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Biomedical subjects

T O'Brien

Publications and source records attributed to T O'Brien.

At least 19 recordsLinked to original sources
PubMed2003

Classic papers in Urology.

OBJECTIVE: Most clinicians are aware of the importance of using "evidence based medicine" to support their clinical practice, but where does the evidence come from? The aim of this study was to examine the concordance between papers deemed "important" by urologists compared with those selected by the more objective criteria of the citation index. METHOD: To achieve this, two approaches were used; firstly "experts" in various fields of urology were asked to select what they felt were classic papers and secondly urology journals were searched to find the 100 most cited papers for 1982-1997 and 1935-1997. The results of both of these "league tables" were then combined. RESULTS: The most cited papers varied depending on the time period studied. When the experts' selections were combined with those obtained via citation index it was found that the experts had chosen papers with a high citation index from non-urological as well as urological journals. CONCLUSION: It is possible to collate the classic papers within urology and the most effective means of doing so is to combine objective selection with expert choice. This is an exercise that can be repeated within any specialty.

Bibliometrics↗
PubMed2003

A direct mechanical method for accurate and efficient adenoviral vector delivery to tissues.

We describe a mechanical method for delivery of adenoviral vector to the adventitial surface of arteries and to other tissues. Our goal was to characterize, principally in intact carotid artery, the morphological, biochemical, and functional effects of mechanical delivery of a recombinant beta-galactosidase-expressing adenoviral vector following its direct application using a small paintbrush. Our ex vivo and in vivo data demonstrate efficient, accurate, and rapid transduction of arteries without compromise of their morphological, biochemical, and functional integrity. We also demonstrate the general applicability of this technique in vivo via transduction of skeletal muscle, fibrotendinous tissue, peritoneum, serosal surface of bowel, and wounded skin. We conclude that direct mechanical delivery of an adenoviral vector to tissues using a suitable paintbrush represents an intuitive, accurate, and effective means of augmenting gene transfer efficiency, and may be a useful adjunct to other delivery methods.

Adenoviridae↗
PubMed2003

A randomised trial of periprostatic local anaesthetic for transrectal biopsy.

Increasingly transrectal ultrasound and biopsy is performed for the detection of prostate cancer. We have conducted a randomised trial to evaluate whether the addition of periprostatic local anaesthetic injection reduces the discomfort of the procedure. A total of 64 patients who attended a specialised prostate clinic and were being evaluated for an elevated prostate-specific antigen agreed to participate in the trial and were randomly allocated to two groups. The intervention group received 10 ml of 1% lignocaine in the periprostatic tissue prior to biopsy and the control group underwent a standard biopsy. All patients had a sextant biopsy under ultrasound guidance. After the procedure, they were asked to determine the severity of the pain on a scale of 0-10 and the whether the quality of the pain was mild, moderate or severe. The responses were distributed normally. The groups were compared using Student's t-test. Pain severity showed no significant difference between the two groups (P=0.14). There was a trend towards a statistical difference (P=0.07) on the qualitative pain scale. In conclusion, no significant difference in overall discomfort in men having sextant biopsies was detected between the two groups, suggesting that the administration of local anaesthetic may not be as valuable as early reports have suggested.

Anesthesia, Local↗
PubMed2003

On using experimentally estimated wall shear stresses to validate numerically predicted results.

The objective of this investigation was to assess the use of experimentally estimated wall shear stresses to validate numerically predicted results. The most commonly cited haemodynamic factor implicated in the disease initiation and proliferation processes at graft/artery junctions is wall shear stress (WSS). WSS can be determined from the product of the viscosity of the fluid and the wall shear rate. Numerically, the wall shear rate is predicted using velocity values stored in the computational cell near the wall and assuming zero velocity at the wall. Experimentally, the wall shear rate is estimated by applying a curve-fit to near-wall velocity measurements and evaluating the shear rate at a specific distance from the wall. When estimating the wall shear rate from the laser Doppler anemometry (LDA) point velocity measurements, large differences between the experimentally estimated and numerically predicted WSSs were introduced. It was found that the estimated WSS distributions from the experimental results are highly dependent on the curve-fitting method used to calculate the wall shear rate. However, the velocity profiles for both the experimental and numerical investigations show extremely good comparison. It is concluded that numerical models should be validated using unprocessed LDA point velocity measurement and not estimated WSS values.

Anastomosis, Surgical↗
PubMed2003

Erectile dysfunction: cardiovascular risk and the role of the cardiologist.

Erectile dysfunction (ED) shares the same risk factors as coronary artery disease, so the level of occult cardiovascular risk in men with ED was assessed. A total of 174 men presenting with ED underwent cardiac risk stratification according to the Princeton Consensus Guidelines. Thirty per cent were stratified as intermediate/high cardiovascular risk and had ED treatment deferred until further cardiological assessment; 37% had abnormal lipid profiles; 24% had elevated HbA1C/glucose levels; 17% had uncontrolled hypertension; and 6% were suspected of having significant angina. ED is associated with a high incidence of occult cardiovascular disease. We suggest that cardiologists can significantly contribute to the management of ED.

Adult↗
PubMed2002

In vitro toxicity of 7H-dibenzo[c,g]carbazole in human liver cell lines.

7H-Dibenzo[c,g]carbazole (DBC) is a model N-heterocyclic aromatic compound (NHA) which is both a hepatotoxin and hepatocarcinogen in rodents. The focus of this investigation was to determine whether human liver cell lines display differential sensitivities to DBC-induced toxicity. Treatment of cell lines with increasing DBC concentrations produced apoptosis only in HepG2 cells. Although DBC inhibited the clonogenic growth of all cell lines at high concentrations, only the survival of HepG2 cells was reduced at lower concentrations. DBC inhibited DNA synthesis in two (HepG2, HLF) of the three cell lines at lower concentrations and was effective only at a high concentration in Mahlavu cells. Differences in DBC uptake were not observed in any of the cell lines, suggesting that bioavailability was not a limiting factor. DBC-DNA adducts were not detected in HLF or Mahlavu cells at either low or high concentrations of DBC. Consistent with the DNA adduct data, RP-HPLC analysis indicated that DBC was metabolized to a lesser degree in the HLF and Mahlavu cells. These results suggest that human liver cell lines differ markedly in the ability to metabolize DBC to toxic species and that DBC-induced apoptosis is only observed in cells that produce detectable metabolites and DBC-DNA adducts.

Apoptosis↗
PubMed2001

Gene transfer of manganese superoxide dismutase reverses vascular dysfunction in the absence but not in the presence of atherosclerotic plaque.

Impaired endothelium-dependent vasorelaxation (EDVR) is observed in hypercholesterolemia both in the presence and absence of morphological abnormalities and may be due to superoxide anions. Our aim was to assess the effect of gene transfer of manganese superoxide dismutase (MnSOD) to blood vessels from hypercholesterolemic animals with and without atherosclerotic plaque and to compare the effects of endothelial nitric oxide synthase (eNOS) and MnSOD over-expression on vascular dysfunction in the setting of atherosclerosis. Rabbits received a high-cholesterol diet for 10 weeks, resulting in abnormal EDVR in the absence of plaque in the carotids and the presence of plaque in the aorta. In Group 1, adenoviral vectors encoding MnSOD (AdMnSOD) or beta-galactosidase (Ad(beta)gal) were delivered to the carotid arteries in vivo. Four days later, transgene expression and vascular reactivity were assessed. In Group 2, segments of the aorta were transduced ex vivo with AdMnSOD, AdeNOS or both. Transgene expression and vascular reactivity were assessed 24 hr later. In Group 1, MnSOD expression was detected in AdMnSOD-ransduced vessels and impaired EDVR was reversed in the absence of atherosclerotic plaque. In Group 2 (with atherosclerotic plaque present), MnSOD and eNOS expression were detected by western analysis, and eNOS, but not MnSOD over-expression, improved EDVR whereas simultaneous over-expression of eNOS and MnSOD was no better than eNOS alone. Adenovirus-mediated gene transfer of MnSOD to nonatherosclerotic carotid arteries, but not atherosclerotic aorta, normalizes EDVR. eNOS gene transfer improves EDVR, even in the presence of plaque.

Acetylcholine↗
PubMed2001

Remnant lipoproteins induce endothelial plasminogen activator inhibitor-1.

Remnant lipoproteins (RLPs) accumulate in type III hyperlipoproteinemia, a condition associated with significant cardiovascular morbidity. The effect of RLPs on fibrinolysis is unknown. Our aim was to study the effect of RLPs on endothelial expression of plasminogen activator inhibitor-1 (PAI-1). After 24-h culture of human aortic endothelial cells with RLPs at concentrations of 0 (control), 0.038, or 0.076 mg triglyceride/mL, postculture PAI-1 antigen concentrations were: 870 +/- 80, 1963 +/- 183 (P = 0.005), and 3551 +/- 177 ng/mL (P < 0.001), respectively. Furthermore, after 24-h incubation of endothelial cells with RLPs (0 or 0.076 mg triglyceride/mL), PAI-1 activity increased from 0.667 +/- 0.144 to 1.268 +/- 0.198 U/mL, respectively (P = 0.008) and endothelial PAI-1 mRNA increased to 2.7 +/- 0.66 that of control (P = 0.048). In conclusion, RLPs from patients with type III hyperlipoproteinemia induce endothelial cell PAI-1 expression, which may contribute to a prothrombotic state.

Cells, Cultured↗
PubMed2001

The effects of CTLA-4Ig on acute lung allograft rejection: a comparison of intrabronchial gene therapy with systemic administration of protein.

BACKGROUND: Blockade of T-cell costimulation by local delivery of an adenoviral vector encoding for CTLA-4Ig and systemic administration of the protein are compared in a rat lung allograft model. METHODS: Left lungs of Brown Norway rats (RT1n) were transplanted into Lewis (RT11) recipients in four groups of six animals each: 1) no treatment; 2) intrabronchial transduction of donor lung with adenovirus encoding mCTLA-4Ig (adeno-mCTLA-4Ig); 3) intrabronchial transduction with empty adenovirus; and 4) intraperitoneal injection of mCTLA-4Ig. Grading of rejection, mCTLA-4Ig measurement in serum and bronchial washings, RT-PCR for virally encoded transcripts, and immunohistochemistry for mCTLA-4Ig were carried out 4 days later. RESULTS: Intrabronchial transduction with adeno-mCTLA-4Ig resulted in detectable transgene expression in graft tissue and bronchial fluid but not in serum. Significant reduction in rejection grade (from grade 3 to 2) occurred after systemic mCTLA-4Ig but not adeno-mCTLA-4Ig transduction. CONCLUSION: Local expression of immunomodulatory proteins can be achieved within lung allografts by intrabronchial delivery of adenoviral vector but may not significantly modify acute rejection.

Abatacept↗
PubMed2001

Effects of immunosuppressants on receptor activator of NF-kappaB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells.

Osteoporosis and vasculopathy are common after organ transplantation and have been largely attributed to the use of immunosuppressants. Osteoprotegerin (OPG) is produced by osteoblastic and arterial cells, and inhibits osteoclast functions by neutralizing receptor activator of NF-kappaB ligand (RANKL). Because OPG-deficient mice develop osteoporosis and arterial calcification, we assessed the effects of immunosuppressants on OPG and RANKL expression by human osteoblastic and coronary artery smooth muscle cells (CASMC). Cyclosporine A, rapamycin, and FK-506 decreased OPG mRNA and protein levels in undifferentiated marrow stromal cells (by 63, 44, and 68%, respectively, P < 0.001). All three immunosuppressants increased RANKL mRNA levels in these cells by 60 to 210%. In contrast to these effects on marrow stromal cells, rapamycin, which may be relatively bone-sparing, increased OPG mRNA and protein production (by 120%, P < 0.001) in mature osteoblastic cells. Cyclosporine A also decreased OPG mRNA and protein production (by 52%, P < 0.001) of CASMC. In conclusion, immunosuppressants decrease OPG mRNA and protein production and increase RANKL gene expression by marrow stromal cells, and cyclosporine suppresses OPG production in CASMC. These studies thus provide a potential mechanism for immunosuppressant-induced bone loss, and the propensity of cyclosporine A to cause vascular disease.

Bone Marrow Cells↗
PubMed2001

Conditions of vector delivery improve efficiency of adenoviral-mediated gene transfer to the transplanted heart.

OBJECTIVES: Conditions for ex vivo gene transfer to the transplanted heart were studied in a model of syngeneic abdominal heterotopic heart transplantation in the rat. Various methods of adenoviral-mediated gene transfer to the transplanted heart were compared. METHODS: In the first experiment, a dose response study, an adenoviral vector encoding the beta-galactosidase gene was infused into the donor heart with the pulmonary artery open and flushed out prior to performing the transplant. In the second experiment, the effects of clamping the pulmonary artery during vector infusion and not flushing out the viral solution, resulting in vector dwell during the warm ischemia, were examined. RESULTS: In the first experiment, gene transfer was relatively inefficient; however, transgene expression improved with increases in the vector dose (range, 1x10(7)-1x10(9)). The efficiency of gene transfer was significantly greater when the conditions of the second experiment were applied. In all models studied, cardiomyocytes and not vascular endothelial cells were the predominant cell type transduced. CONCLUSIONS: This study indicates that the conditions of adenoviral vector delivery are critical for optimizing gene transfer in the transplant setting. In addition, intravascular administration of adenoviral vector to the donor heart results predominantly in cardiomyocyte transgene expression.

Adenoviridae↗
PubMed2001

Efficacy of adenoviral gene transfer with manganese superoxide dismutase and endothelial nitric oxide synthase in reducing ischemia and reperfusion injury.

OBJECTIVE: Both superoxide dismutase (SOD), a free radical scavenger, and nitric oxide (NO), a vasodilator with anti-inflammatory properties, have been shown to protect the myocardium from reperfusion injury. They are known to interact in vivo, the influence of which on myocardial protection has not been studied. METHODS: Four groups of rats (n=7, per group) were subjected to experimental infarction following injections into the anterior wall of the left ventricle with adenoviral vector encoding beta-galactosidase (group A), eNOS (group B), Mn-SOD (group C) and both eNOS and MnSOD (group D). Hearts were assessed for protein expression and size of infarction. RESULTS: Efficiency of gene up regulation was confirmed by immunostaining for eNOS and Mn-SOD, and X-gal staining for beta-gal respectively. In B and D, overexpression of eNOS was demonstrated in cardiac myocytes in addition to that in the endothelium, while in C and D, Mn-SOD was overexpressed in mainly cardiomyocytes. Infarct size was 49.7+/-4.8% in A, and was significantly reduced in the other groups (29.8+/-2.7%, 21.8+/-2.5% and 24.9+/-2.4% in B, C and D respectively). CONCLUSION: Adenoviral gene transfer of Mn-SOD was superior to eNOS in reducing the extent of in vivo ischemia-reperfusion injury in the rat heart in our model. The effect of combined application of Mn-SOD and eNOS was not different from their individual effect.

Adenoviridae↗
PubMed2001

Ability of laboratories to detect emerging antimicrobial resistance: proficiency testing and quality control results from the World Health Organization's external quality assurance system for antimicrobial susceptibility testing.

The accuracy of antimicrobial susceptibility data submitted by microbiology laboratories to national and international surveillance systems has been debated for a number of years. To assess the accuracy of data submitted to the World Health Organization by users of the WHONET software, the Centers for Disease Control and Prevention distributed six bacterial isolates representing key antimicrobial-resistance phenotypes to approximately 130 laboratories, all but one of which were outside of the United States, for antimicrobial susceptibility testing as part of the World Health Organization's External Quality Assurance System for Antimicrobial Susceptibility Testing. Each laboratory also was asked to submit 10 consecutive quality control values for several key organism-drug combinations. Most laboratories were able to detect methicillin (oxacillin) resistance in Staphylococcus aureus, high-level vancomycin resistance in Enterococcus faecium, and resistance to extended-spectrum cephalosporins in Klebsiella pneumoniae. Many laboratories, particularly those using disk diffusion tests, had difficulty in recognizing reduced susceptibility to penicillin in an isolate of Streptococcus pneumoniae. The most difficult phenotype for laboratories to detect was reduced susceptibility to vancomycin in an isolate of Staphylococcus epidermidis. The proficiency testing challenge also included a request for biochemical identification of a gram-negative bacillus, which most laboratories recognized as Enterobacter cloacae. Although only a small subset of laboratories have submitted their quality control data, it is clear that many of these laboratories generate disk diffusion results for oxacillin when testing S. aureus ATCC 25923 and S. pneumoniae ATCC 49619 that are outside of the acceptable quality control range. The narrow quality control range for vancomycin also proved to be a challenge for many of the laboratories submitting data; approximately 27% of results were out of range. Thus, it is important to establish the proficiency of laboratories submitting data to surveillance systems in which the organisms are tested locally, particularly for penicillin resistance in pneumococci and glycopeptide resistance in staphylococci.

Anti-Bacterial Agents↗
PubMed2001

Gene transfer of superoxide dismutase isoforms reverses endothelial dysfunction in diabetic rabbit aorta.

Increased production of oxygen free radicals is an important mechanism of endothelial dysfunction in diabetes mellitus. Our goal was to test whether adenovirus (Ad)-mediated gene transfer of copper/zinc (CuZn) or manganese superoxide dismutase (Mn SOD) improves relaxation of diabetic vessels. The aortas from 9 alloxan-induced diabetic mellitus (DM) and 16 control rabbits were used. Control and DM rings were transduced ex vivo with Ad vectors encoding Mn SOD (AdMn SOD), CuZn SOD (AdCuZn SOD), beta-galactosidase (Ad(beta)gal), or diluents. In the absence of gene transfer, SOD activity was significantly increased in DM aortas. Transgene expression in DM AdCuZn SOD and DM AdMn SOD-transduced vessels was confirmed by Western blot analysis and by increased SOD activity (DM AdCuZn SOD, 76.2 +/- 9.3; DM AdMn SOD, 65.2 +/- 4.8; P < 0.05 vs. DM Ad(beta)gal; 50.9 +/- 4.4 U/mg protein). Superoxide production was increased in DM Ad(beta)gal-transduced aorta and relaxations to acetylcholine were impaired in these vessels. Gene transfer of CuZn SOD and Mn SOD corrected both of these defects. Thus Ad-mediated gene transfer CuZn and Mn SOD to the diabetic aorta improves endothelium-dependent relaxation.

Acetylcholine↗
PubMed2001

Superoxide anions and endothelial cell proliferation in normoglycemia and hyperglycemia.

-Oxygen free radicals are believed to play a key role in cellular proliferation, and increased concentrations of these molecules have been implicated in the pathogenesis of endothelial dysfunction in diabetes mellitus. Our aim was to study the role of superoxide anions in endothelial cell proliferation under conditions of normoglycemia and hyperglycemia. Human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs) exposed to adenoviral vectors encoding CuZnSOD (AdCuZnSOD), ss-galactosidase (Adssgal), or diluent (control) were cultured in normal glucose (NG, 5.5 mmol/L) or high glucose (HG, 28 mmol/L) medium. Cell proliferation was compared by use of [(3)H]thymidine incorporation and cell count in transduced and control cells in the setting of NG and HG. Transgene expression was detected in transduced cells by X-gal staining and by Western analysis and SOD activity assay in AdCuZnSOD-transduced cells. Superoxide production was significantly (P:<0.05) decreased in AdCuZnSOD-transduced cells cultured in both NG and HG medium. In NG, AdCuZnSOD-transduced endothelial cells had decreased proliferation compared with control cells. After 48 hours in HG, superoxide levels were increased and DNA synthesis was decreased (P:<0.05) in control and Adssgal-transduced but were not affected in AdCuZnSOD-transduced cells. In addition, after 7 days in HG, cell counts were reduced (P:<0.05) in control (73+/-2.5%) and Adssgal-transduced (75+/-3.4%) but not in AdCuZnSOD-transduced cells (89+/-3.4%). These results suggest that either a deficiency or an excess of superoxide anions inhibits endothelial cell proliferation, and the inhibitory effect of increased superoxide due to hyperglycemia can be reversed by CuZnSOD overexpression.

Anions↗
PubMed2001

Low-density lipoprotein apheresis for the treatment of refractory hyperlipidemia.

The advent of treatment with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors has meant that, with a combination of diet and drug therapy, adequate control of serum cholesterol concentrations can be achieved in most patients with hypercholesterolemia. However, some patients, primarily those with familial hypercholesterolemia (FH), may require additional therapy to lower their cholesterol levels. In recent years, low-density lipoprotein (LDL) apheresis has emerged as an effective method of treatment in these patients. The criteria for commencement of LDL apheresis are LDL cholesterol levels of 500 mg/dL or higher for homozygous FH patients, 300 mg/dL or higher for heterozygous FH patients in whom medical therapy has failed, and 200 mg/dL or higher for heterozygous FH patients with documented coronary disease and in whom medical therapy has failed. In addition to cholesterol lowering in patients with FH, other indications for LDL apheresis are emerging. These include its use in the treatment of graft vascular disease in patients receiving cardiac transplants as well as in the treatment of certain glomerulonephritides. This review examines the role of LDL apheresis in the management of lipid disorders and the evidence available to support its use in clinical practice.

Blood Component Removal↗
PubMed2001

Effects of glutathione on chromium-induced DNA crosslinking and DNA polymerase arrest.

Hexavalent chromium (Cr (VI)) is reduced intracellularly to Cr (V), Cr (IV) and Cr (III) by ascorbate (Asc), cysteine and glutathione (GSH). These metabolites induce a spectrum of genomic DNA damage resulting in the inhibition of DNA replication. Our previous studies have shown that treatment of DNA with Cr (III) or Cr (VI) plus Asc results in the formation of DNA-Cr-DNA crosslinks (Cr-DDC) and guanine-specific arrests of both prokaryotic and mammalian DNA polymerases. GSH not only acts as a reductant of Cr (VI) but also becomes crosslinked to DNA by Cr, thus, the focus of the present study was to examine the role of GSH in Cr-induced DNA damage and polymerase arrests. Co-incubation of Cr (III) with plasmid DNA in the presence of GSH led to the crosslinking of GSH to DNA. GSH co-treatment with Cr (III) also led to a decrease in the degree of Cr-induced DNA interstrand crosslinks relative to Cr (III) alone, without affecting total Cr DNA binding. DNA polymerase arrests were observed following treatment of DNA with Cr (III) alone, but were markedly reduced when GSH was added to the reaction mixture. Pre-formed polymerase-arresting lesions (Cr-DDC) were not removed by subsequent addition of GSH. Treatment of DNA with Cr (VI), in the presence of GSH, resulted in crosslinking of GSH to DNA, but failed to produce detectable DNA interstrand crosslinks or polymerase arrests. The inhibitory effect of GSH on Cr-induced polymerase arrest was further confirmed in human genomic DNA using quantitative PCR (QPCR) analysis. Treatment of genomic DNA with Cr (III) resulted in a marked inhibition of the amplification of a 1.6 kb target fragment of the p53 gene by Taq polymerase. This was almost completely prevented by co-treatment with GSH and Cr (III). These results indicate that Cr-induced DNA interstrand crosslinks, and not DNA-Cr-GSH crosslinks, are the principal lesions responsible for blocking DNA replication. Moreover, the formation of DNA-Cr-GSH crosslinks may actually preclude the formation of the polymerase arresting lesions.

Binding Sites↗