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Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability 总被引:1,自引:15,他引:1
La Spada AR; Peterson KR; Meadows SA; McClain ME; Jeng G; Chmelar RS; Haugen HA; Chen K; Singer MJ; Moore D; Trask BJ; Fischbeck KH; Clegg CH; McKnight GS 《Human molecular genetics》1998,7(6):959-967
X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG
repeat expansion in the first exon of the androgen receptor (AR) gene.
Disease-associated alleles (37-66 CAGs) change in length when transmitted
from parents to offspring, with a significantly greater tendency to shift
size when inherited paternally. As transgenic mice carrying human AR cDNAs
with 45 and 66 CAG repeats do not display repeat instability, we attempted
to model trinucleotide repeat instability by generating transgenic mice
with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions
in their genomic context. Studies of independent lines of AR YAC transgenic
mice with CAG 45 alleles reveal intergenerational instability at an overall
rate of approximately 10%. We also find that the 45 CAG repeat tracts are
significantly more unstable with maternal transmission and as the
transmitting mother ages. Of all the CAG/CTG repeat transgenic mice
produced to date the AR YAC CAG 45 mice are unstable with the smallest
trinucleotide repeat mutations, suggesting that the length threshold for
repeat instability in the mouse may be lowered by including the appropriate
flanking human DNA sequences. By sequence-tagged site content analysis and
long range mapping we determined that one unstable transgenic line has
integrated an approximately 70 kb segment of the AR locus due to
fragmentation of the AR YAC. Identification of the cis - acting elements
that permit CAG tract instability and the trans -acting factors that
modulate repeat instability in the AR YAC CAG 45 mice may provide insights
into the molecular basis of trinucleotide repeat instability in humans.
相似文献
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In a child with some features of Turner's syndrome, gonosomal mosaicism with an isodicentric nonfluorescent (idic)Y chromosome was detected (mos 45,X/47,X,idic(Y)(q11),idic(Y)(11)/46,X,idic(Y)(q11)). Histopathological examination showed streak gonads with some evidence of ovarian stroma and no sign of gonadoblastoma. Polymerase chain reaction (PCR) analysis in blood lymphocytes and gonadal tissues using primers of seven loci along the Y chromosome, including the sex determined region (SRY), azoospermia factor region (AZF) and the deleted in azoospermia ( DAZ ) gene was positive for all loci tested, confirming the isodicentric character of the Y chromosome and indicating the presence of the AZF region. It is remarkable that the existence of spermatogenesis controlling genes does not play an important role in gonadal development and differentiation in a phenotypic female with some Turner stigmata. The data presented here are briefly discussed with previously-described patients. 相似文献
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Renal transplant (RT) is now a therapy of choice for end stage renal disease (ESRD). The Nephrology Unit, Asvini started functioning in Dec 90 and to date 1298 sittings of hemodialysis have been given to 45 patients. Of these, 35 were in ESRD and 11 patients underwent renal transplantation at this hospital during the period Jan 91 – Dec 93. One patient expired after 18 months of transplantation due to infection. Early experience in screening patients for RT, use of immunosuppression, management of rejection episodes and protocol are presented with special emphasis on its relevance to the Armed Forces.KEY WORDS: Transplantation, Renal Failure, Immunosuppression, Rejection 相似文献
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A meta-analysis of thromboembolic prophylaxis following elective total hip arthroplasty 总被引:24,自引:0,他引:24
Freedman KB Brookenthal KR Fitzgerald RH Williams S Lonner JH 《The Journal of bone and joint surgery. American volume》2000,(7):929-938
BACKGROUND: Although several agents have been shown to reduce the risk of thromboembolic disease, there is no clear preference for thromboembolic prophylaxis in elective total hip arthroplasty. The purpose of this study was to define the efficacy and safety of the agents that are currently used for prophylaxis against deep venous thrombosis -- namely, low-molecular-weight heparin, warfarin, aspirin, low-dose heparin, and pneumatic compression. METHODS: A Medline search identified all randomized, controlled trials, published from January 1966 to May 1998, that compared the use of one of the prophylactic agents with the use of any other agent or a placebo in patients undergoing elective total hip arthroplasty. For a study to be included in our analysis, bilateral venography had to have been performed to confirm the presence or absence of deep venous thrombosis. Fifty-two studies, in which 10,929 patients had been enrolled, met the inclusion criteria and were included in the analysis. The rates of distal, proximal, and total (distal and proximal) deep venous thrombosis; symptomatic and fatal pulmonary embolism; minor and major wound-bleeding complications; major non-wound bleeding complications; and total mortality were determined for each agent in each study. The absolute risk of each outcome was determined by dividing the number of events by the number of patients at risk. A general linear model with random effects was used to calculate the 95 percent confidence interval of risk. A crosstabs of study by outcome was performed to test homogeneity (ability to combine studies). The risk of each outcome was compared among agents and between each agent and the placebo. RESULTS: With prophylaxis, the risk of total (proximal and distal) deep venous thrombosis ranged from 17.7 percent (low-molecular-weight heparin) to 31.1 percent (low-dose heparin); the risk with prophylaxis with any agent was significantly lower than the risk with the placebo (48.5 percent) (p < 0.0001). The risk of proximal deep venous thrombosis was lowest with warfarin (6.3 percent) and low-molecular-weight heparin (7.7 percent), and again the risk with any prophylactic agent was significantly lower than the risk with the placebo (25.8 percent) (p < 0.0001). Compared with the risk with the placebo (1.51 percent), only warfarin (0.16 percent), pneumatic compression (0.26 percent), and low-molecular-weight heparin (0.36 percent) were associated with a significantly lower risk of symptomatic pulmonary embolism. There were no significant differences among agents with regard to the risk of fatal pulmonary embolism or of mortality with any cause. The risk of minor wound-bleeding was significantly higher with low-molecular-weight heparin (8.9 percent) and low-dose heparin (7.6 percent) than it was with the placebo (2.2 percent) (p < 0.05). Compared with the risk with the placebo (0.28 percent), only low-dose heparin was associated with a significantly higher risk of major wound-bleeding (2.56 percent) and total major bleeding (3.46 percent) (p < 0.0001). CONCLUSIONS: The best prophylactic agent in terms of both efficacy and safety was warfarin, followed by pneumatic compression, and the least effective and safe was low-dose heparin. Warfarin provided the lowest risk of both proximal deep venous thrombosis and symptomatic pulmonary embolism. However, there were no identifiable significant differences in the rates of fatal pulmonary embolism or death among the agents. Significant risks of minor and major bleeding complications were observed with greater frequency with certain prophylactic agents, particularly low-molecular-weight heparin (minor bleeding) and low-dose heparin (both major and minor bleeding). 相似文献
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