RESUMEN
A randomized, double-blind, placebo-controlled trial compared efavirenz (600 mg every 24 h) plus indinavir (1000 mg every 8 h) with placebo (every 24 h) plus indinavir (800 mg every 8 h) among 327 nucleoside analogue reverse-transcriptase inhibitor (NRTI)-experienced human immunodeficiency virus (HIV)-infected adults. Patients received 50 cells/mm(3), >10,000 plasma HIV-1 RNA copies/mL, and no prior protease inhibitor or non-NRTI therapy. Patients had a mean of 2.8 years of prior NRTI therapy. At 24 weeks, plasma HIV-1 RNA level was <400 copies/mL in 68.2% of efavirenz versus 52.4% of placebo recipients (P=.004). CD4 cell count increases were 104+/-9 cells/mm(3) and 77+/-10 cells/mm(3) in efavirenz and placebo recipients, respectively (P=.023). Responses in efavirenz recipients were sustained at 48 weeks. Thus, efavirenz plus indinavir with concomitant NRTIs is effective therapy for NRTI-experienced patients.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Indinavir/uso terapéutico , Oxazinas/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adulto , Alquinos , Benzoxazinas , Recuento de Linfocito CD4 , Ciclopropanos , Método Doble Ciego , Quimioterapia Combinada , Femenino , VIH-1/aislamiento & purificación , VIH-1/fisiología , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Resultado del TratamientoRESUMEN
We used segregation analysis to investigate the genetic basis of variation in dystopia canthorum, one of the key diagnostic features of Waardenburg syndrome type 1 (WS1). We sought to determine whether the W-index, a quantitative measure of this craniofacial feature, is influenced primarily either by allelic variation in the PAX3 disease gene or other major loci, by polygenic background effects, or by all of these potential sources of genetic variation. We studied both WS1-affected individuals and their WS1-unaffected relatives. After adjustment of the W-index for WS1 disease status, segregation analyses by the regression approach indicated major-locus control of this variation, although residual parent-offspring and sib-sib correlations are consistent with additional (possibly polygenic) effects. Separate analyses of WS1-affected and WS1-unaffected individuals suggest that epistatic interactions between disease alleles at the PAX3 WS1 locus and a second major locus influence variation in dystopia canthorum. Our approach should be applicable for assessing the genetic architecture of variation associated with other genetic diseases.
Asunto(s)
Párpados/anomalías , Facies , Síndrome de Waardenburg/genética , Alelos , Sordera/genética , Humanos , FenotipoRESUMEN
We performed linkage and locus heterogeneity analyses of Waardenburg syndrome (WS) types 1 and 2 using 9 DNA markers from 2q35-q37, including two highly polymorphic microsatellites very closely linked to the PAX3 candidate gene. None of 5 WS type 2 (WS2) families showed linkage to the PAX3 candidate region. We localized the marker D2S102 to less than 1 cM from PAX3 (lod = 33.7, theta = 0), but a complete absence of crossovers prevented determining whether it maps distal or proximal to PAX3. Study of 14 WS type 1 (WS1) families yielded a maximum lod score of 27.81 at PAX3, theta f = 0.010, theta = 0.007 assuming homogeneity. However, we found significant evidence of locus heterogeneity, with one family initially classified as WS1 unlinked to the PAX3 region. Reevaluation of the clinical features of this family revealed atypical morphology of inner canthi. This produced the appearance of dystopia canthorum and high W-index scores. While our one unlinked WS1 family exhibits atypical canthal morphology, our type 1 families with classic dystopia appear to be homogeneously linked to PAX3. These and other findings identify precautions that need to be addressed before using PAX3-linked markers for diagnostic purposes.
Asunto(s)
Cromosomas Humanos Par 2 , ADN Satélite/genética , Polimorfismo Genético , Factores de Transcripción , Síndrome de Waardenburg/genética , Mapeo Cromosómico , Intercambio Genético , Cartilla de ADN , Proteínas de Unión al ADN/genética , Familia , Femenino , Ligamiento Genético , Marcadores Genéticos , Genotipo , Humanos , Cariotipificación , Escala de Lod , Masculino , Factor de Transcripción PAX3 , Factores de Transcripción Paired Box , Reacción en Cadena de la Polimerasa/métodos , Recombinación GenéticaRESUMEN
Profound, early-onset deafness is present in 4-11 per 10,000 children, and is attributable to genetic causes in at least 50% of cases. Family history questionnaires were sent to 26,152 families of children with profound, early-onset deafness not known to be related to an environmental cause. The probands were ascertained through the 1988-89 Gallaudet University Annual Survey of Hearing Impaired Children and Youth. The analysis is based on the responses that were received from 8,756 families. Classical segregation analysis was used to analyze the family data, and to estimate the proportions of sporadic, recessive and dominant causes of deafness in the families. These data were consistent with 37.2% of the cases due to sporadic causes, and 62.8% due to genetic causes (47.1% recessive, and 15.7% dominant). An earlier study using the 1969-70 Annual Survey found 49.3% sporadic cases and 50.6% genetic, demonstrating that the proportion of sporadic cases of early-onset deafness has significantly decreased since 1970.
Asunto(s)
Sordera/epidemiología , Sordera/genética , Distribución de Chi-Cuadrado , Niño , Estudios Transversales , Femenino , Genes Dominantes , Genes Recesivos , Humanos , Funciones de Verosimilitud , Masculino , Matrimonio , Linaje , Encuestas y Cuestionarios , Estados Unidos/epidemiologíaRESUMEN
We examined the three Alzheimer's disease (AD) family data sets for heterogeneity. Four markers that were represented in all three data sets were selected for analysis. Markers BCL3/EcoR-Mlu and D19S13/TaqI were chosen for chromosome 19 and D21S13/TaqI and D21S16/XbaI for chromosome 21. Homogeneity testing was performed on the data by use of Morton's pre-divided samples test (PS-test) and Smith's admixture test (A-test). The C-test of MacLean et al. [1992] was also used to test for linkage in the presence of heterogeneity. Assuming homogeneity, there was significant evidence of linkage to AD for BCL3, D19S13, D21S16 in the Duke data set and D19S13, D21S16 in the Boston data set. C-tests also provided evidence of linkage for BCL3 and D21S13 in the Duke data set, and D21S16 in the Boston data set. No evidence for heterogeneity within the data sets was found for any of the four markers using either the A-test or the C-test. For marker BCL3, PS-tests found evidence of heterogeneity between the three data sets and between early-versus late-onset families combined over all data sets.
Asunto(s)
Enfermedad de Alzheimer/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Boston/epidemiología , Mapeo Cromosómico , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 21 , Frecuencia de los Genes , Ligamiento Genético , Marcadores Genéticos , Variación Genética , Humanos , Persona de Mediana Edad , North Carolina/epidemiologíaRESUMEN
The detection of linkage in complex traits, although potentially of the greatest value, has proved very difficult. One reason may be the drastic effect that locus heterogeneity has on statistical power. We propose a new test for linkage in the presence of heterogeneity, based upon the sum of individual pedigree maximum lod scores, combined with a bootstrap method for estimating the null-hypothesis distribution. The technique is designed to exploit modern computer capability and to avoid reliance on asymptotic-distribution theory. Numerical comparisons indicate that for small pedigrees this new test can detect linkage with 30%-50% less data than are required by standard methods. A computer program for simulating the distribution and for performing the test of linkage is available from the authors.
Asunto(s)
Tamización de Portadores Genéticos , Enfermedades Genéticas Congénitas/genética , Ligamiento Genético , Femenino , Humanos , Masculino , Linaje , ProbabilidadRESUMEN
Many genetic traits have complex modes of inheritance; they may exhibit incomplete or age-dependent penetrance or fail to show any clear Mendelian inheritance pattern. As primary linkage maps for the human genome near completion, it is becoming increasingly possible to map these traits. Prior to undertaking a linkage study, it is important to consider whether the pedigrees available for the proposed study are likely to provide sufficient information to demonstrate linkage, assuming a linked marker is tested. In the current paper, we describe a computer simulation method to estimate the power of a proposed study to detect linkage for a complex genetic trait, given a hypothesized genetic model for the trait. Our method simulates trait locus genotypes consistent with observed trait phenotypes, in such a way that the probability to detect linkage can be estimated by sample statistics of the maximum lod score distribution. The method uses terms available when calculating the likelihood of the trait phenotypes for the pedigree and is applicable to any trait determined by one or a few genetic loci; individual-specific environmental effects can also be dealt with. Our method provides an objective answer to the question, Will these pedigrees provide sufficient information to map this complex genetic trait?
Asunto(s)
Ligamiento Genético , Genética Médica/métodos , Genotipo , Humanos , Linaje , Probabilidad , Programas InformáticosRESUMEN
The von Recklinghausen neurofibromatosis (NF1) gene has been mapped to the pericentromeric region of chromosome 17. We conducted linkage analyses of NF1 by using 10 polymorphic DNA markers from this chromosomal region. We ascertained 20 American Caucasian NF1 families (163 individuals, 98 NF1 affected) in Michigan and Ohio and also studied a large family ascertained primarily in North Carolina. The following markers were used in this study: HHH202, TH17.19, D17Z1, ERBA1, EW203, EW206, EW207, EW301, CRI-L581, and CRI-L946. NF1 did not recombine with either TH17.19 or HHH202 in any of the informative meioses surveyed (maximum lod scores of 17.04 and 7.21, respectively, at a recombination fraction of .00), indicating that these markers map very close to the NF1 gene. We also report evidence of three instances of recombination between NF1 and the centromeric marker D17Z1 (maximum lod score of 13.43 at a recombination fraction of .04), as well as two crossovers between pairs of marker loci. We find no evidence of locus heterogeneity, and our results support the localization of the NF1 gene to proximal chromosome 17q.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 17 , Neurofibromatosis 1/genética , Femenino , Ligamiento Genético , Marcadores Genéticos , Humanos , Masculino , Recombinación GenéticaRESUMEN
Several recent studies indicate that the von Recklinghausen neurofibromatosis (NF1) gene is located near the centromere of chromosome 17 in some families. However, variable expressivity and a very high mutation rate suggest that defects at several different loci could result in phenotypes categorized as NF1. In order to assess this possibility and to map the NF1 gene more precisely, we have used two polymorphic DNA markers from chromosome 17 to screen several pedigrees for linkage to NF1. We ascertained a large Caucasian pedigree (33 individuals sampled, 17 NF1 affected) as well as eight smaller pedigrees and nuclear families (50 individuals sampled, 30 NF1 affected). Here, we report strong evidence of linkage of NF1 to the centromeric marker D17Z1 (maximum lod = 4.42) and a weaker suggestion of linkage to the ERBA1 oncogene (maximum lod = 0.57), both at a recombination fraction of zero. Since obligate cross-overs with NF1 were not observed for either marker in any of the informative families tested, the possibility of NF1 locus heterogeneity is not supported.
Asunto(s)
Cromosomas Humanos Par 17 , Neurofibromatosis 1/genética , Mapeo Cromosómico , Marcadores Genéticos , Humanos , Escala de Lod , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Linkage relationships of the gene for peripheral neurofibromatosis (NF) were assessed in a large American Caucasian pedigree using two DNA markers located on chromosome 8. Linkage to the thyroglobulin locus, located at 8q24, was excluded (lod less than or equal to -2.0) to 21 cM. Data obtained for the tissue plasminogen activator locus, located at 8p12, excluded linkage to 4 cM. These results exclude between 20 to 30% of chromosome 8 as a possible map location for the NF gene in this family. Comparison of the two DNA markers excluded their linkage to 0.5 cM.
Asunto(s)
Cromosomas Humanos Par 8 , ADN/genética , Neurofibromatosis 1/genética , Ligamiento Genético , Marcadores Genéticos , Humanos , Tiroglobulina/genética , Activador de Tejido Plasminógeno/genéticaRESUMEN
In this prospective, longitudinal study, the relative impact of intracranial hemorrhage and prolonged mechanical ventilation on developmental progress during the first 18 months of life of infants weighing 1,200 g or less at birth was examined. A total of 159 surviving infants were divided into two groups: infants with and those without intracranial hemorrhage. These groups were then subdivided into groups of infants receiving prolonged mechanical ventilation (greater than 21 days) and those mechanically ventilated for 21 days or less, thus creating four subgroups. Group 1 (intracranial hemorrhage and prolonged mechanical ventilation) and group 3 (intracranial hemorrhage and no prolonged mechanical ventilation) showed no statistically significant differences for severity of intracranial hemorrhage, persistence of ventriculomegaly, or presence of periventricular leukomalacia. A repeated-measures analysis of variance demonstrated a main effect for prolonged mechanical ventilation on outcome as measured by the Bayley Mental Development Index and Bayley Psychomotor Development Index at 4, 8, 12, and 18 months of age (corrected for prematurity). Forward stepwise regression revealed prolonged mechanical ventilation to the best predictor of Bayley indexes at all ages except 4 months of age, for which the Psychomotor Development Index was best predicted by length of hospitalization. No main effect for intracranial hemorrhage was demonstrated, but the motor performance of infants with intracranial hemorrhage declined significantly with age. By contrast prolonged mechanical ventilation was associated with uniformly poor performance at every age and serves as a powerful marker for poor developmental progress during the first 18 months of life in infants weighing 1,200 g or less at birth.
Asunto(s)
Hemorragia Cerebral/fisiopatología , Desarrollo Infantil/fisiología , Enfermedades del Prematuro/fisiopatología , Recien Nacido Prematuro/fisiología , Desempeño Psicomotor/fisiología , Respiración Artificial/efectos adversos , Humanos , Lactante , Recién Nacido , Pruebas de Inteligencia , Estudios Longitudinales , Estudios Prospectivos , RiesgoRESUMEN
Severe hypoglycemic episodes, as defined as altered consciousness to the extent that self treatment is impossible, were sought prospectively in pregnant diabetic women. One or more episodes were found in none of 21 gestational onset, insulin-requiring women during their 28 pregnancies but were present in 19 (33%) of the 57 already insulin dependent (Type 1) women during 26 (36%) of their 72 pregnancies. The most common predisposing factors included strict glucose control, anorexia, early morning hours (1200-0900), lack of an adrenergic response and time shortly before the next anticipated meal.