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Biomedical subjects

R J Morgan

Publications and source records attributed to R J Morgan.

At least 37 records · Page 2Linked to original sources
PubMed2001

Short report: Is regional paediatric surveillance useful? Experience in Wales.

The Welsh Paediatric Surveillance Unit was established in 1994 to monitor the incidence and prevalence of a number of uncommon disorders of childhood in Wales. Its work complements that of the British Paediatric Surveillance Unit. Information from consultant paediatricians is obtained by means of a monthly card return system; return rate is over 90%.

Adolescent↗
PubMed2001

Splenogonadal fusion: report of a rare variety.

We report an unusual case of splenogonal fusion in a 10-year-old boy with an undescended left testis. He suffered from congenital limb defects, a known association with splenogonadal fusion, and had originally been admitted for orchidopexy.

Abnormalities, Multiple↗
PubMed2001

Alterations in cholinergic and purinergic signaling in a model of the obstructed bladder.

PURPOSE: There is increasing evidence that purinergic signaling may have a role in the generation of detrusor contractions in the pathologically unstable human bladder. However, study of the rabbit model of partial bladder outlet obstruction showed a loss in cholinergic and purinergic innervation after 3 months. We examined changes in the cholinergic and purinergic components contributing to nerve mediated detrusor contraction in a rabbit model of detrusor instability secondary to bladder outlet obstruction during the early hypertrophic stage. MATERIALS AND METHODS: Partial bladder outlet obstruction was surgically induced in adult male rabbits. At 3 weeks detrusor strips were obtained and contractions were produced by electrical field stimulation in the presence of 1 microM. atropine and/or 30 microM. of the P2-purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2'4'-disulfonic acid, and after adding 1 microM. tetrodotoxin. Purinergic and cholinergic components were calculated and compared with those from sham operated controls. RESULTS: The cholinergic or atropine sensitive component was frequency dependent, that is smaller at lower frequencies. The cholinergic component was decreased in the early obstructed bladder. The pyridoxalphosphate-6-azophenyl-2'4'-disulfonic acid sensitive purinergic component was frequency dependent, that is larger at lower frequencies. The purinergic component was increased in the early obstructed bladder. The overall electrical field stimulation response or the response to KCl was unaltered in the obstructed group. There was no difference in the response in strips from the bladder neck and dome. CONCLUSIONS: The purinergic component of nerve mediated detrusor contraction is increased and the cholinergic component is decreased in early stages of bladder obstruction in this rabbit model.

Animals↗
PubMed2001

Fibrinogen, lipoprotein (a) and lipids in patients with erectile dysfunction. A preliminary study.

BACKGROUND: Erectile dysfunction is associated with cardiovascular risk factors (e.g. hypertension, smoking, dyslipidemia and diabetes) and is more common in patients with cardiovascular disease. We therefore assessed the prevalence of two predictors of vascular events, fibrinogen and lipoprotein-a, in patients with and without erectile dysfunction. METHODS: Men with erectile dysfunction (48 non-smokers, 48 smokers), aged 45-70 years, were compared with controls (21 non-smokers, 21 smokers) with normal erectile function and no known pathology. RESULTS: Serum total cholesterol was significantly higher in non-smokers with erectile dysfunction compared to both control non-smokers and erectile dysfunction smokers. Men with erectile dysfunction who smoked had a significantly higher plasma fibrinogen level than control smokers. Similarly, men with erectile dysfunction, who did not smoke had higher levels of plasma fibrinogen compared to both smokers and non-smokers without erectile dysfunction. No significant difference in serum lipoprotein-a values was found. CONCLUSIONS: These findings support the concept that cardiovascular risk factors are predictors of erectile dysfunction and that this may be another manifestation of vascular disease.

Aged↗
PubMed2000

Relaxation of rabbit lower urinary tract smooth muscle by nitric oxide and carbon monoxide: modulation by hydrogen peroxide.

Recent studies suggest that the body produces two gaseous messengers, nitric oxide (NO) and carbon monoxide (CO), both of which activate soluble guanylyl cyclase and thus modulate the activity of smooth muscle cells. In the present study, the effects of NO and CO on the smooth muscle of the lower urinary tract were compared. In addition, the modulation of tissue NO- and CO-induced relaxation by hydrogen peroxide was examined. NO, produced endogenously by electrical field stimulation (EFS) or applied exogenously as a solution, induced a concentration-dependent relaxation of rabbit cavernosal and urethral smooth muscle strips, but not of bladder tissues. The cavernosal tissue was found to be three times more sensitive to the actions of NO than the urethra. CO also induced relaxation of both tissue types, but with no apparent difference in sensitivity between the tissues. However, CO was much less potent than NO with respect to smooth muscle relaxation. The mechanism of action of the two mediators was cyclic guanosine monophosphate (cGMP)-dependent, as evidenced by enhanced formation of cGMP and inhibition of relaxation by the guanylyl cyclase inhibitor, oxadiazoloquinoxaline-1-one (ODQ.) The data suggests that NO is the dominant messenger in these tissues, but does not exclude a role for CO. In the presence of hydrogen peroxide, the relaxation responses induced by both NO and CO were significantly increased, regardless of tissue type. The mechanism for this effect is unclear, but evidence points to a requirement for the activation of guanylyl cyclase and enhanced formation of cGMP, since potentiation by the peroxide was blocked by a specific guanylyl cyclase inhibitor. We suggest that H(2)O(2) may play a positive role in the amplification or NO and CO-mediated responses.

Animals↗
PubMed2000

Phase II trial of combination intraperitoneal cisplatin and 5-fluorouracil in previously treated patients with advanced ovarian cancer: long-term follow-up.

OBJECTIVES: This trial was performed to determine the response rate and progression-free and overall survivals of patients with advanced recurrent ovarian cancer who were treated with intraperitoneal cisplatin and 5-fluorouracil. METHODS: Twenty-four patients with ovarian cancer were entered on this trial and treated with intraperitoneal (ip) cisplatin (DDP) and ip 5-fluorouracil, every 3 weeks for eight cycles. Following iv hydration, the cisplatin and 5-fluorouracil were administered through an ip catheter in 2 liters of 0.9% normal saline with a 4-h dwell. RESULTS: All patients were evaluable for progression-free and overall survival and toxicity analysis, and 22 patients for response. The median age was 59 (range, 35-71); initial disease status included 9 patients with residual disease following chemotherapy prior to entry on this study; 5 patients had progressed, and 10 patients had recurrent disease more than 6 months following initial chemotherapy. Of the 9 patients with residual disease, 1 complete response and 3 partial responses were observed; of 10 patients with recurrent disease, 1 complete and 1 partial response were observed for an overall response rate of 27%. No objective responses were seen in the 7 patients who were platinum-refractory on protocol entry. The median progression-free and overall survivals are 7.0 (range, 0.5-137) and 15.5 (range, 3-147) months, respectively. Toxicity included hypomagnesemia, vomiting, abdominal pain, and mild anemia. Only one patient required a dosage adjustment of cisplatin for a serum creatinine elevation >2.0 mg/dl. CONCLUSIONS: We conclude that the combination of ip cisplatin and 5-FU is an effective regimen for patients with residual or relapsed epithelial ovarian cancer with survival durations, response rates, and toxicity profiles that compare favorably with those of other second-line ovarian cancer regimens. Patients who are primarily platinum-refractory are unlikely to benefit from these agents administered into the peritoneal cavity.

Adult↗
PubMed2000

Inhibition of diabetic bladder smooth muscle cell proliferation by endothelin receptor antagonists.

Urinary bladder hypertrophy and hyperplasia are well recognised in diabetic cystopathy. The urinary bladder is known to synthesise endothelin-1 (ET-1), a potent vasoconstrictor peptide with mitogenic properties. Using diabetic New Zealand White (NZW) rabbits, we investigated the potential role of ET receptor subtypes (ETA and ET(B)) on the proliferation of bladder smooth muscle cells (SMC). Diabetes mellitus was induced in adult male NZW rabbits. After 6 months, control (n = 6) and diabetic (n = 6) bladders were removed and SMC from the dome and bladder neck were grown using standard explant methodology. At passage two, the cells were made quiescent and then further incubated in foetal calf serum (FCS), control age-matched rabbit serum (CRS) or diabetic rabbit serum (DRS) in the presence or absence of ET(A)-antagonist (BQ123) or ET(B)-antagonist (BQ788). SMC proliferation was then measured with 5-bromo-2'deoxy-uracil 24 h later and by cell counting (using a haemocytometer) at 48 h. Neither BQ123 nor BQ788 influenced detrusor or bladder neck SMC proliferation in FCS or CRS. However, in the presence of DRS, BQ123 and BQ788 significantly inhibited diabetic detrusor and bladder neck SMC proliferation at 30 and 100 nmol/l (P < 0.03 and P < 0.01, respectively). Cell counts were also significantly reduced from the diabetic detrusor and bladder neck (P < 0.01 and P < 0.03 with BQ123 and BQ788, respectively). These results suggest that ET may play a pathophysiological role in the bladder SMC hyperplasia associated with diabetes mellitus.

Animals↗
PubMed2000

Doxazosin modifies serotonin-mediated rabbit urinary bladder contraction. Potential clinical relevance.

5-Hydroxytryptamine (5-HT) induces rabbit detrusor contractions via 5-HT3 receptors. Similarly, 5-HT4 receptors are known to be present in the human bladder. Doxazosin, a non-selective alpha1 antagonist, is used for the symptomatic relief of bladder outflow obstruction. Previous work has shown that doxazosin inhibits 5-HT2-mediated platelet shape change. Hence, the aim of this study was to assess, using organ baths and autoradiography, whether doxazosin has any 5-HT-inhibiting activity in the rabbit detrusor. Detrusor strips from adult New Zealand White rabbits were placed in organ baths; phenoxybenzamine (10(-5) M) was added to block alpha-receptors. After KCl responses were assessed, the tissues were exposed to 10(-3) M 5-HT. Subsequently, the strips were incubated with doxazosin or ondansetron (10(-5) M; 5-HT3 antagonist) followed by a further exposure to 5-HT. In some experiments, after the initial 5-HT-induced contractions, the tissues were washed and then re-exposed to 5-HT. These latter experiments acted as controls. Low-resolution autoradiography was performed on detrusor sections to assess the effect of doxazosin on 5-HT binding. These sections were analyzed densitometrically. Doxazosin and ondansetron produced a significant reduction in 5-HT-mediated contractions. Inhibition by doxazosin was in a concentration-dependent manner. Autoradiography demonstrated a significant reduction in [3H]-5-HT binding by doxazosin. Doxazosin significantly inhibits 5-HT-mediated contractions in the rabbit detrusor. This effect appears to be mainly mediated via 5-HT3 receptor inhibition. Autoradiographic evidence suggests that doxazosin reduces 5-HT binding in the rabbit detrusor. The beneficial effects of doxazosin in bladder outflow obstruction may be due, at least in part, to 5-HT antagonism.

Animals↗
PubMed2000

Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis.

PURPOSE: To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal carcinomatosis. METHODS: Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma were treated with MTX at loading doses of 200-1500 mg/m2, followed by a 23-h infusion of 800-6000 mg/m2. Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared in patients with and without central nervous system (CNS) disease. RESULTS: Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease, who all had CSF MTX concentrations above the target cytotoxic concentration (1 microM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses. The mean half-life of CSF MTX was 8.7 +/- 3.4 h. The mean plasma clearance of MTX was not significantly different in patients with CNS disease (84 +/- 41 ml/min per m2) versus without CNS disease (59 +/- 38 ml/min per m2). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF. CONCLUSION: This trial demonstrates that potentially cytotoxic CSF MTX concentrations (> 1 microM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m2 and a 23-h infusion of 2800 mg/m2 with leucovorin in less heavily pretreated patients with carcinomatous meningitis.

Adult↗
PubMed2000

A phase I study of carboplatin and etoposide administered in conjunction with dipyridamole, prochlorperazine and cyclosporine A.

PURPOSE: In recognition of the variety of available chemotherapeutic modulating agents and their potential to enhance the efficacy of platinum-based therapy, we embarked upon a phase I study to investigate the feasibility of combining fixed doses of carboplatinum (CBDCA) and etoposide (VP-16) with 24-h concurrent infusions of dipyridamole (DP), prochlorperazine (PCZ) and cyclosporine A (CSA) administered in escalating doses. METHODS: Patients received intravenous VP-16 (200 mg/m2) and CBDCA (300 mg/m2), each over 30 min, starting at hour 6 of the modulator infusions. Resistance modulators were escalated sequentially to determine their respective maximally tolerated doses (MTDs). The pharmacokinetics (PK) of VP-16, CBDCA, and the three drug resistance (DR) modifiers were studied in eight patients. RESULTS: A total of 59 patients were entered on study. The MTD was established at DP 5 mg/kg per day, PCZ 24 mg/h, and CSA 9.5 mg/kg per day. Dose-limiting toxicities included hypotension and severe sedation, presumably related to PCZ. No objective responses were seen. PK studies were performed when PCZ and DP doses were 24 mg/h and 3.3 mg/kg, and the CSA dose was either 8.5 mg/kg (five patients) or 9.5 mg/kg (three patients). The median clearance of VP-16 was 0.96 l/h per m2 (range 0.8-1.5 l/h per m2), which is lower than for VP-16 alone and similar to previously reported effects of CSA on VP-16 elimination. The median measured CBDCA AUC was 3.0 mg/ml x min (range 2.4-4.8 mg/ml x min). CBDCA AUC predicted by the Calvert formula using measured creatinine clearance underestimated the actual AUC in seven of the eight patients, in one case by as much as twofold. The median end of infusion PCZ and total DP plasma concentrations were 1.2 microM (range 0.5-2.2 microM) and 4.4 microM (range 1.3-5.9 microM), respectively, consistent with in vitro resistance modulatory levels. However, free DP was only 0.02 microM (range 0.004-0.04 microM). The median CSA level at 24 h of 1450 microg/l (range 1075-1640 microg/l) is in agreement with concentrations required for partial DR reversal in vitro, although it is much lower than levels achieved in our previous phase I study of CBDCA + CSA alone using similar doses of CSA. The CSA dose on the current trial was escalated beyond the MTD for the previous phase I study, suggesting that there may be an interaction between CSA and one of the other modulators. CONCLUSION: These results demonstrate that in vitro DR-reversing levels of two of the three agents used in this study can be achieved in vivo, and that this combination of DR modulators has significant effects on the pharmacokinetics of VP-16.

Adult↗
PubMed2000

Biochemical screening for Down syndrome: patients' perception of risk.

OBJECTIVES: To determine the utility of the triple test in routine clinical practice and in addition to the document, the acceptability of a cut-off of 1:250 for invasive testing. DESIGN: Retrospective analysis of data from screening and invasive testing for Down syndrome over a 5-year period in Hull Maternity Hospital. Computer-based records were accessed and individual data drawn from case notes were analyzed. RESULTS: 14827 (78%) of all patients opted for the triple test. A positive result (1:250 or greater) was found in 586 (4%). Fifteen percent of this group refused further testing with amniocentesis. 0.08% requested amniocentesis despite a negative triple test result. Of the screened pregnancies the triple test and selective invasive testing identified nine out of 15 (60%) of Down syndrome cases. CONCLUSION: Sixty percent of Down syndrome pregnancies were identified with a 4% invasive testing rate. Fifteen percent of women who had a positive test did not agree with the cut-off of 1:250 and therefore declined invasive testing. Invasive procedure complication rates do not equate with patients' perception of Down syndrome.

Amniocentesis↗