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D P Edwards

Publications and source records attributed to D P Edwards.

134 records · Page 8Linked to original sources
PubMed1976

Human placental 3beta-hydroxysteroid dehydrogenase: delta5-isomerase. Demonstration of an intermediate in the conversion of 3beta-hydroxypregn-5-en-20-one to pregn-4-ene-3,20-dione.

3beta-Hydroxypregn-5-en-20-one (pregnenolone) and NAD+ were incubated with a solubilized preparation of the coupled enzyme 3beta-hydroxysteroid:NAD(P) oxidoreductase-3-ketosteroid delta4,delta5-isomerase (3beta-hydroxysteroid dehydrogenase: delta5-isomerase) from the mitochondrial fraction of human placenta. Unconverted pregnenolone, pregn-4-ene-3,20-dione (rogesterone), and a small but detectable amount of pregn-5-ene-3,20-dione were isolated from the medium by Sephadex LH-20 chromomatography. The identification of pregn-5-ene-3,20-dione, confirmed by mass fragmentography, has provided the first direct evidence for the formation of the hypothetical delta5,3-ketone intermediate in the conversion of pregnenolone to progesterone. When tritium-labeled pregnenolone and [4-14C]pregnenolone were incubated simultaneously the 3H:14C ratio in isolated pregn-5-ene-3,20-dione was 4.6 times greater than in isolated progesterone and pregnenolone, indicating a kinetic isotope effect in the enzymatic isomerization of tritium-labeled pregn-5-ene-3,20-dione. Exposure of the enzyme to two steroids which inhibit the overall enzyme reaction, 2alpha-cyano-17beta-hydroxy-4,4,17alpha-trimethylandrost-5-en-3-one (cyanoketone) and 3-hydroxyestra-1,3,5(10),6,8-pentaen-17-one (equilenin), increased the relative yield of labeled pregn-5-ene-3,20-dione as well as the recovery of radioactivity remaining as unconverted pregnenolone, suggesting that both the dehydrogenase and isomerase activities were inhibited. Exposure of the enzyme to equilenin increased the ratio of isolated pregn-5-ene-3,20-dione radioactivity to progesterone radioactivity as progesterone synthesis was inhibited. Equilenin also diminished the tritium isotope effect on the isomerase reaction. Both findings suggest that it is possible to inhibit the isomerase to a greater extent than the dehydrogenase. In order to measure the rate of progesterone produced by the coupled enzymes, we have modified a radiochemical method which involves precipitation of pregnenolone by digitonin. Digitonin precipitation proved to be effective in separating unconverted pregnenolone from the steroid products of both enzyme reactions, progesterone and pregn-5-ene-3,20-dione. Neither the steroidal inhibitors nor the kinetic isotope effect altered the accuracy of the method for routine measurement of the overall rate of conversion of delta5,3beta-hydroxysteroid to delta4,3-ketosteroid.

Female↗
PubMedDate not supplied

Novel mechanisms of progesterone antagonists and progesterone receptor.

The progesterone receptor (PR), as a member of the nuclear receptor superfamily of ligand-dependent transcription factors, activates gene transcription through binding to specific palindromic progesterone response elements (PRE) in the promoter region of progestin-responsive genes. The progesterone antagonists ZK98299 (Onapristone) and RU 486 (Mifepristone) inhibit the transcriptional activity of PR by complex mechanisms at concentrations much lower than the progestins. Altered conformation is central to antagonist inhibition of the transcriptional activity of PR. Antagonists also promote inappropriate association of PR with corepressors. We speculate that the different PR conformations induced by agonist and antagonists results in an asymmetric agonist/antagonist heterodimer that binds inefficiently to palindromic PREs. PR, under the same cellular conditions but with different promotor contexts, can repress (beta-casein) or enhance (3 beta-HSD) signal transducer and activator of transcription (Stat5)-mediated gene activation. The beta-casein promoter appears to contain a composite DNA-binding element for PR and Stat5 and that occupancy by PR in response to progestins or antagonists suppresses Stat5 transactivation function.

Animals↗
PubMedDate not supplied

Should colon-penetrating small missiles be removed? An experimental study of retrocolic wound tracks.

Small-fragment injury to the colon may occur in approximately 5% of battlefield casualties. The surgical management aims to reduce the risk of retrocolic infection and provide optimal conditions for colonic wound healing. This study aimed to quantify the risk of retrocolic infection. Steel fragments were fired through exteriorized porcine colon and caught in 20% gelatin. The fragments, and resultant tracks, were extracted and subjected to quantitative bacteriological examination to determine the extent of contamination. The median bacterial count for complete tracks was 1.2 x 10(4) CFU/g (interquartile range 1.8 x 10(3) to 2.7 x 10(4)). Counts were highest in the initial 1 cm of the track and reduced along its length. This study does not support wound track excision or missile fragment removal in cases of retrocolic trauma following penetrating colonic injury. Either or both procedures will increase local trauma and are likely to prejudice colonic wound repair.

Animals↗
PubMedDate not supplied

Colonic anastomosis in the presence of fecal peritonitis using a disposable skin stapler.

The purpose of this study was to determine if the method of intestinal anastomosis used by British military surgeons for the management of small bowel injuries could be used to manage colonic trauma when fecal peritonitis may be present. Anastomoses were performed using skin staples in lieu of sutures in pig colons in the presence of fecal contamination and early peritonitis. The times taken to complete the anastomoses were recorded. Animals were euthanatized at 2, 5, and 14 days following surgery. Healing was assessed clinically, at postmortem, and by histological examination. In addition, the anastomoses were tested for integrity by intraluminal distension with water, and for healing strength by tensiometry. The mean +/- SD time taken to perform the anastomoses (n = 18) was 10.8 +/- 2.8 min. There were no clinical or postmortem findings suggestive of anastomotic leakage. Only one anastomosis leaked at an intraluminal pressure of less than 100 cm H2O. Testing of ultimate tensile strength of the colon adjacent to the anastomosis showed that the anastomotic line was significantly weaker than the proximal (p < .05 analysis of variance, ANOVA) and distal colon (p < .001) at 5 days and that the colon proximal to the anastomosis was weaker than the colon distally at all time points; this was statistically significant (p < .01, ANOVA) at 5 days. These results suggest that a primary colonic skin-stapled anastomosis in the presence of fecal peritonitis is quick to perform and has a low risk of failure.

Anastomosis, Surgical↗
PubMedDate not supplied

Hickman lines inserted and managed by a general surgical team: longevity and complications.

Long-term venous access lines are commonplace in the management of patients requiring continuous intravenous chemotherapy, intravenous nutrition or simply as a means of avoiding repeated peripheral access lines in patients with difficult venous access. The insertion and maintenance of these lines is not without major complication. Four years' experience with the Hickman catheter in a general surgical oncology setting are reviewed. Thirty-seven lines were inserted in 37 patients with a mean longevity of 107 days (range 2-322) and an overall complication rate of 1.25 per 1000 catheter days. Four catheters were removed prematurely due to late complications. These figures compare favourably with results for long-term venous access from larger specialist units.

Adult↗