D R Fletcher

Laparoscopic cholecystjejunostomy as palliation for obstructive jaundice in inoperable carcinoma of pancreas

SummaryMalignant obstructive jaundice can be palliated by either surgical bypass, which has the advantage of long-term patency, or by stent placement, which has the advantage of initial lower morbidity and mortality. We describe a technique, laparoscopic cholecystjejunostomy, which has the advantage of both. We predict that laparoscopic surgery, which has already had a major impact on biliary stone surgery, will also have a major impact on interventional endoscopic retrograde cholangiopancreatography.

Distal colonic neoplasms predict proximal neoplasia in average-risk, asymptomatic subjects

Flexible sigmoidoscopy has been recommended as a screening method to reduce the incidence of colorectal cancer in asymptomatic, average‐risk subjects through the early detection and removal of polyps. However, the association between distal and proximal colonic neoplasia and, hence, the requirement for colonoscopic follow up of screen‐detected distal neoplasms is unclear. Our aims were: (i) to evaluate the risk of having proximal neoplasms in those with distal colonic neoplasms; and (ii) to determine whether the risk was dependent on the number, size, histology or morphology of the distal lesions. We prospectively evaluated asymptomatic subjects in a flexible sigmoidoscopy based screening programme. Those with rectosigmoid neoplasia underwent colonoscopy. The number, size, histology and morphology of the polyps were recorded. Advanced lesions were defined as adenomas > 1 cm or with a villous component or severe dysplasia, carcinoma in situ or cancer. Adenomatous polyps were found in 17% (135) of screening flexible sigmoidoscopies. At colonoscopy, up to 30% of subjects with distal colonic neoplasms had synchronous proximal lesions at colonoscopy and up to 20% had advanced proximal lesions. The risk of proximal colonic neoplasia was increased in those with distal sessile colonic neoplasms but appeared independent of distal lesion size, number or morphology. In conclusion, distal colonic neoplasia predicts proximal neoplasia in up to 30% of subjects and these were advanced lesions in up to 20%. We recommend that all subjects with biopsy proven distal colonic neoplasia undergo colonoscopy.

The effect of atropine on bombesin and gastrin releasing peptide stimulated gastrin, pancreatic polypeptide and neurotensin release in man

The effects of 1-h infusions of bombesin and gastrin releasing peptide (GRP) at 50 pmol/kg per h and neurotensin at 100 pmol/kg per h on gastrin, pancreatic polypeptide (PP) and neurotensin release in man were determined following either saline or atropine infusion (20 micrograms/kg). Bombesin produced a rise in plasma neurotensin from 32 +/- 6 to 61 +/- 19 pmol/l and of PP from 26 +/- 8 to 36 +/- 7 pmol/l. There was a further rise of plasma PP to 50 +/- 13 pmol/l after cessation of the infusion. GRP had no significant effect on plasma neurotensin, but compared to bombesin, produced a significantly greater rise in plasma PP from 34 +/- 6 to 66 +/- 19 pmol/l during infusion. There was no post-infusional increase. At this dose, GRP was as effective as bombesin in releasing gastrin, although unlike bombesin its effect was enhanced by atropine. Neurotensin produced a rise in plasma PP from 17 +/- 4 to 38 +/- 8 pmol/l. Atropine blocked the release of PP during GRP and neurotensin infusion. Atropine had no effect on neurotensin or PP release during bombesin infusion, but did block the rise in plasma PP following bombesin infusion. We conclude that, in contrast to meal-stimulated neurotensin release, bombesin-stimulated neurotensin release is cholinergic independent. Despite structural homology, bombesin and GRP at the dose used are dissimilar in man in their actions and sensitivity to cholinergic blockade.

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

PTH and calcitonln are the two major hormones controlling calcium metabolism. Recently two new substances related to these hormones have been Isolated: calcitonln 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 hypercalcaemla of malignancy. We report here a patient with a prostatlc tumour presenting with vasodilatlon, diarrhoea and hypercalcaemia. Our investigations revealed that the primary prostatic and liver secondary tumour contained CGRP, calcitonln 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 hypercalcaemla was also unaffected by octreotide administration. This is the first report of a prostatic tumour associated with over‐production of calcltonin, 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.

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.

Elevation of plasma gastrin and pancreatic polypeptide by electrical vagal stimulation in sheep: effects of sequential stimulation.

Gastrin and pancreatic polypeptide (PP) are released into the circulation by vagal stimulation. The individual effects of the anterior and posterior vagal trunks on the release of these peptides are unknown. Four sheep were anaesthetized and studied acutely: both vagi were dissected at the hiatus and the trunks divided. In two sheep, the distal ends of the anterior trunks were stimulated for 5 min with an 8 V, 1 ms impulse at 10 Hz. After 1 h the posterior trunks were stimulated similarly. In the other two sheep, the posterior trunk was stimulated and after 1 h the anterior vagal trunk was stimulated. The anterior and posterior trunk equally stimulated the release of both gastrin and PP in four animals. The second stimulation in these four animals resulted in an 18-fold greater integrated response of gastrin and 20-fold greater response of PP. This potentiation to the second stimulus was observed in further experiments even when the same trunk, posterior or anterior, was stimulated twice. The similarity of influence of the anterior and posterior trunks for the release of PP suggests the existence of mechanisms for vagally stimulated PP release other than branches direct from the vagal trunks.

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.

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.

Biological potency of neurotensin metabolites in vivo: Importance of alcohol ‘fixation’ of blood

Neurotensin (NT), a 13‐amino acid peptide, is released from the ileum following a meal. It is metabolized principally by the kidney and in the circulation to N‐terminal fragments and apparently rapidly degraded C‐terminal fragments. The present study was designed to compare the biological activity (plasma pancreatic polypeptide response) and the clearance kinetics of NT(1‐13), the N‐terminal fragment NT(1‐11) and the C‐terminal fragment NT(8‐13). To measure accurately the circulating concentrations of short‐lived NT fragments in the circulation, a method was devised of collecting blood directly into alcohol (‘alcohol fixation’).

Experimental mesenteric ischaemia in sheep: Gut peptide release and haemodynamic changes

Abstract Mesenteric ischaemia remains a frequently lethal condition. An improvement in survival is only likely with earlier diagnosis. Even with action upon early diagnosis and reestablishment of circulation, fatal shock often follows.