RESUMEN
We report a large compilation of the internal validations of the probabilistic genotyping software STRmix™. Thirty one laboratories contributed data resulting in 2825 mixtures comprising three to six donors and a wide range of multiplex, equipment, mixture proportions and templates. Previously reported trends in the LR were confirmed including less discriminatory LRs occurring both for donors and non-donors at low template (for the donor in question) and at high contributor number. We were unable to isolate an effect of allelic sharing. Any apparent effect appears to be largely confounded with increased contributor number.
Asunto(s)
ADN/genética , Genotipo , Repeticiones de Microsatélite , Probabilidad , Programas Informáticos , Alelos , Dermatoglifia del ADN , Humanos , Laboratorios , Funciones de VerosimilitudRESUMEN
Soluble epoxide hydrolase (sEH, EPHX2) metabolizes eicosanoid epoxides, including epoxyeicosatrienoic acids (EETs) to the corresponding dihydroxyeicosatrienoic acids (DHETs), and leukotoxin (LTX) to leukotoxin diol (LTX diol). EETs, endothelium-derived hyperpolarizing factors, exhibit potentially beneficial properties, including anti-inflammatory effects and vasodilation. A novel, potent, selective inhibitor of recombinant human, rat and mouse sEH, GSK2256294A, exhibited potent cell-based activity, a concentration-dependent inhibition of the conversion of 14,15-EET to 14,15-DHET in human, rat and mouse whole blood in vitro, and a dose-dependent increase in the LTX/LTX diol ratio in rat plasma following oral administration. Mice receiving 10 days of cigarette smoke exposure concomitant with oral administration of GSK2256294A exhibited significant, dose-dependent reductions in pulmonary leukocytes and keratinocyte chemoattractant (KC, CXCL1) levels. Mice receiving oral administration of GSK2256294A following 10 days of cigarette smoke exposure exhibited significant reductions in pulmonary leukocytes compared to vehicle-treated mice. These data indicate that GSK2256294A attenuates cigarette smoke-induced inflammation by both inhibiting its initiation and/or maintenance and promoting its resolution. Collectively, these data indicate that GSK2256294A would be an appropriate agent to evaluate the role of sEH in clinical studies, for example in diseases where cigarette smoke is a risk factor, such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Ciclohexilaminas/farmacología , Epóxido Hidrolasas/antagonistas & inhibidores , Leucocitos/efectos de los fármacos , Pulmón/efectos de los fármacos , Triazinas/farmacología , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/metabolismo , Administración Oral , Adulto , Animales , Quimiocina CXCL1/biosíntesis , Relación Dosis-Respuesta a Droga , Epóxido Hidrolasas/metabolismo , Exotoxinas/metabolismo , Femenino , Humanos , Inflamación/enzimología , Inflamación/etiología , Inflamación/patología , Inflamación/prevención & control , Recuento de Leucocitos , Leucocitos/metabolismo , Leucocitos/patología , Pulmón/enzimología , Pulmón/patología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Ratas , Ácidos Esteáricos/metabolismo , Contaminación por Humo de Tabaco/efectos adversosRESUMEN
A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction.
Asunto(s)
Antagonistas Muscarínicos/síntesis química , Tropanos/síntesis química , Animales , Enfermedades Bronquiales/tratamiento farmacológico , Diseño de Fármacos , Ratones , Antagonistas Muscarínicos/farmacología , Receptores Muscarínicos/efectos de los fármacos , Relación Estructura-Actividad , Tropanos/farmacologíaRESUMEN
Substrates and products of soluble epoxide hydrolase (sEH) such as 14,15-epoxyeicosatrienoic acid (14,15-EET), 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), leukotoxin, and leukotoxin diol are potential biomarkers for assessing sEH activity in clinical trial subjects. To quantify them, we have developed and validated a semi-automated and relatively high-throughput assay in a 96-well plate format using liquid chromatography-mass spectrometry. 14,15-EET, 14,15-DHET, leukotoxin and leukotoxin diol, as well as their deuterium labeled internal standards were extracted from human plasma by liquid-liquid extraction using ethyl acetate. The four analytes were separated from other endogenous lipid isomers using liquid chromatography coupled with tandem mass spectrometry. The method was validated over a concentration range of 0.05-50 ng/mL. The validation results show that the method is precise, accurate and well-suited for analysis of clinical samples. The turn-around rate of the assay is approximately 200 samples per day.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Epóxido Hidrolasas/metabolismo , Ácidos Linoleicos/sangre , Ácidos Esteáricos/sangre , Ácido 8,11,14-Eicosatrienoico/sangre , Biomarcadores/sangre , Cromatografía Liquida , Epóxido Hidrolasas/sangre , Femenino , Humanos , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masas en TándemRESUMEN
The discovery of potent and selective cyanamide-based inhibitors of the cysteine protease cathepsin C is detailed. Optimization of the template with regard to plasma stability led to the identification of compound 17, a potent cathepsin C inhibitor with excellent selectivity over other cathepsins and potent in vivo activity in a cigarette smoke mouse model.
Asunto(s)
Artritis Reumatoide , Enfermería Holística/educación , Enfermería Holística/normas , Rol de la Enfermera , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/enfermería , Artritis Reumatoide/terapia , Diagnóstico Diferencial , Terapia por Ejercicio , Estado de Salud , Humanos , Estilo de Vida , Investigación Metodológica en Enfermería , Osteoartritis/diagnóstico , Osteoartritis/enfermería , Osteoartritis/terapia , Educación del Paciente como Asunto , Pronóstico , Estados UnidosRESUMEN
In the spring of 2003, the board of directors of the American Pain Society asked the APS Ethics Committee to formulate a position statement for the Society concerning the use of placebos in clinical practice (cf, reference ). A subset of the Ethics Committee under my direction composed such a statement based on the available scientific and ethical literature. We then sought feedback from the entire ethics committee as well as numerous prominent voices in the literature and presented the statement to the membership for discussion at the 2004 annual APS meeting in Vancouver, British Columbia, at both a symposium and an ethics special interest group meeting. The resultant document was approved by the APS Board and is published here for widespread distribution to the membership.