RESUMEN
Recent studies of human populations suggest that the genome consists of chromosome segments that are ancestrally conserved ('haplotype blocks'; refs. 1-3) and have discrete boundaries defined by recombination hot spots. Using publicly available genetic markers, we have constructed a first-generation haplotype map of chromosome 19. As expected for this marker density, approximately one-third of the chromosome is encompassed within haplotype blocks. Evolutionary modeling of the data indicates that recombination hot spots are not required to explain most of the observed blocks, providing that marker ascertainment and the observed marker spacing are considered. In contrast, several long blocks are inconsistent with our evolutionary models, and different mechanisms could explain their origins.
Asunto(s)
Cromosomas Humanos Par 19/genética , Haplotipos/genética , Recombinación Genética , Alelos , Mapeo Cromosómico , ADN/genética , Evolución Molecular , Frecuencia de los Genes , Marcadores Genéticos , Humanos , Desequilibrio de Ligamiento , Modelos Genéticos , Polimorfismo de Nucleótido SimpleRESUMEN
Before a company can introduce a new pharmaceutical in the United States, it must receive approval of a New Drug Application (NDA) from the Food and Drug Administration. As a document that may consist of over 100,000 pages, the NDA presents the company's evidence that the new pharmaceutical is safe and effective for treating a particular medical condition. This paper describes four major issues in the NDA process: the role of computers in the FDA review, standards for compound documents and data, substitution of computer-assisted new drug applications (CANDAs) and electronic versions of other documents for paper versions, and management of the heterogeneous collection of material on which an NDA is based.
Asunto(s)
Computadores , Aprobación de Drogas/estadística & datos numéricos , Gráficos por Computador , Bases de Datos Factuales , Estructura Molecular , Diseño de Software , Estados Unidos , United States Food and Drug AdministrationAsunto(s)
Complejo Antígeno-Anticuerpo , Arteriosclerosis/terapia , Inmunoadsorbentes , Lipoproteínas LDL/sangre , Arteriosclerosis/sangre , Circulación Extracorporea/instrumentación , Circulación Extracorporea/métodos , Humanos , Indicadores y Reactivos , Lipoproteínas LDL/inmunología , Lipoproteínas LDL/aislamiento & purificaciónRESUMEN
A new technique called LDL-pheresis was used in patients to lower low-density lipoprotein cholesterol levels. This procedure combines continuous extracorporeal plasma separation with immunoadsorption of low-density lipoprotein on columns containing monospecific antibody to human apolipoprotein B. Six patients underwent a total of 164 procedures without significant side effects or nonspecific protein depletion. Acutely, LDL-pheresis lowered plasma cholesterol levels by removing up to 82 percent of the circulating low-density lipoprotein. Weekly LDL-pheresis combined with a portacaval shunt in a patient with homozygous familial hypercholesterolemia resulted in normalization of plasma cholesterol levels and rapid regression of skin xanthomata. Three of four patients with atherosclerotic coronary artery disease have noted improvement in their angina. LDL-pheresis appears to be a promising new technique capable of safely and efficiently lowering plasma low-density lipoprotein cholesterol levels.
Asunto(s)
Hipercolesterolemia/metabolismo , Técnicas de Inmunoadsorción , Lipoproteínas LDL/análisis , Adulto , Niño , Femenino , Humanos , Hipercolesterolemia/terapia , Técnicas de Inmunoadsorción/normas , Masculino , Persona de Mediana Edad , Intercambio PlasmáticoRESUMEN
A flow-through cartridge for indicating acidic and basic conditions during acid regeneration of immunoadsorption columns is described. Based on a pH dye covalently bound to polyacrylamide beads, it offers a direct visual indication of whether the pH of a column is in a range which is safe for use. The device, mounted in the waste line, may be reused several times.
Asunto(s)
Sangre , Concentración de Iones de Hidrógeno , Técnicas de Inmunoadsorción/instrumentación , Humanos , Indicadores y ReactivosRESUMEN
In order to determine whether newer, possibly safer erythrocyte sedimenting agents could be used during centrifugal leukacytapheresis, we tested seven varieties of plant starch. Only waxy maize prepared by partial acid hydrolysis appeared suitable, and it was tested extensively on an analytical device developed especially for testing erythrocyte sedimentation under the conditions of residence time, force, and sedimenting agent concentration used in a cell separator. This species of waxy maize, however, was not quite as effective a sedimenting agent when compared to hydroxyethyl starch (HES 450/0.70) under the test conditions used. Although chromatographic analysis showed the average molecular weights of the unsubstituted waxy maize were considerably higher than those of HES 450/0.70, degradation of waxy maize to smaller molecular weight fragments occurred more rapidly. The rapid degradation of this material may offer significant advantages during centrifugal leukacytapheresis procedures, but additional studies of its storage stability are needed.
Asunto(s)
Sedimentación Sanguínea , Leucaféresis/métodos , Zea mays , Amilasas/farmacología , Animales , Glucemia/biosíntesis , Centrifugación , Perros , Humanos , Hidrólisis , Derivados de Hidroxietil Almidón/sangre , Sustitutos del Plasma , Almidón/metabolismo , Almidón/farmacología , Ceras/metabolismo , Ceras/farmacología , Zea mays/metabolismoRESUMEN
Whole cells of Pseudomonas testosteroni, induced to synthesize steroid-transforming enzymes beforehand, have been immobilized by entrapment in polyacrylamide gel. The immobilized cells have been used to catalyze the continuous delta1-dehydrogenation of Reichstein's substance S under various conditions in the presence of phenazine methosulfate (PMS), an electron acceptor for the cell-free delta1-dehydrogenase. The presence of PMS substantially increases the rate of reaction when fed with the steroid substrate to a continuous stirred tank reactor containing the immobilized cells. The operational half-life of the delta1-dehydrogenase activity of the cells, about 103 hr under the best operating conditions, is essentially unaffected by the presence of PMS. Though the acceleration of the reaction may be due to PMS-mediated passage of electrons from some component in the electron transport chain to molecular oxygen, the lack of a similar effect with methylene blue is consistent with the conclusion that PMS functions directly as the electron acceptor for the delta1-dehydrogenase.