Biomedical subjects
Publications and source records attributed to D L Brown.
A case is presented of left main coronary artery stenosis in a patient with significant comorbidities who was successfully managed with minimally invasive direct coronary artery bypass as protection before percutaneous transluminal coronary angioplasty. This "hybrid" approach for the management of a high-risk patient led to a favorable outcome.
BACKGROUND: Wound healing is involved in many aspects of care, ranging from anastomoses and skin incisions to foot ulcers and decubitus. Clinical healing failures are a major challenge to the physician and cause significant morbidity and mortality in select patient populations. As we are starting to understand more fully the mechanisms of impaired wound healing, the diabetic mouse (C57BL/KsJ-db/db) has been a good model for research. The diabetic wound exhibits significant delays in healing, previously identified as impaired cellular infiltration and granulation tissue formation. Apoptosis, or programmed cell death, is intimately involved in the regulation of inflammation and ultimately should play a role in the inflammatory phase of wound healing. METHODS: To examine its role in wound healing, patterns of apoptosis in large, full-thickness cutaneous wounds were compared between groups of diabetic and nondiabetic mice. RESULTS: Initially apoptosis was mainly limited to the wound edge and followed the advancing epithelial edge toward the center of the wound as healing progressed. Significant delays in the appearance of the apoptotic pattern were noted in the diabetic mice. Wounds in diabetic mice were then treated with topical application of growth factors. The delay in apoptotic pattern was reversed after treatment with the combination of insulin-like growth factor-II and platelet-derived growth factor, approaching levels in nondiabetic animals. CONCLUSIONS: Apoptosis appears concurrently with reepithelialization of the wound and may signal the end of the inflammatory phase of healing at that site in the wound. One can speculate that a signal for apoptosis and down-regulation of inflammation in the wound is derived from the epithelium.
Chromosomes are located within the interphase nucleus in regions called domains. Using fluorescence in situ hybridization with whole chromosome paints, a pain of homologous chromosomes can be visualized as two discrete domains and their relative spatial location determined. This study examines the effects of an ionizing radiation exposure on the relative spatial location of chromosome 7 and 21 domains in human skin fibroblasts and lung endothelial cells. The distance between homologous chromosome domains was assessed for each nucleus, before and after exposure to ionizing radiation, using conventional epifluorescence and confocal laser scanning microscopy. Results from conventional microscopy indicated that homologous chromosome domains were re-positioned closer to each other within interphase nuclei after exposure to radiation. Analysis of three-dimensional data obtained from confocal microscopy confirmed these results. In control cells, and in cells examined immediately after irradiation, 66.2% +/- 2.1% of the homologous chromosome 21 domains within endothelial cell nuclei were located greater than 4.0 microns apart (33.8% +/- 1.9% were less than 4.0 microns apart). However, when cells were examined 2 h after a 4.0 Gy gamma-ray exposure, only 30.5% +/- 2.1% of the homologous chromosome domains were greater than 4.0 microns apart (69.5% +/- 2.1% were less than 4.0 microns apart). Similar results were obtained for chromosomes 7 and 21 in skin fibroblast nuclei. The results indicate that homologous chromosome domains rearranged and became closer together within the interphase nuclei in response to ionizing radiation. The exact mechanism of this response is unknown, but it may be related to DNA repair processes. It is speculated that chromosome domains are re-positioned to permit repair of radiation-induced DNA damage.
We have investigated the effects of inotropes with different adrenergic receptor specificity on differential white cell count, lymphocyte subtypes and neutrophil function in healthy volunteers. Six healthy, male volunteers were enrolled into this randomized, placebo-controlled pilot study. Each volunteer was studied on four separate occasions during a 2-h infusion of various agents, and for 2 h after stopping the infusion. The agents investigated were adrenaline 0.1 microgram kg-1 min-1, dobutamine 5 micrograms kg-1 min-1, dopexamine 2 micrograms kg-1 min-1 and 5% glucose 0.5 ml kg-1 h-1. Venous blood was sampled at 0, 30, 120 and 240 min. Haemodynamic monitoring was continued throughout the study. Full blood count, white cell differential count and enumeration of lymphocyte subtypes were performed. Neutrophil function tests included chemoluminescence, and assessment of neutrophil chemotaxis, phagocytosis and adhesion. The Wilcoxon signed rank test was used to compare differences between placebo and active drugs at each time compared with baseline. There was a significant increase in white cell count, lymphocyte count and neutrophil count with adrenaline, and a small but significant decrease in these variables with dobutamine and dopexamine. These changes were also apparent for absolute CD3+, CD4+ and CD8+ lymphocyte counts. Neutrophil respiratory burst in response to f-methionyl-leucyl-phenylalanine increased significantly only with adrenaline at 30 min (P = 0.046). There were no other significant changes in tests of neutrophil function. Infusion of inotropes was associated with changes in white cell numbers, lymphocyte subtypes and neutrophil respiratory burst. In healthy volunteers, adrenaline had effects different from those of dobutamine and dopexamine. The clinical relevance of such effects requires further investigation in critically ill patients.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
PURPOSE: To determine if the sonographic appearance of solid extratesticular masses enables distinction of benign from malignant disease. MATERIALS AND METHODS: Sonograms of 19 patients with palpable testicular masses who underwent biopsy were reviewed retrospectively. Appearances of masses on sonograms were correlated with pathologic diagnoses. RESULTS: All masses were well defined and ranged in size from 5.7 to 66.7 mm (mean, 21 mm). On the sonograms, five masses were within the epididymis, and six were distinct from it; seven cases were indeterminate. The epididymis was surgically absent in the remaining patient. Sonographic echogenicity ranged from hypoechoic to hyperechoic relative to that of the testis. At pathologic evaluation, there were 16 (84%) benign and three (16%) malignant lesions. Benign lesions consisted of six adenomatoid tumors, two lipomas, two epidermoid inclusion cysts, two cases of sarcoidosis, and one case each of sperm granuloma, spermatic cord leiomyoma, benign inflammatory nodule, and fibroma. The malignant lesions consisted of scrotal wall liposarcoma, epididymal leiomyosarcoma, and recurrent spindle cell malignancy of the spermatic cord. No sonographic features of masses were useful for distinguishing benign from malignant lesions. CONCLUSION: The frequency of malignancy (16%) contrasts with prior reports that suggest a very low rate of malignancy among these masses. Sonography is useful for identifying the extratesticular location of a mass but not for distinguishing the nature of the lesion.
PURPOSE: To determine if the intradecidual sign at sonography is effective in the diagnosis of early intrauterine pregnancy. MATERIALS AND METHODS: In 102 pregnant patients, transvaginal sonography revealed an intrauterine fluid collection without a yolk sac or embryo. Four observers (experienced sonologist, body imaging fellow, 1st-year radiology resident, and premedical student) determined independently whether the intradecidual sign was absent, present, or indeterminate. Interpretations were limited to visualization of only the uterus. RESULTS: Follow-up revealed intrauterine pregnancy in 91 patients (outcome normal in 48 and abnormal in 43) and ectopic pregnancy in 11 patients. Among the four reviewers, sensitivity for diagnosis of an intrauterine pregnancy was 34%-66%, specificity was 55%-73%, accuracy was 38%-65%, positive predictive value was 91%-93%, and negative predictive value was 12%-16%. Three to five ectopic pregnancies were categorized incorrectly as demonstrating the intradecidual sign, depending on the reviewer. CONCLUSION: The intradecidual sign does not appear to be sensitive or specific in diagnosis of an early intrauterine pregnancy. When an intrauterine fluid collection is present without an embryo or yolk sac (with positive pregnancy test results), a follow-up sonogram should be obtained unless contraindicated clinically.
Explore the source record for details and available documents.
OBJECTIVE: To assess overall perioperative and anesthetic care-specific patient satisfaction. DESIGN: We mailed questionnaires postoperatively to three groups of surgical patients (those who underwent anesthesia without complications, those who experienced airway management difficulties, and those who had cardiovascular perturbations) and analyzed the responses. MATERIAL AND METHODS: All patients 18 to 75 years of age who underwent hospital-based surgical procedures in our acute-care hospitals during the interval from January to September 1993 were eligible for this investigation. We asked a total of 315 patients--105 in each of the three study groups--about their satisfaction with perioperative care. Specific positive or negative comments that the patients returned in their questionnaires were tabulated into the following sub-categories: physician, nurse, technique, time, and institution concerns. RESULTS: Of the 315 questionnaires sent to patients, 239 (75.9%) were returned. No difference in overall patient satisfaction (defined as very satisfied or a combination of very satisfied and satisfied) was noted among the groups. No patients identified themselves as dissatisfied or very dissatisfied with their overall care, although a small percentage expressed dissatisfaction because of time delays. The specific patient comments suggested that the positive interactions with physicians and nurses outweighed the concerns about time delays. CONCLUSION: This study showed that intraoperative anesthetic events did not affect patient satisfaction. Interactions with physicians and nurses dominated the decision about patient satisfaction, and time delays were the most frequently cited negative comment.
OBJECTIVE: To assess whether patients with pancreatic cancer-associated pain living near a pain control center were more likely to undergo neurolytic celiac plexus block (NCPB) than those living at a distance and to determine the rationale of physicians at our institution for referring patients for NCPB. DESIGN: We retrospectively reviewed the frequency of use of NCPB in patients with pancreatic cancer and conducted an anonymous physician survey of referral patterns for NCPB for such patients. MATERIAL AND METHODS: A prospective database of medical diagnoses and a clinical database at our institution were used to identify patients with pancreatic cancer within three geographic regions who were assessed during the inclusive years 1980 through 1989: group I ("local") = all patient with pancreatic cancer in Olmsted County, Minnesota; group II ("surrounding") and group III ("distant") = patients referred for pancreatic cancer evaluation who lived within 100 miles of our institution (excluding Olmsted County) or more than 100 miles from our institution, respectively. Medical records were retrospectively reviewed to assess the use of NCPB at any time during the course of pancreatic cancer. For the physician survey component, all medical oncologists, gastroenterologists, and general surgeons at our institution who might be responsible for the care of patients with pancreatic cancer were sent a questionnaire about their referral patterns for NCPB among patients with pancreatic cancer. RESULTS: Overall, approximately 15% of the 292 patients with pancreatic cancer studied underwent NCPB. Distance from our pain control center was not found to be associated with frequency of use of NCPB. Of the 78 physicians surveyed, 59 (76%) responded, and 35 of the responders (59%) had encountered at least 1 patient with pancreatic cancer during the preceding 12 months. In that subset of physicians, perceived barriers for referral for NCPB were limited appointment availability and need for repeating the procedure. CONCLUSION: On the basis of this study, referral patterns for NCPB in patients with pancreatic cancer do not seem to be associated with the geographic distance of a patient's residence from a pain control center. Improving appointment availability for NCPB might increase the number of patients offered this technique for control of pain.
The purpose of this study was to assess the predictive value and sensitivity of discrepant ventricular size for fetal aortic coarctation. Postnatal follow-up data were obtained in 42 fetuses in whom ventricular size discrepancy (left ventricle smaller than right ventricle) was recognized on an obstetrical sonogram. Additionally, from postnatal records, we identified infants with coarctation who had had an obstetrical sonogram after 16 weeks. Fourteen of the 42 fetuses had coarctation or other aortic arch obstruction after birth (33% positive predictive value). Eight (62%) of 13 fetuses with ventricular discrepancy recognized before 34 weeks had coarctation, compared with six (21%) true positive cases among 29 recognized after 34 weeks (P = 0.01, Fisher's exact test). Of 21 infants with coarctation, ventricular discrepancy had been recognized by prenatal sonography in 13 (62% sensitivity). Ventricular discrepancy has moderate sensitivity and mediocre positive predictive value for coarctation. The limitations of this finding for diagnosing coarctation, particularly a higher false positive rate after 34 weeks, must be recognized, but it is still a useful sign to identify this potentially ductus-dependent lesion.
Neurons are highly polarized cells that extend long processes, the axons and dendrites, to form contacts with target cells. The formation and maintenance of this specialized morphology relies on the assembly of an organized microtubule array that is the predominant component of the neuronal cytoskeleton. During this process there is an evolution in the composition and dynamics of microtubules, resulting in stable microtubule bundles that provide structural support and function in intracellular transport along the axon. In this essay we provide an overview of the mechanisms regulating the synthesis and assembly of tubulin in differentiating neurons with particular attention to the roles of multiple tubulin isotypes, posttranslational modifications of tubulin, and microtubule-associated proteins. We conclude that, ultimately, the developmental regulation of microtubules in neurons may require the coordinated expression and posttranslational modifications of tubulin and microtubule-associated proteins to provide biochemical forms that favour specific interactions, each combination conferring distinctive dynamic and functional properties.
Patients with reflex sympathetic dystrophy (complex regional pain syndromes) are often referred to pain medicine physicians for assistance in providing pain control during rehabilitation of their painful upper extremity. When deciding which pain control technique to use in an individual patient, physicians must consider both somatic and sympathetic blocks. Each of these nerve blocks has advantages and disadvantages that may be tailored to an individual patient's pain state and rehabilitation program to optimize recovery.
Insulin-like growth factor (IGF)-I has profound effects on tissue repair. IGF-II is felt to exert its influence predominately during fetal development. The purpose of this study was to localize and quantify the expression of IGF-I and IGF-II mRNA and protein during early wound healing in diabetic and nondiabetic mice. The hypothesis is that IGF-I and IGF-II are up-regulated in the healing wound, but their expression is inhibited in diabetics. Full-thickness cutaneous wounds were made on genetically diabetic (C57BL/ KsJ-db/db) mice and their nondiabetic littermates. At various times after wounding, one-half of each wound was fixed and paraffin embedded for immunohistochemistry and in situ hybridization. The other half was flash-frozen for quantification of IGF mRNA by competitive reverse transcriptase polymerase chain reaction and protein by radioimmunoassay. IGF-I mRNA rose sharply in nondiabetics at day 3. Expression in diabetic wounds was significantly delayed until 14 days after wounding. Even then, diabetic IGF-I mRNA levels were 50% less than those in the nondiabetics at their peak. Although not usually considered active in adult life, IGF-II mRNA expression was augmented after wounding, peaking at 3 days in nondiabetics. As with IGF-I, diabetic wounds exhibited a delay in IGF-II mRNA expression, with maximal levels at 10 days after wounding. Interestingly, peak concentrations of IGF-II mRNA were four times greater in diabetics versus nondiabetics. Trends in IGF-I protein expression followed the patterns of mRNA expression. IGF-I levels in nondiabetics were initially double those in diabetics and peaked at 5 days. Diabetic wound concentrations of IGF-I did not peak until 21 days after wounding, at which time they rose to nondiabetic levels. IGF-I and IGF-II proteins were localized to the advancing epithelial edge, to the epithelial cells of adjacent hair follicles, and to the granulation tissue of the wounds. IGF-I and IGF-II mRNA expression was noted in the epithelial edge and in the hair follicles adjacent to the wound, paralleling protein expression. Both IGF-I and IGF-II are up-regulated in the healing wound. A delay in IGF-I and -II presence is noted in the diabetic wound. The impairment in tissue repair in diabetic animals is at least partially due to a deficiency in the production of the IGFs.
Taxol is the prototype of a new class of drugs with promise in the treatment of various cancers. Its mechanism of action is not fully understood. We have investigated the effects of taxol on two human cancer cell lines, HT-29, derived from a colon carcinoma, and SK-MEL-28, from a melanoma. Immunofluorescence staining for microtubules, cell cycle analysis by flow cytometry, cytotoxicity assays, and DNA fragmentation studies by agarose gel electrophoresis were performed. The two cell lines responded quite differently to taxol. HT-29 cells, when treated with taxol for 24 h, showed an abundance of multiple microtubule asters and the cells were arrested in mitosis. Flow cytometry also showed arrest in mitosis and development of a hypodiploid region with increasing taxol incubation times. These cells were more sensitive to taxol exposure, which caused internucleosomal DNA fragmentation, indicative of apoptosis. The SK-MEL-28 cells, on the other hand, were less sensitive to taxol. Significant cytotoxic effects were only visible after 72 h. These cells exhibited a predominance of microtubule bundles and multinuclei, and only a few cells were arrested in mitosis. Flow cytometry revealed that the SK-MEL-28 cells became polyploid, as a result of exit from mitosis without cell division. These results suggest that the mechanism involved in taxol-induced cell death is different in these two cell lines.
Misoprostol is an effective agent for cervical ripening and induction of labor. The use of oxytocin was significantly decreased in patients treated with misoprostol versus dinoprostone. It has been used to induce over 1000 women in reported studies and has demonstrated a safety profile comparable with that of endocervical and vaginal dinoprostone. Uterine hyperstimulation was a concern in earlier trials, but at a reduced dose of 25 micrograms, the incidence has decreased to a level that is comparable with the values reported for dinoprostone. Misoprostol tablets are stable at room temperature and are considerably less expensive than the dinoprostone alternatives. Two additional factors pertaining to misoprostol administration must be taken into account before the drug is selected for vaginal use. First, Cytotec tablets are currently available in two strengths, 100 and 200 micrograms. This can lead to confusion or error if the clinician orders a quarter or half tablet. The order should always identify the strength in micrograms (25 or 50 micrograms). Second, the 100-microgram tablet is not scored; therefore, the proper dose should be carefully prepared by a pharmacist using a pill cutter. Key members of the hospital staff must be trained about the proper use of misoprostol for labor induction before initiating therapy. One alternative to directly inserting the tablet is to pulverize it and mix with a gel such as hydroxyethylcellulose gel. However, such compounding introduces the same problems with stability and uniformity of dose as experienced with dinoprostone gels. Despite the success of misoprostol in clinical trials, it is not approved for this indication, and the manufacturer of Cytotec does not plan to pursue approval. Therefore, independent, large-scale studies are warranted to more accurately assess the efficacy and overall safety of using intravaginal alprostadil for cervical ripening and labor induction. Additional clinical experience should also help to determine the best regimen and method of administration. From the data currently available, it appears that either a 25- or 50-microgram dose (one-fourth or one-half of a 100-microgram tablet) inserted into the posterior vaginal fornix and repeated at 4-5-hour intervals if needed, is a clinically effective regimen, and is associated with the least amount of adverse effects and complications. As with all labor inductions, uterine contractions and fetal heart rate should be monitored carefully throughout the procedure.
Nuclear collapse is a key feature of apoptosis, reflecting the DNA and protein fragmentation observed biochemically. We have compared nuclear events during spontaneous and heat-induced (42 degrees C for 30 min) apoptosis at the level of individual cells, monitoring overall chromatin organization by staining with 4,6'-diamidino-2-phenylindole (DAPI), DNA cleavage by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL), and the nuclear antigens NuMA, PI2, and lamin B by immunofluorescence microscopy. The data were correlated with analyses at the population level by flow cytometry and immunoblotting. We show that heat treatment doubles the level of apoptotic splenocytes with respect to the spontaneous apoptosis in controls within 6 honThe organization and disassembly of nuclear envelope antigens is identical during spontaneous and heat-induced apoptosis and proceeds in a temporally and spatially ordered manner relative to DNA fragmentation and chromatin collapse. In contrast, NuMA organization is affected by heat treatment, with about half of the cells containing many bright spots in addition to the usual diffuse labelling. The spots were still visible in many fully collapsed apoptotic nuclei. Further, this novel reorganization of NuMA and the hyperinduction of apoptosis by heat are correlated, suggesting that lymphocytes with reorganized NuMA are destined to undergo apoptosis. The data also indicate that DNA fragmentation precedes extensive remodelling of the nucleoplasm in these cells, and that chromatin begins to collapse before disassembly of nuclear envelope components.