Search PubMed⌕ Search

Biomedical subjects

D R Fletcher

Publications and source records attributed to D R Fletcher.

At least 55 records · Page 3Linked to original sources
PubMed1991

Production of calcitonin gene related peptide, calcitonin and PTH-related protein by a prostatic adenocarcinoma.

PTH and calcitonin are the two major hormones controlling calcium metabolism. Recently two new substances related to these hormones have been isolated: calcitonin gene related peptide (CGRP) and PTH-related protein (PTHrP). CGRP is a potent vasodilator and stimulant of intestinal secretion while PTHrP is probably the agent responsible for humoral hypercalcaemia of malignancy. We report here a patient with a prostatic tumour presenting with vasodilation, diarrhoea and hypercalcaemia. Our investigations revealed that the primary prostatic and liver secondary tumour contained CGRP, calcitonin and PTHrP. Most of the immunoreactive CGRP in the tumour and plasma co-eluted with the biologically active form of CGRP. The circulating levels of CGRP correlated with the presence of the diarrhoea. PTHrP concentration in the tumours was one of the highest reported for any tumour although previous studies may have utilized less than optimal extraction procedures. The somatostatin analogue, octreotide (SMS 201-995), did not reduce the plasma CGRP or the diarrhoea, a finding similar to that seen in patients with medullary thyroid carcinoma and high plasma CGRP. The hypercalcaemia was also unaffected by octreotide administration. This is the first report of a prostatic tumour associated with over-production of calcitonin, PTHrP and CGRP. The major life-threatening effects of this unusual case of prostatic carcinoma were diarrhoea and hypercalcaemia. Both these effects could be tentatively ascribed to newly discovered substances, CGRP and PTHrP. With the greater availability of assays to measure CGRP and PTHrP in plasma, a detailed examination of the incidence of over-production of these substances in various cancers will be possible.

Adenocarcinoma↗
PubMed1991

Laparoscopic cholecystectomy: initial experience.

Twenty-five consecutive patients underwent percutaneous laparoscopic cholecystectomy (PCC). The gallbladder was removed successfully in 18 patients. The mean postoperative hospital stay was 1.4 days and patients returned to normal activity at a mean 8 days after operation. Postoperative pain was minimal. Formal laparotomy was performed in 7 patients due to: bleeding (3 patients), stone spillage (3 patients) and exploration of the common bile duct (1 patient). Complications were reduced with experience and strict adherence to the described operative technique. With obvious advantages for the patient, hospitals and the community an increased demand for PCC is inevitable. However, its role in the management of cholelithiasis and overall safety have yet to be determined. There is a significant learning curve and proper training is necessary. The widespread introduction of PCC has immediate implications for surgical training.

Adolescent↗
PubMed1990

Calcitonin gene related peptide: vasodilator in ovine hepatic and renal vasculature.

1. Calcitonin gene-related peptide (CGRP) is a product of alternate splicing of the calcitonin gene. It is found in nerves in the vasculature and is known from in vitro studies to be a potent vasodilator. It is found abnormally in the circulation of patients with medullary thyroid carcinoma (MTC) and has been proposed to be a cause of symptoms. This study was designed to determine the dose-response effects of CGRP infusion in the intact conscious sheep on blood flow to liver and kidney, organs known to be richly innervated by CGRP-containing nerves. 2. Blood flow was measured by an indicator dilution technique using [131I]-labelled iodohippurate. CGRP infusion at both 1 and 5 pmol/kg per min produced significant (P less than 0.05) increases in both renal and hepatic blood flow. This increase in flow occurred despite a significant fall in perfusion pressure (P less than 0.05) at the higher infusion rate. At the highest infusion rate of 10 pmol/kg per min, when fall in perfusion pressure was even more marked, renal and hepatic blood flow was maintained. 3. We conclude that CGRP is vasodilatory in the renal and hepatic vascular beds and propose that nerves containing CGRP in those vessels may have a role in maintaining blood flow to those organs.

Animals↗
PubMed1989

The effect of selective therapy on malignant obstructive jaundice.

To determine the impact and use of alternative treatment methods of draining malignant obstructive jaundice, a review of 41 patients who were managed by a surgical hepatobiliary service, in which non-surgical (endoscopic and radiological) treatment modalities were available equally, was performed. Of the 41 patients, 39 patients experienced 45 attempted treatments with ultimate success in 35 (90%) patients. The non-operative management of the high-risk patients did not result in a higher mortality at 9% and 25% for endoscopic and radiological management, respectively, than that of 15% which was achieved in the operative series. As a result of treatment selection, the non-operative groups survived for a shorter time (eight weeks) than did those who underwent operation (survival, 30 weeks). This shorter survival time resulted in a similar readmission rate for the non-operative and operative groups; patients did not survive long enough in the non-operative group to develop stent complications. Even if surgery is the chosen treatment modality, preoperative endoscopic retrograde cholangiopancreatography is recommended in planning that surgery. We conclude that in patients with malignant obstructive jaundice, surgical treatment has the advantage of fewer late complications, while non-surgical treatment has the advantage of less initial morbidity or mortality. If the aim is to optimize palliation not only in the short term, but also in the longer term, then the selection of patients for treatment on the basis of pretreatment imaging results, the operative risk and the predicted duration of survival, will result in operative and non-operative methods of treatment being used approximately equally.

Aged↗
PubMed1989

Hepatic resection: value of operative ultrasound and ultrasonic dissection.

Twenty-five patients having a major liver resection at the Austin Hospital were reviewed, 18 of whom had their operation after 1986. The indications were for metastatic disease in 14, hydatid in six and primary tumour in five. There were no operative deaths. Dissection was performed with the Cavitron Ultrasound Surgical Aspirator (CUSA) and peroperative ultrasound used in 18 and without in seven. Mean blood loss was 1.75 u in the CUSA group and 6.5 u in the non-CUSA group (P less than 0.05). It is concluded that intra-operative ultrasound and use of the CUSA makes major liver resection a more precise and less hazardous procedure.

Adolescent↗
PubMed1988

The cardiovascular effects of human calcitonin gene-related peptide in conscious sheep.

Calcitonin gene-related peptide (CGRP) is localized in nerve fibres in close association with the vasculature. The in vivo effect of human CGRP upon the cardiovascular system was investigated by intravenous infusion of CGRP into seven conscious sheep at doses of 1.5 and 10-pmol/kg per min for 75 min. CGRP at the 5- and 10-pmol/kg per min infusions decreased mean arterial pressure (maximal decrease of 10 mmHg) and stroke volume (maximal decrease of 42 ml/min), and increased heart rate by 60 beats/min. No changes in cardiac output were observed and total peripheral resistance only fell with the 5-pmol/kg per min infusion. Increases in both plasma arginine vasopressin and plasma renin concentration and a decrease in total and ionized plasma calcium were also observed. CGRP appears to be a potent vasodilator acting upon both arterioles and capacitance vessels in vivo.

Animals↗
PubMed1988

Effect of vaso-active intestinal polypeptide on systemic and splanchnic haemodynamics: role in vasodilation following mesenteric ischaemia.

Vaso-active intestinal polypeptide (VIP) and the related peptide, peptide histidine isoleucine, were infused intravenously in anaesthetized sheep. The VIP doses were designed to reproduce plasma concentrations seen after mesenteric ischaemia. The vasodilator action of VIP varied between different segments of the circulation and these differences in sensitivity were observed for both the degree and duration of the vaso-active action. A sustained vasodilation was detected in the coeliac artery and portal vein vascular beds during a 30-min VIP infusion. VIP is likely to be a contributory factor involved in the development of circulatory collapse during reperfusion after experimental mesenteric ischaemia.

Animals↗
PubMed1988

Pharmacokinetics and organ-specific metabolism of calcitonin gene-related peptide in sheep.

Calcitonin gene-related peptide (CGRP) is a product of the calcitonin gene with a widespread distribution in neural tissue of the brain, gut and perivascular nerves. Infusion of CGRP produces multiple biological effects, but the physiological significance of these findings will be influenced by the sites and rates of CGRP metabolism. The metabolic clearance rate and half-life of disappearance of human CGRP were estimated in conscious sheep after infusing CGRP at 1 or 5 pmol/kg per min to steady-state conditions. The particular organs involved in the clearance of CGRP were assessed by measuring the inflow and outflow concentrations across the liver, gut, kidney, lung and brain. The metabolic clearance rate at steady state was 22.6 +/- 2.1 (S.E.M.) and 15.0 +/- 17 ml/kg per min for the 1 and 5 pmol/kg per min doses respectively. The half-life of disappearance was bi-exponential: 3.6 +/- 0.3 min for the first phase and 13.6 +/- 1.0 min for the second phase. High-pressure liquid chromatography of plasma at equilibrium revealed only a single peak coeluting with CGRP(1-37): no immunoreactive metabolites were detected. These pharmacokinetic values are intermediate between that of a neurotransmitter and a hormone and are therefore consistent for a peptide with both circulatory and neurotransmitter modes of action. The kidney, with an arterial-renal vein gradient of 14%, and the liver, with a portal-hepatic vein gradient of 25%, were the major organs involved in the clearance of CGRP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

The vagus and neurotensin release in duodenal ulcer--clinical and experimental studies.

Although meal-stimulated neurotensin release from the small intestine is inhibited by cholinergic blockade, it is uncertain whether this cholinergic mechanism involves the vagus. This study examines the role of the vagus in neurotensin release by first determining the effect of vagotomy on meal-stimulated plasma neurotensin in man and second, the effect on plasma neurotensin of electrical stimulation of the vagus in sheep. Six volunteers were studied 6-8 weeks after truncal vagotomy and pyloroplasty. Basal plasma neurotensin at 32(15-67) pmol/l (median, range) was greater than in normal controls at 17 (9-52) pmol/l (P less than 0.05). Following a standard meal, plasma neurotensin rose significantly (P less than 0.05), but similarly in both post-vagotomy and control groups to maxima of 74 (43-76) pmol/l and 52 (35-65) pmol/l, respectively. Basal plasma neurotensin in the six sheep was below the detection limit of the assay and remained undetectable during electrical stimulation of the vagus. Significant rises in plasma pancreatic polypeptide and gastrin confirmed the efficacy of the electrical stimulation. It is concluded that although the vagus might have a tonic inhibitory effect on basal plasma neurotensin, meal-stimulated neurotensin release is vagally independent. The inhibitory cholinergic influence on meal-stimulated release is most likely therefore to be mediated by cholinergic nerves of the enteric nervous system.

Adolescent↗
PubMed1985

The effect of neurotensin and secretin on gastric acid secretion and mucosal blood flow in man.

Neurotensin stimulates pancreatic secretion directly and by potentiating the effect of secretin. Neurotensin also inhibits gastric secretion. Secretin inhibits gastric secretion as well, but whether it also interacts with neurotensin is not known. Secretin is known to inhibit gastric mucosal blood flow (GMBF). The effect of neurotensin on GMBF is not known. Acid secretion (triple lumen perfused orogastric tube) and GMBF ([14C]aminopyrine clearance) were therefore measured in 6 subjects during neurotensin, secretin and neurotensin plus secretin infusions. Neurotensin plus secretin reduced acid secretion by a median 130 (range 34-394) mumol/min which was significantly greater than either neurotensin at 36 (7-67) mumol/min or secretin 54 (20-347) mumol/min alone (P less than 0.05). This effect appeared independent of GMBF. Neurotensin plus secretin reduced GMBF by 14 (12-27) ml/min but not significantly more than neurotensin at 11 (3-20) ml/min or secretin 18 (2-27) ml/min alone. Further, there was no correlation between changes in acid output and GMBF during infusion of the peptides. We conclude that the inhibitory effects of neurotensin and secretin on gastric secretion are at least additive and together they may function as an 'enterogastrone'.

Adult↗
PubMed1985

The effect of cigarette smoking on gastric acid secretion and gastric mucosal blood flow in man.

Smoking leads to a higher incidence of peptic ulcer and delays healing of those ulcers. Possible mechanisms include increased gastric acid secretion, reduced gastric mucosal blood flow, and reduced duodenal bicarbonate production. In six subjects we determined the effect of one hour of cigarette smoking on gastric mucosal blood flow (14C-aminopyrine clearance), acid secretion (triple lumen perfused oro-gastric tube), and plasma levels of gastrin and pancreatic polypeptide. Smoking reduced acid secretion from a median of 433 (range 160-707) mumol/min to 166 (47-340) mumol/min (p less than 0.05) and blood flow from 66 (40-70) ml/min to 36 (22-58) ml/min (p less than 0.05). There was no change in plasma gastrin and the small rise in pancreatic polypeptide would be insufficient to affect duodenal bicarbonate production. We conclude that cigarette smoking decreased gastric acid secretion and gastric mucosal blood flow. The increased incidence of gastric ulcers seen in smokers may be related to this reduction in gastric mucosal blood flow.

Adult↗
PubMed1984

Multiple endocrine neoplasia type II: the role of gastrointestinal humoral factors in calcitonin release following alcohol and pentagastrin stimulation.

Familial medullary carcinoma of thyroid (MCT) can be diagnosed early by measuring stimulated plasma calcitonin following provocation with 50 ml of oral whisky, or 0.5 microgram kg-1 i.v. pentagastrin. The calcitonin release, however, can be variable following both stimuli. To determine whether a humoral mechanism might be involved in mediating this calcitonin release, nine gut peptides, histamine, alcohol, calcium, and calcitonin, were measured in the plasma of eight patients whose family was affected by multiple endocrine neoplasia Type II syndrome. Pentagastrin produced significant rises in plasma calcitonin, histamine and pancreatic polypeptide. Whisky produced a variable rise in plasma alcohol, but significant rises in plasma calcitonin, histamine and pancreatic polypeptide as well as insulin (P less than 0.05). This study suggests that histamine may be the mediator of calcitonin release following provocation by either pentagastrin or alcohol. Histamine infusion requires evaluation as a screening test for MCT in MEN II syndrome.

Adrenal Gland Neoplasms↗
PubMed1984

Metabolism of neurotensin and pancreatic polypeptide in man: role of the kidney and plasma factors.

Neurotensin (NT) is a 13 amino acid peptide found predominantly in the ileum and it is released into the circulation by a meal. Much of the circulating NT consists of N terminal fragments which have no known biological activity. However, the sites and rates of NT metabolism are not known. In the present study the MCR and half-disappearance time of NT were estimated by infusing NT(1-13) into 10 normal subjects. The role of the kidney was assessed by studies in patients with chronic renal failure (CRF). The nature of the metabolites was characterized using region specific antisera and high pressure liquid chromatography (HPLC). The plasma pancreatic polypeptide response to the NT infusion was also measured. The NT MCR in normal subjects was 88 +/- 25 (SEM) ml/min X kg measured with the C terminal antiserum but only 9.9 +/- 0.8 ml/min X kg measured with the N terminal antiserum, a result consistent with the presence of long lasting N terminal fragments. HPLC of the plasma at equilibrium established that only 20% of the immunoreactivity was present as NT(1-13), with the majority as NT(1-8). No C terminal fragment were detected. Similarly, incubation of NT(1-13), 1-8, and 8-13 in plasma in vitro showed that N terminal fragments were stable in plasma, whereas C terminal fragments were completely metabolized. In patients with CRF, basal plasma NT (measured with the C terminal antisera) was significantly elevated and C terminal MCR was reduced by 82% and N terminal MCR by 32%. Thus the major effect of CRF was on the initial degradation of NT(1-13) to N terminal fragments. HPLC showed that over 60% of the NT was present as NT(1-13). In vitro degradation of NT was also slowed in CRF plasma. The increased proportion of intact biologically active NT in the circulation of the CRF patients could also explain the greater increase in pancreatic polypeptide levels during the NT(1-13) infusion. These studies have established that the metabolism of NT is influenced by the kidney and that the presence of predominantly N terminal fragments of NT in the peripheral circulation of normal subjects can be explained by a combination of renal and extrarenal factors.

Chromatography, High Pressure Liquid↗
PubMed1984

Results of a screening program for multiple endocrine neoplasia type II.

After the diagnosis of MEN IIa syndrome in five members of a British family, a further 180 members were identified, 167 of whom were still alive. From death certificates, a further three were found to have been affected. Of these eight patients, only two were diagnosed and survived. Over the next four years, these two survivors and 90 others (those over the age of ten years) attended a screening program using alcohol or pentagastrin stimulated plasma calcitonin for MCT or urinary catecholamines for pheochromocytoma. The two surviving patients and 12 others were thought to have abnormal screening tests. One patient with an abnormal catecholamine excretion level had bilateral pheochromocytomas removed. Of the 13 patients with abnormal stimulated plasma calcitonin levels, five underwent total thyroidectomy, but MCT was found in only two. One of these patients and two of those in whom no tumor was found had persistently elevated stimulated plasma calcitonin levels postoperatively, suggesting the presence of C cells and, thus, persisting risk of MCT. In all patients, plasma calcitonin concentrations were variable, and an established normal range of values is essential if unnecessary surgical treatment is to be avoided. Pheochromocytoma proved difficult to diagnose, and pentagastrin stimulated plasma catecholamines deserves evaluation as a screening test. Despite the large effort involved, permanent screening of all family members is recommended as the only means of reducing mortality. Following any treatment, screening should continue because new disease or recurrence is possible.

Adrenal Gland Neoplasms↗
PubMed1983

Cholinergic inhibition of meal stimulated plasma neurotensin like immunoreactivity in man.

Meal stimulated plasma neurotensin like immunoreactivity (NTLI) was compared during saline or atropine infusion in six volunteers over six hours. Plasma gastrin and pancreatic polypeptide were also measured to compare the timing of their release to that of NTLI. Like plasma gastrin and PP, plasma NTLI rose rapidly following the meal, rising from 27 +/- 7 pmol/l to a peak of 45 +/- 8 pmol/l at 20 minutes (p less than 0.05). Also, like that of pancreatic polypeptide, the release of NTLI was biphasic. Sixty minutes after the meal, plasma NTLI had returned to basal values, followed by a rise to a prolonged peak of 64 +/- 10 pmol/l between 90-180 minutes (p less than 0.05) returning once more to basal values by 240 minutes. Following atropine, basal plasma NTLI fell from 22 +/- 4 pmol/l to 11 +/- 2 pmol/l (p less than 0.05), but rose to basal levels 30-60 minutes after the meal, where it remained unaltered for the remainder of the study. We conclude that both basal and meal stimulated plasma NTLI are inhibited by cholinergic blockade. Further, the similar temporal relationship between plasma NTLI and pancreatic polypeptide in the late phase of the meal response, suggests that a component of NTLI may mediate part of the intestinal phase of pancreatic polypeptide release.

Adolescent↗