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Biomedical subjects

M O'Rourke

Publications and source records attributed to M O'Rourke.

At least 37 records · Page 2Linked to original sources
PubMed1999

Privatising general practice in Mongolia: a trial of needs-adjusted capitation.

Mongolia's family doctors have long been salaried government employees. The crisis caused by the break-up of the Soviet Bloc required the government to seek a balance between command and market economies, and this influenced the decision to introduce capitated private practice for family doctor services on a trial basis. This article explains why and how a risk-adjusted capitation model was developed by a blend of empirical analysis and expert judgement, which comprises ten classes of clients defined by age-sex and poverty groupings. Payment relativities across the classes were set in proportion to a desirable (or target) number of contacts per year. Separate processes were used to set the targets for patient-initiated and active (health promotion and illness prevention) contacts. The model is intended to lead to greater equity of service access and provision. It should also encourage a greater concern for health outcomes, sensitivity to clients' views, and operational efficiency.

Age Factors↗
PubMed1999

Tumor metastasis biopsy as a surrogate marker of response to melanoma immunotherapy.

In patients undergoing immunotherapy for metastatic melanoma, the clinical response in immunotherapeutic trials may be partial or difficult to detect. Tumor metastasis biopsy allows direct characterisation of an anti-tumor immunological response. During a phase I/II trial of granulocyte macrophage colony stimulating factor (GM-CSF) transduced autologous melanoma immunotherapy, the cellular response was examined by immunohistochemical analysis in a limited number of tumor biopsies taken from patients who either responded or progressed. Clinical response was associated with tumor infiltration by CD4+ and CD8+ T-cells, macrophages and differentiated dendritic cells (DC), and expression of HLA-DR by the tumor cells. This tumor infiltration was associated with increased melanoma-specific peripheral blood precursor cytotoxic T-lymphocyte (pCTL) and the ability to obtain tumor-infiltrating lymphocytes in vitro. In contrast, progression or a lack of clinical response was associated with a lack of T-cell and DC infiltration into the tumor tissue in all such biopsies. Macrophages and eosinophils infiltrated these tumors, while T-cells and DC were present at some distance from the tumor. These preliminary data strongly suggest that the location and extent of T-cell and DC infiltration, as well as the expression of HLA-DR by tumor cells are associated with a clinical response in this form of melanoma immunotherapy.

Adult↗
PubMed1999

Regulation of follicle waves to maximize fertility in cattle.

Cattle have recurrent follicular waves every 7-10 days in most physiological situations; an FSH increase is associated with emergence of the wave and LH pulse frequency determines the fate of the dominant follicle. To control oestrus with hormones it is necessary to ensure that either induced corpus luteum regression or the termination of a progestogen treatment coincides with the selection of the dominant follicle during the wave, to give a precise onset of oestrus and high fertility. The exogenous administration of progesterone or progestagen blocks the normal turnover of the dominant follicle once the corpus luteum regresses. Thus, the effects of duration of dominance of the preovulatory follicle on onset of oestrus and fertility were examined. The variation in onset of oestrus was reduced but occurred 5-9 h later after 4 versus 8 days of dominance; pregnancy rate was also affected with dominance periods of 2-4, 4-8 and > 10 days resulting in 0, 10-15% or 20-50% reduction in pregnancy rates, respectively. The necessity for short duration of dominance of the preovulatory follicle means that to ensure high fertility the follicular wave needs to be regulated when using hormones to control oestrus. Two approaches were examined, namely the use of GnRH or oestradiol at time of progesterone intravaginal releasing device insertion. The effect of 250 micrograms of synthetic GnRH on the fate of an existing follicle wave was to ovulate the dominant follicle (20/20 cows) and a new wave emerged 1.6 +/- 0.3 days later; however, there was no effect of GnRH on the wave if administered before dominant follicle selection. The effect of oestradiol concentrations on suppression of FSH in ovariectomized heifers showed that increasing oestradiol to 10-15 pg ml-1 caused a 37 +/- 6.9% decrease in FSH for 24 h, with a subsequent increase to pretreatment values by 57 +/- 13 h. In cyclic heifers, increasing oestradiol to > 10 pg ml-1 in conjunction with progesterone treatment at emergence of the first wave of the cycle affected the current follicle wave by either preventing dominant follicle selection or decreasing diameter of the dominant follicle, without consistently affecting the interval to new wave emergence. Increase of oestradiol after dominance, however, delayed new wave emergence by 2-5 days. A better understanding of the hormonal control of follicle waves will lead to development of improved hormonal regimens to control oestrus sufficiently to give high pregnancy rates to a single AI without recourse to detection of oestrus.

Animals↗
PubMed1998

Effects of a high-cholesterol diet on vascular and endothelial function in rat aorta.

We have examined the effects of high cholesterol (1%) or normal diet for 8 weeks on vascular and endothelial responsiveness of rat aorta. The cholesterol diet produced a small but significant elevation of plasma cholesterol levels (vehicle: 0.95 +/- 0.13 mmol/l, n = 11; cholesterol fed; 1.40 +/- o.12 mmol/1, n = 14; p < 0.05). There were significant differences between control and high cholesterol groups in the contractile response to noradrenaline in rat aortic rings, both in terms of maximum response and potency. Both the potency of noradrenaline (NA) (pD2 values; vehicle diet: 7.84 +/- 0.08; cholesterol diet: 8.27 +/- 0.09; p < 0.01) and the maximum response (vehicle diet: 0.78 +/- 0.05 g; cholesterol diet: 0.95 +/- 0.06 g; p < 0.05) were significantly greater in the high-cholesterol group. There were no significant differences between control and high cholesterol groups in endothelium-independent relaxations to sodium nitroprusside (SNP). When responses were correlated with plasma cholesterol levels, there was a significant negative correlation with maximum endothelium-dependent relaxation to ACh (r = 0.53, n = 16, p < 0.05), so that the maximum relaxation decreased with increasing plasma levels of cholesterol. There were no significant correlations between cholesterol levels and endothelium-independent relaxation to SNP or between cholesterol levels and vascular contractions to NA. In conclusion, cholesterol-fed normal Wistar rats show functional changes in vascular responsiveness even with a relatively small elevation of plasma cholesterol levels.

Animals↗
PubMed1997

Further investigation of the alpha-adrenoceptor-mediated actions of chloroethylclonidine in rat aorta.

We have investigated the interaction between chloroethylclonidine and alpha-adrenoceptors in rat aorta. Chloroethylclonidine has two actions on rat aorta: reduction of the contraction to low concentrations of noradrenaline by alpha1-adrenoceptor antagonism and irreversible partial agonism in combination with high concentrations of noradrenaline. The former antagonist action was found to be more marked in vessels from immature rats (1 month). We have examined further the latter agonist actions in adult rats (3 month). In the absence of chloroethylclonidine, exposure to phenoxybenzamine (10 microM for 15 min) virtually abolished contractions to subsequent noradrenaline. However, when tissues were exposed to chloroethylclonidine (100 microM) for 30 min prior to exposure to phenoxybenzamine, a large contraction was produced by subsequent noradrenaline. Receptor protection with noradrenaline or the alpha2-adrenoceptor antagonists yohimbine or methoxy-idazoxan (all 10 microM), but not the alpha1-adrenoceptor antagonist prazosin (10 microM), significantly reduced the ability of chloroethylclonidine to prevent the actions of phenoxybenzamine against noradrenaline. In ligand binding studies, pre-exposure to chloroethylclonidine (100 microM) for 30 min significantly reduced the maximum binding of [3H]prazosin (Bmax) to alpha1B-adrenoceptors in rat spleen membranes to 21.4 +/- 10.2% (n = 5) and the maximum binding of [3H]yohimbine (Bmax) to alpha2D-adrenoceptors in rat submandibular gland membranes to 34.8 +/- 6.3% (n = 4), as compared to pre-exposure to vehicle. These results suggest that chloroethylclonidine interacts irreversibly with alpha2-adrenoceptors in rat aorta to make contractions to subsequent noradrenaline resistant to alpha-adrenoceptor blockade. Chloroethylclonidine appears to act as a silent irreversible agonist (i.e., an agonist which persists following multiple washout but only produces effects in combination with a classical agonist).

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1997

Cerebral blood flow regulation in neonatal rabbits is altered by chronic cocaine administration.

Maternal cocaine abuse has several deleterious effects in the newborn, including perinatal asphyxia, hypoxia, and hypercapnia. We hypothesized that chronic cocaine exposure during development may alter cerebral blood flow (CBF) regulation. We studied 16 neonatal rabbits that had received cocaine (20 mg/kg, i.p. b.i.d.) or saline since birth. Changes in CBF were measured by laser doppler flowmetry before (baseline), and during hypercapnia (FiCO2 = 7.5%), hypoxia (FiO2 = 12%), and asphyxia (apnea for 1 min). During hypercapnia, CBF increased less in cocaine than in control animals (28 +/- 3% vs. 69 +/- 10%, P < 0.05). During hypoxia, CBF increased similarly in both groups. During reventilation after asphyxia, CBF increased more in cocaine than in control animals (391 +/- 52% vs. 225 +/- 43%, P < 0.05). Chronic cocaine exposure during brain development appears to alter CBF regulation to hypercapnia and asphyxia, which may put the drug exposed newborn at risk for neurologic injury around birth.

Animals↗
PubMed1997

The alpha-adrenoceptor-mediated actions of chloroethylclonidine.

1. Chloroethylclonidine (CEC) has an affinity for all 6 subtypes of alpha-adrenoceptor, but binds irreversibly particularly to alpha 1B-, alpha 1D-, alpha 2C-, and alpha 2A/D-adrenoceptors. 2. Functionally, CEC behaves as an irreversible alpha 1-adrenoceptor antagonist, reducing the maximum response to noradrenaline (NA), and shows subtype selectivity in that alpha 1A-adrenoceptors are relatively insensitive to CEC. CEC also behaves as an irreversible alpha 2-adrenoceptor agonist, both prejunctionally in the rat vas deferens and postjunctionally in the dog saphenous vein. 3. In the rat aorta, CEC does not produce direct contractions, but following exposure to CEC concentrations of NA of 10 microM and above produce contractions resistant to alpha 1- and alpha 2-adrenoceptor blockade. We have investigated this phenomenon in detail. 4. Receptor protection experiments were carried out in the rat aorta, in which the protecting agent was present prior to and during exposure to CEC. The component of the contraction to NA resistant to alpha-blockade was still present following receptor protection with the alpha 1-adrenoceptor antagonist prazosin, but absent following receptor protection with NA and reduced following receptor protection with alpha 2-adrenoceptor antagonists. The resistant response may represent an irreversible agonist interaction between CEC, NA, and normally silent alpha 2-adrenoceptors, that cannot be affected by subsequent competitive antagonism, but that can be prevented by receptor protection with the agonist NA prior to CEC. 5. CEC has two major classes of action at alpha-adrenoceptors: irreversible antagonism at alpha 1-adrenoceptors, and irreversible agonism at alpha 2-adrenoceptors. Both actions can be demonstrated in the rat aorta.

Adrenergic alpha-Antagonists↗
PubMed1997

Telemedicine: evaluation or stagnation.

Telemedicine is attracting attention as a new means of delivery health care, but research indicates a low level of useful analysis of projects. This paper reviews the potential of telemedicine and suggests the use of appropriate evaluation techniques can enable that potential to be realised. The importance of quantifying benefits and introduction of wider perspectives is discussed and advocated.

Europe↗
PubMed1996

Treatment of stage D2 hormone refractory carcinoma of the prostate with 5-fluorouracil and Roferon-A: a Southwest Oncology Group study.

Based upon prior data suggesting that alpha-interferon possesses chemomodulatory activity, the Southwest Oncology Group conducted a study in which patients with hormone refractory, metastatic (stage D2) adenocarcinoma of the prostate were treated with 5-fluorouracil (5-FU) and Roferon-A. All patients had bidimensionally measurable disease. Treatment consisted of 5-FU 750 mg/m2/day by continuous i.v. infusion for 5 days with Roferon-A 9 million units subcutaneously ono days 1, 3 and 5. Roferon-A was continued three times weekly throughout treatment. Following a one week hiatus from 5-FU (week 2), 5-FU was continued at a dose of 750 mg/m2 i.v. bolus weekly. Nineteen patients were evaluable for toxicity. The most common toxicities were gastrointestinal and mucosal, hematologic and a flu-like syndrome. There were no deaths related to treatment. Among the 14 patients evaluable for response, the response rate was 0% (95% confidence interval, 0-18%). Thirteen of the 19 evaluable patients have died with a median survival of 9 months. The combination of 5-FU and Roferon-A does not have sufficient activity against advanced, hormone refractory prostate cancer to warrant further investigation.

Adenocarcinoma↗
PubMed1996

Effect of dopamine antagonism on the behavioral and hemodynamic responses to cocaine in piglets.

Cocaine (1.5 mg/kg i.v.) was administered to awake newborn piglets that were pretreated with either intravenous saline (placebo) or SCH23390, a dopamine antagonist, to study dopamine's role in cocaine's vascular and behavioral actions. In the placebo group, cocaine increased the locomotor activity and cerebellar and cardiac blood flow (31 +/- 36 and 72 +/- 66%), but decreased choroid plexus and renal blood flow (47 +/- 23 and 18 +/- 19%). In the SCH23390-treated group, cocaine did not affect organ blood flow or locomotor activity. Cocaine transiently increased the mean arterial blood pressure in both groups (10 +/- 7 and 18 +/- 13%). These data indicate that the behavioral and blood flow responses to cocaine in cerebellum, choroid plexus, heart, and kidneys are mediated by dopamine, whereas the arterial pressor response to cocaine is not.

Animals↗
PubMed1996

Randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small-cell lung cancer.

PURPOSE: This prospective randomized trial was performed to compare the effectiveness of intravenous vinorelbine tartrate with intravenous fluorouracil and leucovorin (5-FU/LV) on the primary end points of survival, quality of life (QOL), and relief of cancer-related symptoms in patients with advanced non-small-cell lung cancer (NSCLC). Secondary end points included tumor response rates and time to treatment failure. In addition, the safety of both treatment regimens was evaluated in this multicenter study. PATIENTS AND METHODS: Two hundred sixteen patients with stage IV NSCLC were enrolled onto this study from 18 centers. Vinorelbine was administered at a dose of 30 mg/m2/wk. 5-FU/LV was administered at a dose of 425 mg/m2 and 20 mg/m2, respectively, for 5 consecutive days every 4 weeks. Patients with progressive disease or toxicity were removed from study while responding and stable patients were continued on therapy. RESULTS: The median survival time of patients who received vinorelbine was 30 weeks, with 25% of patients alive at 1 year, compared with a median survival time of 22 weeks and 16% of patients alive at 1 year for those treated with 5-FU/LV (P = .03, log-rank test). This improvement in survival was associated with a higher objective response rate (12% v 3%) and time to treatment failure (10 weeks v 8 weeks) for vinorelbine versus 5-FU/LV. The dose-limiting toxicity of vinorelbine was granulocytopenia, with 54% of patients experiencing grade 3/4 granulocytopenia. Nonhematologic toxicity of vinorelbine was generally grade 1 or 2. The most common grade 3 toxicities were related to injection-site reactions. CONCLUSION: This trial confirms the efficacy of vinorelbine in patients with advanced NSCLC. The clinical activity and relatively favorable toxicity profile of this agent make it a reasonable and useful treatment option in the management of patients with this disease.

Adult↗
PubMed1995

Loss of speech after orthotopic liver transplantation.

Alteration of speech is a rare but distressing complication of orthotopic liver transplantation (OLT). We describe a characteristic speech disorder identified in a large series of consecutive patients undergoing OLT. Between 1988 and 1993, 525 adults underwent OLT. For all recipients with neurologic complications, we reviewed clinical findings, imaging and electrophysiologic test results, and perioperative laboratory data. Five patients (ages 23-52; UNOS status 3-4) exhibited a characteristic pattern of stuttering dysarthria, leading to complete loss of speech production, occasionally with elements of aphasia. In four of the five patients, right-sided focal seizures were subsequently noted. All cases presented within the first 10 postoperative days and improved with 1 month of cessation of cyclosporin (CyA), although halting, monotonous speech was evident to some degree in all five for up to 1 year. There was no correlation between onset of symptoms and CyA levels. None of the patients has clinical or radiologic findings suggestive of central pontine myelinolysis or akinetic mutism. EEGs and Spect scan results were consistent with dysfunction in the left frontotemporoparietal regions of the brain. A characteristic speech disorder, which may be described as cortical dysarthria or speech apraxia, occurs in approximately 1% of adults undergoing OLT. Prompt recognition of this syndrome and temporary cessation of CyA therapy may favorable affect the course.

Adult↗
PubMed1995

Phase II evaluation of didemnin B in hormonally refractory metastatic prostate cancer. A Southwest Oncology Group study.

Didemnin B, a dipsipeptide isolated from the Caribbean tunicate Trididemnum with antitumor and antiviral activity was evaluated in a phase II trial in the treatment of metastatic, hormonally refractory adenocarcinoma of the prostate. Thirteen patients were treated with didemnin B at 3.5 mg/m2 and 20 patients were treated at 6.3 mg/m2 intravenously every 28 days. Response was assessed every 8 weeks. Of 32 evaluable patients there was one partial response for an overall response rate of 3% (95% confidence interval of 0.1-16%). The most common toxicities were nausea, vomiting, and diarrhea. Serious cardiac and pulmonary toxicities were also noted. This drug does not appear to warrant further evaluation in this disease as a single agent.

Adenocarcinoma↗
PubMed1995

Effect of absorption of D-glucose and water on paracellular transport in rat duodenum-jejunum.

Paracellular transport is thought to be a major absorptive pathway for small nutrient molecules. The authors used in vivo in situ perfusion of rat duodenum-proximal jejunum to examine paracellular transport using lactulose as a probe. They perfused solutions with a constant lactulose concentration but varied initial D-glucose concentration (range 12-176 mM) to open paracellular pathways and to increase water absorption, thereby optimizing potential for paracellular transport of lactulose and other solutes in its molecular weight range. All solutions contained sodium chloride to approach isotonicity. Water absorption was measured as the difference in weight of solution perfused and sample collected. Absorption of D-glucose increased with mean luminal D-glucose concentration, and water absorption more than doubled (from 0.12 +/- 0.03 to 0.26 +/- 0.05 mL/min per g dry wt of segment) as mean luminal glucose concentration was increased from 10 to 80 mM. Lactulose absorption was at the threshold of detection and did not correlate with D-glucose or water absorption. Expressed as percent per segment, D-glucose absorption ranged from 29-50%, and the lactulose absorption rate was 4-5%. The fraction of D-glucose absorption that could be attributed to lactulose absorptive pathways was 12% at the highest rate of water absorption. In conclusion, based on lactulose as a probe, under conditions of opening tight junctions by D-glucose, the paracellular component of D-glucose absorption was of the order of 1/10 of total D-glucose absorption (ie, not a major absorptive pathway.

Animals↗