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Biomedical subjects

M A O'Reilly

Publications and source records attributed to M A O'Reilly.

At least 19 recordsLinked to original sources
PubMed2003

Influence of building construction work on Aspergillus infection in a hospital setting.

BACKGROUND AND OBJECTIVE: Aspergillus fumigatus is a major pathogen causing nosocomial infections. Hospital outbreaks of invasive aspergillosis have been associated with the renovation and construction of buildings. Building construction work for fire safety upgrading was undertaken during a 16-week period in 2001 at Box Hill Hospital. This study was designed to examine the effect of construction on invasive aspergillosis when using standard and additional protective measures. METHODS: Baseline air sampling was conducted in 18 areas. The validity of the air sampling was assessed by comparing the ability of two air samplers to detect Aspergillus conidia. Surveillance of nosocomial Aspergillus infection was conducted by reviewing the records of patients with a sputum culture positive for Aspergillus and those prescribed amphotericin or itraconazole for the period of construction activity and the same period the previous year. RESULTS: Aspergillus was isolated infrequently and there was no statistically significant difference in the levels of viable pathogenic fungi between areas w here construction work was undertaken and areas where it wasnot undertaken. A moderate agreement was observed between the two air samplers (kappa = 0.4; P < .05). There was no difference in the incidence of invasive aspergillosis between 2000 and 2001 (incidence density ratio, 1.2; 95% confidence interval, 0.3 to 4.1). CONCLUSION: The influence of construction work performed with protective measures needs to be examined in an environment with higher levels of airborne fungi to confirm the findings of this study.

Air Microbiology↗
PubMed2001

p53-dependent induction of p21(Cip1/WAF1/Sdi1) protects against oxygen-induced toxicity.

The beneficial effects of supplemental oxygen delivered to patients suffering from acute respiratory distress is offset by its reduction to genotoxic reactive oxygen species (ROS) that inhibit proliferation and kill pulmonary cells. Cells respond to oxygen-induced damage by expressing the tumor suppressor p53 and the cyclin-dependent kinase inhibitor p21(Cip1/WAF1/Sdi1) (p21), which limits proliferation by blocking entry into S phase. Since preventing DNA synthesis during genotoxic stress may enhance survival, the current study examines whether hyperoxia induces p21 through a p53-dependent pathway and whether p21 protects cells from the toxic effects of oxygen. HCT116 colon carcinoma cells and clonal lines lacking p53 or p21were used in this study because they allow direct cytotoxic comparisons between isogenic cells, without complications arising from unknown genetic differences between nonhomologous cell lines. Hyperoxia (95% O2, 5% CO2) increased p53 abundance, phosphorylation of p53 on serine 15, and p21 mRNA and protein in parental HCT116 cells that ceased proliferation. In contrast, p21 was not detected in either p53- or p21-deficient HCT116 cells, which exited the G1 compartment and were arrested in S and G2/M phases during hyperoxia. Trypan blue-dye exclusion revealed that induction of p21 markedly enhanced survival during exposure and colony survival assays showed that p21 enhanced the ability to resume proliferation during recovery in room air. The observation that p53-dependent induction of p21 prevents exit from G1 and promotes survival during hyperoxia is consistent with the importance of limiting DNA replication during genotoxic stress caused by oxygen exposure.

Blotting, Western↗
PubMed2001

The role of p21(CIP1/WAF1) in growth of epithelial cells exposed to hyperoxia.

Previous studies have shown that hyperoxia inhibits proliferation and increases the expression of the tumor suppressor p53 and its downstream target, the cyclin-dependent kinase inhibitor p21(CIP1/WAF1), which inhibits proliferation in the G1 phase of the cell cycle. To determine whether growth arrest was mediated through activation of the p21-dependent G1 checkpoint, the kinetics of cell cycle movement during exposure to 95% O2 were assessed in the Mv1Lu and A549 pulmonary adenocarcinoma cell lines. Cell counts, 5-bromo-2'-deoxyuridine incorporation, and cell cycle analyses revealed that growth arrest of both cell lines occurred in S phase, with A549 cells also showing evidence of a G1 arrest. Hyperoxia increased p21 in A549 but not in Mv1Lu cells, consistent with the activation of the p21-dependent G1 checkpoint. The ability of p21 to exert the G1 arrest was confirmed by showing that hyperoxia inhibited proliferation of HCT 116 colon carcinoma cells predominantly in G1, whereas an isogenic line lacking p21 arrested in S phase. The cell cycle arrest in S phase appears to be a p21-independent process caused by a gradual reduction in the rate of DNA strand elongation. Our data reveal that hyperoxia inhibits proliferation in G1 and S phase and demonstrate that p53 and p21 retain their ability to affect G1 checkpoint control during exposure to elevated O2 levels.

Adenosine Triphosphate↗
PubMed2001

DNA damage and cell cycle checkpoints in hyperoxic lung injury: braking to facilitate repair.

The beneficial use of supplemental oxygen therapies to increase arterial blood oxygen levels and reduce tissue hypoxia is offset by the knowledge that it injures and kills cells, resulting in increased morbidity and mortality. Although many studies have focused on understanding how hyperoxia kills cells, recent findings reveal that it also inhibits proliferation through activation of cell cycle checkpoints rather than through overt cytotoxicity. Cell cycle checkpoints are thought to be protective because they allow additional time for injured cells to repair damaged DNA and other essential molecules. During recovery in room air, the lung undergoes a burst of proliferation to replace injured and dead cells. Failure to terminate this proliferation has been associated with fibrosis. These observations suggest that growth-suppressive signals, which inhibit proliferation of injured cells and terminate proliferation when tissue repair has been completed, may play an important role in the pulmonary response to hyperoxia. Because DNA replication is coupled with DNA repair, activation of cell cycle checkpoints during hyperoxia may be a mechanism by which cells protect themselves from oxidant genotoxic stress. This review examines the effect of hyperoxia on DNA integrity, pulmonary cell proliferation, and cell cycle checkpoints activated by DNA damage.

Animals↗
PubMed2001

The cyclin-dependent kinase inhibitor p21 protects the lung from oxidative stress.

The lung is a major target tissue for oxidative stress, including hyperoxia used to relieve tissue hypoxia. Unfortunately, severe hyperoxia damages DNA, inhibits proliferation, and kills cells, resulting in morbidity and mortality. Although hyperoxia induces the tumor suppressor p53 and its downstream target, the cyclin-dependent kinase inhibitor p21(Cip1/WAF1/Sdi1) (p21), their role in pulmonary injury remains unknown. Using p53- and p21-deficient mice we demonstrate that hyperoxia induces p21 in the absence of p53, suggesting that previous conclusions that p53 does not modify hyperoxic lung injury cannot be extrapolated to p21. In fact, mean survival of p21-deficient mice decreased by 40% and was associated with terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling staining of alveolar debris, indicative of DNA fragmentation and cell death. Ultrastructural analyses revealed that alveolar endothelial and type I epithelial cells died rapidly by necrosis. Although hyperoxia decreased DNA replication in p21-wild-type lungs, it had no effect on replication in p21-deficient lungs. Our findings suggest that p21 protects the lung from oxidative stress, in part, by inhibiting DNA replication and thereby allowing additional time to repair damaged DNA. Our findings have implications for patients suffering from the toxic effects of supplemental oxygen therapies.

Animals↗
PubMed2000

Relapsing Henoch-Schönlein purpura associated with Pseudomonas aeruginosa pyelonephritis.

Henoch-Schönlein purpura is a systemic vasculitis of unknown cause. It is frequently triggered by a streptococcal upper respiratory tract infection. Other bacteria have been implicated as triggering agents. We report a recurring case of Henoch-Schönlein purpura in a patient with Pseudomonas pyelonephritis. The Henoch-Schönlein purpura remitted only when the infection was eradicated. Pseudomonas infection should be added to the list of bacteria that can trigger Henoch-Schönlein purpura.

Adult↗
PubMed2000

Bcl-2 family gene expression during severe hyperoxia induced lung injury.

Exposure of the lung to severe hyperoxia induces terminal transferase dUTP end-labeling (TUNEL) indicative of DNA damage or apoptosis and increases expression of the tumor suppressor p53 and of members of the Bcl-2 gene family. Because cell survival and apoptosis are regulated, in part, by the relative abundance of proteins of the Bcl-2 family, we hypothesized that lung cells dying during exposure would show increased expression of pro-apoptotic members, such as Bax, whereas surviving cells would have increased expression of anti-apoptotic members, such as Bcl-X(L). The hypothesis is tested in the current study by determining which Bcl-2 genes are regulated by hyperoxia, with specific focus on correlating expression of Bax and Bcl-X(L) with morphologic evidence of apoptosis or necrosis. Adult mice exposed to greater than 95% oxygen concentrations for 48 to 88 hours had increased whole-lung mRNA levels of Bax and Bcl-X(L), no change in Bak, Bad, or Bcl-2, and decreased levels of Bcl-w and Bfl-1. In situ hybridization revealed that hyperoxia induced Bax and Bcl-X(L) mRNA in uniform and overlapping patterns of expression throughout terminal bronchioles and parenchyma, coinciding with TUNEL staining. Electron microscopy and DNA electrophoresis, however, suggested relatively little classical apoptosis. Unexpectedly, Western analysis demonstrated increased Bcl-X(L), but not Bax, protein in response to hyperoxia. Bax and Bfl-1 were not altered by hyperoxia in p53 null mice; however, oxygen toxicity was not lessened by p53 deficiency. These findings suggest that oxygen-induced lung injury does not depend on the relative expression of these Bcl-2 members.

Animals↗
PubMed2000

Pulmonary chemokine and mutagenic responses in rats after subchronic inhalation of amorphous and crystalline silica.

Chronic inhalation of crystalline silica can produce lung tumors in rats whereas this has not been shown for amorphous silica. At present the mechanisms underlying this rat lung tumor response are unknown, although a significant role for chronic inflammation and cell proliferation has been postulated. To examine the processes that may contribute to the development of rat lung tumors after silica exposure, we characterized the effects of subchronic inhalation of amorphous and crystalline silica in rats. Rats were exposed for 6 h/day, on 5 days/week, for up to 13 weeks to 3 mg/m(3) crystalline or 50 mg/m(3) amorphous silica. The effects on the lung were characterized after 6.5 and 13 weeks of exposure as well as after 3 and 8 months of recovery. Exposure concentrations were selected to induce high pulmonary inflammatory-cell responses by both compounds. Endpoints characterized after silica exposure included mutation in the HPRT gene of isolated alveolar cells in an ex vivo assay, changes in bronchoalveolar lavage fluid markers of cellular and biochemical lung injury and inflammation, expression of mRNA for the chemokine MIP-2, and detection of oxidative DNA damage. Lung burdens of silica were also determined. After 13 weeks of exposure, lavage neutrophils were increased from 0.26% (controls) to 47 and 55% of total lavaged cells for crystalline and amorphous silica, with significantly greater lavage neutrophil numbers after amorphous silica (9.3 x 10(7) PMNs) compared to crystalline silica (6.5 x 10(7) PMNs). Lung burdens were 819 and 882 microg for crystalline and amorphous silica, respectively. BAL fluid levels of LDH as an indicator of cytotoxicity were twice as high for amorphous silica compared to those of crystalline silica, at the end of exposure. All parameters remained increased for crystalline silica and decreased rapidly for amorphous silica in the 8-month recovery period. Increased MIP-2 expression was observed at the end of the exposure period for both amorphous and crystalline silica. After 8 months of recovery, those markers remained elevated in crystalline silica-exposed rats, whereas amorphous silica-exposed rats were not significantly different from controls. A significant increase in HPRT mutation frequency in alveolar epithelial cells was detected immediately after 13 weeks of exposure to crystalline, but not to amorphous silica. A significant increase in TUNEL staining was detected in macrophages and terminal bronchiolar epithelial cells of amorphous silica-exposed rats at the end of the exposure period; however, crystalline silica produced far less staining. The observation that genotoxic effects in alveolar epithelial cells occurred only after crystalline but not amorphous silica exposure, despite a high degree of inflammatory-cell response after subchronic exposure to both types of silica, suggests that in addition to an inflammatory response, particle biopersistence, solubility, and direct or indirect epithelial cell cytotoxicity may be key factors for the induction of either mutagenic events or target cell death.

Administration, Inhalation↗
PubMed2000

p53-independent induction of GADD45 and GADD153 in mouse lungs exposed to hyperoxia.

Previous studies have shown that lungs of adult mice exposed to >95% oxygen have increased terminal deoxyribonucleotidyltransferase dUTP nick end-label staining and accumulate p53, the expression of which increases in cells exposed to DNA-damaging agents. The present study was designed to determine whether hyperoxia also increased expression of the growth arrest and DNA damage (GADD) gene 45 and GADD153, which are induced by genotoxic stress through p53-dependent and -independent pathways. GADD proteins have been shown to inhibit proliferation and stimulate DNA repair and/or apoptosis. GADD45 and GADD153 mRNAs were not detected in lungs exposed to room air but were detected after 48 and 72 h of exposure to hyperoxia. In situ hybridization and immunohistochemistry revealed that hyperoxia increased GADD45 and GADD153 expression in the bronchiolar epithelium and GADD45 expression predominantly in alveolar cells that were morphologically consistent with type II cells. Hyperoxia also increased GADD expression in p53-deficient mice. Terminal deoxyribonucleotidyltransferase dUTP nick end-label staining of lung cells from p53 wild-type and p53-null mice exposed to hyperoxia for 48 h revealed that hyperoxia-induced DNA fragmentation was not modified by p53 deficiency. These studies are consistent with the hypothesis that hyperoxia-induced DNA fragmentation is associated with the expression of GADD genes that may participate in DNA repair and/or apoptosis.

Animals↗
PubMed2000

Tumor necrosis factor-alpha-induced lung cell expression of antiapoptotic genes TRAF1 and cIAP2.

Tumor necrosis factor (TNF) receptor (TNFR)-associated factors 1 and 2 (TRAF1 and TRAF2) and inhibitor of apoptosis proteins cIAP1 (MIHB) and cIAP2 (MIHC) were recently identified as proteins that associate with the TNF-alpha receptors TNFRI (p55) and TNFRII (p75) and inhibit TNF-alpha-induced programmed cell death or apoptosis. In the original reports, TRAF1 expression, unlike the ubiquitous TRAF2, was restricted to specific tissues in the lung, spleen, and testis. TNF-alpha is increased in the lung in many forms of pulmonary disease. In the current study, Western analysis, immunohistochemistry, and ribonuclease protection assays were used to determine whether TNF-alpha regulates the expression of these TNFR-associated proteins in lung cells. We demonstrate for the first time TNF-alpha dose-dependent induction of TRAF1 protein and messenger RNA (mRNA) in human H441 and A549 pulmonary adenocarcinoma cell lines, as well as in lung cells of C57BL/6J mice after intratracheal administration of TNF-alpha. In contrast to the epithelial cells, TRAF1 was not induced by TNF-alpha in U937 cells, a human monocytic cell line, suggesting cell type-specific regulation. Similarly, cIAP2 mRNA was induced by TNF-alpha in both H441 and A549 pulmonary epithelial cells but not in U937 cells. TNF-alpha is a primary mediator of acute pulmonary inflammation and contributes to the pathophysiology of chronic lung diseases such as bronchopulmonary dysplasia (BPD), a fibrotic disease of prematurely born infants. Immunohistochemical staining of human neonatal lung tissue demonstrated increased TRAF1 in lungs of infants dying of pneumonia or BPD in comparison with those dying of congenital malformation. These studies support the hypothesis that the TRAF1 and cIAP2 genes are highly regulated in pulmonary cells and may play a role in human lung disease.

Animals↗
PubMed1999

Disseminated tuberculosis: still a diagnostic challenge.

Disseminated tuberculosis is notoriously difficult to diagnose and, with the decrease in tuberculosis incidence in Australia, familiarity with its manifestations has dwindled. We describe four bacteriologically proven cases which illustrate the range of presentations and diagnostic difficulties. Surprisingly, immunosuppressive therapy need not cause rapid deterioration. Disseminated tuberculosis should be considered in any patient with multisystem illness who is at risk of tuberculosis, particularly if born overseas. In the absence of confirmatory results, a prompt therapeutic trial may be life-saving.

Adult↗
PubMed1999

Hyperoxia inhibits proliferation of Mv1Lu epithelial cells independent of TGF-beta signaling.

High concentrations of O(2) inhibit epithelial cell proliferation that resumes on recovery in room air. To determine whether growth arrest is mediated by transforming growth factor-beta (TGF-beta), changes in cell proliferation during exposure to hyperoxia were assessed in the mink lung epithelial cell line Mv1Lu and the clonal variant R1B, which is deficient for the type I TGF-beta receptor. Mv1Lu cells treated with TGF-beta accumulated in the G(1) phase of the cell cycle as determined by propidium iodide staining, whereas proliferation of R1B cells was unaffected by TGF-beta. In contrast, hyperoxia inhibited proliferation of both cell lines within 24 h of exposure through an accumulation in the S phase. Mv1Lu cells treated with TGF-beta and exposed to hyperoxia accumulated in the G(1) phase, suggesting that TGF-beta can inhibit the S phase accumulation observed with hyperoxia alone. Cyclin A was detected in cultures exposed to room air or growth arrested by hyperoxia while decreasing in cells growth arrested in the G(1) phase by TGF-beta. Finally, hyperoxia failed to activate a TGF-beta-dependent transcriptional reporter in both Mv1Lu and R1B cells. These findings reveal that simple growth arrest by hyperoxia involves a defect in S phase progression that is independent of TGF-beta signaling.

Adenocarcinoma↗
PubMed1998

Comparative efficacy of once-daily flurandrenolide tape versus twice-daily diflorasone diacetate ointment in the treatment of psoriasis.

BACKGROUND: Flurandrenolide tape has recently been listed as a group I topical corticosteroid. There are no studies that compare this product to group I ointments in the treatment of steroid-responsive dermatoses. OBJECTIVE: Our purpose was to determine the relative efficacy of flurandrenolide (4 microg/cm2) tape versus 0.05% diflorasone diacetate ointment in plaque psoriasis. METHODS: Thirty patients participated in an investigator-blinded, randomized, bilateral paired-comparison study of flurandrenolide tape applied to lesions of one side of the body once daily for up to 16 hours versus diflorasone diacetate ointment applied contralaterally twice daily. Lesions were assessed at baseline, then reevaluated at 2 and 4 weeks. RESULTS: Flurandrenolide tape-treated plaques showed consistently greater clearing in terms of erythema, scaling, induration, and treatment success for all plaques, as well as the subset of knee and elbow plaques, when compared with the lesions receiving diflorasone diacetate ointment. CONCLUSION: The efficacy of flurandrenolide tape in the treatment of psoriatic plaques surpasses that of diflorasone diacetate ointment.

Administration, Topical↗
PubMed1998

Exposure to hyperoxia induces p53 expression in mouse lung epithelium.

Cells that are exposed to free radicals have increased levels of DNA strand breaks with accumulation of the tumor suppressor protein p53, which induces cell cycle arrest and/or apoptosis. Because oxidants injure pulmonary epithelial cells, it was hypothesized that exposure to hyperoxia promotes DNA strand breaks in lung epithelium, resulting in increased expression of p53 and loss of epithelial cell function. Adult male C57Bl/6J mice were exposed to > 95% oxygen for 72 h and DNA integrity was determined in their lungs by terminal transferase immunoreactivity. Both nonimmunoreactive and lightly stained nuclei were observed in cells comprising the airway and parenchyma. Exposure to hyperoxia resulted in a marked increase in the intensity of nuclear staining in distal bronchiolar epithelium and alveolar epithelial and endothelial cells. Airway epithelial cells from control lungs contained detectable levels of p53 protein, which markedly increased in both nuclei and cytoplasm of distal bronchiolar epithelial cells and to a lesser extent in alveolar epithelial cells that were morphologically consistent with type II cells. Western and Northern blot analyses revealed that hyperoxia increased total lung p53 protein expression but not levels of mRNA. Changes in terminal transferase immunoreactivity and p53 expression were not observed in large airway cells, fibroblasts underlying distal airway, or smooth muscle cells. Expression of SP-B mRNA modestly increased and Clara cell secretory protein and cytochrome P-450 2F2 mRNAs decreased, providing additional evidence that hyperoxia injured pulmonary epithelial cells. These findings support the concept that hyperoxia damages DNA of pulmonary epithelial cells, which respond by accumulating p53 and changes in epithelial cell-specific gene expression.

Animals↗