Report of the second international workshop on human chromosome 5 mapping: consensus genetic map.
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Biomedical subjects
Publications and source records attributed to R White.
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Since Andreas Gruentzig first introduced percutaneous transluminal coronary angioplasty (PTCA) in 1977, the ability to revascularize occluded coronary vessels with a catheter has enjoyed an explosive and unimaginable growth. As the equipment and operator experience improved, the possibilities appeared boundless. However, balloon angioplasty is hampered by a significant restenosis rate in the dilated vessel (approximately 30%), which is higher in selected locations (up to 60% in the proximal left anterior descending artery), even in the best of hands. This fundamental limitation may in part be due to the actual nature of the technique itself--stretching the vessel and fissuring the plaque causing remodeling without removal. The uneven, exposed vessel surface post-plaque rupture may contribute to activation of the hemostatic system, with acute thrombosis and release of various platelet and endothelial-derived growth factors, leading to long-term tissue proliferation and restenosis. Atherectomy, the mechanical removal of plaque from the vessel wall, appears to be an answer. This process actually debulks the culprit tissue and leaves behind a smoother, presumably less thrombogenic surface. We wish to report our first experience with a specific form of this technique in 4 consecutive patients, with a brief discussion of its promises and limitations.
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A review of records of 18,104 Charnley low-friction arthroplasties, performed during a 17-year period, shows a 0.7% incidence of fatal pulmonary embolism. Ninety percent occurred within four weeks of surgery and 71% were submitted to postmortem examination. There was a strong seasonal variation. The incidence from November through February was 1% as compared with 0.42% for the remainder of the year. The difference was statistically significant at 0.01 greater than p greater than 0.001 level. There was no significant seasonal variation in deaths from other causes.
Gout affecting the acromioclavicular joint is extremely rare. We describe a case of acute gout involving the acromioclavicular joint in a patient with seronegative spondyloarthropathy, following use of the fibric acid derivative, gemfibrozil. This case broadens the differential diagnosis of acute acromioclavicular joint arthritis; further studies are needed to determine if there is a causal relationship between use of gemfibrozil and an acute attack of gout.
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OBJECTIVE: To determine the efficacy of ciprofloxacin therapy in eradicating convalescent fecal excretion of salmonellae after acute salmonellosis. DESIGN: Randomized, placebo-controlled, double-blind trial of ciprofloxacin, with prospective follow-up of nonparticipants. SETTING: An acute care community hospital experiencing an outbreak of salmonellosis. PATIENTS: Twenty-eight health care workers developed acute infection with Salmonella java; 15 participated in a placebo-controlled trial of ciprofloxacin, beginning on day 9 after infection. INTERVENTIONS: Eight patients were randomly assigned to receive ciprofloxacin, 750 mg, and 7 patients to receive placebo; both were administered orally twice daily for 14 days. Nonparticipants who received therapy were placed on the same ciprofloxacin regimen. MEASUREMENTS AND MAIN RESULTS: Study participants had follow-up stool cultures every 3 days initially and then weekly for 3 weeks; nonparticipants were followed until three consecutive cultures were negative. All eight ciprofloxacin recipients showed eradication of S. java from stool cultures within 7 days of beginning therapy (compared with 1 of 7 placebo recipients), and their stool cultures remained negative up to 14 days after discontinuing therapy (P less than 0.01). However, 4 of 8 relapsed; their stool cultures became positive between 14 and 21 days after therapy. In addition, 3 of 3 hospitalized patients treated with ciprofloxacin who did not participate in the controlled trial also relapsed. Thus, the total relapse rate was 7 of 11 (64%; 95% CI, 31% to 89%). In 4 of these 7 patients, relapse was associated with a longer duration of fecal excretion of salmonellae than that of the placebo group. Relapse could not be explained on the basis of noncompliance, development of resistance, or presence of biliary disease. CONCLUSIONS: Despite its excellent antimicrobial activity against salmonellae and its favorable pharmacokinetic profile, ciprofloxacin at a dosage of 750 mg orally twice daily had an unacceptably high failure rate in patients with acute salmonellosis and may have prolonged fecal excretion of salmonellae. The late occurrence of relapses indicates the need to obtain stool cultures up to 21 days after therapy to document fecal eradication in acute salmonellosis.
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Our laboratory has constructed linkage maps of the human chromosomes to use as a tool towards the goal of cloning by position the genes responsible for genetic disorders. Construction of the map required the development of polymorphic marker systems in the form of Restriction Fragment Length Polymorphisms (RFLPs). Work by Yusuke Nakamura in the laboratory led to the identification of more than 200 highly informative Variable Number Tandem Repeat (VNTR) markers. The hypervariable nature of these marker loci has allowed individualization at the DNA level. Techniques for individualization have subsequently been adopted by diverse fields including gene mapping, cancer genetics and forensic biology. These markers have also become a resource to test hypotheses as to how the VNTRs generate their intrinsic variability. We have demonstrated that the hypothesis that VNTRs generate their variability by unequal exchange between homologous chromosomes in incorrect (Wolff et al., 1988; Wolff et al., 1989). Our data are consistent with intrachromosomal models such as unequal sister chromatid exchange and replication slippage. Using DNA derived from nonhuman primate species, we have tested hypotheses that try to explain the sequence relationship at dispersed VNTR loci. Our data reveal that VNTR loci are most likely not related by transposition but rather arose independently at multiple loci.
An actinomycete (MA 6474, ATCC 53828) isolated from a soil sample (Mutare, Zimbabwe) was found to biotransform the sodium salt of Simvastatin (MK-733) to 6-alpha-hydroxymethyl MK-733, 6-beta-hydroxymethyl MK-733, and 6-ring-hydroxy MK-733. The bioconversion efficiency to the desired compound, 6-alpha-hydroxymethyl MK-733, was enhanced by optimizing the physico-chemical parameters of the process. In shake flask cultures, addition of magnesium (0.125 mg/l Mg SO4.7H2O) to the medium resulted in a five-fold increase in the rate of bioconversion to the alpha diastereomer. The ratio of bioconversion products (6-alpha-hydroxymethyl,6-beta-hydroxymethyl, and 6-ring-hydroxy MK-733) was regulated by pH. Process improvements and scale up in 23-1 fermentors, which consisted of a controlled addition of substrate (MK-733), resulted in a 2-fold increase in alpha diastereomer production (42 vs. 79 U/ml) and a 23-fold rate increase in the formation of alpha-diastereomer. A high diastereomeric ratio (alpha: beta = 9:1) facilitated downstream processing.