Computed tomography findings of bowel wall thickening: its significance and relationship to endoscopic abnormalities.

INTRODUCTION: The aim of this study was to conduct retrospective analysis of abdominopelvic computed tomography (CT) reports, identifying those patients in whom bowel wall thickening (BWT) was observed, and to correlate these reports with subsequent endoscopic evaluation. METHODS: Formal reports for all patients undergoing abdominopelvic CT between February 2007 and September 2009 were reviewed. Where patients were identified as having colorectal 'wall thickening', results of subsequent endoscopic evaluations were documented. Only those patients with a report of BWT who had follow-up endoscopy (colonoscopy, sigmoidoscopy) were included in the analysis. RESULTS: A total of 165 patients were included. Abnormalities on endoscopy at the exact site of the BWT on CT were found in 95 patients (57.58%); in 36 cases (21.82%) this was a malignant lesion. BWT of the transverse colon was significantly more likely to correspond to an endoscopic finding of cancer than other sites (p=0.034). Rectal bleeding was reported significantly more often in patients with BWT and neoplastic disease on endoscopy compared with those with normal endoscopy (p=0.04). Excluding patients with inflammatory/diverticular lesions, 59.02% of Caucasians had a neoplastic lesion at the site of reported BWT, significantly higher than the other ethnic groups (p=0.008). There were 38 patients (23.03%) who did not present with bowel symptoms and, of these, 6 were diagnosed subsequently with colorectal cancer. CONCLUSIONS: This study supports endoscopic evaluation to investigate patients with CT evidence of BWT, especially in cases involving the transverse colon, in Caucasian patients or in association with symptoms of rectal bleeding.

Cloning and characterization of the cDNA encoding the human neuromedin U (NmU) precursor: NmU expression in the human gastrointestinal tract.

Many peptide precursors encode more than one bioactive peptide. Recent cloning of the rat neuromedin U (NmU) precursor revealed potential proteolytic processing sites which may generate three associated peptides in addition to the NmU peptide, which is known to have potent uterine contractile effects. To assess the degree of evolutionary conservation, which often suggests conserved biological function and hence physiological importance, we have cloned and sequenced the cDNA encoding the human NmU precursor. Sequence analysis revealed a 174 amino acid human precursor containing the 25 residue NmU peptide near the C terminus of the precursor. The human message sequence was 74% homologous with that of the rat, indicating evolutionary conservation of the precursor between these two species. Four out of five of the putative proteolytic processing sites, first revealed in the rat precursor, were conserved in the human precursor, indicating a similar processing mechanism in both species. Two such processing sites flank a 33 residue peptide sequence which differed in only two amino acids compared with the rat homologue. This conservation suggests a possible biological role for this putative peptide. Northern blot analysis of human gastrointestinal tissues revealed a similar level of mRNA throughout the gastrointestinal tract. RIA using a porcine specific assay showed the highest levels of peptide in the jejunum samples.

Influence of temporary faecal diversion on long-term survival after curative surgery for colorectal cancer.

Experimental carcinogenesis is enhanced at colorectal anastomoses, inhibited by proximal faecal diversion and promoted by the closure of a defunctioning stoma. The clinical relevance of these observations was investigated in a retrospective study of curative restorative resection for colorectal carcinoma. The 5-year disease-free survival rate (95 per cent confidence interval) in 122 patients with a temporary stoma (50.4 (41.1-59.7) per cent) was significantly reduced (P < 0.01) compared with that in 218 with no stoma (66.8 (59.4-73.5) per cent). In patients with Dukes B tumours early stoma closure (within 3 months of resection) was associated with a worse survival (P < 0.005) and a higher tumour recurrence rate (P < 0.05) than in those with no stoma. Survival rates after late stoma closure were no different from those in patients with no stoma. Multivariate analysis revealed Dukes stage (P < 0.0001), tumour differentiation (P = 0.02) and timing of stoma closure (P = 0.02) as independent predictors of survival. In curative surgery for colorectal cancer temporary faecal diversion confers a survival disadvantage that can be prevented by delayed closure of the stoma.

Release of vasodilator, but not vasoconstrictor, neuropeptides and of enteroglucagon by intestinal ischaemia/reperfusion in the rat.

Reperfusion of ischaemic intestine is characterised by an initial hyperaemia with ensuing mucosal repair. This study investigated possible roles for gut vasoactive neuropeptides and trophic peptides in these phenomena. Groups of rats were monitored during superior mesenteric artery occlusion for five or 20 minutes, with or without subsequent reperfusion for five minutes. Peptide concentrations (fmol/ml) in arterial blood, were measured using specific radioimmunoassays. Intestinal ischaemia alone did not cause haemodynamic disturbance or peptide release. Reperfusion, after five minutes of ischaemia, resulted in arterial hypotension and a rise in plasma vasoactive intestinal polypeptide (mean (SEM)) (37 (3), control 11 (4), p < 0.001). After 20 minutes of ischaemia, reperfusion resulted in greater hypotension (p < 0.05) and release of both vasoactive intestinal polypeptide (31 (3), p < 0.05 v control) and the more potent vasodilator beta-calcitonin gene related peptide (49 (3), control 23 (1), p < 0.001). By contrast, the vasodilators alpha-calcitonin gene related peptide and substance P and the vasoconstrictors neuropeptide Y, peptide YY, and somatostatin were not released. Bombesin, a stimulatory neuropeptide, was released after 20 minutes of ischaemia/reperfusion (13 (2), control 7 (3), p < 0.05). Plasma enteroglucagon rose from control (51 (4)) to 110 (16) (p < 0.001) and to 158 (27) (p < 0.005) after five and 20 minutes of ischaemia/reperfusion. The potent enteric vasodilators vasoactive intestinal polypeptide and beta-calcitonin gene related peptide, unopposed by vasoconstrictors, may promote post-ischaemic intestinal hyperaemia. The rise in plasma enteroglucagon may point to diffuse mucosal injury and is consistent with the putative trophic role of this peptide.

Atrial natriuretic peptide and glucagon release in experimental intestinal ischaemia and reperfusion.

Intestinal ischaemia and reperfusion cause changes in cardiovascular and pulmonary function. In a rat model, the plasma concentrations of atrial natriuretic peptide (ANP) and pancreatic glucagon rose on reperfusion after 20 min of intestinal ischaemia, coinciding with significant arterial hypotension: mean(s.e.m.) ANP 79(13) versus control 36(4) fmol ml-1 (P < 0.01); and mean(s.e.m.) glucagon 22(2) versus control 10(1) fmol ml-1 (P < 0.001). Glucagon was also released on reperfusion after 5 min of ischaemia: mean(s.e.m.) 18(2) fmol ml-1 (P < 0.001 versus control). In a second experiment, pretreatment of rats with allopurinol did not prevent arterial hypotension but abolished ANP release (mean(s.e.m.) 36(2)fmol ml-1 versus no pretreatment 70(7) fmol ml-1, P < 0.05), while glucagon release was unaffected. The release of ANP, but not that of glucagon, is therefore mediated by oxygen free radicals and may signify cardiac and/or pulmonary injury or dysfunction. The actions of these peptides may be relevant in the pathophysiological perturbation of intestinal ischaemia-reperfusion.

Peptide histidine valine: its haemodynamic actions and pharmacokinetics in man differ from those of vasoactive intestinal peptide and peptide histidine methionine.

1. The effects of intravenous and intra-arterial infusion of the peptides derived from prepro-vasoactive intestinal peptide, vasoactive intestinal peptide, peptide histidine methionine and peptide histidine valine, were examined in six healthy volunteers. 2. Vasoactive intestinal peptide given intravenously caused a significant increase in heart rate and a decrease in diastolic, but not systolic, blood pressure, whereas peptide histidine valine caused an increase in heart rate alone, despite higher achieved circulating peptide concentrations. Peptide histidine methionine did not affect heart rate or blood pressure. Forearm blood flow was increased by vasoactive intestinal peptide and peptide histidine valine when infused locally intra-arterially, although vasoactive intestinal peptide was more potent than peptide histidine valine. 3. Plasma concentrations of cardiodilatin (the N-terminal peptide derived from pro-atrial natriuretic peptide) were increased by intravenous infusion of vasoactive intestinal peptide, but were unaffected by peptide histidine methionine or peptide histidine valine. Circulating plasma concentrations of adrenaline and noradrenaline did not change during infusion of vasoactive intestinal peptide, peptide histidine methionine or peptide histidine valine. 4. Peptide histidine valine had a long half-life when compared with peptide histidine methionine and vasoactive intestinal peptide. 5. We conclude that peptide histidine valine is active in the human cardiovascular system and has a similar, though less potent, vasodilating action to vasoactive intestinal peptide. The higher circulating levels of peptide histidine valine found in man suggest that it may be important in modulating vascular tone.

The hormonal responses to repetitive brief maximal exercise in humans.

The responses of nine men and nine women to brief repetitive maximal exercise have been studied. The exercise involved a 6-s sprint on a non-motorised treadmill repeated 10 times with 30 s recovery between each sprint. The total work done during the ten sprints was 37,693 +/- 3,956 J by the men and 26,555 +/- 4,589 J by the women (M greater than F, P less than 0.01). This difference in performance was not associated with higher blood lactate concentrations in the men (13.96 +/- 1.70 mmol.l-1) than the women (13.09 +/- 3.04 mmol.l-1). An 18-fold increase in plasma adrenaline (AD) occurred with the peak concentration observed after five sprints. The peak AD concentration in the men was larger than that seen in the women (9.2 +/- 7.3 and 3.7 +/- 2.4 nmol.l-1 respectively, P less than 0.05). The maximum noradrenaline (NA) concentration occurred after ten sprints in the men (31.6 +/- 10.9 nmol.l-1) and after five sprints in the women (27.4 +/- 20.8 nmol.l-1). Plasma cardiodilatin (CDN) and atrial natriuretic peptide (ANP) concentrations were elevated in response to the exercise. The peak ANP concentration occurred immediately post-exercise and the response of the women (10.8 +/- 4.5 pmol.l-1) was greater than that of the men (5.1 +/- 2.6 pmol.l-1, P less than 0.05). The peak CDN concentrations were 163 +/- 61 pmol.l-1 for the women and 135 +/- 61 pmol.l-1 for the men. No increases in calcitonin gene related peptide (CGRP) were detected in response to the exercise. These results indicate differences between men and women in performance and hormonal responses. There was no evidence for a role of CGRP in the control of the cardiovascular system after brief intermittent maximal exercise.

Pro-atrial natriuretic peptide (1-98): the circulating cardiodilatin in man.

The nature of plasma cardiodilatin, the amino-terminal product of the human pro-atrial natriuretic peptide, was investigated by two separate radioimmunoassays directed against the N-terminal and the putative C-terminal of the cardiodilatin molecule: ANP-[Asn1-Lys16] and ANP-[Lys87-Arg98], respectively. Serial dilutions of normal and cardiac failure plasma exhibited parallelism with the synthetic peptide standard curves in both assays. The concentrations of N- and C-terminal cardiodilatin-immunoreactivity equivalents (-IE) were significantly higher in cardiac failure patients. N-terminal-IE: 912 +/- 87, normal subjects 129 +/- 13 (mean +/- SEM); C-terminal-IE: 7979 +/- 1784, normal subjects 895 +/- 213 (both p less than 0.001). Although the concentrations determined by the two assays were not identical, significant correlations were found between them in both normal subjects (r = .69, p less than 0.001) and cardiac failure patients (r = .72, p less than 0.01). Characterisation by gel permeation and fast protein liquid chromatography demonstrated coelution of the N- and C-terminal cardiodilatin immunoreactivities in a single chromatographic peak. These results suggest that the circulating cardiodilatin in normal subjects and patients with cardiac failure contains the entire prohormone amino-terminal sequence ANP-[Asn1-Arg98].

Atrial natriuretic peptide levels in plasma and in cardiac tissues after chronic hypoxia in rats.

1. Atrial natriuretic peptide (ANP) levels were measured in cardiac tissues and in plasma from adult rats exposed to chronic alveolar hypoxia for periods of 2 h, 24 h and 7 days. Levels were also measured in rats that were maintained in hypoxia for 7 days and then returned to air for 24 h. 2. Plasma ANP was not altered at 2 h but was significantly increased at both 24 h and at 7 days. Plasma ANP in animals exposed to hypoxia for 7 days was normal 24 h after returning to air breathing, despite the persistence of indices of pulmonary hypertension. 3. No significant right atrial hypertrophy was observed under these conditions of chronic hypoxia. A reduction in right atrial ANP content was found at 24 h and was accompanied by a decrease in the number of electrondense granules per right atrial muscle cell. After exposure to hypoxia for 7 days, right atrial ANP and granule number was not different from control, and no alteration was found in right atrial ANP level after removal from the hypoxic environment. 4. No significant right ventricular hypertrophy was produced by exposure to hypoxia for 2 or 24 h. In the former group ventricular ANP had decreased significantly compared with control. Right ventricular hypertrophy was found in both the hypoxic groups after exposure for 7 days, when selective increases in right ventricular ANP content were found. 5. These findings are consistent with the hypothesis that ANP release occurs on exposure to chronic hypoxia and is independent of the associated cardiac hypertrophy and pulmonary vascular remodelling. The findings may have relevance to the natriuresis and reported changes in the renin-angiotensin-aldosterone axis under hypoxic conditions.

Atrial natriuretic peptide concentrations in hypoxic secondary pulmonary hypertension: relation to haemodynamic and blood gas variables and response to supplemental oxygen.

Plasma atrial natriuretic peptide concentrations, measured in samples drawn from the pulmonary artery, were raised in nine of 17 patients with hypoxic pulmonary hypertension but normal right atrial pressures at rest. No relationship was seen between atrial natriuretic peptide concentrations and mean pulmonary artery or right atrial pressure, or calculated pulmonary or systemic vascular resistance. Patients with the most severe hypoxaemia tended to have higher plasma atrial natriuretic peptide concentrations; three patients with no past history of oedema had concentrations more than twice the upper limit of normal. Treatment with supplementary oxygen for 30 minutes reduced pulmonary vascular resistance in all patients but had no significant effect on plasma atrial natriuretic peptide concentration. These findings suggest that atrial natriuretic peptide may be a factor in the control of sodium and water balance in hypoxic cor pulmonale, where the determinants of individual susceptibility to peripheral oedema are not well understood.

Increase in plasma concentrations of cardiodilatin (amino terminal pro-atrial natriuretic peptide) in cardiac failure and during recumbency.

Plasma concentrations of cardiodilatin, the peptide sequence at the amino terminal of the pro-atrial natriuretic peptide, in 17 normal subjects ranged from 59 to 202 (mean 118 (SEM) (9] pmol/l. Recumbency increased the mean (SEM) concentration to 160 (13) pmol/l. The plasma concentration of cardiodilatin in 24 patients with congestive cardiac failure was much higher (964 (175) pmol/l) than in the normal subjects. It was highest in those with heart failure in New York Heart Association functional classes III and IV and the concentration correlated both with atrial natriuretic peptide concentrations and left ventricular ejection fraction. Concentrations rose during induced tachycardia in three patients tested. Chromatography showed a single clean peak of plasma cardiodilatin immunoreactivity. It seems that cardiodilatin is a second circulating cardiac peptide that is jointly released with atrial natriuretic peptide by common stimuli. Other workers have reported that, like atrial natriuretic peptide, three partial cardiodilatin sequences can stimulate renal particulate guanylate cyclase and increase cyclic guanosine monophosphate. The simultaneous release of cardiodilatin in higher circulating concentrations than atrial natriuretic peptide may be relevant to the finding that appropriate concentrations of exogenous atrial natiuretic peptide alone do not produce the full renal effects associated with endogenous peptide release.

The presence and molecular forms of cardiodilatin immunoreactivity in the human and rat right atrium.

A sensitive and specific radioimmunoassay has been developed for cardiodilatin, the N-terminal peptide sequence of the atrial natriuretic peptide (ANP) prohormone. Cardiodilatin-immunoreactivity (-IR) concentrations in the human right atrial appendage were found to correlate with ANP-IR concentrations, determined by an established radioimmunoassay, (cardiodilatin-IR = 13.2 +/- 1.2 nmol/g, ANP-IR = 19.8 +/- 2.0 nmol/g, r = 0.80, p less than 0.001). Characterisation of the cardiodilatin-IR in the human and rat right atrium by gel permeation and fast protein liquid chromatography revealed only two cardiodilatin-IR molecular forms. The larger more hydrophobic form, the majority of the cardiodilatin-IR, contained in addition ANP-IR and therefore represents the prohormone. The smaller, less hydrophobic form, lacked ANP-IR and thus represents the cleaved N-terminal peptide sequence of the prohormone. These findings indicate that the prohormone is the major molecular form in the human and rat atrium. Furthermore, they demonstrate that a single large N-terminal peptide, cardiodilatin, derived from the prohormone, may exist as a distinct molecular form in the atrium of these species.

Expression of the atrial natriuretic peptide gene in the cardiac muscle of rat extrapulmonary and intrapulmonary veins.

Atrial natriuretic peptide is a peptide regulating salt and water balance, originally isolated from the cardiac atrium, where it is synthesised as part of a precursor molecule in specialised myocardial cells. The myocardium extends into the extrapulmonary part of the pulmonary veins in many species, including man. In some small mammals, however, such as the rat, mouse, and bat, it extends further to veins in the peripheral parts of the lung. Since this myocardial layer is continuous with that in the atrium, we have looked for the possible expression of the atrial natriuretic peptide gene in this tissue in rats. Strong immunoreactivity was seen for both the peptide and the N terminal sequence (cardiodilatin) of its precursor in extrapulmonary veins and in intrapulmonary veins extending into the lung as far as the second branching point, where it was localised in the dense cored granules by electron microscopy; in situ hybridisation showed atrial natriuretic peptide messenger RNA at identical sites. Chromatography and radioimmunoassay of extracts of extrapulmonary and intrapulmonary veins showed most of the atrial natriuretic peptide immunoreactivity to be in the uncleaved (precursor molecule) form. Thus the peptide is synthesised in veins both outside and inside the lung, and these extra-atrial sites may be an important additional source of circulating atrial natriuretic peptide.

Colostomy or ileostomy after colorectal anastomosis?: a randomised trial.

Sixty one patients were entered in a randomised trial to compare transverse loop colostomy with loop ileostomy after a colorectal anastomosis thought to be at risk of dehiscence. Radiologically proven breakdown of the colorectal anastomosis occurred in 13% of these selected patients and most frequently in the colostomy group. Ileostomies functioned earlier than colostomies (P less than 0.001) but there was no other significant difference in outcome between the groups. In 52 patients intestinal continuity was restored by excision of the stoma within a month of construction with no difference in morbidity between the two groups. A loop ileostomy, closed as soon as the colorectal anastomosis has healed, is recommended as an alternative to transverse colostomy.