Utilizing linear dichroism (LD), circular dichroism (CD), and fluorescence energy transfer, the binding geometries of a series of Co(3+)-porphyrins and their free ligands were examined. The compounds studied were Co-meso-tetrakis(N-methylpyridinium-4-yl)porphyrin (CoTMPyP) and its free ligand (H2-TMPyP), Co-meso-tetrakis(N-n-butylpyridinium-4-yl)porphyrin (CoTBPyP) and its free ligand (H2TBPyP), and Co-meso-tetrakis(N-n-octylpyridinium-4-yl)porphyrin (CoTOPyP). The two non-metalloporphyrins exhibit negative LD, having angles of roughly 75 degrees relative to the DNA helix axis. They also display negative CD and a significant contact energy transfer from the DNA bases. On the other hand, the three metalloporphyrins display orientation angles of roughly 45 degrees between the porphyrin plane and the helix axis of DNA. Furthermore, they exhibit positive CD and no contact energy transfer from DNA bases. These observations show that the metalloporphyrins are not intercalated whereas non-metalloporphyrins having four freely rotating meso-aryl groups intercalate between the base pairs of DNA. In the presence of KHSO5, the cobalt porphyrins cleave closed circular PM2 DNA in a single strand manner, i.e., a single activation event on the porphyrin leads to a break in one of the DNA strands. A kinetic analysis of the cleavage data revealed that cleavage rates are in the order CoTMPyP > CoTBPyP > CoTOPyP with the difference being due to different DNA affinities rather than differences in cleavage rate-constants. Based on these and earlier observations, the metalloporphyrins appear bound to a partially melted region of DNA.
To determine if spinal prostaglandins (PG) contribute to tactile allodynia, male, Sprague-Dawley rats were fitted with either intrathecal (i.t.) microdialysis or drug delivery catheters 3 days before tight ligation of the left lumber 5/6 spinal nerves. Paw withdrawal thresholds (PWT) were determined using von Frey filaments. Ligated rats developed tactile allodynia within 24h, as evidenced by a decrease in PWT in the affected hindpaw (<4 g vs. >15 g control). Sham-operated controls were unchanged from baseline (>15 g). Allodynia was also characterized by a significant increase in the evoked release of PGE(2). Thus, brushing the plantar surface of the affected hindpaw with a cotton-tipped applicator, 5 days postligation, increased the [PGE(2)](dialysate) to 199+/-34% of the prestimulus control period. In contrast, brushing had no detectable effect on release before surgery or in sham-operated animals. Basal release (no brushing) was similar before and after surgery (sham-operated and ligated rats). In a separate group of rats and beginning 2 days after ligation, the acute i.t. injection of S(+)-ibuprofen, SC-51322, SC-236, or SC-560 significantly reversed allodynia (maximum effect=69+/-9, 66+/-6, 57+/-4, 20+/-5%, respectively). R(-)-ibuprofen or vehicle were without effect. The results of this study suggest that: (a). spinal PG synthesis and allodynia-like behaviour are triggered by normally innocuous brushing after spinal nerve ligation; (b). pharmacological disruption of this cascade significantly reverses allodynia; (c). COX-2 is the relevant isozyme; and (d). the PG effect is mediated by spinal EP receptors.
Post-market monitoring of medical devices by manufacturers and regulatory agencies aids the identification of novel hazards or increasing trends in the risks associated with devices. This narrative review estimates the rates of under-reporting of medical device adverse events and explores the reasons and possible solutions. Incident reports may be presented to the manufacturer or the regulatory agency spontaneously by consumers, patients, clinicians, or distributors of medical devices. However, it is evident that reporting does not occur to a great extent, with the rate of reporting estimated to be as low as 0.5% of all occurrences. The programmes and processes to increase and support the reporting of adverse events need to be reviewed, with consideration given to the cost-benefit of increased reporting in relation to the regulator, regulated entities, healthcare facilities, and professionals, as well as the public.
BackgroundEach year, approximately 350 000 women in the UK experience perineal suturing following childbirth. For those women whose perineal wound dehisces, the management will vary according to individual practitioner's preferences. For most women, the wound will be managed expectantly (healing by secondary intention), whereas others may be offered resuturing. However, there is limited scientific evidence and no clear guidelines to inform best practice. PREVIEW is a two-part study aiming to identify the best management strategy for dehisced perineal wounds, in terms of clinical effectiveness and women's preferences.Methods/designThe main part of this study is a pilot and feasibility randomised controlled trial designed to provide preliminary evidence of the effectiveness of resuturing versus expectant management for dehisced perineal wounds following childbirth and to feed into the design and feasibility of a larger definitive trial. 144 participants will be randomly allocated to either intervention. The primary outcome is the proportion of women with a healed perineal wound at 6–8 weeks from the trial entry. Secondary outcomes include perineal pain, breast feeding rates, dyspareunia and women's satisfaction with the aesthetic results of the wound healing at 6 weeks, 3 months and 6 months post randomisation. Information will be collected using validated questionnaires. The second part of this study will be to conduct semistructured interviews with 12 study participants, aiming to capture information relating to their physical and psychological experiences following perineal wound dehiscence, assess the acceptability of the research plan and ensure that all outcomes relevant to women are included in the definitive trial.DisseminationThe results of this study will inform a definitive randomised controlled trial that will provide conclusive evidence of what is the best management of perineal wound dehiscence. This will potentially lead to significant improvements in perineal care and will help to reduce the short- and long-term morbidity experienced by women.Clinical trials registrationPREVIEW is registered with the International Standard Research for Clinical Trials (no: ISRCTN05754020) and adopted as a National Institute for Health Research (NIHR) Reproductive Health and Childbirth specialty group portfolio study UKCRN ID 9098.
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