRDN-null patients had strikingly similar phenotypes. Given the recurrent nature of potential lethal arrhythmias, patients fitting this phenotypic profile should undergo cardiac TRDN genetic testing.
Assuntos
Proteínas de Transporte/genética , Parada Cardíaca/genética , Síndrome do QT Longo/genética , Proteínas Musculares/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Desfibriladores Implantáveis , Exoma , Feminino , Mutação da Fase de Leitura , Genes Recessivos , Parada Cardíaca/diagnóstico , Heterozigoto , Homozigoto , Humanos , Lactente , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/terapia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Análise de Sequência de DNA , Simpatectomia , Síncope/diagnóstico , Síncope/genética , Síndrome , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: Mice are increasingly being used as models to investigate aspects of urinary dysfunction that humans with lower urinary tract symptoms (LUTS) experience. One method used to examine voiding function is the spontaneous void spot assay. The purpose of this study was to characterize and identify animal husbandry conditions that might confound results of the spontaneous void spot assay in male C57Bl/6J mice. METHODS: Mice were placed in cages lined with filter paper for 4 hr and urine was visualized with UV transillumination. Voiding parameters including urine spot number, spot size, total urine area, primary void area, corner and center voiding were quantified. RESULTS: Adult male mice void more frequently with advancing age and a subpopulation (5-10%) display a frequent spotting pattern at 6-9 weeks of age. Voiding was not significantly different in male mice weaned to group housing (4-6 per cage) versus single housing, and was not altered when they were used as breeders. Voiding was changed upon transferring group housed adult males to single density cages, which decreased total urine area. Repeated assays of male voiding behavior over three consecutive days increased primary void area by the third day of monitoring and revealed that voiding behavior is impacted by routine cage changes and time of day. CONCLUSIONS: Together these results identify housing and husbandry practices that influence male voiding behaviors in the spontaneous void spot assay and will inform voiding behavior analyses conducted with male C57Bl/6J mice.
Assuntos
Criação de Animais Domésticos/métodos , Técnicas de Diagnóstico Urológico , Abrigo para Animais , Micção , Urodinâmica , Fatores Etários , Animais , Comportamento Animal , Ritmo Circadiano , Manobra Psicológica , Masculino , Camundongos Endogâmicos C57BL , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
BACKGROUND: Epigenetic factors influence stem cell function and other developmental events but their role in prostate morphogenesis is not completely known. We tested the hypothesis that histone deacetylase (HDAC) activity is required for prostate morphogenesis. RESULTS: We identified the presence of class I nuclear HDACs in the mouse urogenital sinus (UGS) during prostate development and found that Hdac 2 mRNA abundance diminishes as development proceeds which is especially evident in prostatic epithelium. Blockade of HDACs with the inhibitor trichostatin A (TSA) decreased the number of prostatic buds formed in UGS explant cultures but not the number of buds undergoing branching morphogenesis. In the latter, TSA promoted an extensive branching phenotype that was reversed by exogenous NOGGIN protein, which functions as a bone morphogenetic protein (BMP) inhibitor. TSA also increased Bmp2 promoter H3K27ac abundance, Bmp2 and Bmp4 mRNA abundance, and the percentage of epithelial cells marked by BMP-responsive phosphorylated SMAD1/5/8 protein. TSA exposed UGS explants grafted under the kidney capsule of untreated host mice for continued development achieved a smaller size without an obvious difference in glandular histology compared with control treated grafts. CONCLUSIONS: These results are consistent with an active role for HDACs in shaping prostate morphogenesis by regulating Bmp abundance.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Histonas/metabolismo , Próstata/crescimento & desenvolvimento , Acetilação , Animais , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 2/farmacologia , Proteína Morfogenética Óssea 4/metabolismo , Cromatina/metabolismo , Imunoprecipitação da Cromatina , Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Histona Desacetilase 2/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Imuno-Histoquímica , Hibridização In Situ , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfogênese , Fenótipo , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de SinaisRESUMO
In prostate and other epithelial cancers, E-cadherin (CDH1) is downregulated inappropriately by DNA methylation to promote an invasive phenotype. Though cancer frequently involves a reawakening of developmental signaling pathways, whether DNA methylation of Cdh1 occurs during organogenesis has not been determined. Here we show that DNA methylation of Cdh1 mediates outgrowth of developing prostate ducts. During the three-day gestational window leading up to and including prostate ductal initiation, Cdh1 promoter methylation increases and its mRNA and protein abundance decreases in epithelium giving rise to prostatic buds. DNA methylation is required for prostate specification, ductal outgrowth, and branching morphogenesis. All three endpoints are impaired by a DNA methylation inhibitor, which also decreases Cdh1 promoter methylation and increases Cdh1 mRNA and protein abundance. A CDH1 function-blocking antibody restores prostatic identity, bud outgrowth, and potentiates epithelial differentiation in the presence of the DNA methylation inhibitor. This is the first study to mechanistically link acquired changes in DNA methylation to the normal process of prostate organogenesis. We propose a novel mechanism whereby Cdh1 promoter methylation restricts Cdh1 abundance in developing prostate epithelium to create a permissive environment for prostatic bud outgrowth. Thus, DNA methylation primes the prostate primordium to respond to developmental cues mediating outgrowth, differentiation and maturation of the ductal network.
Assuntos
Caderinas/genética , Proteínas Cdh1/metabolismo , Metilação de DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Próstata/embriologia , Animais , Anticorpos Bloqueadores/imunologia , Proteínas Cdh1/genética , Proteínas Cdh1/imunologia , Diferenciação Celular/imunologia , Epitélio/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfogênese/genética , Regiões Promotoras Genéticas/genética , Próstata/metabolismo , RNA Mensageiro/metabolismoRESUMO
Androgen receptor (AR) signaling initiates mouse prostate development by stimulating prostate ductal bud formation and specifying bud patterns. Curiously, however, prostatic bud initiation lags behind the onset of gonadal testosterone synthesis by about three days. This study's objective was to test the hypothesis that DNA methylation controls the timing and scope of prostate ductal development by regulating Ar expression in the urogenital sinus (UGS) from which the prostate derives. We determined that Ar DNA methylation decreases in UGS mesenchyme during prostate bud formation in vivo and that this change correlates with decreased DNA methyltransferase expression in the same cell population during the same time period. To examine the role of DNA methylation in prostate development, fetal UGSs were grown in serum-free medium and 5 alpha dihydrotestosterone (DHT) and the DNA methylation inhibitor 5'-aza-2'-deoxycytidine (5AzadC) were introduced into the medium at specific times. As a measure of prostate development, in situ hybridization was used to visualize and count Nkx3-1 mRNA positive prostatic buds. We determined that inhibiting DNA methylation when prostatic buds are being specified, accelerates the onset of prostatic bud development, increases bud number, and sensitizes the budding response to androgens. Inhibition of DNA methylation also reduces Ar DNA methylation in UGS explants and increases Ar mRNA and protein in UGS mesenchyme and epithelium. Together, these results support a novel mechanism whereby Ar DNA methylation regulates UGS androgen sensitivity to control the rate and number of prostatic buds formed, thereby establishing a developmental checkpoint.
Assuntos
Metilação de DNA/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Modelos Biológicos , Organogênese/fisiologia , Próstata/embriologia , Receptores Androgênicos/metabolismo , Transdução de Sinais/fisiologia , Análise de Variância , Animais , Azacitidina/análogos & derivados , Sequência de Bases , Primers do DNA/genética , Decitabina , Di-Hidrotestosterona , Proteínas de Homeodomínio/metabolismo , Imuno-Histoquímica , Imunoprecipitação , Hibridização In Situ , Técnicas In Vitro , Masculino , Camundongos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase em Tempo Real , Receptores Androgênicos/genética , Análise de Sequência de DNA , Fatores de Transcrição/metabolismoRESUMO
Aging men are susceptible to developing lower urinary tract symptoms, but the underlying etiology is unknown and the influence of dietary and environmental factors on them is unclear. We tested whether a folic acid-enriched diet changed urinary tract physiology and biology in control male mice and male mice with urinary dysfunction induced by exogenous testosterone and estradiol (T+E2), which mimics changing hormone levels in aging humans. T+E2 treatment increased mouse urine output, time between voiding events, and bladder capacity and compliance. Consumption of a folic acid-enriched diet moderated these changes without decreasing prostate wet weight or threshold voiding pressure. One potential mechanism for these changes involves water balance. T+E2 treatment increases plasma concentrations of anti-diuretic hormone, which is offset at least in part by a folic acid-enriched diet. Another potential mechanism involves neural control of micturition. The folic acid-enriched diet, fed to T+E2-treated mice, increased voiding frequency in response to intravesicular capsaicin infusion and increased mRNA abundance of the capsaicin-sensitive cation channel transient receptor potential vanilloid subfamily member 1 (Trpv1) in L6 and S1 dorsal root ganglia (DRG) neurons. T+E2 treatment and a folic acid-enriched diet also modified DNA methylation, which is capable of altering gene expression. We found the enriched diet increased global DNA methylation in dorsal and ventral prostate and L6 and S1 DRG. Our results are consistent with folic acid acting to slow or reverse T+E2-mediated alteration in urinary function in part by normalizing water balance and enhancing or preserving afferent neuronal function.
Assuntos
Estradiol/farmacologia , Ácido Fólico/farmacologia , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Testosterona/farmacologia , Fenômenos Fisiológicos do Sistema Urinário/efeitos dos fármacos , Ração Animal , Animais , Capsaicina/administração & dosagem , Capsaicina/farmacologia , Dieta , Estradiol/administração & dosagem , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Testosterona/administração & dosagem , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismoRESUMO
Objective: Older adults experience numerous changes in their social networks and social environment that may worsen preexisting posttraumatic stress disorder (PTSD) symptoms. This study tested whether tangible support, appraisal support, belonging support, and self-esteem were associated with trauma symptom burden among community-dwelling older Black and White adults at baseline and over 12 months of follow-up.Methods: This study used data collected from a randomized controlled trial for depression prevention in adults 50 years of age or older who had subsyndromal depression (2006-2011). Two hundred forty-four participants (including 90 older Black adults) were randomly assigned to a problem-solving therapy arm or an active control arm. The Interpersonal Support Evaluation List (ISEL) was administered at baseline and 12 months later. Linear regression analysis was used to examine associations of each of the ISEL dimensions with DSM-IV-defined PTSD symptoms at baseline and over time, with control for well-established correlates of PTSD including depression, anxiety, and sleep quality.Results: Participants were a mean (SD) of 65.6 (11.0) years of age, and 71% percent were female. Belongingness support was the only dimension of interpersonal support significantly associated with PTSD symptoms at baseline (ß = -0.192, t = -3.582, P < .001) and 12 months later (ß = -0.183, t = -2.735, P < .01). Regression models accounted for a large proportion of variance in PTSD symptoms. The association between belongingness support and PTSD symptoms did not vary by participant race.Conclusions: A strong perception of belongingness to family and/or friends was associated with fewer PTSD symptoms at baseline and over 12 months. This observation generates the hypothesis that behavioral interventions which directly target and modify interpersonal support may benefit both older Black and older White adults who have experienced trauma.Trial Registration: ClinicalTrials.gov identifier: NCT00326677.
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Apoio Social , Transtornos de Estresse Pós-Traumáticos , Idoso , Feminino , Humanos , Masculino , Transtornos de Ansiedade/complicações , Terapia Comportamental , Psicoterapia/métodos , Transtornos de Estresse Pós-Traumáticos/diagnóstico , População Branca , Negro ou Afro-Americano , Pessoa de Meia-IdadeRESUMO
Sudden cardiac death (SCD) in patients with heart failure (HF) is allied with an imbalance in reduction and oxidation (redox) signaling in cardiomyocytes; however, the basic pathways and mechanisms governing redox homeostasis in cardiomyocytes are not fully understood. Here, we show that cytochrome b5 reductase 3 (CYB5R3), an enzyme known to regulate redox signaling in erythrocytes and vascular cells, is essential for cardiomyocyte function. Using a conditional cardiomyocyte-specific CYB5R3-knockout mouse, we discovered that deletion of CYB5R3 in male, but not female, adult cardiomyocytes causes cardiac hypertrophy, bradycardia, and SCD. The increase in SCD in CYB5R3-KO mice is associated with calcium mishandling, ventricular fibrillation, and cardiomyocyte hypertrophy. Molecular studies reveal that CYB5R3-KO hearts display decreased adenosine triphosphate (ATP), increased oxidative stress, suppressed coenzyme Q levels, and hemoprotein dysregulation. Finally, from a translational perspective, we reveal that the high-frequency missense genetic variant rs1800457, which translates into a CYB5R3 T117S partial loss-of-function protein, associates with decreased event-free survival (~20%) in Black persons with HF with reduced ejection fraction (HFrEF). Together, these studies reveal a crucial role for CYB5R3 in cardiomyocyte redox biology and identify a genetic biomarker for persons of African ancestry that may potentially increase the risk of death from HFrEF.
Assuntos
Insuficiência Cardíaca , Miócitos Cardíacos , Animais , Morte Súbita Cardíaca , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Masculino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Oxirredução , Volume SistólicoRESUMO
BACKGROUND/OBJECTIVES: Gait speed and psychomotor speed slow with age and may predict neuropsychiatric disease such as depression and anxiety. We explored the relative predictive values of gait speed, psychomotor slowing, and a composite index of these two measures on time to new episode depression or anxiety in older adults at risk for these common psychiatric conditions. DESIGN: Randomized controlled prevention trial with 15-month follow-up. SETTING: University-based late-life mental health research clinic. PARTICIPANTS: Two hundred thirteen individuals, age 60+ years, with subsyndromal symptoms of depression or anxiety and one of the following risk factors for these common conditions: mild cognitive impairment, knee osteoarthritis, or disabilities requiring home-based care. INTERVENTION: Participants in each of the risk factor groups were randomized to a depression-specific preventive intervention or usual care. MEASUREMENTS: Gait speed: 4-m walk test from the Short Physical Performance Battery. Psychomotor speed: Coding task of the Repeatable Battery for the Assessment of Neuropsychological Status. We created a composite index of slowing by determining whether participants exceeded established cut-offs for slow performance in both gait speed (≤0.8 m/s) and psychomotor speed (<7 on the coding task). Time to new onset syndromal depression/anxiety was measured using research diagnostic criteria. RESULTS: Fifty-four participants developed syndromal depression/anxiety (19.5%) over the course of 15 months. Participants with slowing in both areas were over twice as likely to experience new onset depression/anxiety (hazard ratio (HR) = 2.11; 95% confidence interval (CI) = 1.02-4.40, P = .046) compared to participants with no slowing in either area. Slowed gait (HR = 1.88; 95% CI = 0.992-3.55; P = .052) or slowed psychomotor speed (HR = 0.60; 95% CI = 0.14-2.58; P = .488) alone did not increase risk for depression/anxiety. CONCLUSION: Evaluating both gait and psychomotor speed in older adults with medical comorbidities and sub-syndromal depression may predict incident mental illness and inform prevention planning. Future research is needed to validate our observations and explore shared neurobiological mechanisms that explain this elevated risk.
Assuntos
Ansiedade/etiologia , Depressão/etiologia , Depressão/prevenção & controle , Desempenho Psicomotor , Velocidade de Caminhada , Idoso , Idoso de 80 Anos ou mais , Ansiedade/epidemiologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Comorbidade , Depressão/epidemiologia , Pessoas com Deficiência/psicologia , Pessoas com Deficiência/estatística & dados numéricos , Feminino , Seguimentos , Avaliação Geriátrica/métodos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/fisiopatologia , Osteoartrite do Joelho/psicologia , Valor Preditivo dos TestesRESUMO
The mouse prostate develops from a component of the lower urinary tract (LUT) known as the urogenital sinus (UGS). This process requires androgens and signaling between mesenchyme and epithelium. Little is known about DNA methylation during prostate development, including which factors are expressed, whether their expression changes over time, and if DNA methylation contributes to androgen signaling or influences signaling between mesenchyme and epithelium. We used in situ hybridization to evaluate the spatial and temporal expression pattern of mRNAs which encode proteins responsible for establishing, maintaining or remodeling DNA methylation. These include DNA methyltransferases, DNA deaminases, DNA glycosylases, base excision repair and mismatch repair pathway members. The mRNA expression patterns were compared between male and female LUT prior to prostatic bud formation (14.5 days post coitus (dpc)), during prostatic bud formation (17.5 dpc) and during prostatic branching morphogenesis (postnatal day (P) 5). We found dramatic changes in the patterns of these mRNAs over the course of prostate development and identified examples of sexually dimorphic mRNA expression. Future investigation into how DNA methylation patterns are established, maintained and remodeled during the course of embryonic prostatic bud formation may provide insight into prostate morphogenesis and disease.