RESUMEN
To understand the role of symptom attribution in treatment-seeking behaviours, survey results of 1356 veterans (age = 38-72 years) were analysed. Controlling for symptom frequency, significant relationships were found for specialist and psychological-related consultations. Those who favoured psychological explanations for symptoms were more likely to attend specialist and psychology-related consultations and filled significantly more prescriptions than people who predominantly explained symptoms by situational factors (normalisers). Veterans who favoured somatic explanations attended more general practitioner consultations than normalisers. Attributional style should be considered part of the constellation of factors influencing healthcare usage. Normalisers, the predominant group, used fewest health services and filled fewest prescriptions; this may have important implications for healthcare considering their tendency to minimise or downplay symptoms.
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Conductas Relacionadas con la Salud , Encuestas Epidemiológicas , Trastornos Mentales/psicología , Trastornos Mentales/terapia , Cooperación del Paciente , Veteranos/psicología , Adulto , Anciano , Australia , Humanos , Masculino , Persona de Mediana Edad , PsicologíaRESUMEN
OBJECTIVE: To examine the psychometric properties of the Demoralisation Scale II (DS-II) and adapt it for use with women in the postnatal period. BACKGROUND: Demoralisation is a psychological state characterised by a sense of incompetence and feelings of helplessness and hopelessness in response to a stressful situation. The postnatal period is a life stage of many disruptions. Women may lose their confidence and become demoralised if feeling unprepared for the tasks of motherhood. The DS-II is a 16-item scale developed among cancer patients, but with content that is also relevant postnatally, including items on sense of failure, helplessness, hopelessness, isolation, entrapment and loss of purpose. METHODS: Rasch analysis was used to investigate the psychometric properties of the DS-II and refine the scale for postnatal use. RESULTS: Participants were 209 women admitted with their babies to a residential early parenting programme. A 14-item revised scale was derived, the Postnatal DS-II, showing good psychometric properties, discriminant validity and sensitivity to change, and being well targeted to the sample. CONCLUSION: The Postnatal DS-II could have utility as an assessment tool, helping clinicians to understand better women's postnatal experiences, assess the effectiveness of interventions and communicate with women in a meaningful and non-stigmatising way.
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Adaptación Psicológica , Responsabilidad Parental/psicología , Periodo Posparto , Psicometría , Estrés Psicológico/epidemiología , Encuestas y Cuestionarios , Adulto , Femenino , Humanos , Lactante , Madres/psicología , Reproducibilidad de los Resultados , Autoimagen , Estrés Psicológico/diagnóstico , Estrés Psicológico/etiologíaRESUMEN
INTRODUCTION: The impact of medical student psychological distress on academic performance has not been systematically examined. This study provided an opportunity to closely examine the potential impacts of workplace and study related stress factors on student's psychological distress and their academic performance during their first clinical year. METHODS: This one-year prospective cohort study was performed at a tertiary hospital based medical school in Melbourne, Australia. Students completed a questionnaire at three time points during the year. The questionnaire included the validated Kessler psychological distress scale (K10) and the General Health Questionnaire-28 (GHQ-28), as well as items about sources of workplace stress. Academic outcome scores were aggregated and correlated with questionnaire results. RESULTS: One hundred and twenty six students participated; 126 (94.7%), 102 (76.7%), and 99 (74.4%) at time points one, two, and three, respectively. 33.1% reported psychological distress at time point one, increasing to 47.4% at time point three. There was no correlation between the K10 scores and academic performance. There was weak negative correlation between the GHQ-28 at time point three and academic performance. Keeping up to date with knowledge, need to do well and fear of negative feedback were the most common workplace stress factors. CONCLUSIONS: Poor correlation was noted between psychological distress and academic performance.
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Rendimiento Académico/psicología , Estrés Psicológico/epidemiología , Estrés Psicológico/psicología , Estudiantes de Medicina/psicología , Adulto , Femenino , Humanos , Masculino , Estudios Prospectivos , Facultades de Medicina , Encuestas y Cuestionarios , Victoria/epidemiología , Adulto JovenRESUMEN
P-glycoprotein (P-gp) is an ATP-dependent drug pump that protects us from toxic agents and confers multidrug resistance. It has a tweezer-like structure with each arm consisting of a transmembrane domain (TMD) and a nucleotide-binding domain (NBD). Drug substrates bind to sites within the TMDs to activate ATPase activity by promoting a tweezer-like closing of the gap between the NBDs. The catalytic carboxylates may be critical for NBD movements because the E556Q(NBD1) or E1201Q(NBD2) mutation inhibited drug-stimulated ATPase activity. If the catalytic carboxylates were components of the mechanism to bring the NBDs together, then we predicted that insertion of a flexible cross-linker between the arms would increase ATPase activity of the mutants. We found that cross-linking (between L175C(TMD1) and N820C(TMD2)) with a short flexible cross-linker (7.8Å maximum) restored high levels of drug-stimulated ATPase activity of the E556Q or E1201Q mutants. Cross-linking with a longer cross-linker (22Å maximum) however, did not restore activity. Cross-linking could not rescue all ATPase deficient mutants. For example, cross-linking L175C/N820C with short or long cross-linkers did not activate the H-loop mutants H587A or H1232A or the Walker A K433M or K1076M mutants. The results suggest that the E556 and E1201 catalytic carboxylates are part of a spring-like mechanism that is required to facilitate movements between the open and closed conformations of P-gp during ATP hydrolysis.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfatasas/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Adenosina Trifosfatasas/genética , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Transporte Biológico , Dominio Catalítico , Línea Celular , Cricetinae , Regulación Enzimológica de la Expresión Génica , Humanos , Modelos Moleculares , Mutación , Conformación Proteica , Vinblastina/metabolismo , Vinblastina/farmacologíaRESUMEN
P-glycoprotein (P-gp, ABCB1) is an ABC drug pump that is clinically important because it is involved in multidrug resistance. Many studies have used purified P-gp in detergent (n-dodecyl-ß-D-maltoside; DM) micelles to map the locations of the drug-binding sites. A potential problem is that DM could be a substrate and affect binding of drugs to P-gp. To test whether DM was a substrate of P-gp, we used an assay involving drug-rescue of the immature 150 kDa misprocessed P-gp mutant (L1260A) to show that DM is not substrate. By contrast, the detergents Triton X-100 or NP-35 were substrates because they rescued the L1260A P-gp mutant such that the major product was the mature 170 kDa protein. Cross-linking of mutant A80C/R741C in membranes can only be inhibited by the P-gp substrate tariquidar. We show that cross-linking A80C/R741C mutant was also inhibited by tariquidar in the presence of excess DM. This result suggests that the presence of DM did not affect the tariquidar-binding site. Similarly, the presence of DM did not alter the locations of other drug-binding sites since the thiol reactive forms of the substrates verapamil or rhodamine labeled the same sites in transmembrane segments 5 (I306C for verapamil) and 6 (F343C for rhodamine) whether P-gp was in native membranes or in detergent micelles. These results suggest that the presence of DM does not alter the locations of the P-gp drug-binding sites and that the detergent purified protein is suitable for mapping their locations using biochemical or structural assays.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Adenosina Trifosfatasas/metabolismo , Detergentes/química , Glucósidos/química , Micelas , Quinolinas/farmacología , Rodaminas/farmacología , Verapamilo/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Sitios de Unión/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/enzimología , Activación Enzimática/efectos de los fármacos , HumanosRESUMEN
A large number of correctors have been identified that can partially repair defects in folding, stability and trafficking of CFTR processing mutants that cause cystic fibrosis (CF). The best corrector, VX-809 (Lumacaftor), has shown some promise when used in combination with a potentiator (Ivacaftor). Understanding the mechanism of VX-809 is essential for development of better correctors. Here, we tested our prediction that VX-809 repairs folding and processing defects of CFTR by promoting interactions between the first cytoplasmic loop (CL1) of transmembrane domain 1 (TMD1) and the first nucleotide-binding domain (NBD1). To investigate whether VX-809 promoted CL1/NBD1 interactions, we performed cysteine mutagenesis and disulfide cross-linking analysis of Cys-less TMD1 (residues 1-436) and ΔTMD1 (residues 437-1480; NBD1-R-TMD2-NBD2) truncation mutants. It was found that VX-809, but not bithiazole correctors, promoted maturation (exited endoplasmic reticulum for addition of complex carbohydrate in the Golgi) of the ΔTMD1 truncation mutant only when it was co-expressed in the presence of TMD1. Expression in the presence of VX-809 also promoted cross-linking between R170C (in CL1 of TMD1 protein) and L475C (in NBD1 of the ΔTMD1 truncation protein). Expression of the ΔTMD1 truncation mutant in the presence of TMD1 and VX-809 also increased the half-life of the mature protein in cells. The results suggest that the mechanism by which VX-809 promotes maturation and stability of CFTR is by promoting CL1/NBD1 interactions.
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Aminopiridinas/metabolismo , Benzodioxoles/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Secuencia de Aminoácidos/genética , Sitios de Unión/fisiología , Células HEK293 , Humanos , Unión Proteica/fisiologíaRESUMEN
P-glycoprotein (P-gp) is an ABC (ATP-Binding Cassette) drug pump that is clinically important because it confers multidrug resistance. Drugs bind at the interface between the transmembrane domains to activate ATPase activity at the two nucleotide-binding domains (NBDs). Drug transport involves ATP-dependent conformational changes between inward- (open, NBDs far apart) and outward-facing (closed, NBDs close together) conformations. Recently, it was reported that the conserved glutamines residues (Gln475 in NBD1 and Gln1118 in NBD2) in the Q loops of P-gp when mutated to alanine completely inhibited the drug-stimulated ATPase activity. It is unknown why the glutamine residues (Gln475 and Gln1118) in the Q loops of the NBDs of P-gp are required for drug-stimulated ATPase activity. Here we show that introduction of these mutations into the L175C/N820C mutant (L175C/N820C/Q475A/Q1118A) also abolished drug-stimulated ATPase activity. The ATPase activity was restored however, when the L175C/N820C/Q475A/Q1118A mutant was cross-linked with a flexible disulfide cross-linker. These results suggest that both Q-loop glutamines are not required for ATP hydrolysis and they might function as part of a spring-like mechanism in facilitating the open (inactive) to closed (active) conformational change during ATP hydrolysis. The molecular spring-like action of the Q-loop glutamines during drug-stimulated ATPase activity is likely mimicked by the attachment of the flexible cross-linker.
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Adenosina Trifosfatasas/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Línea Celular , Cricetinae , Reactivos de Enlaces Cruzados/química , Detergentes/química , Disulfuros/química , Resistencia a Medicamentos , Resistencia a Múltiples Medicamentos , Glutamina/química , Células HEK293 , Humanos , Hidrólisis , Lípidos/química , Conformación Molecular , Mutación , Conformación Proteica , Dominios ProteicosRESUMEN
BACKGROUND: The recently refined Demoralization Scale-II (DS-II) is a 16-item, self-report measure of demoralization. Its 2 factors-Meaning and Purpose and Distress and Coping Ability-demonstrate sound internal validity, including item fit, unidimensionality, internal consistency, and test-retest reliability. The convergent and discriminant validity of the DS-II with various measures is reported here. METHODS: Patients who had cancer or other progressive diseases and were receiving palliative care (n = 211) completed a battery of questionnaires, including the DS-II and measures of symptom burden, quality of life, depression, and attitudes toward the end of life. Spearman ρ correlations were determined to assess convergent validity. Mann-Whitney U tests with calculated effect sizes were used to examine discriminant validity and establish the minimal clinically important difference (MCID). Cross-tabulation frequencies with chi-square analyses were used to examine discriminant validity with major depression. RESULTS: The DS-II demonstrated convergent validity with measures of psychological distress, quality of life, and attitudes toward the end of life. It also demonstrated discriminant validity, as the DS-II differentiated patients who had different functional performance levels and high/low symptoms, with a difference of 2 points between groups on the DS-II considered clinically meaningful. Furthermore, discriminant validity was demonstrated, as comorbidity with depression was not observed at moderate levels of demoralization. CONCLUSIONS: The DS-II has sound psychometric properties and is an appropriate measure of demoralization. Given its structural simplicity and brevity, it is likely to be a useful tool in meaning-centered therapies. Cancer 2016;122:2260-7. © 2016 American Cancer Society.
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Neoplasias/psicología , Psicometría , Adaptación Psicológica , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/terapia , Cuidados Paliativos , Psicometría/métodos , Calidad de Vida , Reproducibilidad de los Resultados , Factores de Riesgo , Factores Socioeconómicos , Estrés Psicológico/diagnóstico , Encuestas y CuestionariosRESUMEN
BACKGROUND: The Demoralization Scale (DS) was initially validated in 2004 to enable the measurement of demoralization in patients with advanced cancer. Subsequent shortcomings indicated the need for psychometric strengthening. Here, the authors report on the refinement and revalidation of the DS to form the DS-II, specifically reporting the scale's internal validity. METHODS: Patients with cancer or other progressive diseases who were receiving palliative care (n = 211) completed a revised version of the 24-item DS and a measure of symptom burden (the Memorial Symptom Assessment Scale). Exploratory factor analysis and Rasch modeling were used to evaluate, modify, and revalidate the scale, providing information about dimensionality, suitability of response format, item fit, item bias, and item difficulty. Test-retest reliability was examined for 58 symptomatically stable patients at a 5-day follow-up. RESULTS: Exploratory factor analysis supported a 22-item, 2-component model. Separate Rasch modeling of each component resulted in collapsing the response option categories and removing 3 items from each component. Both final 8-item subscales met Rasch model expectations and were appropriate to sum as a 16-item total score. The DS-II demonstrated internal consistency and test-retest reliability (Meaning and Purpose subscale: α = .84; intraclass correlation [ICC] = 0.68; Distress and Coping Ability subscale: α = .82; ICC = 0.82; total DS: α = .89; ICC = 0.80). CONCLUSIONS: The DS-II is a 3-point response, self-report scale comprising 16 items and 2 subscales. Given its revalidation, psychometric strengthening, and simplification, the DS-II is an improved and more practical measure of demoralization for research and clinical use. External validation of the DS-II will be reported subsequently. Cancer 2016;122:2251-9. © 2016 American Cancer Society.
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Neoplasias/psicología , Psicometría , Adaptación Psicológica , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Neoplasias/terapia , Cuidados Paliativos , Psicometría/métodos , Reproducibilidad de los Resultados , Autoinforme , Estrés PsicológicoRESUMEN
Drug substrates stimulate ATPase activity of the P-glycoprotein (P-gp) ATP-binding cassette drug pump by an unknown mechanism. Cross-linking analysis was performed to test if drug substrates stimulate P-gp ATPase activity by altering cross-talk at the first transmission interface linking the drug-binding [intracellular loop 4 (S909C)] and first nucleotide-binding domains [NBD1 (V472C or L443C)]. In the absence of lipid (inactive P-gp), only V472C/S909C showed cross-linking. Drugs blocked V472C/S909C cross-linking. In the presence of lipids (active P-gp), drug substrates promoted only L443C/S909C cross-linking. This suggests that drug substrates stimulate ATPase activity through a conformational change that shifts Ser909 away from Val472 and toward Leu443.
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Adenosina Trifosfatasas/química , Subfamilia B de Transportador de Casetes de Unión a ATP/química , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Sustitución de Aminoácidos , Humanos , Mutación Missense , Dominios Proteicos , Estructura Secundaria de ProteínaRESUMEN
P-glycoprotein (P-gp) is an ABC (ATP-Binding Cassette) drug pump. A common feature of ABC proteins is that they are organized into two wings. Each wing contains a transmembrane domain (TMD) and a nucleotide-binding domain (NBD). Drug substrates and ATP bind at the interface between the TMDs and NBDs, respectively. Drug transport involves ATP-dependent conformational changes between inward- (open, NBDs far apart) and outward-facing (closed, NBDs close together) conformations. P-gps crystallized in the presence of detergent show an open structure. Human P-gp is inactive in detergent but basal ATPase activity is restored upon addition of lipids. The lipids might cause closure of the wings to bring the NBDs close together to allow ATP hydrolysis. We show however, that cross-linking the wings together did not activate ATPase activity when lipids were absent suggesting that lipids may induce other structural changes required for ATPase activity. We then tested the effect of lipids on disulfide cross-linking of mutants at the first transmission interface between intracellular loop 4 (TMD2) and NBD1. Mutants L443C/S909C and L443C/R905C but not G471C/S909C and V472C/S909C were cross-linked with oxidant when in membranes. The mutants were then purified and cross-linked with or without lipids. Mutants G471C/S909C and V472C/S909C cross-linked only in the absence of lipids whereas mutants L443C/S909C and L443C/R905C were cross-linked only in the presence of lipids. The results suggest that lipids activate a switch at the first transmission interface and that the structure of P-gp is different in detergents and lipids.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/ultraestructura , Adenosina Trifosfatasas/química , Adenosina Trifosfatasas/ultraestructura , Detergentes/química , Lípidos/química , Sitios de Unión , Activación Enzimática , Estabilidad de Enzimas , Humanos , Modelos Químicos , Simulación del Acoplamiento Molecular , Unión Proteica , Conformación Proteica , Relación Estructura-ActividadRESUMEN
OBJECTIVE: To explore the contribution of health anxiety to disability and use of mental health and medical services, independently of co-occurring mental and physical conditions. METHODS: Data from the Australian National Survey of Mental Health and Wellbeing 2007 were analyzed (n = 8841). Participants were aged 16 to 85 years (mean [standard deviation] = 46.3 [19.0] years) and 54% were women. RESULTS: Health anxiety accounted independently for high disability and service use. People with health anxiety were more likely to use both mental health (for psychiatrists: odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.2-3.5; for psychologists: OR = 1.9, 95% CI = 1.2-3.3) and specialist medical services (OR = 1.7, 95% CI = 1.2-2.3) than people without health anxiety. However, they were not high-frequency attenders to specialist mental health services (OR = 1.6 [95% CI = 0.9-3.0] and OR = 1.3 [95% CI = 0.6-2.9]) compared with people with other mental disorders (OR = 11.7 [95% CI = 4.3-31.8] and OR = 29.5 [95% CI = 13.5-64.6] for psychiatrists and psychologists, respectively). People with health anxiety were likely to be high-frequency attenders to general practice (OR = 2.0, 95% CI = 1.4-2.8) and specialist medical services (OR = 2.4, 95% CI = 1.7-3.6). CONCLUSIONS: It is important to recognize and treat health anxiety, even when coexisting with other conditions, to prevent high disability burden and excessive service use. The cross-sectional design and self-reported outcomes may have resulted in overestimation of the associations. Future work is needed on actual service use using reviews of medical records.
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Ansiedad/epidemiología , Actitud Frente a la Salud , Servicios de Salud/estadística & datos numéricos , Aceptación de la Atención de Salud/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica/epidemiología , Comorbilidad , Estudios Transversales , Evaluación de la Discapacidad , Personas con Discapacidad/psicología , Femenino , Medicina General , Humanos , Hipocondriasis/epidemiología , Hipocondriasis/psicología , Masculino , Medicina , Trastornos Mentales/epidemiología , Servicios de Salud Mental/estadística & datos numéricos , Persona de Mediana Edad , Prevalencia , Autoimagen , Estrés Psicológico/epidemiología , Victoria/epidemiología , Poblaciones Vulnerables/psicología , Adulto JovenRESUMEN
ABC (ATP-binding cassette) transporters are clinically important because drug pumps like P-glycoprotein (P-gp, ABCB1) confer multidrug resistance and mutant ABC proteins are responsible for many protein-folding diseases such as cystic fibrosis. Identification of the tariquidar-binding site has been the subject of intensive molecular modeling studies because it is the most potent inhibitor and corrector of P-gp. Tariquidar is a unique P-gp inhibitor because it locks the pump in a conformation that blocks drug efflux but activates ATPase activity. In silico docking studies have identified several potential tariquidar-binding sites. Here, we show through cross-linking studies that tariquidar most likely binds to sites within the transmembrane (TM) segments located in one wing or at the interface between the two wings (12 TM segments form 2 divergent wings). We then introduced arginine residues at all positions in the 12 TM segments (223 mutants) of P-gp. The rationale was that a charged residue in the drug-binding pocket would disrupt hydrophobic interaction with tariquidar and inhibit its ability to rescue processing mutants or stimulate ATPase activity. Arginines introduced at 30 positions significantly inhibited tariquidar rescue of a processing mutant and activation of ATPase activity. The results suggest that tariquidar binds to a site within the drug-binding pocket at the interface between the TM segments of both structural wings. Tariquidar differed from other drug substrates, however, as it stabilized the first TM domain. Stabilization of the first TM domain appears to be a key mechanism for high efficiency rescue of ABC processing mutants that cause disease.
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Quinolinas/química , Subfamilia B de Transportador de Casetes de Unión a ATP/química , Adenosina Trifosfatasas/química , Arginina/química , Sitios de Unión , Membrana Celular/metabolismo , Reactivos de Enlaces Cruzados/química , Disulfuros/química , Resistencia a Múltiples Medicamentos , Glicósido Hidrolasas/metabolismo , Células HEK293 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Mutación , Unión Proteica , Pliegue de Proteína , Estructura Secundaria de Proteína , Estructura Terciaria de ProteínaRESUMEN
OBJECTIVE: Major depression occurs frequently in veterans, and is associated with comorbid psychological and physical disorders and poorer quality of life. Depression can be difficult to detect in primary care, while lengthy assessment instruments can deter use. Our study aimed to develop a brief depression screen that could be used by veterans and caregivers, and then to compare the association between the brief screen and comorbidities and quality of life with that of a longer instrument. METHODS: Our dataset comprised 1204 male Royal Australian Navy veterans of the 1990/91 Gulf War. Depressive symptoms were assessed using the General Health Questionnaire (GHQ-12), health-related quality of life by the Short-Form Health Survey (SF-12), major depression and comorbid psychiatric diagnoses such as posttraumatic disorder (PTSD) using Diagnostic and Statistical Manual (DSM-IV) criteria. Comorbid physical illnesses including musculoskeletal disorders, chronic fatigue and diabetes were examined. RESULTS: A brief depression screen of three key self-reported symptoms was identified. Veterans with major depression present according to the screen were over four times more likely to have multisymptom illness or PTSD, and almost twice as likely to have musculoskeletal disorders. Having depression according to the brief screen and having at least one other physical or psychological condition was associated with poorer quality of life. Similar results were obtained for a longer screen based on all GHQ-12 items. CONCLUSION: A 3 item depression screen performed as well as a 12 item one in identifying major depression, comorbid physical and psychological illness and poorer quality of life in veterans.
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Depresión/diagnóstico , Depresión/psicología , Guerra del Golfo , Trastornos Mentales/diagnóstico , Trastornos Mentales/psicología , Pruebas Neuropsicológicas , Veteranos/psicología , Adulto , Australia/epidemiología , Comorbilidad , Estudios Transversales , Depresión/complicaciones , Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/psicología , Diabetes Mellitus/epidemiología , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Síndrome de Fatiga Crónica/epidemiología , Humanos , Masculino , Trastornos Mentales/complicaciones , Persona de Mediana Edad , Enfermedades Musculoesqueléticas/complicaciones , Enfermedades Musculoesqueléticas/epidemiología , Calidad de Vida , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/psicología , Encuestas y CuestionariosRESUMEN
BACKGROUND: Demoralisation is a psychological state occurring in stressful life situations where a person feels unable to respond effectively to their circumstances, characterised by feelings of distress, subjective incompetence, helplessness and hopelessness. The period after the birth of a first baby is a time of great changes and disruptions to many aspects of the mother's physical, psychological and social functioning. This can lead to feelings of distress, a sense of incompetence and helplessness. This study aimed to examine: (1) the psychometric properties of the Demoralisation Scale in a community setting; (2) the prevalence of demoralisation symptoms among primiparous women in the community; and (3) factors that are uniquely associated with demoralisation in the early postnatal period. METHODS: Primiparous women attending community maternal health centres (n = 400) were recruited and administered the study's questionnaires through a telephone interview. RESULTS: The Demoralisation Scale was found to be a reliable and valid tool among women in the community who had recently given birth. Higher levels of demoralisation were independently associated with lower confidence on going home from the hospital after birth, lower rating of mother's self-rated global health, more than 3 h of infant crying and fussing in the last 24 h, and a controlling partner, after symptoms of depression and anxiety, and vulnerable personality characteristics were controlled for. CONCLUSIONS: The relevance of demoralisation to postnatal health practitioners in the community is in helping them to better understand women's experiences and to intervene in a way that is more meaningful and less stigmatising to women.
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Madres/psicología , Responsabilidad Parental/psicología , Escalas de Valoración Psiquiátrica , Estrés Psicológico/diagnóstico , Estrés Psicológico/epidemiología , Adolescente , Adulto , Llanto , Análisis Factorial , Femenino , Estado de Salud , Humanos , Recién Nacido , Relaciones Interpersonales , Paridad , Periodo Posparto , Embarazo , Prevalencia , Psicometría , Reproducibilidad de los Resultados , Autoeficacia , Estrés Psicológico/etiología , Evaluación de Síntomas , Adulto JovenRESUMEN
OBJECTIVE: To better understand the consistent elevated symptom reporting by Gulf War veterans; we compared Australian Gulf War veterans and military-comparison group on symptom attributional styles and the relationship with total number and grouping of somatic and psychological symptoms. METHOD: Postal questionnaires were completed by Australian Gulf War veterans (n=697) and military-comparison group (n=659) in 2000-2002 and 2011-2012. Data were collected on deployments, military-psychological stressors, symptom reporting, symptom factors and attributional style (normalising, psychologising, somatising, mixed-attribution). RESULTS: Gulf War veterans did not differ in attributional style from comparison group (p>0.05); normalising was the predominant style. Groups were combined for analyses. Psychologisers reported the highest overall symptoms (mean(M)=10.95, standard deviation(SD)=9.15), the most psychophysiological (M=1.71, SD=2.82), cognitive (M=5.79, SD=5.09) and arthro-neuromuscular symptoms (M=1.53, SD=1.73). Psychologisers and somatisers reported significantly more symptoms across overall symptoms, all three symptom factors and psychological distress than normalisers. Normalisers consistently reported fewest overall symptoms (M=2.85, SD=4.49), psychophysiological (M=0.40, SD=0.98), cognitive (M=1.14, SD=2.22), and arthro-neuromuscular symptoms (M=0.72, SD=1.31). Persistent symptoms, rather than remitted, between baseline and follow-up were associated with increased rates of psychologising and mixed-attribution compared with normalising. For incident symptoms a similar pattern was observed, some symptoms also showed increased rates of somatising. CONCLUSIONS: In veterans, psychologising was associated with higher symptom reporting, whilst somatisers and mixed-attribution also demonstrated higher reporting than normalisers. Symptom persistence and incidence were associated with symptom attribution. The findings indicate that attributional style is associated with patterns of symptom reporting and highlights both past and present symptoms may influence attributional style.
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Conductas Relacionadas con la Salud , Trastornos Mentales/psicología , Personal Militar/psicología , Evaluación de Síntomas/psicología , Veteranos/psicología , Adulto , Anciano , Australia/epidemiología , Autoevaluación Diagnóstica , Femenino , Guerra del Golfo , Humanos , Masculino , Trastornos Mentales/epidemiología , Persona de Mediana Edad , Personal Militar/estadística & datos numéricos , Síndrome del Golfo Pérsico , Encuestas y Cuestionarios , Veteranos/estadística & datos numéricosRESUMEN
P-glycoprotein (P-gp; ABCB1) is an ABC drug pump that protects us from toxic compounds. It is clinically important because it confers multidrug resistance. The homologous halves of P-gp each contain a transmembrane (TM) domain (TMD) with 6 TM segments followed by a nucleotide-binding domain (NBD). The drug- and ATP-binding sites reside at the interface between the TMDs and NBDs, respectively. Each NBD is connected to the TMDs by a transmission interface involving a pair of intracellular loops (ICLs) that form ball-and-socket joints. P-gp is different from CFTR (ABCC7) in that deleting NBD2 causes misprocessing of only P-gp. Therefore, NBD2 might be critical for stabilizing ICLs 2 and 3 that form a tetrahelix bundle at the NBD2 interface. Here we report that the NBD1 and NBD2 transmission interfaces in P-gp are asymmetric. Point mutations to 25 of 60 ICL2/ICL3 residues at the NBD2 transmission interface severely reduced P-gp assembly while changes to the equivalent residues in ICL1/ICL4 at the NBD1 interface had little effect. The hydrophobic nature at the transmission interfaces was also different. Mutation of Phe-1086 or Tyr-1087 to arginine at the NBD2 socket blocked activity or assembly while the equivalent mutations at the NBD1 socket had only modest effects. The results suggest that the NBD transmission interfaces are asymmetric. In contrast to the ICL2/3-NBD2 interface, the ICL1/4-NBD1 transmission interface is more hydrophilic and insensitive to mutations. Therefore the ICL2/3-NBD2 transmission interface forms a precise hydrophobic connection that acts as a linchpin for assembly and trafficking of P-gp.
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Subfamilia B de Transportador de Casetes de Unión a ATP/química , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Sitios de Unión , Línea Celular , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Mutación , Pliegue de Proteína , Estructura Secundaria de Proteína , Estructura Terciaria de ProteínaRESUMEN
P-glycoprotein (P-gp, ABCB1) is a drug pump that confers multidrug resistance. Inhibition of P-gp would improve chemotherapy. Tariquidar is a potent P-gp inhibitor but its mechanism is unknown. Here, we tested our prediction that tariquidar inhibits P-gp cycling between the open and closed states during the catalytic cycle. Transition of P-gp to an open state can be monitored in intact cells using reporter cysteines introduced into extracellular loops 1 (A80C) and 4 (R741C). Residues A80C/R741C come close enough (<7Å) to spontaneously cross-link in the open conformation (<7Å) but are widely separated (>30Å) in the closed conformation. Cross-linking of A80C/R741C can be readily detected because it causes the mutant protein to migrate slower on SDS-PAGE gels. We tested whether drug substrates or inhibitors could inhibit cross-linking of the mutant. It was found that only tariquidar blocked A80C/R741C cross-linking. Tariquidar was also a more potent pharmacological chaperone than other P-gp substrates/modulators such as cyclosporine A. Only tariquidar promoted maturation of misprocessed mutant F804D to yield mature P-gp. Tariquidar interacted with the transmembrane domains because it could rescue a misprocessed truncation mutant lacking the nucleotide-binding domains. These results show that tariquidar is a potent pharmacological chaperone and inhibits P-gp drug efflux by blocking transition to the open state during the catalytic cycle.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Adenosina Trifosfatasas/metabolismo , Quinolinas/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfatasas/química , Animales , Línea Celular , Cricetinae , Resistencia a Múltiples Medicamentos , Conformación Proteica , Quinolinas/farmacocinéticaRESUMEN
P-glycoprotein (P-gp) is an ATP-binding cassette drug pump that protects us from toxic compounds and confers multidrug resistance. The protein is organized into two halves. The halves contain a transmembrane domain (TMD) with six transmembrane segments and a nucleotide-binding domain (NBD). The drug- and ATP-binding sites reside at the TMD1/TMD2 and NBD1/NBD2 interfaces, respectively. ATP-dependent drug efflux involves changes between the open inward-facing (NBDs apart, extracellular loops (ECLs) close together) and the closed outward-facing (NBDs close together, ECLs apart) conformations. It is controversial, however, whether the open conformation only exists transiently in intact cells because of the presence of high levels of ATP. To test for the presence of an open conformation in intact cells, reporter cysteines were placed in extracellular loops 1 (A80C, N half) and 4 (R741C, C half). The rationale was that cysteines A80C/R741C would only come close enough to form a disulfide bond in an open conformation (6.9 Å apart) because they are separated widely (30.4 Å apart) in the closed conformation. It was observed that the mutant A80C/R741C cross-linked spontaneously (>90%) when expressed in cells. In contrast to previous reports showing that trapping P-gp in a closed conformation highly activated ATPase activity, here we show that A80C/R741C cross-linking inhibited ATPase activity and drug efflux. Both activities were restored when the cross-linked mutant was treated with a thiol-reducing agent. The results show that an open conformation can be readily detected in cells and that cross-linking of cysteines placed in ECLs 1 and 4 inhibits activity.
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Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfatasas/metabolismo , Cisteína/metabolismo , Disulfuros/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/química , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adenosina Trifosfato/metabolismo , Animales , Sitios de Unión/genética , Línea Celular , Cisteína/química , Cisteína/genética , Disulfuros/química , Ditiotreitol/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Glicósido Hidrolasas/metabolismo , Células HEK293 , Humanos , Hidrólisis , Immunoblotting , Modelos Moleculares , Mutación , Preparaciones Farmacéuticas/metabolismo , Conformación Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de ProteínaRESUMEN
Dysfunction of the hypothalamic-pituitary-adrenal axis, particularly the glucocorticoid receptor, is a commonly implicated link between stress and psychopathology. GR abnormalities are frequently reported in depression, and these anomalies must be resolved before depressive symptoms remit. This biological finding is rendered clinically relevant by the knowledge that only select antidepressants alter GR function. The relationship between GR dysfunction and other diseases associated with psychiatric stress, such as post-traumatic stress disorder (PTSD) and fibromyalgia, is also documented. However, as laboratory constraints limit the utility of GR testing, other measures of GR activity, such as levels of GR-induced genes, may have greater clinical value. In this review, glucocorticoid-induced leucine zipper (GILZ), a product of GR-initiated gene transcription, will be discussed in the context of GR dysfunction in psychopathology.