Topoisomerases (topos) maintain DNA topology and influence DNA transaction processes by catalysing relaxation, supercoiling and decatenation reactions. In the cellular milieu, division of labour between different topos ensures topological homeostasis and control of central processes. In Escherichia coli, DNA gyrase is the principal enzyme that carries out negative supercoiling, while topo IV catalyses decatenation, relaxation and unknotting. DNA gyrase apparently has the daunting task of undertaking both the enzyme functions in mycobacteria, where topo IV is absent. We have shown previously that mycobacterial DNA gyrase is an efficient decatenase. Here, we demonstrate that the strong decatenation property of the enzyme is due to its ability to capture two DNA segments in trans. Topo IV, a strong dedicated decatenase of E. coli, also captures two distinct DNA molecules in a similar manner. In contrast, E. coli DNA gyrase, which is a poor decatenase, does not appear to be able to hold two different DNA molecules in a stable complex. The binding of a second DNA molecule to GyrB/ParE is inhibited by ATP and the non-hydrolysable analogue, AMPPNP, and by the substitution of a prominent positively charged residue in the GyrB N-terminal cavity, suggesting that this binding represents a potential T-segment positioned in the cavity. Thus, after the GyrA/ParC mediated initial DNA capture, GyrB/ParE would bind efficiently to a second DNA in trans to form a T-segment prior to nucleotide binding and closure of the gate during decatenation.
Aims A postmarketing Prescription-Event Monitoring study was undertaken to monitor the safety of rofecoxib, a cyclo-oxygenase (COX)-2 selective inhibitor prescribed in primary care in England. Methods Questionnaires requesting clinical event data were sent to prescribing physicians between February and November 2000, and the data analysed for all events. Results There were 15 268 patients identified, mean age 62 years, 67% female. The commonest specified indication was osteoarthritis (24%). Dyspepsia and nausea were the most frequently reported adverse events. A history of dyspeptic or upper gastrointestinal (GI) conditions, recent use of other nonsteroidal anti-inflammatory drugs (NSAIDs), use of selected concomitant gastroirritant drugs (NSAIDs, aspirin, anticoagulants, antiplatelet drugs), or gastroprotective drugs (misoprostol, antacids, proton-pump inhibitors, histamine-2 antagonists), and age ( ≥ 65 years) modified the risk of having minor GI events. During treatment or within 1 month of stopping, 110 serious GI events were reported (including 76 upper GI bleeds/peptic ulcers, one perforated colon), 101 thromboembolic events, three reports of acute renal failure, one each of Stevens-Johnson syndrome, severe anaphylaxis and angio-oedema. Conclusions Doctors should continue to prescribe NSAIDs including COX-2 selective inhibitors with caution.
Aims A postmarketing Prescription-Event Monitoring study was undertaken to monitor the safety of rofecoxib, a cyclo-oxygenase (COX)-2 selective inhibitor prescribed in primary care in England. Methods Questionnaires requesting clinical event data were sent to prescribing physicians between February and November 2000, and the data analysed for all events. Results There were 15 268 patients identified, mean age 62 years, 67% female. The commonest specified indication was osteoarthritis (24%). Dyspepsia and nausea were the most frequently reported adverse events. A history of dyspeptic or upper gastrointestinal (GI) conditions, recent use of other nonsteroidal anti-inflammatory drugs (NSAIDs), use of selected concomitant gastroirritant drugs (NSAIDs, aspirin, anticoagulants, antiplatelet drugs), or gastroprotective drugs (misoprostol, antacids, proton-pump inhibitors, histamine-2 antagonists), and age ( ≥ 65 years) modified the risk of having minor GI events. During treatment or within 1 month of stopping, 110 serious GI events were reported (including 76 upper GI bleeds/peptic ulcers, one perforated colon), 101 thromboembolic events, three reports of acute renal failure, one each of Stevens-Johnson syndrome, severe anaphylaxis and angio-oedema. Conclusions Doctors should continue to prescribe NSAIDs including COX-2 selective inhibitors with caution.
SUMMARY Dogs with naturally occurring aerobic or anaerobic bacterial overgrowth have been examined before and after antibiotic therapy in order to assess reversibility of damage to the jejunal mucosa. Histological changes in peroral jejunal biopsies were relatively minor before and after treatment, but sucrose density gradient centrifugation revealed specific biochemical abnormalities that responded to antibiotic therapy. Aerobic overgrowth was initially associated with a marked loss of the main brush border component of alkaline phosphatase activity; this recovered following treatment, suggesting that aerobic bacteria may cause reversible damage to the hydrophobic region of the brush border membrane. In contrast, anaerobic overgrowth was initially associated with a marked reduction in brush border density, indicative of a considerable fall in the glycoprotein-tolipid ratio of the membrane. Density increased from 1.17 to 1.21 g/ml after antibiotic therapy, consistent with recovery from this relatively severe damage to the brush border caused by anaerobic bacteria. Reductions in soluble and peroxisomal catalase activities which could compromise mucosal protection against free radicals in dogs with aerobic overgrowth, and a loss of particulate malate dehydrogenase activity indicative of mitochondrial disruption in dogs with anaerobic overgrowth, were also reversed after treatment. These findings indicate that aerobic and anaerobic bacterial overgrowth can result in contrasting but potentially reversible damage to the jejunal mucosa which would not be detected by conventional investigative procedures.In the blind loop syndrome in man' and in experimental animals2 -an association has been established between chronic overgrowth of predominantly obligate anaerobic bacteria and functional damage to enterocytes. In addition, it has been suggested that longterm colonisation, particularly with coliform bacteria, might play a role in the pathogenesis of the relatively severe morphological damage to the small intestine in chronic tropical sprue in man.'"'I While the potential longterm consequences of an abnormal flora on the mucosa of the small intestine have been studied extensively, the possibility that there may be irreversible components to these mucosal abnormalities236'4 '5 has received relatively little attention.A naturally occurring disease in the dog associated with bacterial overgrowth in the proximal small Address for correspondence: Dr R M Batt, Department of Veterinary Pathology, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK. Received for publication 23 October 1987. intestine has provided the opportunity to explore relationships between an abnormal flora and mucosal damage.'7 A comparison between dogs with aerobic and anaerobic overgrowth has revealed differences in biochemical abnormalities which indicate that the composition of the overgrowth flora can have an important influence on the nature of mucosal damage.' The present study examines the effects of antibiotic treatment on these mucosal...
Diversion of portal blood in congenital portosystemic shunts (CPSS) results in liver atrophy and passage of toxins into the systemic circulation causing hepatic encephalopathy. In some dogs, there is indirect evidence for hepatic insufficiency, but histologic findings are equivocal. This study determined whether hepatocyte integrity in PSS is comprised at a subcellular level using analytical subcellular fractionation of liver biopsies. Six dogs with CPSS had hypoproteinemia (6/6), increased serum alkaline phosphatase (6/6) and alanine aminotransferase (4/6) activity, hypocholesterolemia (6/6), and decreased blood urea (2/6). Liver biopsy specimens had increased activities (mU/mg protein) of alkaline phosphatase (17.9 f 10.1; controls 5.1 f 5.3: P < 0.01), but not of other plasma membrane enzymes. There were increased activities of endoplasmic reticular (neutral a-glucosidase: 1.67 t 0.7; controls 0.86 i 0.2: P < 0.01) and lysosomal enzymes (N-acetyl-8-glucosaminidase: 12.6 t 2.3; controls 6.24 k 2.7: P < 0.01; a-mannosidase: 0.85 f 0.5; controls 0.39 f 0.3: P < 0.05). Subcellular fractionation on reorientating sucrose density gradients showed a high-density peak of alkaline phosphatase suggestive of a specific increase in the biliary canalicular component of enzyme activity. Neutral a-glucosidase was shifted to denser fractions, indicative of an increase in the proportion of rough-to-smooth endoplasmic reticulum and consistent with enhanced synthesis of membranous enzymes. There was also evidence for increased fragility of intracellular organelles, particularly lysosomes. In contrast, histology showed either no abnormalities or minor degenerative changes compatible with hepatic underperfusion. These findings indicate that CPSS may be associated with hepatocellular damage compatible with hepatic dysfunction and potentially overlooked by conventional morphologic criteria. (Journal of Veterinary Internal Medicine 1991; 5351-356) DURING THE past several years, congenital portosystemic shunts (CPSS) have been described with increasing frequency in dogs.'-'' CPSS are vascular communications between the portal and systemic venous circulations that allow the portal blood to bypass the liver. Consequently, substances that are normally cleared by the liver such as enteric toxins are present in increased concentrations in the systemic circulation, resulting in clinical signs of hepatoencephalopathy. In addition, decreased hepatic blood flow and lack of hepatotrophic factors from portal blood lead to hepatocyte atrophy.'' Common laboratory abnormalities associated with CPSS are increased retention of sulfobromophthalein soFrom the Departments of Veterinary Clinical Sciences (Rutgers) and Veterinary Pathology (Batt, Haywood, Riley),
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