PubMed · 5071707
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E A Burkitt, M Faulkner. 1972-09-09. Pimozide.. https://doi.org/10.1136/bmj.3.5827.643-a
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A key step in the supercoiling reaction is the DNA gyrase-mediated cleavage and religation step of double-stranded DNA. Footprinting studies suggest that the DNA gyrase binding site is 100-150 bp long and that the DNA is wrapped around the enzyme with the cleavage site located near the center of the fragment. Subunit A inhibitors interrupt this cleavage and resealing cycle and result in cleavage occurring at preferred sites. We have been able to show that even a 30 bp DNA fragment containing a 20 bp preferred cleavage sequence from the pBR322 plasmid was a substrate for the DNA gyrase-mediated cleavage reaction in the presence of inhibitors. This DNA fragment was cleaved, although with reduced efficiency, at the same sites as a 122 bp DNA fragment. A 20 bp DNA fragment was cleaved with low efficiency at one of these sites and a 10 bp DNA fragment was no longer a substrate. We therefore propose that subunit A inhibitors interact with DNA at inhibitor-specific positions, thus determining cleavage sites by forming ternary complexes between DNA, inhibitors and DNA gyrase.
Viable, healthy sperm are preferred for oocyte fertilization with intracytoplasmic sperm injection. Currently, motility is the most widely applied measure of sperm viability. However, with this criterion, viable but immotile sperm are overlooked as candidates for micromanipulation. Supravital stains identify viable sperm but may be toxic to the gamete or embryo. We tested the hypothesis that hypo-osmotic swelling, developed to assess sperm membrane integrity, can accurately determine sperm viability. Thawed sperm from 12 fertile donors were exposed to a hypo-osmotic solution and to two supravital stains. A total of 2,010 sperm were assessed for tail coiling after a 30-min exposure to hypoosmotic solution. By supravital stains, 31% of thawed sperm were viable; 23% showed tail coiling. Among coiled-tail sperm, 100% were viable by supravital stain. As a measure of viability, tail coiling exhibited a sensitivity of 30%, specificity of 100%, and positive predictive value of 100% compared to supravital stains. With a 60-min hypo-osmotic incubation, the specificity (89%) and positive predictive value (78%) decreased significantly (P < 0.05). Therefore, hypo-osmotic swelling accurately detects viable sperm among a nonmotile population. Assay accuracy, however, is very sensitive to the incubation time in hypo-osmotic solution.
BACKGROUND: Despite the advances in therapy for heart failure with the use of angiotensin-converting enzyme inhibitors, heart failure remains a major medical problem, impacting on well-being and survival. HYPOTHESIS: Mibefradil is a member of new class of agents that, due to its unique mechanism of action and pharmacologic and physiologic profile, may offer a significant advance in the treatment of heart failure. Mibefradil is a nonvoltage-regulated T-channel calcium blocker that differs from all the other currently available L-channel calcium blockers. The drug is a potent peripheral and coronary vasodilator, with no clinical negative inotropic activity. Furthermore, because of its long half-life, it can be given once a day and appears to be free of the common side effects seen with other calcium-channel blockers. The trial was designed to investigate whether the addition of mibefradil to standard therapy for heart failure will reduce mortality in patients with symptomatic heart failure. METHODS: This manuscript describes the design, organization, and status of MACH-1 (Mortality Assessment in Congestive Heart Failure), a double-blind, placebo-controlled study. It is to be a 2,400-patient international trial assessing the ability of mibefradil to impact upon survival and symptoms of heart failure in patients who are in NYHA classes II-IV and who were already treated with standard therapy.