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Biomedical subjects

K O'Rourke

Publications and source records attributed to K O'Rourke.

At least 19 recordsLinked to original sources
PubMed1995

Elevated levels of syndecan-1 expression confer potent serum-dependent growth in human 293T cells.

Syndecan-1 is the best studied integral membrane proteoglycan and functions to modulate epithelial cell attachment and physiology. Extracellularly, syndecan-1 binds both growth factors and extracellular matrix components, and intracellularly, its cytoplasmic portion interacts with cytoskeletal components. To investigate the possible role of syndecan-1 in epithelial cell transformation that is characterized by alteration in extracellular matrix interactions and cytoskeleton architecture, we established stable transfectants of syndecan-1 in a highly transformed human renal epithelial line expressing two viral oncogenes, adenovirus E1a and SV40 large T antigen (293T cell line). Expression of syndecan-1 core protein and appropriate posttranslational attachment of glycosaminoglycan chains was confirmed by enzymatic digestion and Western blot analysis. Overexpresser cells grew at a significantly faster rate than the vector-transfected control cells in serum-rich media but showed a proliferative disadvantage in serum-reduced media. In addition to this serum dependency, syndecan-1 overexpression caused a partial reversal of the transformed phenotype with the expressing clones becoming more anchorage dependent and less motile than the vector-transfected counterparts. Surprisingly, the overexpressers were more tumorigenic when injected s.c. into nude mice. These results indicate that syndecan-1 expression plays a role in the control of cell proliferation and suggest that serum-dependent growth may be the more reflective of tumorigenicity in nude mice.

Animals↗
PubMed1995

Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase.

Although the mechanism of mammalian apoptosis has not been elucidated, a protease of the CED-3/ICE family is anticipated to be a component of the death machinery. Several lines of evidence predict that this protease cleaves the death substrate poly(ADP-ribose) polymerase (PARP) to a specific 85 kDa form observed during apoptosis, is inhibitable by the CrmA protein, and is distinct from ICE. We cloned a ced-3/ICE-related gene, designated Yama, that encodes a protein identical to CPP32 beta. Purified Yama was a zymogen that, when activated, cleaved PARP to generate the 85 kDa apoptotic fragment. Cleavage of PARP by Yama was inhibited by CrmA but not by an inactive point mutant of CrmA. Furthermore, CrmA blocked cleavage of PARP in cells undergoing apoptosis. We propose that Yama may represent an effector component of the mammalian cell death pathway and suggest that CrmA blocks apoptosis by inhibiting Yama.

Apoptosis↗
PubMed1995

FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis.

Using the cytoplasmic domain of Fas in the yeast two-hybrid system, we have identified a novel interacting protein, FADD, which binds Fas and Fas-FD5, a mutant of Fas possessing enhanced killing activity, but not the functionally inactive mutants Fas-LPR and Fas-FD8. FADD contains a death domain homologous to the death domains of Fas and TNFR-1. A point mutation in FADD, analogous to the lpr mutation of Fas, abolishes its ability to bind Fas, suggesting a death domain to death domain interaction. Overexpression of FADD in MCF7 and BJAB cells induces apoptosis, which, like Fas-induced apoptosis, is blocked by CrmA, a specific inhibitor of the interleukin-1 beta-converting enzyme. These findings suggest that FADD may play an important role in the proximal signal transduction of Fas.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn's disease.

BACKGROUND & AIMS: Recurrence of Crohn's disease frequently occurs after surgery. A randomized controlled trial was performed to determine if mesalamine is effective in decreasing the risk of recurrent Crohn's disease after surgical resection is performed. METHODS: One hundred sixty-three patients who underwent a surgical resection and had no evidence of residual disease were randomized to a treatment group (1.5 g mesalamine twice a day) or a placebo control group within 8 weeks of surgery. The follow-up period was a maximum of 72 months. RESULTS: The symptomatic recurrence rate (symptoms plus endoscopic and/or radiological confirmation of disease) in the treatment group was 31% (27 of 87) compared with 41% (31 of 76) in the control group (P = 0.031). The relative risk of developing recurrent disease was 0.628 (90% confidence interval, 0.40-0.97) for those in the treatment group (P = 0.039; one-tail test) using an intention-to-treat analysis and 0.532 (90% confidence interval, 0.32-0.87) using an efficacy analysis. The endoscopic and radiological rate of recurrence was also significantly decreased with relative risks of 0.654 (90% confidence interval, 0.47-0.91) in the effectiveness analysis and 0.635 (90% confidence interval, 0.44-0.91) in the efficacy analysis. There was only one serious side effect (pancreatitis) in subjects in the treatment group. CONCLUSIONS: Mesalamine (3.0 g/day) is effective in decreasing the risk of recurrence of Crohn's disease after surgical resection is performed.

Adult↗
PubMed1995

The effect of hospital staff training on management of obstetrical patients referred by traditional birth attendants.

A hospital staff training program was conducted in Guatemala to improve outcomes for patients with obstetrical and neonatal complications. This study examines the effect of the training program on the subset of women referred to the hospital by traditional birth attendants (TBAs). The program's goals were to institute standards of care for obstetrical and neonatal patients as well as to improve relations between hospital staff and TBAs. The training program was evaluated by comparing changes in the number of referrals, patient satisfaction, patient management, as well as Apgar scores and perinatal mortality. Evaluations were based on 756 questionnaires administered to TBA referred mothers. There was a significant increase in the overall numbers of referred women as well as improvement in patient satisfaction and decreased waiting time between admission and treatment. Apgar scores and perinatal mortality also improved, but changes were not statistically significant.

Adolescent↗
PubMed1995

Müller and retinal pigment epithelial (RPE) cell expression of NGFI-A and c-fos mRNA in response to medium conditioned by the RPE.

Retinal pigment epithelial (RPE) cells secrete a factor(s) which promotes Müller and RPE cell survival and proliferation in vitro. These influences may play developmental and functional roles as well as contribute to ocular pathologies such as proliferative vitreoretinopathy (PVR). In the past few years, a number of immediate early genes (IEGs) have been identified. Many IBGs encode transcription factors, the expression of which is altered by stimuli such as growth factors. Since an RPE-derived factor(s) elicits proliferation of Müller and RPE cells, we investigated the expression of two IEGs, NGFI-A and c-fos, in both cell types after treatment with medium conditioned by the RPE (RPE-CM). We found that Müller and RPE cells had increased levels of NGFI-A mRNA following treatment with RPE-CM; in contrast, only a slight increase in c-fos mRNA was induced in RPE, but not Müller cells. Immunolabeling for NGFI-A protein revealed nuclear staining in both cell types which corresponded with the increased mRNA levels in RPE-CM-treated cultures. This in vitro study demonstrates a potential mechanism by which RPE-secreted factors may exert autocrine or paracrine effects on retinal cells in vivo. Specifically, NGFI-A may be the primary target of a second messenger system that is regulated by an RPE-derived factor(s).

Animals↗
PubMed1995

Postoperative analgesia after lumbar laminectomy: epidural fentanyl infusion versus patient-controlled intravenous morphine.

We compared the efficacy and safety of continuous epidural fentanyl infusion with intravenous morphine via a patient-controlled analgesia system (IV-PCA) in the management of postoperative pain after lumbar laminectomy. Twenty patients undergoing elective lumbar laminectomy were randomly allocated to one of two groups. The epidural group (n = 10) received an epidural fentanyl infusion (2 micrograms/mL at 4-10 mL/h) while the IV-PCA group (n = 10) received IV morphine through a PCA system. The general anesthetic technique was standardized. Visual analog pain scores were recorded at 12, 24, and 48 h after the operation. The amount of morphine (or its equivalent in fentanyl) used over the 48-h postoperative period was documented. The postoperative pain scores were significantly lower in the epidural group than in the IV-PCA group throughout the study period. The total consumption of morphine (or its fentanyl equivalent) over the 48-h period was significantly lower (P < 0.001) in the epidural group compared to the IV-PCA group. Although more patients in the IV-PCA group required urinary catheterization and had somnolence than the epidural group, there was no difference in the incidence of vomiting or pruritus. No patient developed respiratory depression or wound infection. We conclude that continuous epidural infusion of fentanyl is superior to IV-PCA morphine in the management of pain after lumbar laminectomy.

Analgesia, Patient-Controlled↗
PubMed1995

Do geriatric programs decrease long-term use of acute care beds?

OBJECTIVE: To determine whether the introduction of coordinated geriatric and discharge planning services at teaching and community hospitals in Toronto has changed the number of beds occupied by patients awaiting transfer to long-term care institutions. DESIGN: Retrospective review of social work records for the period 1985-1992. SETTING: Two tertiary and four primary acute care hospitals in Metropolitan Toronto. PARTICIPANTS: Hospitals were matched for location, acuity, and teaching affiliation. MAIN OUTCOME MEASURES: The numbers of beds occupied by patients awaiting transfer to nursing homes or chronic care hospitals were noted. RESULTS: In those teaching and community hospitals that had introduced coordinated geriatric and discharge planning services, there was a reduction in the percentage of beds occupied by patients awaiting long-term care placement (average-51%), whereas in hospitals without geriatric services, the percentage of beds occupied by patients awaiting long-term care placement increased (average + 25%) (P = .05 by Fisher's exact method, 95% confidence limit odds ratio 0, .9999). CONCLUSION: The introduction of coordinated geriatric and discharge planning services was associated with a decrease in the percentage of beds occupied by patients awaiting long-term care in both teaching and community hospitals.

Aged↗
PubMed1995

Age as a determinant of cardiopulmonary resuscitation outcome in the coronary care unit.

OBJECTIVE: To determine whether age is associated with the outcome of cardiopulmonary resuscitation (CPR) in the coronary care unit (CCU). DESIGN: Retrospective chart review. SETTING: The coronary care units of two Canadian tertiary care teaching hospitals. PATIENTS: Two hundred sixty-four coronary care unit patients undergoing cardiopulmonary resuscitation between January 1, 1985 and June 30, 1992. RESULTS: There was no significant difference in survival to discharge after CPR between patients less than 70 years of age (17.0%) and patients 70 years of age and older (17.2%) (odds ratio = 0.99; 95% confidence interval = 0.46, 1.80). Patients 70 years of age and older who survived to discharge after CPR had significantly greater lengths of stay (28.1 vs 19.3 days, P = .008). CONCLUSIONS: Age was not associated with a difference in survival to discharge after CPR in the CCU, although a clinically significant difference could not be excluded because of limited power.

Adult↗
PubMed1995

Expression and chromosomal localization of cDNA clones from an enriched human retinal pigment epithelial (RPE) cell line library: identification of two RPE-specific genes.

We have previously constructed an enriched cDNA library from a human retinal pigment epithelium (RPE) cell line and generated expressed sequence tags (ESTs) from novel clones. Here, we report the analysis of expression of 14 cDNAs and identify two clones, AA1 and AA28, that appear to be specifically expressed in RPE but not in any other tissue tested. We have also localized 15 novel cDNAs (including the two RPE-specific cDNAs) to human chromosomes using in situ hybridization or in conjunction with somatic cell hybrid analysis. The cDNAs were mapped to the following chromosomal regions: 1p35-->p33, 1q41-->q42 (two clones), 3q11.2-->q13.1, 3q24-->q25, 4q13-->q21, 6q22-->q23, 7q34-->q36, 10q23-->q24, 11q23-->q24, 15q25-->q26, 19p13.3, 20p13, 21q11.2-->q21, and 21q22.2-->q22.3. The genetic and functional analysis of the two RPE-specific genes should contribute to a better understanding of RPE function. Chromosomal localization of RPE cDNAs will be valuable in identifying candidate genes for inherited diseases involving RPE dysfunction and aid in establishing the expression map of the human genome.

Blotting, Northern↗
PubMed1994

A novel RING finger protein interacts with the cytoplasmic domain of CD40.

CD40 is a member of the tumor necrosis factor receptor family and, like other members, it appears to possess no intrinsic signaling capacity (e.g. kinase activity), suggesting that signal transduction is likely mediated by associating molecules. To identify such molecules, we have utilized the yeast two-hybrid system to clone cDNAs encoding proteins that bind the CD40 cytoplasmic domain. One such interacting protein, designated CD40-binding protein, has a N-terminal RING finger motif that is found in a number of DNA-binding proteins, including the V(D)J recombination activating gene RAG1. In addition, it contains a prominent central coiled-coil segment that may allow homo- or hetero-oligomerization. The C terminus possesses substantial homology to the tumor necrosis factor receptor-associated factor (TRAF) domain that is found in two proteins (TRAF1 and TRAF2) that associate with the cytoplasmic domain of the related 75-kDa tumor necrosis factor receptor. This is the first identification of a molecule that interacts with CD40 and whose sequence suggests a potential role in signaling.

Amino Acid Sequence↗
PubMed1994

Lymphocyte function-associated antigen 1 overexpression and T cell autoreactivity.

OBJECTIVE: To determine if DNA methylation inhibitors make T cells autoreactive by inducing lymphocyte function-associated antigen type 1 (LFA-1) (CD11a/CD18) overexpression. METHODS: T cell clones were treated with 3 distinct DNA methylation inhibitors or were stably transfected with a CD18 cDNA in a mammalian expression vector, and the effects on LFA-1 expression and activation requirements were examined. RESULTS: LFA-1 overexpression, caused by DNA methylation inhibitors or by transfection, correlates with the development of autoreactivity. CONCLUSION: LFA-1 overexpression may contribute to T cell autoreactivity.

Azacitidine↗
PubMed1994

A randomized crossover trial of Quick Medical Reference (QMR) as a teaching tool for medical interns.

OBJECTIVE: To determine whether the addition of Quick Medical Reference (QMR) to usual educational tools improves an intern's performance in managing clinical cases that test diagnostic and investigative skills. DESIGN: Randomized, controlled, single-blinded crossover study. SETTING: Tertiary care teaching hospital. SUBJECTS: Comprehensive medical interns who are proficient in the use of QMR. INTERVENTION: A total of 16 interns trained in the use of QMR were randomized to work up a total of six diagnostically challenging cases, three using medical textbooks plus access to QMR and three using textbooks and no access to QMR. MEASUREMENTS: The interns provided their solutions to the cases, which consisted of the differential diagnosis and investigations. They were scored by comparing their answers with the consensus answers provided by subspecialty consultants. For each intern, the difference in mean total scores with and without QMR was calculated. RESULTS: The mean difference in total scores was 7.2% benefit (p < 0.05, 95% CI = 0.05 to 14.4) using QMR. The beneficial difference was driven mainly by improvement in diagnostic scores, with the mean difference being 11.6% (p = 0.01, 95% CI = 2.4 to 20.8). Regression analysis showed that the more difficult the case, the greater the benefit of QMR. CONCLUSIONS: Quick Medical Reference may be a useful adjunct to interns in formulating diagnostic strategies for difficult clinical cases. However, since optimal conditions were chosen for QMR benefit in this study design, the small benefit in test scores must be weighed against the time required to teach QMR to interns.

Adult↗
PubMed1994

Risk factor analysis of peri-neonatal mortality in rural Guatemala.

Peri-neonatal mortality is a serious health problem in Guatemala, especially in rural areas where most deliveries occur at home and are overseen by traditional birth attendants (TBAs) who function in the role of midwives. The three aims of the work reported here were to identify important predictors of peri-neonatal mortality within a rural area of Guatemala; to assess the effects of traditional and modern health care providers on such mortality; and to find ways of identifying high-risk women who might benefit from transfer to a hospital or clinic. For these purposes a case-control study was conducted of 120 women in the rural department of Quetzaltenango who had lost their babies from the 20th week of pregnancy through the 28th day of life. These women and 120 controls were interviewed in their homes by trained physicians, using questionnaires in Spanish or the appropriate Indian dialect, and the results were analyzed through a series of statistical tests. It was found that the complications of pregnancy and delivery with the greatest statistical significance were prematurity, malpresentation, and prolonged labor. Population-based attributable risks of these complications demonstrated that they accounted for significant proportions of the observed peri-neonatal mortality. While these conditions cannot be eliminated, within the rural Guatemalan context it appears that early referral of women with these complications to more specialized care settings could result in improved delivery outcomes.

Adolescent↗
PubMed1994

Meta-analysis of highly selective vagotomy versus truncal vagotomy and pyloroplasty in the surgical treatment of uncomplicated duodenal ulcer.

OBJECTIVE: To compare critically by meta-analysis the postoperative outcomes after truncal vagotomy and pyloroplasty (TVP) and after highly selective vagotomy (HSV). DATA SOURCES: A search was conducted on MEDLINE with the keywords "peptic ulcer" and "vagotomy". Bibliographics of the articles retrieved and review articles pertaining to the subject were scanned further. STUDY SELECTION: Included were only published prospective, randomized controlled trials comparing TVP and HSV in the English-language literature up to April 1991. Twelve studies were found. DATA EXTRACTION: Two authors, working independently, abstracted raw data on mortality, recurrence, dumping, diarrhea and postoperative Visick grading. DATA SYNTHESIS: A ratio greater than 1.0 indicates a higher proportion occurring with TVP and less than 1.0 a higher proportion with HSV. [Table: See Text] CONCLUSION: The results suggest that the likelihood of adverse long-term sequelae is higher with TVP whereas the likelihood of recurrence is higher with HSV.

Confidence Intervals↗
PubMed1993

Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis.

PURPOSE: To determine whether alpha-interferon is effective in terminating viral replication and in eradicating the carrier state in patients with chronic hepatitis B virus (HBV) infection. DATA SOURCES: Randomized controlled studies published in the English literature between January 1966 and June 1992 were identified through a MEDLINE computer search. STUDY SELECTION: Fifteen randomized controlled studies with a total of 837 adult chronic HBV carriers who were positive for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were identified. Studies were included if patients were treated for at least 3 months and followed for at least 6 months after cessation of therapy. RESULTS: Overall, the loss of HBsAg occurred 6% more often in interferon-treated patients than the natural seroconversion seen in controls (7.8% compared with 1.8%, P = 0.001), and the loss of viral replication occurred approximately 20% more often in treated patients than in controls (33% compared with 12% for loss of HBeAg and 37% compared with 17% for the loss of HBV DNA, P = 0.0001) if patients received interferon for 3 to 6 months and were followed for 6 to 12 months. Interferon also had a significant treatment effect on the development of antibodies to HBsAg (anti-HBs), antibodies to HBeAg (anti-HBe), and on the normalization of alanine aminotransferase levels. CONCLUSIONS: Alpha-interferon is effective in terminating viral replication and in eradicating the carrier state in patients with chronic HBV infection who are HBeAg positive when these patients are treated for 3 to 6 months and followed for 6 to 12 months after cessation of therapy. Follow-up studies are required to determine whether interferon reduces the risk for developing cirrhosis or hepatocellular carcinoma.

Adolescent↗
PubMed1993

High level thrombospondin 1 expression in two NIH 3T3 cloned lines confers serum- and anchorage-independent growth.

Thrombospondin (TSP) is a trimeric molecule synthesized by a variety of normal and transformed cells and secreted into the extracellular matrix. A number of studies have shown TSP to be intimately involved in the regulation of cellular proliferation. These include the findings that TSP is a mitogen-inducible immediate-early response gene; it localizes to areas of cellular proliferation in the developing mouse embryo; it augments the proliferative response to epidermal growth factor; anti-TSP monoclonal antibodies block cell proliferation; and TSP levels correlate directly with the growth and invasive phenotype and inversely with the degree of differentiation of squamous carcinoma cells. To determine whether TSP could behave as an oncogene, conferring serum and anchorage independence, NIH 3T3 cells were stably transfected with a TSP expression vector. Clones producing high levels of TSP displayed enhanced viability and a proliferative advantage in serum-reduced media. Moreover, this growth advantage could be specifically negated by treatment of the transfected cells with anti-TSP monoclonal antibodies. While the TSP overexpressing clones were capable of anchorage-independent growth in soft agar, surprisingly, they were incapable of forming tumors in nude mice, possibly due to the in vivo antiangiogenic activity of TSP. Regardless, these studies demonstrate that overexpression of thrombospondin, a constituent of the extracellular matrix, results in serum and anchorage independent growth, attributes normally associated with the transformed phenotype.

3T3 Cells↗