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Biomedical subjects

K O'Rourke

Publications and source records attributed to K O'Rourke.

At least 55 records · Page 3Linked to original sources
PubMed1998

Elevated hepatitis A and E seroprevalence rates in a Texas/Mexico border community.

Two seroprevalence studies of viral hepatitis A and hepatitis E were conducted in El Paso, Tex, and Cd Juárez, Mexico. Subjects were randomly selected, low-income pregnant women. Blood from 557 women in El Paso and 307 women in Cd Juárez, obtained from routine prenatal testing, was analyzed for antibodies to hepatitis A and hepatitis E. Women from both cities showed high seroprevalence rates of hepatitis A (75.8% in El Paso and 96.1% in Cd Juárez). Rates increased significantly by age, with 100% of women in Cd Juárez older than 28 years testing positive. Nationality and ethnicity were significantly associated with hepatitis A seroprevalence: Mexican nationals, 96.1%; US Hispanics, 78.8%; and US Caucasians, 36.4% (P < .001). With respect to hepatitis E, 0.4% of women in El Paso and 1.6% of women in Cd Juárez tested positive for anti-HEV. The rate of hepatitis A seroprevalence was higher for women with lower educational levels and for women residing in crowded households, but these findings were not statistically significant.

Adolescent↗
PubMed1998

Reflex sympathetic dystrophy associated with extraforaminal disc herniation at the L5-S1 level.

We report an association between an extraforaminal disc herniation at the L5-S1 level causing an L5 radiculopathy and a reflex sympathetic dystrophy (RSD) in the affected foot. This is only the second reported case of a disc herniation at this level causing an RSD syndrome. We opted to treat both problems through a retroperitoneal approach involving a discectomy and a surgical sympathectomy. There was immediate and lasting relief from all symptoms, which has been maintained at 18 months' follow-up. The possible mechanisms for this condition are discussed as well as the various treatment options.

Adult↗
PubMed1997

The receptor for the cytotoxic ligand TRAIL.

TRAIL (also known as Apo-2L) is a member of the tumor necrosis factor (TNF) ligand family that rapidly induces apoptosis in a variety of transformed cell lines. The human receptor for TRAIL was found to be an undescribed member of the TNF-receptor family (designated death receptor-4, DR4) that contains a cytoplasmic "death domain" capable of engaging the cell suicide apparatus but not the nuclear factor kappa B pathway in the system studied. Unlike Fas, TNFR-1, and DR3, DR4 could not use FADD to transmit the death signal, suggesting the use of distinct proximal signaling machinery. Thus, the DR4-TRAIL axis defines another receptor-ligand pair involved in regulating cell suicide and tissue homeostasis.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death.

Previous genetic studies of the nematode Caenorhabditis elegans identified three important components of the cell death machinery. CED-3 and CED-4 function to kill cells, whereas CED-9 protects cells from death. Here CED-9 and its mammalian homolog Bcl-xL (a member of the Bcl-2 family of cell death regulators) were both found to interact with and inhibit the function of CED-4. In addition, analysis revealed that CED-4 can simultaneously interact with CED-3 and its mammalian counterparts interleukin-1beta-converting enzyme (ICE) and FLICE. Thus, CED-4 plays a central role in the cell death pathway, biochemically linking CED-9 and the Bcl-2 family to CED-3 and the ICE family of pro-apoptotic cysteine proteases.

Animals↗
PubMed1997

Primary biliary cirrhosis, sicca complex, and dysphagia.

We investigated symptoms suggestive of swallowing problems in patients with primary biliary cirrhosis, some of whom displayed features of sicca complex. A prospective study of 95 consecutive patients with primary biliary cirrhosis was conducted at a single teaching hospital using a questionnaire administered over the telephone. Some symptoms of sicca complex (dry mouth and/or dry eyes) were found in 65 patients (68.4%). Subjective xerostomia alone was present in 45 patients (47.4%). The questionnaire revealed an increase in incidence of dysphagia in xerostomia subjects, affecting 21 of 45 patients, compared with 6 of 50 non-xerostomia patients. Multivariate logistic regression analysis showed that confounding factors such as age, obesity, cigarette smoking, and medications associated with a dry mouth could not explain these findings. Twenty-eight patients complained of hoarseness, 23 of coughing, and 14 of wheezing, all of which were significantly more frequent than in the 50 patients without xerostomia. Heartburn affected 17 xerostomia patients and 15 non-xerostomia patients, indicating no difference in frequency between these two groups, even after age, obesity, cigarette smoking, and medications associated with heartburn were considered in the multivariate analysis. Acid regurgitation, nausea, and vomiting were also similar in frequency between patients with and without xerostomia. Swallowing problems, manifested primarily as dysphagia, are common in primary biliary cirrhosis patients who have subjective xerostomia.

Adult↗
PubMed1997

Risk and significance of endoscopic/radiological evidence of recurrent Crohn's disease.

BACKGROUND & AIMS: The aim of this study was to determine the risk of endoscopic/radiological recurrence of Crohn's disease postoperatively and the long-term outcome. METHODS: A randomized placebo-controlled trial was performed to determine the effectiveness of mesalamine in preventing recurrent Crohn's disease postoperatively. Patients in the control group were examined endoscopically/radiologically before entry into and annually during the trial. Findings were classified as minimal or severe. RESULTS: There were 76 patients (49 men and 37 women; mean age, 37.1 +/- 13.2 years). Fifty (61.7%) had terminal ileal resections. Overall, 55 endoscopic/radiological recurrences were observed in 51 patients (67.1%). Expressed actuarially, the recurrence rate was 27.5% at 1 year (95% confidence interval [CI], 15.8%-37.6%), 60.8% at 2 years (95% CI, 46%-71.3%), and 77.3% at 3 years (95% CI, 62.7%-86.3%). Nineteen (37%) were symptomatic and 12 (24%) were initially asymptomatic but later became symptomatic (mean, 13.0 +/- 8.8 months), whereas 20 (39%) remained asymptomatic (mean, 16.9 +/- 17.4 months). Patients with severe endoscopic/radiological disease were significantly more likely to be or become symptomatic than those with minimal disease (23 of 32 vs. 8 of 19, respectively; P = 0.0437). CONCLUSIONS: This study suggests that postoperative endoscopic/radiological recurrences occur later than previously reported. Furthermore, many of these patients, especially with minimal disease, will remain asymptomatic.

Actuarial Analysis↗
PubMed1997

Hepatitis A among schoolchildren in a US-Mexico border community.

OBJECTIVES: A cross-sectional study investigated the association of hepatitis A seropositivity with environmental and personal risk factors among children in a United States-Mexico border community. METHODS: Hepatitis A serological markers and a questionnaire identifying risk factors were evaluated for 523 primary school children. RESULTS: Of the children studied, 16.9% tested positive for total antihepatitis A virus. Risk factors included being in the first grade, low maternal educational attainment, living in Mexico for more than 6 months, household crowding, and inadequate excreta disposal systems. CONCLUSIONS: To decrease enteric disease, improvements in excreta disposal infrastructures and educational programs are needed. Hepatitis A vaccine should be administered before school age.

Child↗
PubMed1996

Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95.

Tumor necrosis factor receptor-1 (TNFR-1) and CD95 (also called Fas or APO-1) are cytokine receptors that engage the apoptosis pathway through a region of intracellular homology, designated the "death domain." Another death domain-containing member of the TNFR family, death receptor 3 (DR3), was identified and was shown to induce both apoptosis and activation of nuclear factor kappaB. Expression of DR3 appears to be restricted to tissues enriched in lymphocytes. DR3 signal transduction is mediated by a complex of intracellular signaling molecules including TRADD, TRAF2, FADD, and FLICE. Thus, DR3 likely plays a role in regulating lymphocyte homeostasis.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Molecular ordering of apoptotic mammalian CED-3/ICE-like proteases.

Apoptosis is executed by cysteine proteases belonging to the CED-3/ICE family, which, unlike other mammalian cysteine proteases, cleave their substrates following aspartate residues. Proteases belonging to this family exist in the cytosol as zymogens that require accurate processing at internal aspartate residues to generate the two-chain active enzymes. As such, CED-3/ICE family members are capable of activating each other in a manner analogous to the protease zymogens of the coagulation or complement cascades. At present, it is unknown whether such mutual processing exists in vivo, and if so whether it is sequential, implying an order to the death pathway. Using a cell-free apoptosis system, recombinant ICE proteases and both biochemical and morphological criteria, we demonstrate an ordering of the mammalian ICEs that are most related to the Caenorhabditis elegans death protease CED-3.

Animals↗
PubMed1996

Immunocytochemical colocalization of clusterin in apoptotic photoreceptor cells in retinal degeneration slow rds mutant mouse retinas.

In the rds mutant mouse the photoreceptor cells differentiate normally for the first few postnatal days, with the inner segments projecting an extended cilium. However, outer segments fail to form and only rudimentary disks and opsin-laden vesicles assemble at the tip of the cilium. These are shed into the interphotoreceptor space where they are phagocytosed by the retinal pigment epithelial cells. In this animal model, the photoreceptors undergo a slow degeneration via apoptosis leading to eventual loss of the entire photoreceptor population. Since increased expression of clusterin has been implicated in apoptosis, we studied the expression of clusterin in the rds mutant mouse retina and compared it to normal BALB/ c retinas. Small intestinal microvillus epithelium was used as a positive control tissue for apoptosis. Immunocytochemistry revealed the presence of clusterin in the ganglion cell, inner nuclear and outer plexiform layers and in the retinal pigment epithelium of both the rds and the BALB/c retinas. Interestingly, scattered clusterin-positive cells were observed in the outer nuclear layer (onl) of dystrophic retinas. Since the increased presence of clusterin protein in the onl of dystrophic retina may indicate dying photoreceptor cells due to apoptosis, we utilized a co-localization procedure for apoptotic nuclei and clusterin. For apoptosis we utilized an in situ 3' end labeling of fragmented DNA (TUNEL) and immunohistochemistry for clusterin using brown and red colored substrates respectively. Small intestine tissue sections were also included as positive controls for apoptosis. Our results show that clusterin is co-localized with apoptotic nuclei both in the onl of rds mutant retinas as well as in the small intestine epithelial cells undergoing cell turnover and exfoliation. These results are of interest since overexpression of clusterin is also observed in other neuro-degenerative diseases such as Alzheimer's and Pick's disease.

Animals↗
PubMed1996

FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex.

To identify CAP3 and CAP4, components of the CD95 (Fas/APO-1) death-inducing signaling complex, we utilized nano-electrospray tandem mass spectrometry, a recently developed technique to sequence femtomole quantities of polyacrylamide gel-separated proteins. Interestingly, CAP4 encodes a novel 55 kDa protein, designated FLICE, which has homology to both FADD and the ICE/CED-3 family of cysteine proteases. FLICE binds to the death effector domain of FADD and upon overexpression induces apoptosis that is blocked by the ICE family inhibitors, CrmA and z-VAD-fmk. CAP3 was identified as the FLICE prodomain which likely remains bound to the receptor after proteolytic activation. Taken together, this is unique biochemical evidence to link a death receptor physically to the proapoptotic proteases of the ICE/CED-3 family.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Proteolytic activation of the cell death protease Yama/CPP32 by granzyme B.

The serine protease granzyme B, which is secreted by cytotoxic cells, is one of the major effectors of apoptosis in susceptible targets. To examine the apoptotic mechanism of granzyme B, we have analyzed its effect on purified proteins that are thought to be components of death pathways inherent to cells. We demonstrate that granzyme B processes interleukin 1beta-converting enzyme (ICE) and the ICE-related protease Yama (also known as CPP32 or apopain) by limited proteolysis. Processing of ICE does not lead to activation. However, processing by granzyme B leads directly to the activation of Yama, which is now able to bind inhibitors and cleave the substrate poly(ADP-ribose) polymerase whose proteolysis is a marker of apoptosis initiated by several other stimuli. Thus ICE-related proteases can be activated by serine proteases that possess the correct specificity. Activation of pro-Yama by granzyme B is within the physiologic range. Thus the cytotoxic effect of granzyme B can be explained by its activation of an endogenous protease component of a programmed cell death pathway.

Apoptosis↗
PubMed1996

Molecular ordering of the cell death pathway. Bcl-2 and Bcl-xL function upstream of the CED-3-like apoptotic proteases.

Genetic analyses of Caenorhabditis elegans has identified three genes that function in the regulation of nematode cell death. Mammalian homologs of two of these genes, ced-9 and ced-3, have been identified and comprise proteins belonging to the Bcl-2 and ICE families, respectively. To date, it is unclear where the negative regulators, ced-9 and bcl-2, function relative to the death effectors, ced-3 and the mammalian ced-3 homologs, respectively. Here, the molecular order of the cell death pathway is defined. Our results establish that Bcl-2 and Bcl-xL function upstream of two members of the ICE/CED-3 family of cysteine proteases, Yama (CPP32/apopain) and ICE-LAP3 (Mch3).

Amino Acid Sequence↗
PubMed1996

FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis.

CD95 (Fas/APO-1) and tumor necrosis factor receptor-1 (TNFR-1) are related molecules that signal apoptosis. Recently, a number of novel binding proteins have been proposed to mediate the signaling of these death receptors. Here we report that an N-terminal truncation of one of these candidate signal transducers, FADD/MORT1, abrogates CD95-induced apoptosis, ceramide generation, and activation of the cell death protease Yama/CPP32. In addition, this dominant-negative derivative of FADD (FADD-DN) blocked TNF-induced apoptosis while not affecting NF- kappaB activation. FADD-DN bound both receptors, and in the case of CD95, it disrupted the assembly of a signaling complex. Taken together, our results functionally establish FADD as the apoptotic trigger of CD95 and TNFR-1.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Is the Mayo model for predicting survival useful after the introduction of ursodeoxycholic acid treatment for primary biliary cirrhosis?

Treatment of patients with primary biliary cirrhosis (PBC) using ursodeoxycholic acid (UDCA) leads to a reduction in serum bilirubin. The first objective of this study was to assess the performance of certain prognostic indicators for PBC after the introduction of treatment with UDCA. Serum bilirubin is an important prognostic indicator for PBC and an important component of the Mayo model for grading patients into risk categories. In an analysis of patients enrolled in the Canadian multicenter trial, the Mayo score was calculated before and after treatment with UDCA. After treatment, the Mayo score continued to divide patients with PBC into groups with varying risk. In addition, the serum bilirubin alone was shown to do the same even after the introduction of treatment with UDCA. A second objective was to establish whether UDCA had an effect on long-term (2- to 6-year) survival in patients with PBC.

Adult↗