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Biomedical subjects

B O'Connor

Publications and source records attributed to B O'Connor.

At least 19 recordsLinked to original sources
PubMed2001

Dose-ranging study of mometasone furoate dry powder inhaler in the treatment of moderate persistent asthma using fluticasone propionate as an active comparator.

BACKGROUND: Mometasone furoate (MF; Schering-Plough, Madison, NJ), is a glucocorticoid with high local potency and low potential systemic availability. OBJECTIVES: To compare the relative efficacy and safety of a new formulation of MF, coupled with a recently designed dry powder inhaler (DPI), in the treatment of patients with moderate persistent asthma. Fluticasone propionate administered by Diskhaler (FP Diskhaler, 250 microg twice a day; Glaxo Wellcome, Research Triangle Park, NC) was used as an active control. DESIGN: A randomized, parallel group, double-blind (for MF-DPI dosage), evaluator-blind (for MF-DPI vs FP) trial. SETTING: Sixty centers in 20 countries. PATIENTS: Seven hundred thirty-three patients with moderate persistent asthma on inhaled corticosteroid treatment. INTERVENTIONS: Discontinuation of previous inhaled corticosteroid and initiation of one of four study treatments: three doses of MF-DPI (100, 200, and 400 microg twice daily) and one of FP (250 microg twice daily >12 weeks). RESULTS: FEV1 (primary efficacy variable) was evaluated as the mean change from baseline to endpoint (last evaluable visit). All dosage groups showed improvement at endpoint. Only 400 microg twice daily of MF-DPI (+0.19 L) was statistically different from 100 microg twice daily of MF-DPI (+0.07 L; P = 0.02). MF-DPI (200 microg twice daily) and FP Diskhaler groups showed similar improvement (+0.16 L). Greater improvement in most secondary variables (forced expiratory flow between 25% and 75% of vital capacity, and morning and evening peak expiratory flows) also resulted from treatment with 200 or 400 microg twice daily of MF-DPI or with FP Diskhaler, compared with 100 microg twice daily of MF-DPI. Overall, a total daily 800-microg dose of MF-DPI conferred no significant additional benefit >400 microg of MF-DPI. The incidence of oral candidiasis was 1%, 7%, 10%, and 10% in the 100, 200, and 400 microg twice daily of MF-DPI and FP groups, respectively. CONCLUSIONS: A total daily dose of 400 microg of MF-DPI provides clinical benefit comparable to that observed with a total daily dose of 500 microg of FP Diskhaler.

Administration, Inhalation↗
PubMed2001

Hydrodynamic function of a biostable polyurethane flexible heart valve after six months in sheep.

Survival to six months for sheep with a non-biostable polyurethane mitral heart valve prosthesis has been reported previously, however, with surface degradation and accumulation of calcified fibrin/thrombus that impaired leaflet motion and compromised hydrodynamic function. Newly available biostable polyurethanes may overcome this problem. Six adult sheep with biostable polyurethane trileaflet heart valve prostheses of documented hydrodynamic performance, implanted in the mitral position, were allowed to survive for 6 months. Explanted valves were photographed, resubmitted to hydrodynamic function testing, and studied by light and electron microscopy. Explanted valves were structurally intact and differed little in appearance from their preimplant state. Hydrodynamic testing showed no deterioration in pressure gradient or energy losses compared with pre-implant values. Biostable polyurethanes demonstrated improved blood compatibility leaving leaflets flexible and valve function unimpaired. Biostable polyurethanes may thus improve prospects for prolonged function of synthetic heart valve prostheses.

Animals↗
PubMed2001

Multiple porcine circovirus 2-associated abortions and reproductive failure in a multisite swine production unit.

Porcine circovirus type 2 was detected in several stillborn and nonviable neonatal piglets presenting with chronic passive congestion, cardiac hypertrophy, and severe diffuse myocarditis. The presence of the virus in the heart and other tissues of affected piglets was confirmed by polymerase chain reaction, immunohistochemistry, and virus isolation techniques. Other reproductive losses and associated infectious agents in the herd are discussed.

Abortion, Veterinary↗
PubMed2001

Enhancing capacity for cardiovascular disease prevention: an overview of the British Columbia Heart Health Dissemination Research Project.

British Columbia (population 3.88 million) is located on the West Coast of Canada (Statistics Canada, 1996). Primary resource activities are the province's traditional sources of economic strength, but there is also a growing economy based on knowledge-intensive secondary manufacturing, high-technology, tourism, film and international business (Ministry of Employment and Investment, 2000). Approximately one-third of the government's total expenditures go to health care (BC Stats, 2000). In 1997, health care in BC was regionalized and responsibility for health services decentralized to 52 health authorities serving eighteen regions.

British Columbia↗
PubMed1999

Plasma lipids and lipoprotein reference values, and the prevalence of dyslipoproteinemia in Canadian adults. Canadian Heart Health Surveys Research Group.

OBJECTIVE: To report reference values for plasma lipids and lipoproteins in Canadian adults and the prevalence in the population of various levels of risk for coronary artery disease from dyslipoproteinemia. DESIGN, SETTING AND PARTICIPANTS: Population- based provincial heart health cross-sectional surveys in 10 provinces between 1986 and 1992 invited 29,855 men and women aged 18 to 74 years to participate. During a clinic visit after a home interview a blood sample was obtained following a fast of 8 h or more from 18,555 people. Plasma lipid levels were determined at the J Alick Little Lipid Research Laboratory, Toronto, with standardization of the Centers for Disease Control Lipid Standardization Program, Atlanta. OUTCOME MEASURES: Fasting plasma total cholesterol, triglyceride, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and non-HDL-C levels. MAIN RESULTS: Mean plasma total cholesterol, LDL-C, non-HDL-C and triglyceride levels increased with age in men to a peak at around age 54 years, while in women the increases were more gradual at a lower level until age 54 years, after which they increased appreciably eventually exceeding values for men. A high percentage of adults were at increased risk for coronary artery disease: 44% had elevated total cholesterol levels above 5.2 mmol/L; 14% had LDL-C levels above 4.1 mmol/L; 8% had HDL-C values below 0.9 mmol/L; and 14% had triglyceride levels above 2.3 mmol/L. Eleven per cent of adults had both total cholesterol level above 6.2 mmol/L and LDL-C level above 4.1 mmol/L. CONCLUSION: The high prevalence of Canadian adults at risk because of elevated plasma lipid levels strongly indicates the need for comprehensive public health programs to reduce plasma lipid levels in the population and the need to encourage physicians to treat those at high risk.

Adult↗
PubMed1999

Impact of different blood lipid evaluation and treatment guidelines on the proportion of Canadians identified and treated for elevated blood cholesterol. Canadian Heart Health Surveys Research Group.

OBJECTIVE: To report on the impact of different blood lipid evaluation and treatment guidelines on the proportion of Canadians identified and treated for high blood cholesterol. DESIGN, SETTING AND PARTICIPANTS: The Canadian Heart Health Surveys were carried out in Canada between 1986 and 1991. The data used in this study were from cross-sectional probability samples of adults aged 18 to 74 years, gathered in four provincial health surveys (Quebec, Alberta, Manitoba and Ontario) between 1989 and 1992, which obtained information on family history of heart disease. Data reported are for 7238 subjects fasting 8 h or more and providing a blood sample. All blood lipid analysis were done at the J Alick Little Lipid Research Laboratory, University of Toronto, which is standardized according to the National Heart, Lung, and Blood Institute, Centers for Disease Control (Atlanta) Lipid Standardization Program. OUTCOME MEASURES: With respect to the four guidelines examined--the Canadian Consensus Conference on Cholesterol (CCCC), 1987; the Toronto Working Group on Cholesterol Policy (TWG), 1990; the Canadian Task Force on the Periodic Health Examination (PHE), 1993; and the National Cholesterol Education Program (NCEP), 1993, in the United States--a comparison of the proportion of individuals in the population for whom a lipid profile was constructed, and who were prescribed a diet and drug therapy under different assumptions of success with dietary therapy for each guideline. MAIN RESULTS: Major differences were observed in the impact of the various guidelines with respect to the percentage of subjects who were tested, provided with a lipid profile, and eligible for diet and/or drug therapy. In general the percentages in each group were higher for the CCCC and the NCEP guidelines than for the PHE and TWG guidelines. CONCLUSION: The divergent results obtained from the application of the various guidelines are cause for concern and explain in part the confusion that surrounds the topic of blood cholesterol in public health and clinical contexts. Public health policy in the area of cardiovascular disease prevention would benefit from explicit consideration of various types of criteria for formulation of identification and treatment guidelines.

Adolescent↗
PubMed1999

DMEPOS (Durable Medical Equipment, Prosthetics, Orthotics and Supply) model compliance program: does the OIG have it right?

Companies of every size and structure can and should develop an ethical culture of compliance in which prevention, detection, and resolution of abusive practices are "core values." OIG has released a draft Compliance Guideline that includes a seven-element plan to which all agencies must comply. Yet, compliance programs simply are not a "one-size-fits-all" item.

Communication↗
PubMed1998

Pyroglutamyl peptidase: an overview of the three known enzymatic forms.

Pyroglutamyl peptidase can be classified as an omega peptidase which hydrolytically removes the amino terminal pyroglutamate (pGlu) residue from specific pyroglutamyl substrates. To date, three distinct forms of this enzyme have been identified in mammalian tissues. Type I is typically a cytosolic, cysteine peptidase displaying a broad pyroglutamyl substrate specificity and low molecular mass. Type II has been shown to be a membrane anchored metalloenzyme of high molecular mass with a narrow substrate specificity restricted to the hypothalamic releasing factor, thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH2). A third pyroglutamyl peptidase activity has also been observed in mammalian serum which displays biochemical characteristics remarkably similar to those of tissue Type II, namely a high molecular mass, sensitivity to metal chelating agents, and a narrow substrate specificity also restricted to TRH. This serum activity has subsequently been designated 'thyroliberinase'. This review surveys the biochemical, enzymatic, and structural properties of this interesting and unique class of peptidases. It also addresses the putative physiological roles which have been ascribed to these enzymes. Pyroglutamyl peptidase activities isolated and characterized from bacterial sources are also reviewed and compared with their mammalian counterparts.

Aminopeptidases↗
PubMed1998

A study of a highly specific pyroglutamyl aminopeptidase type-II from the membrane fraction of bovine brain.

Pyroglutamyl aminopeptidase type-II is reported to be a highly specific, membrane-bound neuropeptidase, which has the ability to hydrolytically remove the L-pyroglutamyl residue (pGlu) from the N-terminus of thyrotropin releasing hormone (TRH, pGlu-His-Pro-NH2) and closely related tripeptides or tripeptide amides. The primary aim of this study was to purify this enzyme from bovine brain and to compare its characteristics with those previously reported. Following solubilization from the membrane fraction by limited proteolysis with trypsin, the enzyme was purified approximately 3000-fold with a 24% recovery of activity. A native molecular mass of 214,000 Da was determined for the purified enzyme by gel-filtration chromatography. A pH optimum of 6.8-7.6 was observed for the enzyme, with rapid inactivation occurring below pH 4.0 and above pH 9.2. Optimal enzyme activity was observed at 45 degrees C. On the basis of its inhibition, in a time-dependent manner, by metal complexing agents and its subsequent reactivation in the presence of metal ions, the enzyme was identified as a metallopeptidase. Substrate specificity studies revealed that, with the exception of pGlu-Phe-Pro-NH2, pGlu-7-amino-4-methyl-coumarin and pGlu-beta-naphthylamide, the purified enzyme removes N-terminal pGlu from only tri- and tetrapeptides with a histidine residue in the penultimate position. A number of N-terminal pyroglutamyl peptides of varying length were shown to competitively inhibit the enzyme. Of these, luteinizing hormone releasing hormone (LHRH) and LHRH 1-5, although not substrates for the enzyme, were found to be potent inhibitors, with Ki values of 8 and 11 microM, respectively. The study shows that while bovine brain PAPII shares many of the characteristics of PAPII from other mammalian tissues, its substrate specificity is not as narrow as previously reported.

Aminopeptidases↗
PubMed1998

A study of prolyl endopeptidase in bovine serum and its relevance to the tissue enzyme.

Prolyl endopeptidase (PE) belongs to a group of enzymes that specifically recognise the imino acid proline. The characterisation of bovine serum PE was undertaken so that its relationship to its tissue counterparts could be considered. Using various chromatographic methods, PE was partially purified from bovine serum. This preparation was deemed to be enzymatically pure, based on its failure to hydrolyse a wide range of fluorimetric substrates. A native molecular mass of 69.7 kDa was estimated for the enzyme. PE was optimally active at pH 8.0-8.5, demonstrated a preference for phosphate buffer and remained stable over a pH range of 5.0-9.0. A narrowly focused optimal assay temperature of 37 degrees C was evident. Functional reagent studies indicated that this enzyme was a serine protease with a cysteine residue located near or at the active site. The enzyme was also sensitive to heavy metal inhibition. Substrate specificity investigations revealed that the bioactive peptides angiotensin II, bradykinin, luliberin and substance P were hydrolysed by the enzyme preparation, but lower specificities were evident towards these peptides in comparison with the enzyme's tissue counterparts. Specific inhibitor studies, using a range of compounds previously untested against a single PE source, indicated that alpha-ketobenzothiazole was the most effective PE inhibitor, with an IC50 value of 41 pM. In conclusion, the results presented in this paper indicate that bovine serum PE shares many of the characteristics associated with its tissue counterparts, with the exception of its specificity towards certain bioactive peptides.

Angiotensin II↗
PubMed1998

Remifentanil in combination with propofol for spontaneous ventilation anaesthesia.

We have investigated the effect of four doses of remifentanil on the incidence of respiratory depression and somatic response at incision. Remifentanil was administered as a loading dose of 0.125, 0.25, 0.375 or 0.5 microgram kg-1 and at a maintenance infusion rate of 0.025, 0.05, 0.075 or 0.1 microgram kg-1 min-1, respectively, with an infusion of propofol 6 mg kg-1 h-1. Responses occurred in 88% of patients with remifentanil 0.025 microgram kg-1 min-1 compared with 30-40% in the other groups. Respiratory depression after incision increased from 6% with remifentanil 0.025 microgram kg-1 min-1 to 73% with 0.1 microgram kg-1 min-1. Increases in propofol infusion rate to 7.2-8.4 mg kg-1 h-1 produced adequate maintenance of anaesthesia. Reductions in remifentanil doses to 0.025-0.05 microgram kg-1 min-1 resulted in adequate respiration at the end of surgery in 88% of patients. Maintenance infusions of the two drugs for spontaneous ventilation are likely to be in these ranges. However, the ideal loading doses and infusion rates for induction remain to be established.

Adolescent↗
PubMed1998

Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-1alpha, granulocyte-macrophage colony-stimulating factor, and interferon-gamma release from alveolar macrophages in asthma.

We determined the effect of inhaled corticosteroid, budesonide, on the release of the anti-inflammatory cytokine, interleukin-10 (IL-10), and of pro-inflammatory cytokines, macrophage inflammatory protein-1alpha (MIP-1alpha), interferon-gamma (IFN-gamma), and granulocyte-macrophage colony-stimulating factor (GM-CSF), from blood monocytes and alveolar macrophages of mild asthmatic subjects in a double-blind, cross-over, placebo-controlled study. Budesonide reduced bronchial hyperresponsiveness and improved baseline FEV1. Alveolar macrophages were obtained by bronchoalveolar lavage performed at the end of each treatment phase. IL-10 from blood monocytes was not altered, but both IL-10 mRNA and protein expression from alveolar macrophages stimulated by lipopolysaccharide and IL-1beta were increased after corticosteroid therapy. By contrast, alveolar macrophages released significantly less MIP-1alpha, IFN-gamma, and GM-CSF after steroid treatment. In comparison to alveolar macrophages from normal nonasthmatic volunteers, those from asthmatic patients released more MIP-1alpha, IFN-gamma, and GM-CSF but lower amounts of IL-10 particularly at baseline and after IL-1beta stimulation. The ability of steroids to inhibit pro-inflammatory cytokines but to enhance the anti-inflammatory cytokine such as IL-10 may contribute to their beneficial actions in asthma. Asthma is characterized by alveolar macrophages exhibiting both an enhanced capacity to release pro-inflammatory cytokines and a reduced capacity to produce IL-10.

Administration, Inhalation↗
PubMed1997

Proline specific peptidases.

Proline is unique among the 20 amino acids due to its cyclic structure. This specific conformation imposes many restrictions on the structural aspects of peptides and proteins and confers particular biological properties upon a wide range of physiologically important biomolecules. In order to adequately deal with such peptides, nature has developed a group of enzymes that recognise this residue specifically. These peptidases cover practically all situations where a proline residue might occur in a potential substrate. In this paper we endeavour to discuss these enzymes, particularly those responsible for peptide or protein hydrolysis at proline sites. We have detailed their discovery, biochemical attributes and substrate specificities and have provided information as to the methodology used to detect and manipulate their activities. We have also described the roles, or potential roles that these enzymes may play physiologically and the consequences of their dysfunction in varied disease states.

Amino Acid Sequence↗
PubMed1997

The development of two fluorimetric assays for the determination of pyroglutamyl aminopeptidase type-II activity.

Two fluorimetric assays for the determination of pyroglutamyl aminopeptidase type-II activity have been developed. The assays are based on hydrolysis of the quenched-fluorimetric substrate <Glu-His-Pro-7-amino-4-methylcoumarin. Following the removal of the N-terminal <Glu by pyroglutamyl aminopeptidase type-II, liberation of 7-amino-4-methylcoumarin from the metabolite His-Pro-7-amino-4-methylcoumarin is catalyzed by one of two methods: (i) the addition of partially purified bovine serum dipeptidyl aminopeptidase type-IV or (ii) by incubating the reaction mixture for up to 2 h at 80 degrees C, thus promoting the nonenzymatic cyclization of His-Pro-7-amino-4-methylcoumarin to cyclo His-Pro and free 7-amino-4-methylcoumarin. Pyroglutamyl aminopeptidase type-II from bovine brain is used to establish appropriate assay conditions. These fluorimetric assays offer expeditious alternatives to the existing radiolabeled thyrotropin-releasing hormone assays for the determination of PAPII activity.

Aminopeptidases↗
PubMed1997

Intracellular location of thymidylate synthase and its state of phosphorylation.

Thymidylate synthase (TS), an enzyme that is essential for DNA synthesis, was found to be associated mainly with the nucleolar region of H35 rat hepatoma cells, as determined both by immunogold electron microscopy and by autoradiography. In the latter case, the location of TS was established through the use of [6-3H]5-fluorodeoxyuridine, which forms a tight ternary complex of TS with 5-fluorodeoxyuridylate (FdUMP) and 5, 10-methylenetetrahydrofolylpolyglutamate within the cell. However, with H35 cells containing 50-100-fold greater amounts of TS than unmodified H35 cells, the enzyme, although still in the nucleus, was located primarily in the cytoplasm as shown by autoradiography and immunohistochemistry. In addition, TS was also present in mitochondrial extracts of both cell lines, as determined by enzyme activity measurements and by ternary complex formation with [32P]FdUMP and 5,10-methylenetetrahydrofolate. Another unique observation is that the enzyme appears to be a phosphoprotein, similar to that found for other proteins associated with cell division and signal transduction. The significance of these findings relative to the role of TS in cell division remains to be determined, but suggest that this enzyme's contribution to the cell cycle may be more complex than believed previously.

Animals↗