RESUMEN
BRCA1 interacts in vivo with a novel protein, BACH1, a member of the DEAH helicase family. BACH1 binds directly to the BRCT repeats of BRCA1. A BACH1 derivative, bearing a mutation in a residue that was essential for catalytic function in other helicases, interfered with normal double-strand break repair in a manner that was dependent on its BRCA1 binding function. Thus, BACH1/BRCA1 complex formation contributes to a key BRCA1 activity. In addition, germline BACH1 mutations affecting the helicase domain were detected in two early-onset breast cancer patients and not in 200 matched controls. Thus, it is conceivable that, like BRCA1, BACH1 is a target of germline cancer-inducing mutations.
Asunto(s)
Proteína BRCA1/metabolismo , Neoplasias de la Mama/genética , ADN Helicasas/metabolismo , Reparación del ADN/genética , Proteínas de Unión al ADN , ARN Helicasas/metabolismo , Adulto , Secuencias de Aminoácidos/genética , Sitios de Unión/fisiología , Boston/epidemiología , Neoplasias de la Mama/epidemiología , Línea Celular , Cromosomas Humanos Par 17/genética , ADN Helicasas/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi , Femenino , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Humanos , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Unión Proteica/fisiología , Estructura Terciaria de Proteína/genética , ARN Helicasas/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Homología de Secuencia de Aminoácido , Espectrometría de Masa por Ionización de Electrospray , TransfecciónRESUMEN
The metabolic and genetic determinants of HDL cholesterol (HDL-C) levels and HDL turnover were studied in 36 normolipidemic female subjects on a whole-food low-fat metabolic diet. Lipid, lipoprotein, and apolipoprotein levels, lipoprotein size, and apolipoprotein turnover parameters were determined, as were genetic variation at one site in the hepatic lipase promoter and six sites in the apolipoprotein AI/CIII/AIV gene cluster. Menopause had no significant effect on HDL-C or turnover. Stepwise multiple regression analysis revealed that HDL-C was most strongly correlated with HDL size, apolipoprotein A-II (apoA-II), and apolipoprotein A-I (apoA-I) levels, which together could account for 90% of the variation in HDL-C. HDL size was inversely correlated with triglycerides, body mass index, and hepatic lipase activity, which together accounted for 82% of the variation in HDL size. The hepatic lipase promoter genotype had a strong effect on hepatic lipase activity and could account for 38% of the variation in hepatic lipase activity. The apoA-I transport rate (AI-TR) was the major determinant of apoA-I levels, but AI-TR was not associated with six common genetic polymorphism in the apoAI/CIII/AIV gene cluster.A simplified model of HDL metabolism is proposed, in which A-I and apoA-II levels combined with triglycerides, and hepatic lipase activity could account for 80% of the variation in HDL-C.
Asunto(s)
Lipasa/metabolismo , Lipoproteínas HDL/metabolismo , Hígado/enzimología , Adulto , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Apolipoproteína A-II/metabolismo , Índice de Masa Corporal , LDL-Colesterol/sangre , Estudios de Cohortes , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Regiones Promotoras Genéticas , Valores de Referencia , Triglicéridos/sangreRESUMEN
BACKGROUND: Rickettsialpox is caused by Rickettsia akari, which is transmitted from rodents to humans by bloodsucking mites. The initial skin lesion forms an eschar and is followed by the development of fever, malaise, myalgia, and 5 to 40 maculopapules and papulovesicles. The disease, which responds to tetracycline, can be mistaken for chickenpox. The diagnosis has been based on an increase in serum antibody titers against R. akari over a period of three to eight weeks. We discuss a more rapid technique that uses direct immunofluorescence to identify R. akari in paraffin-embedded tissue, and we describe the histopathological findings of lesional skin. METHODS: We studied 13 patients (age, 11 months to 58 years) who were seen at Lincoln Hospital in New York City from 1980 to 1989 and were suspected of having rickettsialpox. In nine patients serum samples were obtained during the acute and convalescent phases of the illness for indirect fluorescent-antibody testing. Punch-biopsy specimens of skin lesions were examined by microscopy and by direct fluorescent-antibody testing with an anti-R. rickettsii globulin conjugated with fluorescein isothiocyanate. RESULTS: The diagnosis was confirmed in all 13 patients by indirect or direct fluorescent-antibody techniques. Direct fluorescent-antibody testing of eschars from seven patients was positive in five patients, but negative in two patients who had serologically confirmed rickettsialpox. In contrast, direct fluorescent-antibody testing of papulovesicles from nine patients was positive in only one patient. Histopathological analysis of the eschars revealed extensive necrosis and inflammation. In biopsy specimens of papulovesicles, dermal edema, subepidermal vesicles, and vascular changes were present. CONCLUSIONS: The combination of direct fluorescent-antibody testing of an eschar from the presumed site of inoculation and histopathological examination of papulovesicles for distinctive features represents an improved method of diagnosing rickettsialpox.
