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Biomedical subjects

M O'Rourke

Publications and source records attributed to M O'Rourke.

At least 19 recordsLinked to original sources
PubMed2004

Alpha-2 adrenergic receptor development in rat CNS: an autoradiographic study.

During development norepinephrine plays a role in determining the morphologic organization of the CNS and the density and future responsiveness of adrenergic receptors. alpha-2 Adrenergic receptors, one of three adrenergic receptor types, regulate important adult CNS functions and may have a distinct role during development. We examined alpha-2 receptor distribution and density in the rat brain at postnatal days 1, 5, 10, 15, 21, 28 and in adults using the antagonist [(3)H]RX821002 for autoradiography. Binding kinetics and pharmacology for alpha-2 adrenergic receptors were the same in adults and neonates. There was an overall increase in alpha-2 receptor levels during postnatal development with great variability in pattern and timing of receptor density changes among brain regions. Three major patterns were apparent. First, in many regions receptor density increased during postnatal development, generally reaching adult levels around postnatal day 15. Within this group there was variability in timing between regions and there were several regions with receptor densities higher than adult levels during the postnatal period. Second, there were regions with very high levels of receptors at birth and little or no change in density during the postnatal period. Third, some regions demonstrated decreasing or transient expression of alpha-2 adrenergic receptors in the course of postnatal development, including white matter regions, cerebellum and many brainstem nuclei, suggesting specific roles for alpha-2 receptors during development. This study investigates the development of alpha-2 adrenergic receptors in the rat CNS. It demonstrates there is region-specific regulation of alpha-2 receptor development and identifies brain regions where these receptors may play a specific and critical role in the regulation normal development.

Animals↗
PubMed2003

Essential Bacillus subtilis genes.

To estimate the minimal gene set required to sustain bacterial life in nutritious conditions, we carried out a systematic inactivation of Bacillus subtilis genes. Among approximately 4,100 genes of the organism, only 192 were shown to be indispensable by this or previous work. Another 79 genes were predicted to be essential. The vast majority of essential genes were categorized in relatively few domains of cell metabolism, with about half involved in information processing, one-fifth involved in the synthesis of cell envelope and the determination of cell shape and division, and one-tenth related to cell energetics. Only 4% of essential genes encode unknown functions. Most essential genes are present throughout a wide range of Bacteria, and almost 70% can also be found in Archaea and Eucarya. However, essential genes related to cell envelope, shape, division, and respiration tend to be lost from bacteria with small genomes. Unexpectedly, most genes involved in the Embden-Meyerhof-Parnas pathway are essential. Identification of unknown and unexpected essential genes opens research avenues to better understanding of processes that sustain bacterial life.

Bacillus subtilis↗
PubMed2001

Pulse wave analysis in the assessment of patients with left ventricular assist device.

Central aortic pressure determines perfusion of vital organs, and its precise determination is particularly important in low-output syndromes. Because peripheral pressure values are not equal to the corresponding pressures in the aorta, we used a validated system that employs the principle of applanation tonometry for non-invasive recording of radial arterial pulse and determination of central aortic pressure waveform in patients who underwent implantation of left ventricular assist device. We observed significant improvement after assist device implantation; however, a discrepancy between peripheral and central pressure values was evident both before and after implantation. This non-invasive technique may prove particularly useful in repeat evaluation of patients in long-term follow-up and may provide valuable insights for coupling between the assist device and the vascular system.

Aorta↗
PubMed2001

Mongolia's system-wide health reforms: lessons for other developing countries.

Mongolia is a poor country that lost 30% of its GDP when the Soviet Bloc collapsed in 1990. Its health care system had the typical weaknesses of centrally planned economies--quantity rather than quality, excessive medical specialisation, dominance of the hospital sector, weak policy and management capabilities, little community participation in decision making, and so on. This paper describes Mongolia's attempts to resolve these problems through a radical program of reform that began in 1998. There have been significant successes in spite of almost overwhelming difficulties, and this may be a consequence of the strong sense of community that has been present for five hundred years and re-emerged intact at the end of 70 years of Soviet dominance. We argue, however, that good design and skillful implementation of the reform program may have made a contribution. Its notable features have included the use of a comprehensive and integrated model rather than piecemeal reform, the generation of political support for change through social marketing campaigns, a team approach using local and international experts, and co-ordination of international donor activities. Some of these features may be relevant to other transitional and developing countries.

Developing Countries↗
PubMed2001

Determining the efficacy of glucosamine and chondroitin for osteoarthritis.

Glucosamine sulfate and chondroitin sulfate are being used by many patients for the treatment of osteoarthritis. Despite a number of studies supporting efficacy of these agents for palliation of joint pain in patients with osteoarthritis, the American College of Rheumatology Subcommittee on Osteoarthritis believes that it is too early to issue recommendations for use. Currently, the National Institute of Arthritis and Musculoskeletal and Skin Diseases in collaboration with the National Center for Complementary and Alternative Medicine have begun a pivotal study to thoroughly evaluate these agents.

Chondroitin↗
PubMed2001

A new articulated elbow external fixation technique for difficult elbow trauma.

Articulated external fixation of the elbow allows aggressive elbow range of motion while protecting the joint and periarticular structures from excessive forces. A technique for aligning a monolateral-hinged fixator to the rotational axis of the elbow without the use of an invasive axis pin has been developed. Thirteen patients with acute and chronic post-traumatic elbow problems were treated over a four year period with this technique. An average arc of motion of 84 degrees was achieved in the frame. Frames were removed at an average of 7.6 weeks. Complications were confined to pin tract infections. In 11 patients followed for an average of 35 weeks the average arc of motion was 81 degrees. Further experience is required to determine the role of this device and to identify which elbows achieve the most benefit compared to conventional techniques.

Adult↗
PubMed2000

The effect of dose and route of oestradiol benzoate administration on plasma concentrations of oestradiol and FSH in long-term ovariectomised heifers.

Oestradiol (E(2)) suppresses FSH and affects follicle wave dynamics in cattle. However, neither the optimum dose of ODB required to suppress FSH nor the effect of route of ODB administration on blood concentrations of E(2) are known; hence, the aim of this experiment was to answer these questions. Ovariectomised heifers received Progesterone Releasing Intravaginal Device (PRID) for 7 days, and 4 days later heifers received one of eight ODB treatments at second PRID insertion as follows; (1) 0.0 mg (Control; n=3), (2) 0.5 mg (n=4), (3) 1.0 mg (n=4), (4) 2.5 mg (n=6), (5) 5.0 mg (n=4), (6) 10. 0 mg (n=4), (7) 5.0 mg (n=4), and (8) 10.0 mg (n=5). For treatments 2-6 inclusive, ODB was administered intramuscularly in oil, while for treatments 7 and 8, the ODB in powder form was administered topically in the vagina by gelatine capsule attached to the PRID. Blood samples were collected every 6 h for the first 48 h, every 12 h for the next 48 h, and twice daily for a further 6 days. The interval from ODB administration to peak E(2) concentration was similar (P0.05) for treatments 2-6 where ODB was administered intramuscularly (mean 13.4+/-1.24 h), and was longer (P<0.05) for the intravaginal capsule treatments (mean 25.5+/-2.84 h). Plasma concentrations of E(2) increased with increasing intramuscular dose of ODB injected, (plasma E(2)=-0.237+16.109 (dose)-0.74 (dose)(2), R(2)=0.75; P<0.05). Peak plasma concentrations of E(2) following the 5- and 10-mg capsules were similar to each other and to those following the 0.5-mg injection (P0.05), but were lower than concentrations obtained following injection of 1.0-5.0 mg (P<0.05). Across all treatments, both the maximum percentage decline in FSH and the interval to FSH nadir were related to the peak plasma concentrations of E(2) (maximum % decline in FSH=11.17+1.564 (peak E(2))-0.009 (peak E(2))(2), R(2)=0.75; P<0.01), (hours to FSH nadir=10.628+1.486(hours to peak E(2))-0.0282(hours to peak E(2))(2), R(2)=0.22; P<0.05). Concentrations of FSH increased as E(2) declined from its peak value, irrespective of maximum value achieved. It was concluded that the intramuscular administration of ODB in oil to ovariectomised heifers given a PRID results in higher plasma concentrations of E(2) and causes a greater reduction in FSH than administration topically by intravaginal gelatine capsule. E(2) transiently suppresses FSH in ovariectomised heifers, and the magnitude of the suppression is dose-dependent; however FSH concentrations begin to increase 1-2 days after ODB administration while concentrations of E(2) were declining but still high.

Animals↗
PubMed2000

Diastolic pressure, systolic pressure, or pulse pressure?

Diastolic pressure, systolic pressure, and pulse pressure have all been assigned the role of the best predictor of cardiovascular events during the 20th century. At the dawn of the new millennium, concepts that draw attention to vascular mechanics reconcile the seemingly conflicting results of epidemiologic studies, better define the hypertensive patient, evaluate more accurately the risk and set its markers, and ultimately optimize treatment through a logical approach that aims at the mechanism and not at the manifestation. Pulse wave analysis and measurement of arterial stiffness are valuable tools in the assessment and management of the hypertensive patient.

Age Factors↗
PubMed2000

A multicenter phase II study of a five-day regimen of oral 5-fluorouracil plus eniluracil with or without leucovorin in patients with metastatic colorectal cancer.

PURPOSE: To evaluate the safety and efficacy of a five-day regimen of oral 5-fluorouracil (5-FU) plus eniluracil (776C85) in patients with metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Seventy-five patients with metastatic CRC that was previously untreated or refractory to 5-FU-leucovorin (LV) were enrolled and divided into two strata based upon their treatment history. Twenty-four had not previously received chemotherapy or had received adjuvant chemotherapy that ended > 6 months prior to enrollment on study (previously untreated stratum). Fifty-one patients had disease refractory to intravenous (i.v.) 5-FU-LV (previously treated stratum). All patients received seven consecutive daily doses of eniluracil (20 mg/day) with once daily oral 5-FU given on days 2-6, repeated every four weeks. One-half of the patients in each stratum also received 50 mg/day oral LV on days 2-6. The 5-FU dose was 25 mg/m2 when administered without LV and 20 mg/m2 when administered with LV. RESULTS: Partial response (PR) was noted in 2 of 12 patients receiving eniluracil-5-FU and in 3 of 12 patients receiving eniluracil-5-FU-LV in the previously untreated stratum. No responses were observed in the refractory disease stratum, however, 15 patients (30%) demonstrated stable disease over 2-18+ courses of therapy. Non-hematologic toxicities were mild; only 7% of patients experienced grade 3 diarrhea. Myelosuppression was frequent and dose limiting. Neutropenic sepsis was reported in 13.5% of patients. CONCLUSIONS: Eniluracil with 5-FU administered orally with or without LV on a five-day schedule is active and well tolerated when given as primary therapy to patients with metastatic CRC.

Administration, Oral↗
PubMed2000

Modification of vascular tone using iNOS under the control of a radiation-inducible promoter.

It may be therapeutically advantageous to alter tumour blood supply specifically. Nitric oxide is a potent vasodilator which is produced in many tissues by the enzyme nitric oxide synthase (NOS). We have transfected cDNA for the inducible isoform of this enzyme (iNOS), under the control of the radiation-inducible promoter WAF1. The activity of the promoter was initially assessed using green fluorescent protein (GFP) in both endothelial cells and rat tail artery segments. Induction of protein expression by 9.5- and 4.5-fold respectively, was observed after a radiation dose of 4 Gy. Artery sections were then transfected with the WAF1/iNOS construct; this gave five-fold induction of iNOS protein after a dose of 4 Gy. The transfected artery was also tested functionally for relaxation, indicative of NO production. One hour after exposure to 4 Gy there was a significant (65%) relaxation of artery segments that had been preconstricted with phenylephrine. This could be partially reversed by the NOS inhibitor nitro-L-arginine. This study demonstrates that we can regulate vascular tone using an X-ray inducible promoter.

Animals↗
PubMed2000

Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.

PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life. PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m(2) (49 patients) or 75 mg/m(2) (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks. RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7. 1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P <.001), as was median survival (7.0 v 4.6 months; log-rank test, P =.047). The difference was more significant for docetaxel 75 mg/m(2) patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P =.010; 1-year survival, 37% v 11%; chi(2) test, P =.003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m(2), three of whom died, and in one patient treated with docetaxel 75 mg/m(2). Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups. CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m(2), the benefits of docetaxel therapy outweigh the risks.

Adult↗
PubMed1999

Improvements in clinical benefit with vinorelbine in the treatment of hormone-refractory prostate cancer: a phase II trial.

BACKGROUND: Clinical activity is difficult to assess by traditional response endpoints in patients with advanced prostate cancer. We used clinical benefit response to assess the activity of vinorelbine (Navelbine) in patients with hormone-refractory prostate cancer. PATIENTS AND METHODS: Forty-nine men with hormone-refractory prostate cancer received vinorelbine weekly for eight weeks followed by every-other-week dosing. Clinical benefit response was defined by improvement in 1 of the following categories for at least 12 weeks and stable response or better in the other 2: pain index (analgesic consumption and pain intensity), Karnofsky performance status, and tumor status. RESULTS: Of 37 evaluable patients, 14 (39%) achieved clinical benefit for a median duration of 6 months (range 3-24 months). Toxicities consisted primarily of brief neutropenia and mild nausea. CONCLUSION: These findings indicate that vinorelbine is well tolerated in men with hormone-refractory prostate cancer and produces durable clinical benefit as defined by improvement in pain index and performance status.

Adenocarcinoma↗
PubMed1999

Vinorelbine as first-line chemotherapy for advanced breast cancer in women 60 years of age or older.

BACKGROUND: Older patients with advanced breast cancer are less likely to receive chemotherapy than younger patients. Vinorelbine is an attractive alternative in this setting because of its clinical activity and low frequency of side effects. This multicenter, phase II trial was designed to assess the safety and efficacy of intravenous vinorelbine as first-line therapy in women > or = 60 years old. PATIENTS AND METHODS: Fifty-six women (median age, 72 years; range 60-84 years), with measurable advanced breast cancer and no prior chemotherapy for metastatic disease, were enrolled and included in the analysis. Vinorelbine 30 mg/m2 was administered weekly for 13 weeks and then every two weeks until development of progressive disease; doses were reduced or delayed to manage toxicity. RESULTS: The objective response rate was 38% (95% confidence interval (95% CI): 24%-51%); median duration of response, nine months; median time to disease progression in all patients, six months. The major dose-limiting toxicity was hematologic, which led to a median dose intensity of 20.6 mg/m2/week. Grade 3-4 nonhematologic toxicity consisted of asthenia (7%); nausea and generalized pain (5%); vomiting, chest pain, abdominal pain, and elevated AST (4%); fever, diarrhea, constipation, and injection site reaction (2%). Neurotoxicity and alopecia were grade 1-2 and relatively infrequent. CONCLUSIONS: Vinorelbine offers a promising alternative for the management of advanced breast cancer in elderly patients who are concerned about the subjective side effects of cytotoxic chemotherapy. The dose-limiting toxicity is neutropenia, which is readily managed with dose adjustment. Nonhematologic toxicity, including gastrointestinal side effects, is minimal. Randomized studies are warranted to compare the activity of vinorelbine with that of other regimens in elderly patients.

Aged↗