RESUMEN
The Social Vulnerability Index (SVI) is used to stratify community need for support during disasters. We evaluated relationships between the SVI and personal protective equipment shortages, COVID-19 caseload, and mortality rates in skilled nursing facilities (SNFs). In SVI quartile 4, personal protective equipment shortages were 2.3 times those in SNFs in quartile 1; COVID-19 case loads were 1.6 times those of SNFs in quartile 1; and mortality rates in were 1.9 times those of SNFs in SVI quartile 1.
Asunto(s)
COVID-19 , Pandemias , Humanos , Michigan/epidemiología , Equipo de Protección Personal , SARS-CoV-2 , Instituciones de Cuidados Especializados de EnfermeríaRESUMEN
BACKGROUND: The role of sex hormones on cellular function is unclear. Studies show androgens and estrogens are protective in the CNS, whereas other studies found no effects or damaging effects. Furthermore, sex differences have been observed in multiple oxidative stress-associated CNS disorders, such as Alzheimer's disease, depression, and Parkinson's disease. The goal of this study is to examine the relationship between sex hormones (i.e., androgens and estrogens) and oxidative stress on cell viability. METHODS: N27 and PC12 neuronal and C6 glial phenotypic cell lines were used. N27 cells are female rat derived, whereas PC12 cells and C6 cells are male rat derived. These cells express estrogen receptors and the membrane-associated androgen receptor variant, AR45, but not the full-length androgen receptor. N27, PC12, and C6 cells were exposed to sex hormones either before or after an oxidative stressor to examine neuroprotective and neurotoxic properties, respectively. Estrogen receptor and androgen receptor inhibitors were used to determine the mechanisms mediating hormone-oxidative stress interactions on cell viability. Since the presence of AR45 in the human brain tissue was unknown, we examined the postmortem brain tissue from men and women for AR45 protein expression. RESULTS: Neither androgens nor estrogens were protective against subsequent oxidative stress insults in glial cells. However, these hormones exhibited neuroprotective properties in neuronal N27 and PC12 cells via the estrogen receptor. Interestingly, a window of opportunity exists for sex hormone neuroprotection, wherein temporary hormone deprivation blocked neuroprotection by sex hormones. However, if sex hormones are applied following an oxidative stressor, they exacerbated oxidative stress-induced cell loss in neuronal and glial cells. CONCLUSIONS: Sex hormone action on cell viability is dependent on the cellular environment. In healthy neuronal cells, sex hormones are protective against oxidative stress insults via the estrogen receptor, regardless of sex chromosome complement (XX, XY). However, in unhealthy (e.g., high oxidative stress) cells, sex hormones exacerbated oxidative stress-induced cell loss, regardless of cell type or sex chromosome complement. The non-genomic AR45 receptor, which is present in humans, mediated androgen's damaging effects, but it is unknown which receptor mediated estrogen's damaging effects. These differential effects of sex hormones that are dependent on the cellular environment, receptor profile, and cell type may mediate the observed sex differences in oxidative stress-associated CNS disorders.
Asunto(s)
Andrógenos/farmacología , Estradiol/farmacología , Estrógenos/farmacología , Neuroprotección/efectos de los fármacos , Estrés Oxidativo , Testosterona/farmacología , Anciano , Anciano de 80 o más Años , Animales , Línea Celular , Femenino , Humanos , Masculino , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/metabolismo , Caracteres SexualesRESUMEN
Neuropeptide release in the brain has traditionally been difficult to observe. Existing methods lack temporal and spatial resolution that is consistent with the function and size of neurons. We use cultured "sniffer cells" to improve the temporal and spatial resolution of observing neuropeptide release. Sniffer cells were created by stably transfecting Chinese Hamster Ovary (CHO) cells with plasmids encoding the rat angiotensin type 1a receptor and a genetically encoded Ca2+ sensor. Isolated, cultured sniffer cells showed dose-dependent increases in fluorescence in response to exogenously applied angiotensin II and III, but not other common neurotransmitters. Sniffer cells placed on the median preoptic nucleus (a presumptive site of angiotensin release) displayed spontaneous activity and evoked responses to either electrical or optogenetic stimulation of the subfornical organ. Stable sniffer cell lines could be a viable method for detecting neuropeptide release in vitro, while still being able to distinguish differences in neuropeptide concentration.
Asunto(s)
Angiotensina II/metabolismo , Neuronas/metabolismo , Animales , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Fluorescencia , Masculino , Optogenética , Ratas Sprague-DawleyRESUMEN
Oxidative stress (OS) is a common characteristic of several neurodegenerative disorders, including Parkinson disease (PD). PD is more prevalent in men than in women, indicating the possible involvement of androgens. Androgens can have either neuroprotective or neurodamaging effects, depending on the presence of OS. Specifically, in an OS environment, androgens via a membrane-associated androgen receptor (mAR) exacerbate OS-induced damage. To investigate the role of androgens on OS signaling and neurodegeneration, the effects of testosterone and androgen receptor activation on the major OS signaling cascades, the reduced form of NAD phosphate (NADPH) oxidase (NOX)1 and NOX2 and the Gαq/inositol trisphosphate receptor (InsP3R), were examined. To create an OS environment, an immortalized neuronal cell line was exposed to H2O2 prior to cell-permeable/cell-impermeable androgens. Different inhibitors were used to examine the role of G proteins, mAR, InsP3R, and NOX1/2 on OS generation and cell viability. Both testosterone and DHT/3-O-carboxymethyloxime (DHT)-BSA increased H2O2-induced OS and cell death, indicating the involvement of an mAR. Furthermore, classical AR antagonists did not block testosterone's negative effects in an OS environment. Because there are no known antagonists specific for mARs, an AR protein degrader, ASC-J9, was used to block mAR action. ASC-J9 blocked testosterone's negative effects. To determine OS-related signaling mediated by mAR, this study examined NOX1, NOX2, Gαq. NOX1, NOX2, and the Gαq complex with mAR. Only NOX inhibition blocked testosterone-induced cell loss and OS. No effects of blocking either Gαq or G protein activation were observed on testosterone's negative effects. These results indicate that androgen-induced OS is via the mAR-NOX complex and not the mAR-Gαq complex.
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Supervivencia Celular/fisiología , Dihidrotestosterona/farmacología , Neuronas/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Superficie Celular/metabolismo , Testosterona/farmacología , Antagonistas de Receptores Androgénicos/farmacología , Anilidas/farmacología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Neuronas/efectos de los fármacos , Nitrilos/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Compuestos de Tosilo/farmacologíaRESUMEN
Sleep apnea has been associated with elevated risk for metabolic, cognitive, and cardiovascular disorders. Further, the role of hypothalamic-pituitary-adrenal (HPA) activation in sleep apnea has been controversial in human studies. Chronic intermittent hypoxia (CIH) is a rodent model, which mimics the hypoxemia experienced by patients with sleep apnea. Most studies of CIH in rats have been conducted in the Sprague Dawley rat strain. Previously published literature suggests different strains of rats exhibit various responses to disease models, and these effects can be further modulated by the housing conditions experienced by each strain. This variability in response is similar to what has been observed in clinical populations, especially with respect to the HPA system. To investigate if strain or housing (individual or pair-housed) can affect the results of CIH (AHI 8 or 10) treatment, we exposed individual and pair-housed Sprague Dawley and Long-Evans male rats to 7 days of CIH treatment. This was followed by biochemical analysis of circulating hormones, oxidative stress, and neurodegenerative markers. Both strain and housing conditions altered oxidative stress generation, hyperphosphorylated tau protein (tau tangles), circulating corticosterone and adrenocorticotropic hormone (ACTH), and weight metrics. Specifically, pair-housed Long-Evans rats were the most sensitive to CIH, which showed a significant association between oxidative stress generation and HPA activation under conditions of AHI of 8. These results suggest both strain and housing conditions can affect the outcomes of CIH.
RESUMEN
Sleep apnea is associated with testosterone dysregulation as well as increased risk of developing neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). A rodent model of the hypoxemic events of sleep apnea, chronic intermittent hypoxia (CIH), has been previously documented to impair cognitive function and elevate oxidative stress in male rats, while simultaneously decreasing testosterone. Therefore, androgens may modulate neuronal function under CIH. To investigate the role of androgens during CIH, male rats were assigned to one of four hormone groups: 1) gonadally intact, 2) gonadectomized (GDX), 3) GDXâ¯+â¯testosterone (T) supplemented, or 4) GDXâ¯+â¯dihydrotestosterone (DHT) supplemented. Each group was exposed to either normal room air or CIH exposure for one week, followed by memory and motor task assessments. Brain regions associated with AD and PD (entorhinal cortex, dorsal hippocampus, and substantia nigra) were examined for oxidative stress and inflammatory markers, key characteristics of AD and PD. Gonadally intact rats exhibited elevated oxidative stress due to CIH, but no significant memory and motor impairments. GDX increased memory impairments, regardless of CIH exposure. T preserved memory function and prevented detrimental CIH-induced changes. In contrast, DHT was not protective, as evidenced by exacerbated oxidative stress under CIH. Further, CIH induced significant spatial memory impairment in rats administered DHT. These results indicate androgens can have both neuroprotective and detrimental effects under CIH, which may have clinical relevance for men with untreated sleep apnea.
Asunto(s)
Andrógenos/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Hipoxia/fisiopatología , Hipoxia/psicología , Animales , Encéfalo/fisiopatología , Enfermedad Crónica , Hipoxia/patología , Masculino , Trastornos de la Memoria/etiología , Estrés Oxidativo/efectos de los fármacos , Periodicidad , Ratas , Ratas Long-Evans , Síndromes de la Apnea del Sueño/patología , Síndromes de la Apnea del Sueño/fisiopatología , Síndromes de la Apnea del Sueño/psicología , Memoria Espacial/efectos de los fármacos , Testosterona/farmacologíaRESUMEN
Sleep apnea is a common sleep disorder characterized by intermittent periods of low blood oxygen levels. The risk for sleep apnea increases with age and is more prevalent in men than women. A common comorbidity of sleep apnea includes male sexual dysfunction, but it is not clear if a causal relationship exists between sleep apnea and sexual dysfunction. Possible mechanisms that link these two disorders include oxidative stress and testosterone. Oxidative stress is elevated in clinical patients with sleep apnea and in rodents exposed to chronic intermittent hypoxia (CIH), an animal model for apnea-induced hypopnea. Further, oxidative stress levels increase with age. Therefore, age may play a role in sleep apnea-induced sexual dysfunction and oxidative stress generation. To investigate this relationship, we exposed gonadally intact 3 (young) and 12 (middle-aged) month old male F344/BN F1 hybrid male rats to 8â¯days of CIH, and then examined male sexual function. Plasma was used to assess circulating oxidative stress and hormone levels. Middle-aged male rats had lower testosterone levels with increased sexual dysfunction and oxidative stress, independent of CIH. However, CIH decreased testosterone levels and increased sexual dysfunction and oxidative stress only in young gonadally intact male rats, but not in gonadectomized young rats with physiological testosterone replacement. In sum, CIH had a greater impact on younger gonadally intact animals, with respect to sexual behaviors, testosterone, and oxidative stress. Our data indicate CIH mimics the effects of aging on male sexual behavior in young gonadally intact male rats.
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Envejecimiento/fisiología , Corticosterona/sangre , Hipoxia/fisiopatología , Estrés Oxidativo/fisiología , Conducta Sexual/fisiología , Síndromes de la Apnea del Sueño/fisiopatología , Testosterona/sangre , Animales , Hormona Folículo Estimulante/sangre , Hipoxia/sangre , Hipoxia/complicaciones , Hormona Luteinizante/sangre , Masculino , Orquiectomía , Oxitocina/sangre , Ratas , Síndromes de la Apnea del Sueño/complicacionesRESUMEN
Sex steroid receptors act as ligand activated nuclear transcription factors throughout the body, including the brain. However, post-translational modification of these receptors can direct them to extranuclear sites, including the plasma membrane, where they are able to initiate rapid signaling. Because of the conserved domain structure of these receptors, alternative exon splicing can result in proteins with altered nuclear and extranuclear actions. Although much attention has focused on internal and C-terminal splice variants, both estrogen and androgen receptors undergo N-terminal truncations, as well. These truncated proteins not only influence the transcriptional activity of the full-length receptors, but also associate with caveolin and initiate signaling at the plasma membrane. Such actions may have important physiological consequences in neuronal, endothelial, and cancer signaling and cell survival.
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Receptores de Esteroides/genética , Eliminación de Secuencia , Esteroides/metabolismo , Animales , Humanos , Ligandos , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Esteroides/química , Receptores de Esteroides/metabolismoRESUMEN
Fast, nongenomic androgen actions have been described in various cell types, including neurons. However, the receptor mediating this cell membrane-initiated rapid signaling remains unknown. This study found a putative androgen receptor splice variant in a dopaminergic N27 cell line and in several brain regions (substantia nigra pars compacta, entorhinal cortex, and hippocampus) from gonadally intact and gonadectomized (young and middle-aged) male rats. This putative splice variant protein has a molecular weight of 45 kDa and lacks an N-terminal domain, indicating it is homologous to the human AR45 splice variant. Interestingly, AR45 was highly expressed in all brain regions examined. In dopaminergic neurons, AR45 is localized to plasma membrane lipid rafts, a microdomain involved in cellular signaling. Further, AR45 protein interacts with membrane-associated G proteins Gαq and Gαo. Neither age nor hormone levels altered AR45 expression in dopaminergic neurons. These results provide the first evidence of AR45 protein expression in the brain, specifically plasma membrane lipid rafts. AR45 presence in lipid rafts indicates that it may function as a membrane androgen receptor to mediate fast, nongenomic androgen actions.
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Microdominios de Membrana/metabolismo , Neuronas/metabolismo , Receptores Androgénicos/metabolismo , Envejecimiento/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Línea Celular , Corteza Entorrinal/metabolismo , Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Masculino , Orquiectomía , Porción Compacta de la Sustancia Negra/metabolismo , Isoformas de Proteínas/metabolismo , ARN Mensajero/metabolismo , Ratas , Receptores Androgénicos/genética , Testículo/metabolismo , Testosterona/administración & dosificación , Testosterona/metabolismoRESUMEN
BACKGROUND: The relative effectiveness of inhaled corticosteroids and leukotriene receptor antagonists in asthma therapy continues to be the subject of clinical studies. Recent studies have examined the impact of these therapies using a retrospective design. Retrospective studies require special attention to nonrandom assignment of participants to treatment groups and, consequently, to the need to appropriately account for baseline differences. OBJECTIVE: To examine the relative effectiveness of montelukast sodium vs fluticasone propionate as controller monotherapy in patients with asthma. METHODS: A retrospective cohort analysis of claims data from 6,160 individuals continuously enrolled in 1 of 20 US managed care plans. Patients using fluticasone were matched to those treated with montelukast using propensity scores and age (2-55 years). Health care use was determined for the 12-month periods before and after the initial controller prescription. Outcomes included asthma-related hospitalizations and emergency department visits, along with use of oral corticosteroids and short-acting beta-agonists. Logistic regression analyses were also performed. RESULTS: Overall, controller therapy significantly reduced the odds of postindex asthma-related hospitalizations (odds ratio, 0.56; 95% confidence interval, 0.38-0.79); no significant difference was observed with asthma-related emergency department visits (odds ratio, 0.89; 95% confidence interval, 0.76-1.04). Differences in the relative effect in the montelukast and fluticasone groups were not observed. Similarly, increases in the postindex rate of short-acting beta-agonist use and increases in oral corticosteroid use for both montelukast and fluticasone patients were noted. CONCLUSIONS: Similar outcomes were observed in montelukast and fluticasone users in this matched cohort analysis.
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Acetatos/uso terapéutico , Androstadienos/uso terapéutico , Antiasmáticos/uso terapéutico , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Antagonistas de Leucotrieno/uso terapéutico , Quinolinas/uso terapéutico , Administración por Inhalación , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Ciclopropanos , Femenino , Fluticasona , Hospitalización , Humanos , Revisión de Utilización de Seguros , Masculino , Programas Controlados de Atención en Salud , Persona de Mediana Edad , Estudios Retrospectivos , Sulfuros , Resultado del TratamientoRESUMEN
When anti-inflammatory/analgesic agents are not well tolerated, patients with arthritis may be prescribed a cyclooxygenase-2 (COX-2) inhibitor. Since these patients often require daily treatment and COX-2 inhibitors are more expensive than nonselective nonsteroidal anti-inflammatory agents, it is important to assess their patterns of use. In this retrospective study, rofecoxib and celecoxib were compared, in a managed care population with arthritis, in terms of average daily medication consumption and cost. Celecoxib was found to be significantly more costly than rofecoxib, and certain factors, such as the treating physician's specialty, correlated with prescribing patterns. Given the high prevalence of arthritic conditions, these results suggest that the selection of a COX-2 inhibitor may substantially affect health care costs.
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Artritis/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Utilización de Medicamentos , Programas Controlados de Atención en Salud/organización & administración , Adulto , Anciano , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/economía , Costos de los Medicamentos , Femenino , Investigación sobre Servicios de Salud , Humanos , Masculino , Persona de Mediana Edad , Minnesota , Estudios RetrospectivosRESUMEN
The authors conducted a retrospective database study of patients with asthma (age range, 6-55 yr) who initiated fluticasone propionate or montelukast sodium treatment between an index period of July 1998 and June 1999. All patients were observed for 12 months before and after the index period. Changes in asthma-related hospitalizations, emergency department visits, oral corticosteroid use, and short-acting beta-agonist use were analyzed. The odds of postindex asthma-related events were estimated. In multivariate analysis, use of a short-acting beta agonist (SABA) was significantly associated with fluticasone treatment (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.21-2.26) and preindex use of SABAs (OR, 1.84; 95% CI, 1.34-2.53). In this managed care population, fluticasone and montelukast provided similar effectiveness.
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Acetatos/uso terapéutico , Androstadienos/uso terapéutico , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud , Quinolinas/uso terapéutico , Adolescente , Adulto , Niño , Ciclopropanos , Servicio de Urgencia en Hospital/estadística & datos numéricos , Femenino , Fluticasona , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Sulfuros , Estados UnidosRESUMEN
We compared measures of treatment effectiveness when inhaled corticosteroids (ICSs) or leukotriene modifiers (LMs) were used as controller monotherapy for asthma. Asthma patients aged 6-55 years initiating ICS or LM monotherapy between July 1998 and June 1999 (index prescription) were identified using a managed care claims database. Asthma-related hospitalizations, emergency department (ED) visits, and use of short-acting beta-agonists and oral corticosteroids (OCSs) were assessed as proxies for treatment effectiveness. Propensity score was used to adjust for baseline differences between treatment cohorts. The change in the annual rate of claims from the preindex to postindex period for each measure was compared across treatment groups. Logistic regression models of the postindex composite events (hospitalization and/or ED) and OCS use were estimated. Nine hundred sixty patients were initiated on LMs (n = 153) and ICSs (n = 807). The mean annual rate of claims for OCSs increased in the ICS group (0.2) but was unchanged in the LM group (adjusted mean difference in change, 0.2; 95% CI, 0.05-0.4; p = 0.01). The mean annual rate of claims for short-acting beta-agonists increased in both the ICS and LM groups by 1.1 and 0.5, respectively (adjusted mean difference in change, 0.6; 95% CI, -0.06. 1.1; p = 0.08). Similar changes in annualized rates of claims for hospitalizations and ED visits were observed between treatment groups. In logistic regression models, greater odds of postindex OCS use was observed among the ICS group (odds ratio for ICS versus LM = 1.7; 95% CI, 1.04-2.8; p = 0.04). No association between treatment groups and postindex hospitalization and/or ED events was observed. In this managed care population, patients treated with ICSs or LMs had similar measures of treatment effectiveness, as measured by asthma-related health care resource use.