RESUMEN
Huntington disease (HD) is a progressive neurodegenerative disorder. Presymptomatic genetic testing allows at-risk individuals to clarify their risk status. Understanding the characteristics and motivations of individuals seeking HD presymptomatic genetic testing better equips genetic counselors and other healthcare professionals to provide comprehensive and personalized care. The aims of this study were to (1) determine whether the average age when individuals seek presymptomatic HD genetic testing has decreased over time, (2) assess motivations for seeking testing, (3) explore whether there is a relationship between age and motivations, and (4) explore genetic counselors' perceptions of the shift in age. Data from the US HD testing centers (N = 4) were analyzed. A small but statistically significant decrease in age of individuals seeking presymptomatic testing was observed (p = 0.045). HD community members (N = 77) were surveyed regarding presymptomatic testing motivations. Younger individuals were more likely than older individuals to cite "To learn whether or not you would develop HD" and "To make choices about further education or a career" compared to older individuals (p < 0.05). Conversely, older individuals more frequently cited "To give children a better idea of their risk" (p < 0.002). Sixteen percent of genetic counselors surveyed (6/37) perceived a change in age of testing. All of these respondents had provided HD testing for ten or more years and anecdotally believed the age at testing has decreased over time. Study results help providers personalize counseling based on patient's age and serve as a starting point for more research into the relationship between age at testing and motivations for testing.
Asunto(s)
Pruebas Genéticas/métodos , Enfermedad de Huntington/genética , Adulto , Anciano , Femenino , Asesoramiento Genético , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/psicología , MasculinoRESUMEN
AIMS: GSK3050002, a humanized IgG1κ antibody with high binding affinity to human CCL20, was administered in a first-in-human study to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). An experimental skin suction blister model was employed to assess target engagement and the ability of the compound to inhibit recruitment of inflammatory CCR6 expressing cells. METHODS: This study was a randomized, double-blind (sponsor open), placebo-controlled, single-centre, single ascending intravenous dose escalation trial in 48 healthy male volunteers. RESULTS: GSK3050002 (0.1-20 mg kg-1 ) was well tolerated and no safety concerns were identified. The PK was linear over the dose range, with a half-life of approximately 2 weeks. Complex of GSK3050002/CCL20 increased in serum and blister fluid with increasing doses of GSK3050002. There were dose-dependent decreases in CCR6+ cell recruitment to skin blisters with maximal effects at doses of 5 mg kg-1 and higher, doses at which GSK3050002/CCL20 complex in serum and blister fluid also appeared to reach maximum levels. CONCLUSIONS: These results indicate a relationship between PK, target engagement and PD, suggesting a selective inhibition of recruitment of CCR6+ cells by GSK3050002 and support further development of GSK3050002 in autoimmune and inflammatory diseases.
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Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales/inmunología , Vesícula/inmunología , Quimiocina CCL20/inmunología , Receptores CCR6/inmunología , Adolescente , Adulto , Anciano , Vesícula/metabolismo , Recuento de Células , Quimiocina CCL20/sangre , Quimiocina CCL20/metabolismo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Succión/efectos adversos , Adulto JovenRESUMEN
Exercise-induced bronchoconstriction (EIB) describes the condition whereby exercise causes airflow obstruction that lasts for up to 90 minutes without treatment. This double-blind, placebo-controlled, five-way crossover study investigated the dose response and duration of action of a 5-lipoxygenase-activating protein inhibitor, GSK2190915, to inhibit EIB in subjects with asthma. Forty-seven subjects with EIB were enrolled. Exercise challenge testing was scheduled at 2, 9.5, and 24 hours after receiving a single dose of GSK2190915 (10, 50, 100, and 200 mg) or placebo in randomized order. GSK2190915 at 200 and 100 mg significantly attenuated the response to exercise at 2 and 9.5 hours postdose, respectively, compared with placebo. The adjusted mean maximum percentage change from baseline forced expiratory volume at 1 second within 60 minutes postexercise challenge (FEV1 (0-60)) treatment difference for GSK2190915 at 200 mg compared with placebo at 2 hours postdose was 6.30% (95% CI, 3.06, 9.54), corresponding to a 40% attenuation of the placebo response to exercise; the treatment difference between GSK2190915 at 100 mg and placebo at 9.5 hours postdose was 3.49% (95% CI, 1.02, 5.95), corresponding to a 41% attenuation of the placebo response to exercise. No significant effect was seen at 24 hours postdose with any dose; however, investigation of statistically significant treatment-related effects at this time point was limited because of the small fall in adjusted mean FEV1 (0-60) (-7.61%; 95% CI, -10.23, -4.99) after placebo. GSK2190915 may be of benefit in EIB prevention. GSK Clinical Study LPA112025; ClinicalTrials.gov identifier number: NCT00812929.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/uso terapéutico , Enfermedades Bronquiales/tratamiento farmacológico , Enfermedades Bronquiales/etiología , Ejercicio Físico , Indoles/uso terapéutico , Ácidos Pentanoicos/uso terapéutico , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Adulto , Asma , Constricción Patológica , Estudios Cruzados , Prueba de Esfuerzo , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Indoles/farmacología , Masculino , Ácidos Pentanoicos/farmacología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: There is a need to better measure and improve the quality of oncology care and improve communication with patients and other providers. The American Society of Clinical Oncology Breast Cancer Registry (BCR) pilot evaluated the feasibility and acceptability of prospective data collection for quality assessment in daily clinical practice. Data were used to create and share treatment plans/summaries (TPSs) at the point of care. METHODS: Using a web-based tool, 20 diverse practices entered clinical data on each new early-stage breast cancer patient into the BCR for 14 months (September 2009 through November 2010). The tool created individual TPSs that were shared with patients. Practices received practice-specific and aggregate BCR quality measures data, participated in a survey, and received a participation stipend. RESULTS: Twenty practices entered 2014 patients into the BCR, collecting demographic, clinical, and treatment information. Fifty-two percent of practice participants replied to an end-of-pilot survey: 73% were satisfied with the BCR and web-based tool, 31% expressed concern regarding time and effort, and 52% reported additional practice costs during the pilot. Among those who created or shared the TPSs, 90% thought the documents improved oncologist-patient communication, and 95% favored using BCR data for practice quality improvement. CONCLUSIONS: Prospective data collection for quality assessment is feasible and allows sharing of TPSs with patients at the point of care. Future efforts should focus on decreasing implementation burden to practices, broadening participation, examining costs, and, most importantly, assessing its effects on patient outcomes.
Asunto(s)
Neoplasias de la Mama/terapia , Planificación de Atención al Paciente , Desarrollo de Programa , Sistema de Registros , Comunicación , Recolección de Datos , Femenino , Humanos , Proyectos Piloto , Garantía de la Calidad de Atención de SaludRESUMEN
BACKGROUND: Although the routine use of treatment plans and summaries (TPSs) has been recommended to improve the quality of cancer care, limited data exist about their impact on quality, including patient satisfaction and coordination of care. METHODS: Patients received TPSs as part of the American Society of Clinical Oncology Breast Cancer Registry (BCR) pilot program of 20 community oncology practices. Participants were surveyed 2 to 4 weeks after receiving a TPS to evaluate their perceptions of the document. Patients who were receiving chemotherapy received the TPS as separate plan and summary documents (at the start and the end of treatment) and could complete 2 surveys. Others received a single integrated TPS. Eligible survey participants had stage 0 through III breast cancer and were enrolled in the BCR. RESULTS: Of 292 consented patients, 174 (60%) completed at least 1 survey. Of 157 patients who recalled receiving a TPS, 148 (94%) believed that the documents improved patient-physician communication, and 128 (82%) believed that they improved communication between physicians; 113 (72%) said the documents increased their peace of mind, whereas 2 (1%) had less peace of mind. Of 152 patients (97%) who still had their documents, 147 (97%) said they were useful, and 94 (62%) had given or planned to give the documents to another physician. All 63 patients who were surveyed after receiving a summary recommended that practices continue to provide TPSs to patients. CONCLUSIONS: Participants in this study expressed high satisfaction with TPSs. Additional research is needed to study the broad-scale implementation of the BCR and to evaluate the impact of routine use of TPSs on the quality of care delivered.
Asunto(s)
Neoplasias de la Mama/terapia , Planificación de Atención al Paciente , Satisfacción del Paciente , Adulto , Anciano , Anciano de 80 o más Años , Comunicación , Servicios de Salud Comunitaria , Recolección de Datos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Relaciones Médico-Paciente , Proyectos PilotoRESUMEN
BACKGROUND: There are few data on the bronchodilatory effects of adding short-acting bronchodilators (SABA) to maintenance, long-acting bronchodilator therapy. This study assessed the additional bronchodilation and safety of adding supratherapeutic doses of salbutamol (SALB) or ipratropium bromide (IPR) to the novel bi-functional molecule (or dual pharmacophore) GSK961081 400 µg (MABA 400) or 1200 µg (MABA 1200). METHODS: This randomised, double-blind, complete, crossover study in 44 patients with moderate to severe COPD, evaluated 6 treatments with a washout of at least 7 days between treatments: single doses of MABA 400 or MABA 1200 followed by cumulative doses of either SALB (3× 200 µg at 20 min intervals), IPR (20 µg, 20 µg and 40 µg at 20 min intervals) or placebo (PLA) (three doses at 20 min intervals) at 1 h, 12 h and 24 h post-MABA dose. The primary endpoint was maximal increase in FEV1, from pre-dose bronchodilator (SABA/PLA), measured 15 min after each cumulative dose of SALB, IPR or PLA. Systemic pharmacodynamics (potassium, heart rate, glucose and QTc), adverse events and systemic pharmacokinetics were also assessed. RESULTS: The additional bronchodilatory effects at 12 h and 24 h for both SALB and IPR were of a similar magnitude and statistically significant relative to PLA; mean differences (SE) (L) following MABA 400 dosing: 0.139 (0.023) after SALB at 12 h; 0.123 (0.022) after SALB at 24 h; 0.124 (0.023) after IPR at 12 h; 0.141 (0.021) after IPR at 24 h; and after MABA 1200 dosing: 0.091 (0.023) after SALB at 12 h; 0.126 (0.022) after SALB at 24 h; 0.055 (0.023) after IPR at 12 h; 0.122 (0.022) after IPR at 24 h. Any additional bronchodilator effects at 1 h were small and not clinically significantly different from PLA. There were small, non-clinically significant increases in mean heart rate after both MABA doses plus SALB, and decreased potassium levels in four patients after MABA 1200 plus SALB (×3) or PLA (×1) were observed but overall all treatments were well tolerated and raised no significant safety signals. CONCLUSION: The additional bronchodilation achieved following supratherapeutic doses of SALB and IPR on top of single doses of MABA 400 or 1200 was comparable for the two agents and neither were associated with any clinically relevant systemic pharmacodynamic effects other than the small transient hypokalemic effect in a 3 out of 41 patients receiving additional high dose salbutamol and MABA 1200. Either short-acting bronchodilator could potentially be used as rescue medication on top of MABA therapy.
Asunto(s)
Albuterol/uso terapéutico , Broncodilatadores/uso terapéutico , Carbamatos/uso terapéutico , Ipratropio/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinolonas/uso terapéutico , Anciano , Albuterol/administración & dosificación , Albuterol/efectos adversos , Broncodilatadores/administración & dosificación , Broncodilatadores/efectos adversos , Carbamatos/administración & dosificación , Carbamatos/efectos adversos , Estudios Cruzados , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Volumen Espiratorio Forzado , Humanos , Ipratropio/administración & dosificación , Ipratropio/efectos adversos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Quinolonas/administración & dosificación , Quinolonas/efectos adversos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Vilanterol (VI; GW642444M) is a novel inhaled long-acting ß2-agonist with inherent 24 h activity in vitro in development as a combination with the inhaled corticosteroid fluticasone furoate for both COPD and asthma. These studies were conducted to determine the safety, tolerability, pharmacodynamics and pharmacokinetics of VI in healthy subjects and subjects with mild to moderate persistent asthma and moderate to severe COPD. Single doses of VI (25-100 µg) were given once daily to subjects with asthma and COPD and repeat doses once daily for 14 days to healthy subjects. Adverse events (AEs), vital signs, ECGs, pharmacodynamic endpoints, FEV(1) and VI plasma pharmacokinetics (AUC, Cmax and Tmax) were determined following dosing. VI (25-100 µg) was well tolerated. The incidence and severity of AEs were comparable to placebo. Following VI administration there were no clinically significant abnormalities in vital signs, 12-lead ECG, Holter ECG, blood glucose or potassium. There were no statistically significant effects on QTc of single and repeat VI doses up to 50 µg; some differences were seen following the 100 µg VI dose after single and repeat dose in healthy subjects and single dose in asthmatic subjects. All VI doses produced increases in FEV(1) from as early as 5 min after dosing which were maintained up to 24 h post-dose in subjects with asthma and COPD. In all subjects VI was rapidly absorbed (healthy subjects median Tmax at 5 min; asthma and COPD subjects median Tmax at 10 min) with systemic exposure increasing in an approximately dose proportional manner across the VI dose range. Marginal accumulation was seen on repeat dosing. Single doses of inhaled VI in subjects with asthma and COPD and repeat doses in healthy subjects were well tolerated with no clinically significant unwanted systemic effects. VI produced a rapid and prolonged bronchodilation over 24 h suggesting the potential for once daily administration.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Asma/tratamiento farmacológico , Alcoholes Bencílicos/uso terapéutico , Broncodilatadores/uso terapéutico , Clorobencenos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Adolescente , Adulto , Anciano , Asma/fisiopatología , Alcoholes Bencílicos/efectos adversos , Glucemia/análisis , Clorobencenos/efectos adversos , Electrocardiografía , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatologíaRESUMEN
GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and ß2-agonism (MABA) properties. This randomised, double-blind, double-dummy, crossover study evaluated 14 days treatment with the MABA GSK961081 400 µg and 1200 µg once daily and tiotropium 18 µg once daily plus salmeterol 50 µg twice daily (TIO + SAL), versus placebo in 50 patients with moderate COPD. The primary endpoint was forced expiratory volume in 1 s (FEV1) at 24 h on Days 1 and 14. MABA 400 (n = 29), MABA 1200 (n = 32) and TIO + SAL (n = 41) resulted in significant increases in FEV1 over 24 h. Mean (95% CI) 24 h trough FEV1 (L) values relative to placebo (n = 43) were, for Day 1, MABA 400: 0.141 (0.060, 0.222); MABA 1200: 0.184 (0.105, 0.263); TIO + SAL: 0.162 (0.092, 0.231); for Day 14, MABA 400: 0.115 (0.024, 0.205); MABA 1200: 0.168 (0.080, 0.255); TIO + SAL: 0.103 (0.026, 0.180). Onset of bronchodilation was faster for both MABA doses versus TIO + SAL. No clinically relevant systemic pharmacodynamic effects were observed. Adverse events were similar across groups; however tremor (n = 2, MABA 1200), dysgeusia (n = 2, MABA 1200; n = 2, MABA 400) and dry mouth (n = 1, MABA 1200) were reported after GSK961081 only. GSK961081 demonstrated sustained bronchodilation similar to TIO + SAL, but with a more rapid onset, and was well tolerated at the tested doses.
Asunto(s)
Albuterol/análogos & derivados , Broncodilatadores/uso terapéutico , Carbamatos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinolonas/uso terapéutico , Derivados de Escopolamina/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Adulto , Anciano , Albuterol/administración & dosificación , Albuterol/efectos adversos , Albuterol/uso terapéutico , Broncodilatadores/administración & dosificación , Broncodilatadores/efectos adversos , Carbamatos/administración & dosificación , Carbamatos/efectos adversos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/efectos adversos , Antagonistas Muscarínicos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Quinolonas/administración & dosificación , Quinolonas/efectos adversos , Xinafoato de Salmeterol , Derivados de Escopolamina/administración & dosificación , Derivados de Escopolamina/efectos adversos , Factores de Tiempo , Bromuro de Tiotropio , Resultado del TratamientoRESUMEN
AIM: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5-lipoxygenase-activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations. METHOD: Western European subjects received single (50-1000 mg) or multiple (10-450 mg) oral doses of GSK2190915 or placebo in a dose-escalating manner. Japanese subjects received three of four GSK2190915 doses (10-200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B4 and leukotriene E4, respectively, as pharmacodynamic markers of drug activity. RESULTS: There was no clear difference in adverse events between placebo and active drug-treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose-related manner and mean half-life values ranged from 16-34 h. Dose-dependent inhibition of blood leukotriene B4 production was observed and near complete inhibition of urinary leukotriene E4 excretion was shown at all doses except the lowest dose. The EC50 values for inhibition of LTB4 were 85 nM and 89 nM in the Western European and Japanese studies, respectively. CONCLUSION: GSK2190915 is well-tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E4 at 24 h post-dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB4.
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Inhibidores de Proteína Activante de 5-Lipoxigenasa , Indoles , Leucotrieno E4/sangre , Ácidos Pentanoicos , Inhibidores de Proteína Activante de 5-Lipoxigenasa/efectos adversos , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacocinética , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Administración Oral , Adolescente , Adulto , Anciano , Área Bajo la Curva , Pueblo Asiatico , Biomarcadores/sangre , Biomarcadores/orina , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Indoles/efectos adversos , Indoles/farmacocinética , Indoles/farmacología , Leucotrieno B4/sangre , Leucotrieno B4/orina , Leucotrieno E4/orina , Masculino , Persona de Mediana Edad , Ácidos Pentanoicos/efectos adversos , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacología , Población Blanca , Adulto JovenRESUMEN
Macrolide compounds, many of which are derived from natural sources, all share a lactone ring structure, but of varying sizes. Their biological activities differ with structure and size but tend to overlap. Marketed macrolide drugs include immunosuppressives and antibiotics. Some of the latter have been shown to exert anti-inflammatory activities, due to direct effects on inflammatory cells and processes when used for respiratory infections. Consequently, azithromycin is included in clinical guidelines for COPD and asthma treatment, though it has the disadvantage, as an antibiotic, of increasing bacterial resistance. COPD and asthma, however, like several chronic inflammatory diseases involving other organs, are driven to a large extent by epithelial barrier dysfunction. Recently, azithromycin was shown to directly enhance epithelial barrier function and a new class of derivatives, barriolides, is under development with the lead indication COPD. It is thus likely that by circumventing antibiosis and acting on a crucial etiological disease process, this type of agent will open up a new, safer approach to COPD and asthma therapy with macrolides.
Asunto(s)
Asma , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Macrólidos/farmacología , Macrólidos/uso terapéutico , Azitromicina/uso terapéutico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Asma/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológicoRESUMEN
PURPOSE: The aim of this study was to characterize the genetic, audiologic, and epidemiologic characteristics of unilateral hearing loss (HL) in a national hereditary deafness repository. MATERIALS AND METHODS: This is a prospective clinical study involving 34 subjects identified in a national hereditary deafness repository. Clinical data and family history of HL were obtained on enrollment. Candidate deafness genes were screened by single-stranded conformation polymorphism, and mutations were confirmed with sequencing. RESULTS: Thirty-four subjects (19 males, 15 females) with unilateral HL were identified, ranging in age from 2 months to 36 years. The mean age at diagnosis was 7 years, and the left ear was affected in 62% of the cases. The racial distribution of our sample was 62% white, 23% African American, and 15% Hispanic. Imaging results were available in 47%, and most (69%) were considered normal. Nineteen percent had enlarged vestibular aqueducts, 2 had ipsilateral Mondini dysplasia, and 1 had a common cavity deformity. Twenty subjects (59%) had a family history of HL, with 26% specifically reporting familial unilateral HL. Mutational screening revealed sequence variants in the GJB2 (connexin 26), GJB3 (connexin 31), TECTA, and COCH genes. Two novel mutations were detected in COCH and TECTA. CONCLUSIONS: Sequence variants in known deafness genes were detected in more than one-third of our study population, suggesting that gene/gene or gene/environmental interactions may indeed play a role in the etiology of some cases of unilateral deafness. Further prospective studies including congenital cytomegalovirus screening at birth and molecular screening of deafness genes in children with congenital unilateral HL will be required to establish the etiology of unilateral deafness with certainty.
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Conexinas/genética , ADN/genética , Sordera/congénito , Pérdida Auditiva Unilateral/etiología , Mutación , Adolescente , Adulto , Niño , Preescolar , Conexina 26 , Conexina 30 , Sordera/diagnóstico , Sordera/genética , Femenino , Estudios de Seguimiento , Pruebas Genéticas , Genotipo , Audición , Pérdida Auditiva Unilateral/genética , Pérdida Auditiva Unilateral/fisiopatología , Humanos , Lactante , Masculino , Polimorfismo Conformacional Retorcido-Simple , Estudios Prospectivos , Adulto JovenRESUMEN
In 1898, E.A. Fay published an analysis of nearly 5000 marriages among deaf individuals in America collected during the 19(th) century. Each pedigree included three-generation data on marriage partners that included at least one deaf proband, who were ascertained by complete selection. We recently proposed that the intense phenotypic assortative mating among the deaf might have greatly accelerated the normally slow response to relaxed genetic selection against deafness that began in many Western countries with the introduction of sign language and the establishment of residential schools. Simulation studies suggest that this mechanism might have doubled the frequency of the commonest forms of recessive deafness (DFNB1) in this country during the past 200 years. To test this prediction, we collected pedigree data on 311 contemporary marriages among deaf individuals that were comparable to those collected by Fay. Segregation analysis of the resulting data revealed that the estimated proportion of noncomplementary matings that can produce only deaf children has increased by a factor of more than five in the past 100 years. Additional analysis within our sample of contemporary pedigrees showed that there was a statistically significant linear increase in the prevalence of pathologic GJB2 mutations when the data on 441 probands were partitioned into three 20-year birth cohorts (1920 through 1980). These data are consistent with the increase in the frequency of DFNB1 predicted by our previous simulation studies and provide convincing evidence for the important influence that assortative mating can have on the frequency of common genes for deafness.
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Sordera/epidemiología , Sordera/genética , Estudios de Cohortes , Conexina 26 , Conexina 30 , Conexinas/genética , Salud de la Familia , Femenino , Heterocigoto , Homocigoto , Humanos , Masculino , Mutación , Linaje , Personas con Deficiencia Auditiva , Proyectos de Investigación , Estados UnidosRESUMEN
Mutations of GJB2 and GJB6 (connexin-26 and 30) at the DFNB1 locus are the most common cause of autosomal recessive, nonsyndromic deafness. Despite their widespread expression throughout the vestibular system, vestibular dysfunction has not been widely recognized as a commonly associated clinical feature. The observations of vertigo accompanying DFNB1 deafness in several large families prompted our hypothesis that vestibular dysfunction may be an integral, but often overlooked, component of DFNB1 deafness. Our aim was to define the prevalence of vestibular dysfunction in Cases of DFNB1 deafness and Controls with other forms of deafness. We developed and used a survey to assess symptoms of vestibular dysfunction, medical, and family history was distributed to Cases with deafness due to pathogenic GJB2 and/or GJB6 mutations and deaf Controls without DFNB1 deafness. Our results showed: Surveys were returned by 235/515 Cases (46%) with DFNB1 mutations and 121/321 Controls (38%) without these mutations. The mean age of Cases (41) was younger than Controls (51; P < 0.001). Vestibular dysfunction was reported by 127 (54%) of Cases and was present at significantly higher rates in Cases than in deaf Controls without DFNB1 deafness (P < 0.03). Most (63%) had to lie down in order for vertigo to subside, and 48% reported that vertigo interfered with activities of daily living. Vertigo was reported by significantly more Cases with truncating than non-truncating mutations and was also associated with a family history of dizziness. We conclude that vestibular dysfunction appears to be more common in DFNB1 deafness than previously recognized and affects activities of daily living in many patients.
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Conexinas/genética , Sordera/fisiopatología , Enfermedades Vestibulares/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Conexina 26 , Sordera/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Enfermedades Vestibulares/genética , Adulto JovenRESUMEN
Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome.
Asunto(s)
GTP Fosfohidrolasas/genética , Predisposición Genética a la Enfermedad/genética , Pérdida Auditiva/genética , Proteínas de la Membrana/genética , Mutación Missense/genética , Atrofia Óptica/genética , Síndrome de Wolfram/genética , Secuencia de Bases , Línea Celular , Cartilla de ADN/genética , Femenino , GTP Fosfohidrolasas/metabolismo , Perfilación de la Expresión Génica , Genes Dominantes , Haplotipos , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Datos de Secuencia Molecular , Linaje , Análisis de Secuencia de ADN , Suecia , Reino Unido , Estados UnidosRESUMEN
Survey and medical record data from 482 Veterans Affairs (VA) patients who recently received diagnoses of posttraumatic stress disorder (PTSD) were examined to determine need and predisposing factors associated with utilization of psychotherapy and counseling. More than half (58%) of participants initiated VA psychotherapy for PTSD within a year of diagnosis. Of those, one third completed eight or more sessions. Roughly two thirds of participants initiated counseling at a Vet Center. Initiating PTSD psychotherapy was associated with greater impairment but not with stigma, concerns about fitting in, or satisfaction with care. The use of Vet Center counseling was associated with desire for help, concerns about fitting in, and satisfaction with care. Unexpectedly, veterans with greater stigma concerns completed more psychotherapy visits and Vet Center counseling. Negative attitudes about mental health treatment did not seem to be substantial barriers to engaging in psychotherapy among these VA patients. Future research should consider enabling treatment system factors in addition to predisposing patient characteristics.
Asunto(s)
Aceptación de la Atención de Salud/psicología , Psicoterapia , Estereotipo , Trastornos por Estrés Postraumático/psicología , Veteranos/psicología , Adolescente , Adulto , Anciano , Actitud Frente a la Salud , Consejo , Recolección de Datos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos por Estrés Postraumático/terapia , Estados Unidos , Adulto JovenRESUMEN
The genetic fitness of an individual is influenced by their phenotype, genotype and family and social structure of the population in which they live. It is likely that the fitness of deaf individuals was quite low in the Western European population during the Middle Ages. The establishment of residential schools for deaf individuals nearly 400 years ago resulted in relaxed genetic selection against deaf individuals which contributed to the improved fitness of deaf individuals in recent times. As part of a study of deaf probands from Gallaudet University, we collected pedigree data, including the mating type and the number and hearing status of the children of 686 deaf adults and 602 of their hearing siblings. Most of these individuals had an onset of severe to profound hearing loss by early childhood. Marital rates of deaf adults were similar to their hearing siblings (0.83 vs. 0.85). Among married individuals, the fertility of deaf individuals is lower than their hearing siblings (2.06 vs. 2.26, p = 0.005). The fitness of deaf individuals was reduced (p = 0.002). Analysis of fertility rates after stratification by mating type reveals that matings between two deaf individuals produced more children (2.11) than matings of a deaf and hearing individual (1.85), suggesting that fertility among deaf individuals is influenced by multiple factors.
Asunto(s)
Sordera/genética , Aptitud Genética , Adulto , Niño , Femenino , Fertilidad , Pérdida Auditiva/genética , Humanos , Masculino , Estado Civil , Persona de Mediana Edad , Linaje , HermanosRESUMEN
Hearing loss is a common neuro-sensory deficit; nearly 50% of children with hearing loss have a genetic etiology. With the discovery of 40 genes and more than 100 loci involved in hearing loss, genetic testing is becoming more widely available. The information obtained through genetic testing can be perceived and used in different ways by parents of deaf children and deaf adults, based on their prior knowledge and understanding of these advances. It is therefore important to clarify the feelings of these potential consumers towards genetic services for hearing loss and understand their goals for genetic testing. The present study evaluates the feelings of consumers towards the advances in the genetics of hearing loss, the motivations for pursuing testing, and the perceived impact testing may have on their lives. We surveyed 808 parents of children with hearing loss nationally and 156 young deaf adults at Gallaudet University. In this study, learning the etiology of the hearing loss was the most commonly cited motivation for pursuing genetic testing and for parents was the most commonly cited outcome that genetic testing may have on their children's lives. Culturally Deaf respondents were less likely to believe that genetic testing will impact their lives or their children's lives and were less likely to report positive feelings about advances in the genetics of hearing loss. Cultural affiliation and genetic testing status, rather than hearing status, contributed more to the participants' responses.
Asunto(s)
Actitud Frente a la Salud , Sordera/genética , Pruebas Genéticas/psicología , Pérdida Auditiva/genética , Motivación , Adolescente , Adulto , Niño , Características Culturales , Recolección de Datos , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Padres/psicología , Encuestas y Cuestionarios , Estados Unidos , Adulto JovenRESUMEN
Hearing loss is a common sensory deficit and more than 50% of affected individuals have a genetic etiology. The discovery of 40 genes and more than 100 loci involved in hearing loss has made genetic testing for some of these genes widely available. Genetic services for deafness are also being sought more often due to the early identification of hearing loss through newborn screening services. The motivations for pursuing genetic testing, and how genetic services are provided to the client may differ among individuals. Additionally, information obtained through genetic testing can be perceived and used in different ways by parents of deaf children and deaf adults. This study aimed to follow up on focus group studies published earlier with a quantitative survey instrument and assess the preference of consumers for provision of genetic services. We conducted a national survey of hearing and deaf parents of children with hearing loss and of deaf adults. Data was compared and analyzed by hearing status of the participant, their community affiliation and the genetic testing status using nominal logistic regression. Consistent with our focus group results, the survey participants thought that a genetic counselor/geneticist would be the most appropriate professional to provide genetics services. Statistically significant differences were noted in the preferred choice of provider based on the genetic testing status. Parents preferred that genetic evaluation, including testing, occur either immediately at or a few months after the audiologic diagnosis of hearing loss. This data should help providers in clinical genetics keep patient preferences at the helm and provide culturally competent services.
Asunto(s)
Pruebas Genéticas/métodos , Trastornos de la Audición/diagnóstico , Trastornos de la Audición/genética , Encuestas y Cuestionarios , Adulto , Sordera/diagnóstico , Sordera/epidemiología , Sordera/genética , Femenino , Trastornos de la Audición/epidemiología , Humanos , Masculino , Estados Unidos/epidemiologíaRESUMEN
Interferon beta-1a (IFNß-1a) 30 µg weekly by intramuscular (IM) injection is used to treat relapsing forms of multiple sclerosis. We assessed if it can be given safely by inhalation. Twenty-one healthy volunteers inhaled IFNß-1a 300 µg, formulated for deep delivery to the lungs, in a randomized, parallel-group, repeat-dose trial. Comparators were room air and placebo. The primary outcome measure was carbon monoxide transfer factor corrected for hemoglobin (TLCOc), which measures the CO transfer from inspired gas to pulmonary capillary blood. After 3 and 4 once-weekly doses, IFNß-1a significantly reduced TLCOc compared with room air: after the third dose, mean standard deviation (SD) change in percent predicted TLCOc was-10.9 (2.8), and after the fourth dose was-12.1 (2.7). After 2, 3, and 4 doses, IFNß-1a significantly reduced TLCOc compared with placebo: after the second dose, mean (SD) change in percent predicted TLCOc was-8.8 (5.5), after the third dose was-10.9 (2.8), and after the fourth dose was-12.1 (2.7). Circulating IFNß-1a concentrations were about one-third those of the intramuscular dose regimen. Tolerability of IFNß-1a and the comparators was equally good. In conclusion, IFNß-1a reduced TLCOc, whereas placebo and room air did not. A dose of IFNß-1a 300 µg by inhalation may not be safe for general use.
Asunto(s)
Monóxido de Carbono/metabolismo , Interferón beta-1a/administración & dosificación , Administración por Inhalación , Adolescente , Adulto , Femenino , Voluntarios Sanos , Humanos , Interferón beta-1a/farmacocinética , Pulmón/efectos de los fármacos , Pulmón/fisiología , Masculino , Pruebas de Función Respiratoria , Adulto JovenRESUMEN
PURPOSE: The objective of this study was to explore the pharmacology of GSK961081, a bi-functional bronchodilator, in healthy volunteers. METHODS: Two randomized, double-blind, placebo-controlled studies were conducted. Following optimization of the propranolol dosing regimen (study 1), we conducted a five-period crossover study (study 2) in which subjects received the following treatments: dry powder inhaler (DPI) GSK961081 400 µg + oral placebo, DPI GSK961081 1,200 µg + oral placebo, DPI GSK961081 400 µg + oral propranolol 80 mg, DPI GSK961081 1,200 µg + oral propranolol 80 mg and DPI and oral placebo. GSK961081 (or inhaled placebo) was dosed at 0 h. Propranolol (or oral placebo) was dosed at -8, -2, 4, 10, and 16 h. The primary endpoint for both studies was bronchodilation, measured by specific airway conductance (sGaw), which was assessed at 0, 1, 4, 7, 12, 22, and 24 h in study 2. Tolerability and pharmacokinetics were secondary endpoints. RESULTS: Studies 1 and 2 enrolled 18 and 23 subjects, respectively. In study 2, bronchodilation was seen for 24 h following GSK961081 400 and 1,200 µg. In the presence of ß2 blockade, GSK961081 1,200 µg demonstrated bronchodilation in the first 4 h after dosing (treatment difference from placebo at 1 h: 1.206; 90% confidence interval [CI] 1.126-1.292; and at 4 h: 1.124; 90% CI 1.078-1.173) but not at 7 h onwards. In the presence of ß2 blockade, GSK961081 400 µg demonstrated bronchodilation in the first 1 h after dosing (treatment difference from placebo: 1.193; 90% CI 1.117-1.274), but not at 4 h onwards. Adverse events were reported for 21 (study 1) and 15 subjects (study 2); none were serious, and there were no deaths. CONCLUSION: The duration of bronchodilation as a result of receiving the muscarinic antagonist component alone was shorter than that from the muscarinic antagonist ß2 agonist combination. Removing the ß2 agonist component may underestimate the contribution of the muscarinic antagonist component to the bronchodilation of the combination.