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ABSTRACTART-related medication errors occur at high rates in hospitalized people with HIV (PWH), but few studies included modern regimens. As such, we evaluated ART-related medication errors in hospitalized PWH in an era where use of INSTI-based regimens dominate. This multi-center, retrospective cohort included PWH at least 18 years hospitalized in South Georgia, U.S. between March 2016 and March 2018. Of those eligible for inclusion, 400 were randomly selected and included. Three hundred sixty-three inpatient ART-related medication errors occurred in 203 patients during the study period due to incorrect scheduling (44%), an incorrect or incomplete regimen (27%), and drug-drug interactions (27%). Approximately 25% of errors persisted to discharge. Medication errors were more likely to occur in patients receiving NNRTI- or PI-containing multi-tablet regimens, whereas those receiving INSTI-containing multi-tablet regimens were less likely to experience a medication error. ART-related medication errors are less likely in patients receiving INSTI-containing multi-tablet regimens. Ensuring appropriate transition of ART throughout hospitalization remains an area in need of significant improvement.
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We conducted a preregistered multilaboratory project (k = 36; N = 3,531) to assess the size and robustness of ego-depletion effects using a novel replication method, termed the paradigmatic replication approach. Each laboratory implemented one of two procedures that was intended to manipulate self-control and tested performance on a subsequent measure of self-control. Confirmatory tests found a nonsignificant result (d = 0.06). Confirmatory Bayesian meta-analyses using an informed-prior hypothesis (δ = 0.30, SD = 0.15) found that the data were 4 times more likely under the null than the alternative hypothesis. Hence, preregistered analyses did not find evidence for a depletion effect. Exploratory analyses on the full sample (i.e., ignoring exclusion criteria) found a statistically significant effect (d = 0.08); Bayesian analyses showed that the data were about equally likely under the null and informed-prior hypotheses. Exploratory moderator tests suggested that the depletion effect was larger for participants who reported more fatigue but was not moderated by trait self-control, willpower beliefs, or action orientation.
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Ego , Autocontrol , Teorema de Bayes , Humanos , Proyectos de InvestigaciónRESUMEN
The present work examines how judgments of others' commitment to a goal are influenced by three factors that influence one's own goal commitment (satisfaction, investment, and alternatives). In two studies these three factors were manipulated. The results indicated that people rate another's goal commitment higher when goal satisfaction is high, goal investment is high and goal alternatives are low. It was also found that satisfaction and investments alter perceptions of the other's abilities, and that this relationship is partially mediated by perceived goal commitment. The present studies offer novel findings that highlight the information we use to judge the goal commitment of others and the consequences that are incurred when these judgments are formed.
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Objetivos , Motivación , Humanos , Juicio , Satisfacción PersonalRESUMEN
BACKGROUND: Depression is a heterogeneous disorder with multiple aetiological pathways and multiple therapeutic targets. This study aims to determine whether atypical depression (AD) characterized by reversed neurovegetative symptoms is associated with a more pernicious course and a different sociodemographic, lifestyle, and comorbidity profile than nonatypical depression (nonAD). METHODS: Among 157 366 adults who completed the UK Biobank Mental Health Questionnaire (MHQ), N = 37 434 (24%) met the DSM-5 criteria for probable lifetime major depressive disorder (MDD) based on the Composite International Diagnostic Interview Short Form. Participants reporting both hypersomnia and weight gain were classified as AD cases (N = 2305), and the others as nonAD cases (N = 35 129). Logistic regression analyses were conducted to examine differences between AD and nonAD in depression features, sociodemographic and lifestyle factors, lifetime adversities, psychiatric and physical comorbidities. RESULTS: Persons with AD experienced an earlier age of depression onset, longer, more severe and recurrent episodes, and higher help-seeking rates than nonAD persons. AD was associated with female gender, unhealthy behaviours (smoking, social isolation, low physical activity), more lifetime deprivation and adversity, higher rates of comorbid psychiatric disorders, obesity, cardiovascular disease (CVD), and metabolic syndrome. Sensitivity analyses comparing AD persons with those having typical neurovegetative symptoms (hyposomnia and weight loss) revealed similar results. CONCLUSIONS: These findings highlight the clinical and public health significance of AD as a chronic form of depression, associated with high comorbidity and lifetime adversity. Our findings have implications for predicting depression course and comorbidities, guiding research on aetiological mechanisms, planning service use and informing therapeutic approaches.
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Trastorno Depresivo Mayor/epidemiología , Edad de Inicio , Anciano , Trastornos de Ansiedad/epidemiología , Trastorno Bipolar/epidemiología , Comorbilidad , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Síndrome Metabólico/epidemiología , Persona de Mediana Edad , Prevalencia , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Encuestas y Cuestionarios , Reino Unido/epidemiologíaRESUMEN
Hantaviruses, causal agents of the potentially lethal hantavirus pulmonary syndrome, have widely distributed rodent hosts. Using an enzyme-linked immunosorbent assay, we tested blood from 398 wild rodents captured in eastern New Mexico, US in 2015-17 and found 42 antibody-positive samples representing six genera.
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Anticuerpos Antivirales/sangre , Infecciones por Hantavirus/veterinaria , Orthohantavirus/inmunología , Enfermedades de los Roedores/virología , Roedores/sangre , Animales , Infecciones por Hantavirus/epidemiología , Infecciones por Hantavirus/virología , New Mexico/epidemiología , Factores de Riesgo , Enfermedades de los Roedores/sangre , Enfermedades de los Roedores/epidemiología , Estaciones del AñoRESUMEN
Some mitochondrial long noncoding RNAs (lncRNAs) are encoded by nuclear DNA, but the mechanisms that mediate their transport to mitochondria are poorly characterized. Using affinity RNA pull-down followed by mass spectrometry analysis, we found two RNA-binding proteins (RBPs), HuR (human antigen R) and GRSF1 (G-rich RNA sequence-binding factor 1), that associated with the nuclear DNA-encoded lncRNA RMRP and mobilized it to mitochondria. In cultured human cells, HuR bound RMRP in the nucleus and mediated its CRM1 (chromosome region maintenance 1)-dependent export to the cytosol. After RMRP was imported into mitochondria, GRSF1 bound RMRP and increased its abundance in the matrix. Loss of GRSF1 lowered the mitochondrial levels of RMRP, in turn suppressing oxygen consumption rates and modestly reducing mitochondrial DNA replication priming. Our findings indicate that RBPs HuR and GRSF1 govern the cytoplasmic and mitochondrial localization of the lncRNA RMRP, which is encoded by nuclear DNA but has key functions in mitochondria.
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Núcleo Celular/metabolismo , Proteína 1 Similar a ELAV/metabolismo , Mitocondrias/metabolismo , Proteínas de Unión a Poli(A)/metabolismo , ARN Largo no Codificante/metabolismo , Transporte Activo de Núcleo Celular , Células HEK293 , Células HeLa , Humanos , Unión Proteica , Transporte de ProteínasRESUMEN
Cytochrome b5 reductases (CYB5R) are required for the elongation and desaturation of fatty acids, cholesterol synthesis and mono-oxygenation of cytochrome P450 enzymes, all of which are associated with protection against metabolic disorders. However, the physiological role of CYB5R in the context of metabolism, healthspan and aging remains ill-defined. We generated CYB5R-overexpressing flies (CYB5R-OE) and created a transgenic mouse line overexpressing CYB5R3 (CYB5R3-Tg) in the C57BL/6J background to investigate the function of this class of enzymes as regulators of metabolism and age-associated pathologies. Gender- and/or stage-specific induction of CYB5R, and pharmacological activation of CYB5R with tetrahydroindenoindole extended fly lifespan. Increased expression of CYB5R3 was associated with significant improvements in several metabolic parameters that resulted in modest lifespan extension in mice. Diethylnitrosamine-induced liver carcinogenesis was reduced in CYB5R3-Tg mice. Accumulation of high levels of long-chain polyunsaturated fatty acids, improvement in mitochondrial function, decrease in oxidative damage and inhibition of chronic pro-inflammatory pathways occurred in the transgenic animals. These results indicate that CYB5R represents a new target in the study of genes that regulate lipid metabolism and healthspan.
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Mitofusin 2 (Mfn2), a mitochondrial protein, was shown to have antiproliferative properties when overexpressed. In this article, we show that activation of resting human peripheral blood T cells caused downregulation of Mfn2 levels. This downregulation of Mfn2 was blocked by different inhibitors (mTOR inhibitor rapamycin, PI3K inhibitor LY294002, and Akt inhibitor A443654), producing cells that were arrested in the G0/G1 stage of the cell cycle. Furthermore, the activation-induced downregulation of Mfn2 preceded the entry of the cells into the cell cycle, suggesting that Mfn2 downregulation is a prerequisite for activated T cell entry into the cell cycle. Accordingly, small interfering RNA-mediated knockdown of Mfn2 resulted in increased T cell proliferation. Overexpression of constitutively active AKT resulted in the downregulation of Mfn2, which can be blocked by a proteasome inhibitor. Akt-mediated downregulation of Mfn2 was via the mTORC1 pathway because this downregulation was blocked by rapamycin, and overexpression of wild-type, but not kinase-dead mTOR, caused Mfn2 downregulation. Our data suggested that activation-induced reactive oxygen species production plays an important role in the downregulation of Mfn2. Collectively, our data suggest that the PI3K-AKT-mTOR pathway plays an important role in activation-induced downregulation of Mfn2 and subsequent proliferation of resting human T cells.
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GTP Fosfohidrolasas/metabolismo , Leucocitos Mononucleares/inmunología , Proteínas Mitocondriales/metabolismo , Linfocitos T/fisiología , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Cromonas/farmacología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , GTP Fosfohidrolasas/genética , Humanos , Indazoles/farmacología , Indoles/farmacología , Activación de Linfocitos , Proteínas Mitocondriales/genética , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/genética , Sirolimus/farmacología , Linfocitos T/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The mammalian RNA-binding protein AUF1 (AU-binding factor 1, also known as heterogeneous nuclear ribonucleoprotein D [hnRNP D]) binds to numerous mRNAs and influences their posttranscriptional fate. Given that many AUF1 target mRNAs encode muscle-specific factors, we investigated the function of AUF1 in skeletal muscle differentiation. In mouse C2C12 myocytes, where AUF1 levels rise at the onset of myogenesis and remain elevated throughout myocyte differentiation into myotubes, RNP immunoprecipitation (RIP) analysis indicated that AUF1 binds prominently to Mef2c (myocyte enhancer factor 2c) mRNA, which encodes the key myogenic transcription factor MEF2C. By performing mRNA half-life measurements and polysome distribution analysis, we found that AUF1 associated with the 3' untranslated region (UTR) of Mef2c mRNA and promoted MEF2C translation without affecting Mef2c mRNA stability. In addition, AUF1 promoted Mef2c gene transcription via a lesser-known role of AUF1 in transcriptional regulation. Importantly, lowering AUF1 delayed myogenesis, while ectopically restoring MEF2C expression levels partially rescued the impairment of myogenesis seen after reducing AUF1 levels. We propose that MEF2C is a key effector of the myogenesis program promoted by AUF1.
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Ribonucleoproteína Heterogénea-Nuclear Grupo D/fisiología , Desarrollo de Músculos/genética , Músculo Esquelético/embriología , Proteínas de Unión al ARN/fisiología , Regiones no Traducidas 3'/genética , Animales , Diferenciación Celular/genética , Línea Celular , Regulación del Desarrollo de la Expresión Génica , Ribonucleoproteína Nuclear Heterogénea D0 , Ribonucleoproteína Heterogénea-Nuclear Grupo D/genética , Factores de Transcripción MEF2/biosíntesis , Factores de Transcripción MEF2/genética , Ratones , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Unión Proteica/genética , Biosíntesis de Proteínas/genética , Interferencia de ARN , ARN Mensajero/genética , ARN Interferente Pequeño , Proteínas de Unión al ARN/genética , Regeneración/genética , Transcripción Genética/genética , Activación Transcripcional/genéticaRESUMEN
Calorie restriction is the most powerful method currently known to delay aging-associated disease and extend lifespan. Use of this technique in combination with genetic models has led to identification of key metabolic regulators of lifespan. Limiting energy availability by restricting caloric intake leads to redistribution of energy expenditure and storage. The signaling required for these metabolic changes is mediated in part by the sirtuins at both the posttranslational and transcriptional levels, and consequently, sirtuins are recognized as instigating factors in the regulation of lifespan. This family of class III protein deacetylases is responsible for directing energy regulation based on NAD(+) availability. However, there are many effectors of NAD(+) availability, and hence sirtuin action, that should be considered when performing experiments using calorie restriction. The methods outlined in this chapter are intended to provide a guide to help the aging community to use and interpret experimental calorie restriction properly. The importance of healthspan and the use of repeated measures to assess metabolic health during lifespan experiments are strongly emphasized.
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Envejecimiento/fisiología , Restricción Calórica , Estado de Salud , Longevidad/fisiología , Sirtuinas/fisiología , Animales , Metabolismo Energético , Ratones , Ratones Endogámicos C57BLRESUMEN
Carbonylation is the covalent, non-reversible modification of the side chains of cysteine, histidine, and lysine residues by lipid peroxidation end products such as 4-hydroxy- and 4-oxononenal. In adipose tissue the effects of such modifications are associated with increased oxidative stress and metabolic dysregulation centered on mitochondrial energy metabolism. To address the role of protein carbonylation in the pathogenesis of mitochondrial dysfunction, quantitative proteomics was employed to identify specific targets of carbonylation in GSTA4-silenced or overexpressing 3T3-L1 adipocytes. GSTA4-silenced adipocytes displayed elevated carbonylation of several key mitochondrial proteins including the phosphate carrier protein, NADH dehydrogenase 1α subcomplexes 2 and 3, translocase of inner mitochondrial membrane 50, and valyl-tRNA synthetase. Elevated protein carbonylation is accompanied by diminished complex I activity, impaired respiration, increased superoxide production, and a reduction in membrane potential without changes in mitochondrial number, area, or density. Silencing of the phosphate carrier or NADH dehydrogenase 1α subcomplexes 2 or 3 in 3T3-L1 cells results in decreased basal and maximal respiration. These results suggest that protein carbonylation plays a major instigating role in cytokine-dependent mitochondrial dysfunction and may be linked to the development of insulin resistance in the adipocyte.
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Adipocitos/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Carbonilación Proteica/fisiología , Células 3T3-L1 , Adipocitos/citología , Animales , Silenciador del Gen , Resistencia a la Insulina/fisiología , Ratones , Mitocondrias/genética , Proteínas Mitocondriales/genética , Consumo de Oxígeno/fisiologíaRESUMEN
Oxidative stress is linked to the production of reactive lipid aldehydes that non-enzymatically alkylate cysteine, histidine, or lysine residues in a reaction termed protein carbonylation. Reactive lipid aldehydes and their derivatives are detoxified via a variety of phase I and phase II systems, and when antioxidant defenses are compromised or oxidative conditions are increased, protein carbonylation is increased. The resulting modification has been implicated as causative in a variety of metabolic states including neurodegeneration, muscle wasting, insulin resistance, and aging. Although such modifications usually result in loss of protein function, protein carbonylation may be regulatory and activate signaling pathways involved in antioxidant biology and cellular homeostasis.
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Homeostasis , Metabolismo , Carbonilación Proteica/fisiología , Envejecimiento , Aldehídos/metabolismo , Antioxidantes , Humanos , Resistencia a la Insulina , Metabolismo de los Lípidos , Fase I de la Desintoxicación Metabólica/fisiología , Fase II de la Desintoxicación Metabólica/fisiología , Atrofia Muscular , Degeneración Nerviosa , Oxidación-Reducción , Estrés OxidativoRESUMEN
OBJECTIVE: Hyponatremia (serum sodium concentration [Na+] <136 mEq/L) is a potentially life-threatening condition often found chronically in patients with psychotic disorders. Vasopressin antagonists have recently been shown in short-term studies to correct hyponatremia in diverse patient populations, including individuals with both psychosis and idiopathic hyponatremia. However, the safety and efficacy of long-term administration of vaptans is only beginning to be investigated. The objective of this study was to assess whether one of the vaptans, specifically tolvaptan, maintained its safety and efficacy over a prolonged period in patients with psychosis and chronic idiopathic hyponatremia. METHODS: SALTWATER was a multicenter, open-label extension of the Study of Ascending Levels of Tolvaptan in Hyponatremia. Of the 111 patients enrolled in SALTWATER, eight were patients with both psychosis and idiopathic hyponatremia. These eight subjects provided a total of 7,406 patient days of exposure to oral tolvaptan. RESULTS: Mean serum [Na+] in the eight psychotic patients increased from 131.6 mEq/L at baseline to >135 mEq/L throughout the observation period (p<0.05 versus baseline at most points). No drug-related adverse events led to study discontinuation. CONCLUSIONS: Chronic hyponatremia is known to have deleterious effects on the quality of life for many patient groups. These preliminary results suggest that oral tolvaptan provides rapid, effective, and safe treatment of chronic hyponatremia in patients with psychotic disorders and that the effect is safely sustained over long periods of time. These findings represent an important step forward in treating a significant unmet need in psychotic populations.
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Antagonistas de los Receptores de Hormonas Antidiuréticas , Benzazepinas/administración & dosificación , Hiponatremia/tratamiento farmacológico , Trastornos Psicóticos/tratamiento farmacológico , Administración Oral , Adulto , Benzazepinas/efectos adversos , Enfermedad Crónica , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Hiponatremia/sangre , Cuidados a Largo Plazo , Masculino , Persona de Mediana Edad , Trastornos Psicóticos/sangre , Sodio/sangre , Tolvaptán , Resultado del TratamientoRESUMEN
Hyponatremia (serum sodium concentration [Na+] < 136 mEq/L) is a potentially life-threatening condition. Recent evidence (Renneboog, Musch, Vandemergel, Manto, & Decaux, 2006) shows that even mild hyponatremia is associated with disorders of balance/gait. This retrospective analysis explored the influence of serum [Na+] on neuropsychological (NP) measurements at baseline from 44 patients with chronic hyponatremia who participated in an efficacy and safety study of an experimental compound over a decade ago. Group mean serum [Na+] was 124.8 ± 4.9 mEq/L. Age-adjusted partial correlations were computed between serum [Na+] and NP measurements, 39% of which were statistically significant--all involving psychomotor functioning. These findings replicate and extend previous observations that psychomotor deficits are, at least in part, associated with hyponatremia in these patients. While chronic hyponatremia is known to have deleterious effects on quality of life, motor and gait disturbances represent manifestations of mild hyponatremia that have until now gone unrecognized. A new class of medication, vasopressin antagonists, has been shown to correct hyponatremia. It will be important to explore the effects of correcting hyponatremia on psychomotor functioning in individuals with hyponatremia.
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Trastornos Neurológicos de la Marcha/etiología , Hiponatremia/complicaciones , Trastornos Psicomotores/etiología , Adulto , Anciano , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Femenino , Trastornos Neurológicos de la Marcha/sangre , Humanos , Hiponatremia/sangre , Inteligencia , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Trastornos Psicomotores/sangre , Trastornos Psicomotores/diagnóstico , Análisis de Regresión , Estudios Retrospectivos , Sodio/sangreRESUMEN
Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal coping response to more toxic forms of polyQ. The exact structure of these more toxic forms is unknown. Here we show that the monoclonal antibody 3B5H10 recognizes a species of polyQ protein in situ that strongly predicts neuronal death. The epitope selectively appears among some of the many low-molecular-weight conformational states assumed by expanded polyQ and disappears in higher-molecular-weight aggregated forms, such as inclusion bodies. These results suggest that protein monomers and possibly small oligomers containing expanded polyQ stretches can adopt a conformation that is recognized by 3B5H10 and is toxic or closely related to a toxic species.
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Enfermedades Neurodegenerativas/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Péptidos/química , Péptidos/toxicidad , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos , Muerte Celular/efectos de los fármacos , Células Cultivadas , Epítopos/química , Epítopos/inmunología , Epítopos/toxicidad , Células HEK293 , Humanos , Cuerpos de Inclusión/química , Peso Molecular , Enfermedades Neurodegenerativas/metabolismo , Neuronas/metabolismo , Péptidos/inmunología , Relación Estructura-Actividad , Expansión de Repetición de TrinucleótidoRESUMEN
OBJECTIVE: To investigate available shielding methods in an effort to further awareness and understanding of existing preventive measures related to patient exposure in computed tomography (CT) scanning. METHODS: Searches were conducted to locate literature discussing the effectiveness of commercially available shields. Literature containing information regarding breast, gonad, eye and thyroid shielding was identified. Because of rapidly advancing technology, the selection of articles was limited to those published within the past 5 years. The selected studies were examined using the following topics as guidelines: the effectiveness of the shield (percentage of dose reduction), the shield's effect on image quality, arguments for or against its use (including practicality) and overall recommendation for its use in clinical practice. RESULTS: Only a limited number of studies have been performed on the use of shields for the eyes, thyroid and gonads, but the evidence shows an overall benefit to their use. Breast shielding has been the most studied shielding method, with consistent agreement throughout the literature on its effectiveness at reducing radiation dose. The effect of shielding on image quality was not remarkable in a majority of studies. Although it is noted that more studies need to be conducted regarding the impact on image quality, the currently published literature stresses the importance of shielding in reducing dose. CONCLUSION: Commercially available shields for the breast, thyroid, eyes and gonads should be implemented in clinical practice. Further research is needed to ascertain the prevalence of shielding in the clinical setting.
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Traumatismos por Radiación/prevención & control , Protección Radiológica/métodos , Tomografía Computarizada por Rayos X , Mama/efectos de la radiación , Ojo/efectos de la radiación , Gónadas/diagnóstico por imagen , Humanos , Dosis de Radiación , Glándula Tiroides/efectos de la radiaciónRESUMEN
OBJECTIVE: The objective was to compare short-term effectiveness of aripiprazole with three other second-generation antipsychotics (SGAs) in the treatment of first-episode psychosis. METHOD: In a naturalistic, 'single-blind' design, 60 subjects experiencing their first psychotic episode were treated for 8 weeks with aripiprazole (n = 19), risperidone (n = 16), olanzapine (n = 14) or quetiapine (n = 11). Medication and dosing decisions were made by treating psychiatrists, constrained to once-a-day dosing, low initial doses and no clozapine. Weekly ratings were obtained using the Positive and Negative Syndrome Scale (PANSS), Simpson-Angus Rating Scale and Barnes Akathasia Rating Scale. Weight and vital signs were also collected weekly. RESULTS: The group presented with severe psychotic symptoms (mean baseline PANSS total score of 105.2), which were reduced rapidly (P < 0.0005). The between-group and group by time interaction terms were non-significant. Similar reductions were seen across all PANSS sub-scales. At Week 1 the mean PANSS Activation Scale score was reduced more with olanzapine than in the other groups (P < 0.002). Few instances of extrapyramidal symptoms occurred; all were sporadic and did not require treatment. Group body weight increased by 7.3% over the study. Vital signs remained unchanged. CONCLUSIONS: Early intervention with low doses of four SGAs led to rapid symptom reduction in first-episode psychotic patients with severe psychopathology. Although no clear medication advantages were observed in the short term, longer duration studies with larger samples will be required for determining efficacy, rates of compliance, relapse prevention and diminished incidence of extrapyramidal signs and symptoms.