Biomedical subjects
P R Williamson
Publications and source records attributed to P R Williamson.
Twenty-year review of the surgical management of perianal Crohn's disease.
PURPOSE: A retrospective analysis of 48 patients treated over a 20-year period (March 1973-April 1993) was undertaken to assess the results of our practice of early surgical intervention in suppurative complications of perianal Crohn's disease. METHODS: All patients were either seen in the office within the last six months or contacted by phone. RESULTS: The average age of our patients was 30 years at initial diagnosis. Thirty-four patients (71 percent) initially presented with intestinal disease and four (8 percent) with only perianal disease. Thirteen patients (27 percent) initially presented with simultaneous intestinal and perianal disease. The various fistulas at initial presentation included 8 intersphincteric (17 percent), 14 transphincteric (29 percent), 11 complex or multiple (23 percent), 5 rectovaginal (10 percent), and 2 unclassified, for a total of 40 patients. Eight patients (17 percent) presented with only an abscess. Eighty five percent of our patients healed after their first procedure, with an average time to heal of 2.8 months. Thirteen (27 percent) patients had recurrences after initial healing of their wounds. The mean time to recurrence after healing was 5.25 years. Fifty-four percent of our recurrences (7 patients) were treated by incision and drainage of an abscess only. Seven of 13 recurrences healed after the second procedure (54 percent), and 5 of 6 healed after a third procedure (83 percent). Only seven (14 percent) of our patients underwent a proctocolectomy during the study period, through September, 1993. Our overall probability of avoiding proctectomy and healing perineal wounds of 86 percent is consistent with published literature. CONCLUSIONS: Early aggressive surgical management of suppurative complications of perianal Crohn's disease before complex management problems ensue results in a high incidence of healing and a low risk of subsequent proctectomy.
Molecular approaches to identify novel targets for future development of antifungal agents.
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Biochemical and molecular characterization of the diphenol oxidase of Cryptococcus neoformans: identification as a laccase.
Melanin production is a major virulence factor for Cryptococcus neoformans, an organism causing life-threatening infections in an estimated 10% of AIDS patients. In order to characterize the events involved in melanin synthesis, an enzyme having diphenol oxidase activity was purified and its gene was cloned. The enzyme was purified as a glycosylated 75-kDa protein which migrated at 66 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis after deglycosylation by endoglycosidase F. Substrate specificity resembled that of a laccase in that it oxidized multiple diphenolic and diamino compounds. Dopamine was shown by mass spectroscopy to be oxidized to decarboxy dopachrome, an intermediate of melanin synthesis. The enzyme contained 4.1 +/- 0.1 mol of copper per mol. It resembled a laccase in its absorbance spectrum, containing a peak of 610 nm and the shoulder at 320 nm, corresponding to the absorbance of a type I and type III copper, respectively. The cloned gene of C. neoformans laccase (CNLAC1) contained a single open reading frame encoding a polypeptide 624 amino acids in length. The encoded polypeptide contained a presumptive leader sequence, on the basis of its relative hydrophobicity and by comparison of the sequence to that of the N-terminal sequence of the purified enzyme. CNLAC1 also contained 14 introns ranging from 52 to 340 bases long. Transcriptional activity of CNLAC1 was found to be derepressed in the absence of glucose and to correspond to an increase in enzymatic activity.
Role of maltase in the utilization of sucrose by Candida albicans.
Two isoenzymes of maltase (EC 3.2.1.20) were purified to homogeneity from Candida albicans. Isoenzymes I and II were found to have apparent molecular masses of 63 and 66 kDa on SDS/PAGE with isoelectric points of 5.0 and 4.6 respectively. Both isoenzymes resembled each other in similar N-terminal sequence, specificity for the alpha(1-->4) glycosidic linkage and immune cross-reactivity on Western blots using a maltase II antigen-purified rabbit antibody. Maltase was induced by growth on sucrose whereas beta-fructofuranosidase activity could not be detected under similar conditions. Maltase I and II were shown to be unglycosylated enzymes by neutral sugar assay, and more than 90% of alpha-glucosidase activity was recoverable from spheroplasts. These data, in combination with other results from this laboratory [Geber, Williamson, Rex, Sweeney and Bennett (1992) J. Bacteriol. 174, 6992-6996] showing lack of a plausible leader sequence in genomic or mRNA transcripts, suggest an intracellular localization of the enzyme. To establish further the mechanism of sucrose assimilation by maltase, the existence of a sucrose-inducible H+/sucrose syn-transporter was demonstrated by (1) the kinetics of sucrose-induced [14C]sucrose uptake, (2) recovery of intact [14C]sucrose from ground cells by t.l.c. and (3) transport of 0.83 mol of H+/mol of [14C]sucrose. In total, the above is consistent with a mechanism whereby sucrose is transported into C. albicans to be hydrolysed by an intracellular maltase.
Subcutaneous morphine pump for postoperative hemorrhoidectomy pain management.
PURPOSE: Many anorectal procedures are currently being performed on an outpatient basis, hemorrhoidectomy being the exception because of the need for parenteral narcotics postoperatively. We investigated the effectiveness of a subcutaneous morphine pump (SQMP) for outpatient posthemorrhoidectomy pain control. METHODS: In Phase 1 of our study, 22 patients undergoing radical hemorrhoidectomy were started on an SQMP protocol postoperatively. Twenty-nine patients received conventional postoperative narcotic dosing. In Phase 2, 19 patients enrolled in an SQMP protocol underwent hemorrhoidectomy in an ambulatory setting. Length of hospitalization, catheterization rate, and pain control were evaluated. RESULTS: In Phase 1, zero patients in the study group and two in the control group required additional hospitalization beyond 23 hours for pain control. The rates of catheterization were similar between the two groups. Pain control was considered satisfactory in 21 of 22 study patients. There was no correlation between pain level and morphine dose. Eighteen of 22 patients experienced minor side effects, necessitating pump removal in two patients. In Phase 2, 18 of 19 patients on the SQMP were discharged from the recovery room. Cost analysis shows the combination of outpatient hemorrhoidectomy and the SQMP to be cost-effective in comparison with an inpatient stay. CONCLUSIONS: The SQMP enables hemorrhoidectomy to be done on an outpatient basis. It provides effective pain control, enjoys high patient acceptance, and is cost-effective.
A more functional loop ileostomy rod.
The use of a flat Jackson-Pratt drain for a loop ileostomy rod is described. It elevates the loop, prevents its retraction into the abdomen, and can be cut to precisely the size of the stoma, thereby alleviating the problem of skin excoriation from a poorly fitting appliance.
Pelvic fractures associated with open perineal wounds: a survivable injury.
Blunt pelviperineal trauma has been associated with mortality rates of 32% to 58% in recent literature. A review of our institution's experience revealed a much lower mortality rate, prompting further investigation. Nine hundred-seventy five patients with pelvic fractures were admitted to our institution from July 1984 through June 1991. The mortality rate for all pelvic fractures was 7.3%. During this interval 21 patients (2.2%) were admitted with open pelvic fractures. Only one patient in this group died. Our low mortality figures were the result of better control of pelvic hemorrhage and sepsis, and a lower incidence of associated injuries to the head and thorax, representing a more favorable mechanism of injury.
Early reocclusion after successful thrombolysis is related to lesion length and roughness.
BACKGROUND: Reocclusion is a significant problem after thrombolysis. Results of previous studies conflict regarding the association of various features of postlytic lesions that might predict reocclusion. METHODS: A computer-assisted algorithm was therefore used to quantitatively measure edge roughness in the 90-minute postlysis angiogram of 84 patients receiving recombinant tissue plasminogen activator within 6 hours of chest pain. RESULTS: Twenty-five patients had reocclusion, and 59 did not. The baseline angiogram showed no differences between these two groups with respect to minimal dimensions or relative percentage of stenosis. Length was greater in the reocclusion group (12.2 +/- 5.0 vs 10.0 +/- 4.2 mm, P < 0.05). Three of four roughness indices based on curvature analysis indicated greater roughness in those patients with reocclusion. These differences were largely due to the increased length of these lesions. The scaled edge-length ratio, an index of roughness that is independent of length, was, however, significantly greater in the reocclusion group (1.15 +/- 0.10 vs 1.09 +/- 0.08, P < 0.006). Multiple regression analysis showed that lesion length, the scaled edge-length ratio, and the number of features (invaginations and evaginations) per cm correlated independently with the risk for reocclusion. CONCLUSIONS: The length and roughness of postlytic residual lesions are determinants of reocclusion.
Laparoscopic assisted abdominoperineal resection.
A technique is described for laparoscopic abdominoperineal resection (APR). Three of four such cases could be successfully completed laparoscopically. One major complication was directly related to the laparoscopic approach, an enterotomy caused by the Babcock clamp, which was discovered at the time of conversion to laparotomy for bleeding. A minor complication related to the laparoscopic procedure, subcutaneous emphysema, required no treatment. There was one postoperative death unrelated to the laparoscopic technique. The intraoperative advantage was enhanced visualization; the intraoperative disadvantages were increased operative time and cost. Postoperative advantages were earlier mobilization, oral intake, and discharge; decreased pain; and improved cosmesis. Laparoscopic APR is both feasible and safe and with more experience should prove to be cost effective.
Prognostic importance of quantitative analysis of coronary cineangiograms.
Many studies have shown the prognostic value of angiographic data, but few have examined quantitative parameters of wall motion and shape or coronary stenosis severity. To determine whether these parameters have prognostic importance, baseline angiograms of 283 patients with up to 11.2 years (mean 8.3) of follow-up were quantitated. Event-free survival curves were constructed using log-rank testing. These indexes were also considered in 2 predictive models (Cox regression models): 1 with ("clinical") and 1 without ("quantitative") subjective angiographic analysis and clinical information. Regional shape (anterior and inferior walls) and motion (anterior wall only) indexes were predictive of event-free survival when considered singly. But these parameters were not of independent prognostic importance in the regression models. The most important independent parameters in the quantitative model for predicting overall cardiac mortality or an initial lethal cardiac event were the ejection fraction and the percent diameter narrowing of each major coronary artery. Myocardial infarction was predicted by the percent diameter stenosis of the left main and left anterior descending arteries but not the ejection fraction. In the clinical model, the factors of overriding prognostic importance were the ejection fraction and the subjective determination of the number of vessels involved with "significant" stenoses. Quantitative coronary arteriography still contributed independent prognostic value. Thus, quantification of the ejection fraction and severity of coronary lesions were of independent, prognostic importance, whereas indexes of regional function and shape were not.
Effect of coronary stenosis severity on variability of quantitative arteriography, and implications for interventional trials.
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Establishing comprehensive, quantitative criteria for detection of restenosis and remodeling after percutaneous transluminal coronary angioplasty.
To establish comprehensive criteria for detecting restenosis and remodeling, inter- and intraobserver reproducibility of quantitative arteriography in the analysis of 20 lesions immediately after and 6 months after percutaneous transluminal coronary angioplasty (PTCA) were assessed. Geometric single-plane (minimum, maximum, mean diameter and percent diameter stenosis), biplane (absolute and relative cross-sectional area stenosis), relative densitometric area stenosis and the average of densitometric area stenosis in orthogonal views were compared. A high intra- and interobserver reproducibility of all absolute measurements was found, with the highest correlations for minimum diameter and cross-sectional area (interobserver, r = 0.85 and 0.85; intraobserver, r = 0.93, and 0.95 for minimum diameter and cross-sectional area, respectively). Of the relative measurements, biplane geometric percent cross-sectional area stenosis was the most reliable and percent densitometric area stenosis was the most variable (interobserver, r = 0.67; intraobserver, r = 0.71). Only small differences were demonstrated for the absolute measurements between the analysis of lesions immediately after PTCA and after follow-up, whereas a greater variability was found for relative measurements, especially videodensitometry. In both circumstances, a poor correlation between relative densitometric cross-sectional area from orthogonal views was found, whereas geometric elliptical cross-sectional area correlated quite well with the average of densitometric percent cross-sectional area in orthogonal views (interobserver, r = 0.86; intraobserver, r = 0.84). Thus, data in this study support the suitability of geometric quantitative analysis for the assessment of PTCA results. Densitometry was the least reliable quantitative parameter.
Successful treatment of Paecilomyces varioti infection in a patient with chronic granulomatous disease and a review of Paecilomyces species infections.
An 8-year-old boy who had chronic granulomatous disease developed a soft tissue infection of the right heel after riding on a motor scooter. Infection was insidious, and minor heel pain and fevers occurred only on the day interferon-gamma was injected. Soft tissue biopsy showed hyphal elements, and Paecilomyces varioti grew in culture. The infection was treated with amphotericin B for 7 weeks (total dose, 40 mg/kg) followed by 1 year of therapy with itraconazole (100 mg twice daily). Complete cure was achieved during the follow-up period of 10 months.
Analysis of local recurrence of midrectal cancer after low anterior resection and stapled anastomosis.
We evaluated local recurrences of midrectal cancer in 33 patients treated with low anterior resection and stapled end-to-end anastomosis. All patients had follow-up for at least 2 years or until death. There were 21 men and 12 women. Data were analyzed with attention to Astler-Coller modified Dukes' stage, distal margin of resection, degree of histologic differentiation, location of the tumor, blood transfusion, and adjuvant therapy. Distal margin of resection, histologic differentiation, and location of the tumor had no prognostic significance regarding local recurrence. The use of adjuvant therapy remains controversial. The immunosuppressive effects of blood transfusion may affect local recurrence. Dukes' staging remains the standard for prognosis of recurrence in rectal cancer.
Cloning and characterization of a Candida albicans maltase gene involved in sucrose utilization.
In order to isolate the structural gene involved in sucrose utilization, we screened a sucrose-induced Candida albicans cDNA library for clones expressing alpha-glucosidase activity. The C. albicans maltase structural gene (CAMAL2) was isolated. No other clones expressing alpha-glucosidase activity. were detected. A genomic CAMAL2 clone was obtained by screening a size-selected genomic library with the cDNA clone. DNA sequence analysis reveals that CAMAL2 encodes a 570-amino-acid protein which shares 50% identity with the maltase structural gene (MAL62) of Saccharomyces carlsbergensis. The substrate specificity of the recombinant protein purified from Escherichia coli identifies the enzyme as a maltase. Northern (RNA) analysis reveals that transcription of CAMAL2 is induced by maltose and sucrose and repressed by glucose. These results suggest that assimilation of sucrose in C. albicans relies on an inducible maltase enzyme. The family of genes controlling sucrose utilization in C. albicans shares similarities with the MAL gene family of Saccharomyces cerevisiae and provides a model system for studying gene regulation in this pathogenic yeast.
Healthy approaches to physician stress.
Many studies demonstrate that physicians in training and in practice experience considerable distress, with a high incidence of dysfunction and dissatisfaction. Little is known about the strategies employed by practicing physicians who find enjoyment and satisfaction in their work. We conducted an open-ended survey about how a group of physicians cope with common dilemmas they face today such as mistakes, death, self-care, uncertainty, patient demands, and time demands. We describe the techniques employed by those who felt they were effectively coping. Responses were organized into five general requirements for personal growth: (1) self-awareness, (2) sharing of feelings and responsibilities, (3) self-care, (4) developing a personal philosophy, and (5) nontraditional coping skills of reframing and limit setting. General descriptions of these requirements are followed by tables of specific examples from the survey. The application of these strategies to the dilemmas cited above are presented. These descriptive findings emphasize the need for training programs and governing bodies to incorporate strategies for physicians' personal growth into their priorities. The five basic areas described herein can provide a framework for formal attention to physicians' personal development.
Electronegativity of aromatic amines as a basis for the development of ground state inhibitors of lysyl oxidase.
Benzylamine derivatives containing para substituents of differing electronegativity as well as isomers of aminomethylpyridine have been assessed for their substrate and inhibitor potentials toward lysyl oxidase. Substituted benzylamines with increasingly electronegative para substituents had the lowest KI values and thus were the most effective inhibitors of the oxidation of elastin by lysyl oxidase. The kcat values for these compounds as substrates of lysyl oxidase were also reduced with increasingly electronegative para substituents. Both the Dkcat and D(kcat/Km) kinetic isotope effects decreased with increasingly electronegative p-substituents in [alpha, alpha'-2H]benzylamines. In contrast, there was no Dkcat solvent isotope effect with [2H] H2O while the D(kcat/Km) solvent isotope effect tended to increase with increasingly electronegative p-substituents. These results are consistent with the stabilization of an enzyme-generated substrate carbanion and thus the retardation of substrate oxidation by electronegative substituents. Such ground state stabilization thus can result in compounds with increased potential for the inhibition of the oxidation of protein substrates of lysyl oxidase.