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a Department of Gastroenterology, Beaujon Hospital, Clichy , France; b Department of Digestive and Liver Disease, Ospedale S. Andrea, Rome , Italy; c Department of Hepatology and Gastroenterology, CHU Bichat – B. Claude Bernard University, Paris , France; d Department of Pathology, Kantonsspital Baden , Switzerland; e Department of Gastroenterology, Massachussetts General Hospital, Boston , Mass. , USA; f B. Kos-Kudla, Department of Endocrinology, Slaska University, Zabrze , Poland; g Department of Surgery, UFR Bichat-Beaujon-Louis Mourier Hospital, Colombes , France; h Department of Oncology, Royal Free University, London , UK; i Department of Gastroenterology, Philipps University, Marburg , Germany; j Department of Surgery, Gothenburg University, Gothenburg , Sweden; k Department of Nuclear Medicine, Catholique de Louvain University, Brussels , Belgium; l Department of Nuclear Medicine, Erasmus MC University, Rotterdam , The Netherlands; m Department of Pathology and Laboratory Medicine, Universita degli Studi, Parma , Italy

The innervation of ileal mucosa of normal, unanaesthetized male Wistar rats was investigated electronmicroscopically. The presence of RBC inside intestinocytes was a secondary, but frequent observation in 4 of 20 rats. No sign of hemorrhage or trauma of the tissue was noted, and the rats had not been exposed to any known toxic agent. The study demonstrates that also intestinocytes have the capacity to engulf RBC, as many other types of epithelial cells. However, previous demonstration of RBC phagocytosis of epithelia was performed in tissues where hemorrhage had occurred for various reasons. In contrast, the rats of the present study were considered normal, although the influence of unknown agents cannot be ruled out.

Secretin, gastrin and cholecystokinin were the first discovered gut hormones. Today we recognize more than 30 gut hormone genes and a multitude of bioactive peptides, which make the gut the largest endocrine organ in the body. Due to structural homologies gut peptide hormones/growth factors have been divided into separate families. It has been emphasized that those peptides are widely distributed, but have a specific expression in different cell types. The intestine can also be regarded as a sensory organ operating via neurons, endocrine cells and immune cells with gut peptides as signalling substances. Expression studies of peptide receptors in gut neuroendocrine tumours in combination with tailored peptide analogs have been helpful in developing new diagnostic and therapeutic strategies. New fields of research will relate to gut peptides associated with deficiency diseases and as potential growth factors in malignancies. Enterochromaffin cells, interspersed throughout the entire gastrointestinal mucosa, form the largest endocrine cell system. The physiological role of hormonal messengers, peptide receptors and amine transporters is currently under investigation as well as their potential involvement in disease, e.g. the secretory diarrhea associated with midgut carcinoid tumours.

a Department of Gastroenterology, North Hampshire Hospital, Basingstoke , UK; b Stadtisches Klinikum Neuss, Lukaskrankenhaus, Chirurgische Klinik I, Neuss , Germany; c Istituto di Radiologia, Policlinco GB Rossi, Verona , Italy; d Institute for Pathology, Kantonsspital, Baden , Switzerland; e Departments of Internal Medicine and Endocrinological and Metabolic Sciences, University of Genoa, Genoa , Italy; f II. Internal Medical Department, University Hospital Martin, Martin , Slovakia; g G. Genimatas Hospital, Athens , Greece; h Erciyes University Medical School, Department of Endocrinology and Metabolism, Kayseri , Turkey; i H. Lee Moffitt Cancer Center/ University of South Florida, Tampa, Fla. , USA; j Anatomie Pathologique, Hopital Edouard Herriot, Lyon , France

a Digestive Diseases Branch, NIH, Bethesda, Md. , USA; b Division of General Surgery, Department of Surgery, Medical University of Vienna, Vienna , Austria; c Department of Hepatology and Gastroenterology, CHV A Pare Hospital, Boulogne , France; d Department of Gastroenterology, North Hampshire Hospital, Hampshire , UK; e Department of Surgery, Vivantes Humboldt Hospital, Berlin , Germany; f Department of Radiology, Royal Marsden Hospital, Sutton , UK; g Department of Pathology, Verona University, Verona , Italy; h Department of Radiology, Uppsala University, Uppsala , Sweden; i Department of Pathology, Universitatsspital Zurich, Zurich , Switzerland; j Department of Endocrinology and Metabolism, Hadassah University, Jerusalem , Israel; k Department of Oncology, Alexander Fleming Institute, Buenos Aires , Argentina; l Laboratory of Molecular Imaging and Experimental Radiotherapy, Universite Catholique de Louvain, Brussels , Belgium; m Department of Pathology, University Hospital of Kiel, Kiel , Germany

The effects of bilateral adrenalectomy on the serotonin-, somatostatin-, and gastrin-immunoreactive cells in the rat gastrointestinal tract were studied four weeks after surgery. Body weight was reduced and the small intestine shorter in adrenalectomized animals compared with controls, while no changes were found in the histology of the mucosa. In the adrenalectomized animals the number of serotonin-immunoreactive cells was increased in the cecum and large intestine, while the somatostatin-immunoreactive cells were decreased in number in the antrum and increased in the corpus, cecum, and large intestine. The gastrin-immunoreactive cells in the antrum were not affected in number, but their nuclear size was enlarged, possibly indicating increased cellular activity.

The urinary excretion of the histamine metabolite, tele-methylimidazoleacetic acid (MemAA), was measured in 15 patients with foregut carcinoid tumours (5 ECLomas, 4 gastric carcinoids of the mixed type and 6 bronchial carcinoids), High levels were related to tumour burden and presence of the foregut carcinoid syndrome. Control of symptoms was either achieved by octreotide in combination with blockade of histamine receptors or by hyperthermic liver perfusion chemotherapy. MemAA served as an exellent tumour marker for diagnosis and guidance of therapy.

Summary— Diabetic cystopathy (DCP) is a well known complication in diabetes mellitus (DM). In the present experimental study, DM was induced in rats by streptozotocin and DCP was confirmed on cystometry. In vitro studies on detrusor strips from diabetic rats showed an increased contractile response to substance P (SP) compared with controls, indicating denervation supersensitivity. A decreased response to capsaicin in diabetic detrusor strips indicated a decreased neuronal content of SP or a diminished number of SP-containing sensory nerves. This suggests that DM induces alterations in nerves containing SP which may be at least partly responsible for sensory loss and the development of DCP.

A missense mutation at codon 618 of the RET proto-oncogene is a rather unusual cause of multiple endocrine neoplasia 2A. We report the phenotypic expression of this specific RET mutation in a large Swedish family. The family was mapped back to the 18th century. Since 1971 the family has been included in a biochemical screening program, and since 1994 has undergone genetic screening. Twenty-seven individuals were found to have medullary thyroid carcinoma (MTC). Eighteen were detected by screening. The incidence of pheochromocytoma (4%) and hyperparathyroidism (7%) was low. Five individuals died of MTC, but of these none had been included in the screening program. One patient underwent prophylactic thyroidectomy after positive genetic screening. MTC tumor aggressivity differed markedly between gene carriers. The screening program shows that the clinical aggressivity of MTC can be mitigated by early and adequate surgical intervention.

Measurement of gastrin in serum or plasma in patients with gastrinoma may be complicated by the presence of circulating biosynthetic intermediates which may not be detected by commonly available immunoassays. In contrast, the "processing-independent analysis" of gastrins developed by professor Jens Rehfeld et al in Copenhagen detects gastrin forms irrespective of their size. The authors review gastrinoma pathophysiology, the biochemistry of gastrin and other biomarkers of gastrinoma, the differential diagnosis of hypergastrinemia as well as other methods currently employed in the workup of gastrinoma patients, and illustrate with a clinical case.

Gastric carcinoid tumours can be divided into subtypes with a different pathogenesis and biological behaviour. Individualized surgical treatment of these tumour types is discussed. Liver metastases imply a major problem in patients with carcinoid tumours. Patients with distant metastases can undergo resection for potential cure, or for symptom palliation, due to the slow growth rate of many carcinoid tumours. In patients with the midgut carcinoid syndrome and bilobar liver metastases, interventional treatment by tumour removal and liver embolization followed by medical therapy (octreotide and/or interferon) seem to prolong survival and reduce hormonal symptoms. Patients with the foregut carcinoid syndrome may present special problems with life-threatening release of histamine during interventional treatment.

Adult hyperinsulinaemia is usually caused by benign insulinomas. These tumours are often small, and are associated with excellent outcome of surgical removal. In cases of negative outcome of surgical exploration, or of persistent hyperinsulinaemic hypoglycaemia, the possibility must be considered of some rare condition such as the presence of metastatic insulinoma, B-cell hyperplasia, multiple micro- or macro-adenomas, hyperinsulinaemia factitia, or nesidiodysplasia. The latter is the most common cause of hyperinsulinaemia in children but is rare in adults. It is defined as a maldistributed islet cell mass within the normal exocrine pancreas, with disturbed control of hormone synthesis/secretion resulting in hormone overproduction, usually hyperinsulinaemia. In persistent hyperinsulinaemic hypoglycaemia of infancy, inactivating mutations of the sulphonylurea receptor gene is one possible cause of nesidiodysplasia. Adult nesidiodysplasia is discussed in the article, and illustrated by the case of a patient undergoing distal pancreatectomy for hyperinsulinaemia, the diagnosis being subsequently established histologically. Following spleen- and duodenum-preserving subtotal (95%) pancreatectomy, the patient was symptom-free.

Several neuroendocrine tumours, such as carcinoids and pancreatic endocrine tumours, may manifest relatively slow tumour growth. The patients may suffer from severe hormonal symptoms, largely due to liver metastases which sometimes are amenable to cytoreductive surgery. If residual tumour after primary tumour resection is multilobar, liver transplantation may be one way to treat hormonal symptoms and possibly prolonging survival. Early long-term outcome of liver transplantation in patients with neuroendocrine tumours suggests prognosis to be more favourable for carcinoids than for endocrine pancreatic tumours. It is suggested that liver transplantation may be appropriate for patients with isolated hepatic tumour disease in the following situations: 1, tumour recurrence after liver surgery for cure; 2, non-resectable liver disease, especially in cases of severe hormonal symptoms; and 3, disease progression after hepatic arterial embolisation and medical therapy. These indications are discussed in the light of three case reports.

1. The enteric nervous system (ENS) is activated when exposing the intestinal mucosa to cholera toxin or certain bile salts. Cholera toxin stimulates ENS, at least in part, by the release of 5-hydroxytryptamine (5-HT) from the enterochromaffin cells. Calcium channel blockers of the L-type markedly attenuate the fluid secretion and the luminal release of 5-HT caused by cholera toxin. 2. The objective of the present study was to elucidate if sodium deoxycholate activated ENS in a similar manner as cholera toxin. Furthermore, the effect of several calcium channel blockers was tested on the fluid secretion caused by cholera toxin or bile salt. 3. Sodium deoxycholate (4 mM) caused a release of 5-HT into the intestinal lumen, which was inhibited by calcium channel blockade. Granisetron, a 5-HT3 receptor blocker, partly inhibited the fluid secretion caused by bile salt. 4. The effects of nifedipine, felodipine, R-felodipine, H186/86 (t-butyl analogue of felodipine) on the fluid secretion caused by cholera toxin or sodium deoxycholate were studied. Both secretory states were markedly attenuated in a dose dependent manner by all calcium channel blockers tested regardless of their effects on arterial pressure. 5. It is concluded that both cholera toxin and bile salt activate ENS, at least in part, via a release of 5-HT from the enterochromaffin cells. The antisecretory effect calcium channel blockers is partly explained by an inhibition of this release of 5-HT.

A major aim of the present study was to investigate whether exposing the jejunal mucosa to a noxious stimulus induces a net fluid secretion by activating the enteric nervous system (ENS) and, if so, to what extent an axon reflex was involved. Net fluid transport was measured in vivo with a gravimetric method. The intestinal mucosa was exposed to an isotonic solution with an unphysiologically low pH (1.0). This evoked a fluid secretion, which was markedly attenuated by giving hexamethonium (nicotinic receptor antagonist) i.v. or exposing the intestinal serosa to lidocaine (local anaesthetic). Atropine (muscarinic receptor antagonist) had no effect. Luminal acid evoked a fluid secretion of the same magnitude in acutely denervated segments and in segments denervated about 3 weeks prior to the experiments. Luminal capsaicin (1.6-16 mM) did not influence jejunal net fluid transport. A second aim of the study is to investigate the effect of nifedipine (Ca channel blocker of L-type) on the acid-induced fluid secretion. Nifedipine markedly attenuated acid-induced fluid secretion. In contrast to cholera toxin-evoked secretion, the nifedipine effect was not mediated via 5 hydroxytryptamine (5-HT) as judged by measurements of 5-HT release into the intestinal lumen and the lack of effect of granisetron (5-HT3 receptor antagonist). It is concluded that the net fluid secretion evoked by hydrochloric acid in the small intestine is mainly mediated via an intramural reflex in the ENS. No experimental evidence was obtained for the involvement of an axon reflex. The site of action of the calcium channel blocker is tentatively discussed.

Hormonal overproduction is a significant problem in patients with disseminated midgut carcinoid tumors. Serotonin (5-HT) is one major product secreted from such tumors and the urinary excretion of its metabolite (5-hydroxyindoleacetic acid, 5-HIAA) serves as an important tumor marker. The present study aimed at elucidating mechanisms of tryptophan metabolite secretion to facilitate the treatment of the carcinoid syndrome. When midgut carcinoid tumors were studied in primary cell cultures, several similarities with adrenergic neurons could be demonstrated. A marked dose-dependent depletion of intracellular 5-HT could be induced by reserpine, and monoamine oxidase-activity was revealed both in functional studies and by immunocytochemistry. Differences between tumors in the ratios of tryptophan metabolites released indicated that enzymes for synthesis and degradation of 5-HT were individually expressed. Treatment with the somatostatin analogue octreotide or with dexamethasone decreased the extracellular levels of tryptophan metabolites, but the mechanisms were partly different. In some tumors octreotide also decreased the synthesis of 5-HT, while dexamethasone markedly increased the intracellular 5-HIAA levels. It is of clinical interest to further elucidate these mechanisms, since the two drugs may have complementary actions in carotid crisis reactions.

The effects of bilateral adrenalectomy on the serotonin-, somatostatin-, and gastrin-immunoreactive cells in the rat gastrointestinal tract were studied four weeks after surgery. Body weight was reduced and the small intestine shorter in adrenalectomized animals compared with controls, while no changes were found in the histology of the mucosa. In the adrenalectomized animals the number of serotonin-immunoreactive cells was increased in the cecum and large intestine, while the somatostatin-immunoreactive cells were decreased in number in the antrum and increased in the corpus, cecum, and large intestine. The gastrin-immunoreactive cells in the antrum were not affected in number, but their nuclear size was enlarged, possibly indicating increased cellular activity.

111In-radiolabelled (DTPA-D-Phe1)-octreotide scintigraphy can be used to localize neuroendocrine tumours expressing somatostatin receptors (SSTRs). The aim of this paper was to analyse the importance of tumour volume and growth for the visualization by SSTR scintigraphy of metastases from medullary thyroid carcinoma (MTC).Serum calcitonin concentrations were used to estimate volume and growth rate of MTC. Twenty-two patients who had persistent hypercalcitoninaemia after total thyroidectomy for MTC, indicating the presence of metastases, were studied.SSTR scintigraphy visualized 15 tumours in 11 patients. Patients with scintigraphically visualized tumours had higher serum calcitonin and carcinoembryonic antigen concentrations and larger tumours, and the serum calcitonin concentration increased more rapidly with time. Tumour-associated symptoms and death from MTC occurred only in patients with scintigraphically visualized tumours.Scintigraphically visualized tumours grow more rapidly and are more aggressive than nonvisualized lesions. SSTR scintigraphy can be helpful in the planning of palliative surgery for MTC and for diagnosing distant metastases, but cannot localize microscopic metastases.

A rat model of colitis [dextran sulfate (DSS)] was used to study the permeation of Evans blue (EB) from the lumen into the wall of proximal and distal colonic loops after exposure to the dye for 2 hr. Topical application of drugs used in human ulcerative colitis (lidocaine, mesalazine, prednisolone, or sucralfate) was given daily during induction of colitis to protect the mucosa. The mucosal changes were evaluated with special regard to peptidergic innervation [substance P (SP) and neuropeptide Y (NPY)], invasion of antigen-presenting polydendritic cells, and mucin-containing goblet cells. DSS-treatment caused a significantly increased permeation of EB. In the proximal loops a significant inhibition was obtained after treatment with lidocaine, prednisolone, or sucralfate. In the distal loops only treatment with lidocaine had a preventive effect. Immunocytochemically there was a clear hyperplasia of both mucosal SP- and NPY-immunoreactive nerve fibers in regions with crypt abnormalities. In these regions also most of the goblet cells were devoid of mucus. Like the changes in permeation, these morphological changes were most prominent in the distal loops. With induction of colitis, the mucosa and lamina propria were invaded by polydendritic cells; the visual score was markedly decreased in the proximal loops treated with lidocaine, prednisolone, or sucralfate. In the distal loops similar effects were obtained after treatment with lidocaine or prednisolone. Prevention of the influx of antigens in both loops after lidocaine treatment with reduced recruitment of polydendritic cells into the lamina propria is suggested. The nerve hyperplasia may thus be secondary to luminal challenge with antigens during induction of colitis. The discrepancy between increased permeation and absence of polydendritic cell response in the distal loops after prednisolone may reflect separate actions of steroids on the intestinal epithelium and the immune cells.

Malignant endocrine tumors of the pancreas are a heterogenous group of tumors with a multipotential secretory capacity. The lesions are generally slow growing with a relatively long life expectancy from the time of diagnosis. Death results from a combination of local and metastatic disease and the sequelae of excess hormone secretion. While potentially successful curative resections are rare, long term survival is frequently possible based on the rate of growth and the inhibition of the bioactive effects of the secretory products of the tumor. Regional control with palliative surgical debulking and transcatheter arterial embolization of hepatic metastases has an important role in terms of symptomatic relief and long term survival. These tumors respond frequently to chemotherapy. Combination chemotherapy is more effective than single agent treatment. Preliminary information suggests that leukocyte interferon is useful in treatment, but this agent still requires careful prospective evaluation. While current data do not support the use of octreotide for an antitumor effect, it is capable of producing prompt and substantial symptomatic relief with minimal side effects in a large proportion of patients with functional malignant endocrine tumors of the pancreas. Many advances have been made in the recognition, diagnosis and management of patients with malignant endocrine tumors of the pancreas. Additional basic cellular research is necessary to define the molecular and cell biologic factors of these tumor cells. Particular facets that require further understanding include their basic cytogenetic abnormality, regulation of peptide production and the role of peptides and other growth factors in endocrine, paracrine and autocrine regulatory relationships. The answers to these questions will hopefully promulgate the discovery of improved cytotoxic agents, better peptide pharmacotherapeutic agents and improve the overall management of patients with unresectable malignant endocrine tumors of the pancreas.

The effect of acid inhibition on gastric endocrine cells was investigated in Praomys (Mastomys) natalensis. Long-term treatment (1 to 32 weeks) with an irreversible histamine 2-receptor blocker (loxtidine) caused a sustained increase in plasma gastrin levels, which was accompanied by a gradual increase in histamine and histidine decarboxylase activity of the gastric oxyntic mucosa. The density of endocrine cells in the oxyntic mucosa increased gradually, doubled by 8 weeks, and was three times that of controls after 24 weeks of treatment. Hyperplastic changes in the endocrine cell population were evident after 2 to 8 weeks in all animals, whereas dysplastic or neoplastic lesions were observed in half the animals after 16, 24, and 32 weeks of treatment. Gross tumors in the oxyntic mucosa were observed in 1/4 of the animals treated for 24 or 32 weeks. Proliferating cells were identified as enterochromaffinlike cells because they were argyrophilic and immunopositive for chromogranin A and histamine. The results demonstrate that histamine 2-receptor blockade initiated by loxtidine promotes a rapid development of enterochromaffinlike cell tumors in Mastomys and suggest a critical role for gastrin in the formation of these tumors. However, the rate and frequency by which carcinoid tumors appeared in Mastomys after acid inhibition was much greater than that reported in other species, indicating that several factors, including hormonal and genetic factors, are important in the development of gastric endocrine tumors.

To evaluate the results of treatment of a consecutive series of patients with adrenocortical carcinoma who presented during the six year period 1985 to 1991.Open study.Departments of Surgery, Pathology, Endocrinology, and Clinical Chemistry, Sahlgren Hospital, Göteborg, Sweden.10 consecutive patients, two with recurrent and eight with primary adrenocortical carcinoma.All patients were treated surgically. Two required preoperative embolisation of the tumour vessels to facilitate excision of particularly large tumours, and eight were given adjuvant treatment with mitotane (o,p'-DDD).At a median follow up of 1.5 years (range 3 months, to 21 years) 6 patients were alive with no radiological or biochemical signs of disease; 2 were alive, but with signs of recurrence (at 3 months and 6 years, respectively); and two had died of their disease (at 4 and 8 months, respectively). For the past two years all patients have had their urinary steroid profiles monitored by gas chromatography and mass spectrometry to detect recurrence of the tumour at the earliest possible stage.Operation is the treatment of choice for patients with adrenocortical carcinoma, particularly stages I-III. The role of mitotane as adjuvant treatment can be evaluated only in multicentre studies.

10087 Background: The tyrosine kinase inhibitor (TKI) imatinib is the first-line palliative treatment inhibiting mutated KIT. Our aim was to compare the survival of patients only surgically treated...

The aims of this study were to calculate the true incidence of colonic carcinoids in Connecticut from 1976 to 1986 and to determine the outcome of patients with these lesions. Fifty-four patients with carcinoids of the colon were identified (23 male and 31 female patients). Their average age was 64.1 +/- 2.1 years, with a range of 12 to 83 years. The age-adjusted incidence was 0.31 cases/100,000 population/year. Forty-eight percent of the carcinoids were located in the cecum; 16%, ascending colon; 6%, transverse colon; 11%, descending colon; 13%, sigmoid colon; and 6%, not assigned. Follow-up information was available in all cases. The crude 2-year survival rate was 63%, whereas the 5-year survival rate was 37%. Only one of six (16.6%) lesions that were 2 cm or smaller metastasized, whereas 23 of 31 lesions larger than 2 cm metastasized (74%). Six patients have survived an average of 43.5 months after local excision of their carcinoids. Fourteen patients died of their carcinoids. Metachronous gastrointestinal malignant neoplasms developed in six patients. These results suggest that, when found at an early stage, carcinoids of the colon (2 cm or smaller) can be treated by local excision. The vast majority of colonic carcinoids, however, are discovered at an advanced stage and should be treated aggressively with standard colonic resection. In addition, surveillance of the entire gastrointestinal tract should be initiated in these patients because of a high rate of other gastrointestinal malignant neoplasms.

A new paradigm for the treatment of ulcerative colitis has recently been presented: Treatment of the mucosa with lidocaine (2%) enemas for prolonged periods. This therapy was introduced based on the hypothesis that hyperreactive autonomic nerves may play a pathogenetic role in the disease. One hundred consecutive patients have now been treated and the results presented. The proctitis patients all responded to the treatment, despite previous therapeutic failures in more than two-thirds of the cases. They were treated for 3-12 weeks, but 68% had a relapse (observation period 20 months). Of the 49 patients with proctosigmoiditis, two-thirds had chronic symptoms resistant to previous therapy. One of these patients did not respond to lidocaine, but developed fulminant total colitis. The other patient had therapeutic failure with lidocaine but responded well to subsequent cortisone enemas. The patients were treated until the subsets of T-lymphocytes (OKT4+ and OKT8+) disappeared from the mucosa. This occurred in parallel with symptomatic relief and eventual healing in 83% of the patients after treatment for 6-34 weeks. Of all the patients with proctosigmoiditis, 42% presented with recurrent symptoms (observation period 16 months). Of the 17 patients with left-sided colitis, all went primarily into remission within 2-4 months, but 23% had a relapse (observation period 13 months). The 6 patients with total colitis had symptomatic relief and improvement of histology when treated over 3-8 months. One patient had recurrence after 12 months. Treatment with a local anaesthetic in ulcerative colitis is a new approach to mucosal inflammation. The beneficial effects may be due to blockade of certain neural effects, such as epithelial proliferation and shedding and congestion of the mucosal vasculature, with actions on cells of the immune system.

A patient with pernicious anemia, atrophic non-antral gastritis, hypergastrinemia, and widespread hyperplasia of enterochromaffin-like cells and manifest enterochromaffin-like cell carcinoma was followed up during 39 months, including 15 months after gastric resection. In this case normalization of gastrin levels did not prevent the development of multiple gastric carcinoids in the fundic mucosa, suggesting that factors other than gastrin are of importance in the pathogenesis.

Intravesical pressure recordings of the urinary bladder in anesthetized rats were performed and the role of substance P (SP) in the motor control of this organ was evaluated. Regional injection of SP (0.4 nmoles i.a.) into the superior vesical artery elicited a prompt bladder contraction; this motor response was dosedependent. The detrusor contraction could be completely inhibited by a SP-analogue, (D-Pro2, D-Trp7, 9)-SP (45–90 nmoles i.a.). Further-more, the detrusor contraction evoked by preganglionic stimulation of the pelvic nerves was partially inhibited by the same antagonist in a higher dose (65% reduction at a total dose of 150–300 nmoles). The contractile response to SP (0.5 nmoles i.a.) was also significantly reduced after blockade of muscarinic receptors with atropine (50% reduction at 1 mg/kg i.a.) or after ganglionic blockade with hexamethonium (75% reduction at 25 mg/kg i.v. +50 mg/kg hr i.a.). Immunocytochemical studies demonstrated the occurrence of SP-immunopositive nerve terminals in the detrusor part of the rat urinary bladder. Based on these findings it is suggested that SP may act as a neurotransmitter/modulator in this organ. The mechanism of action for SP on the detrusor seems to be complex and may involve ganglionic transmission via both types of cholinoceptors as well as direct activation of smooth muscle.

The blood levels of serotonin (5-HT) and substance P (SP) in the portal vein were studied after splanchnic nerve stimulation in the cat. The portal levels of both substances were studied before, during and after splanchnic nerve stimulation. There was a twofold increase in 5-HT during stimulation whilst the SP concentration remained unchanged. These results suggest that the nervous control of the amine release into the portal stream and the mechanism that regulates the release of the polypeptide is not the same.

Gastric motility and pyloric contractility were studied in laparotomized cats under chloralose anaesthesia by recording the intragastric volume and changes in an applied constant transpyloric flow of body-warm saline. Unilateralefferent electrical stimulation of the cervical vagi resulted in a prompt gastric contraction and a delayed pyloric contraction. In one third of the animals abiphasic pyloric motor response, consisting of a short period of increased flow preceding the longlasting decrease or cessation of the flow was observed. Afteratropine (0.2 mg/kg b.w.) the vagal nerve stimulation resulted in agastric relaxation, while the biphasic pyloric motor response was even more pronounced, with a significantly longer latency of the contractile phase. Addition ofguanethidine (2 mg/kg b.w.) did not affect these motor responses. Afterhexamethonium (25 mg/kg i.v. and 50±10 mg per kg i.a. b.w.) the stimulation procedure still resulted in a slight gastric relaxation, while the pyloric contraction was effectively blocked. However, the relaxatory phase required theaddition of atropine to become antagonized indicating separate transmission mechanisms for the relaxatory and contractile components of the pyloric motor response at efferent vagal stimulation.

Serotonin immunoreactive material was localized to rat enterochromaffin cells (EC cells) at the subcellular level using antibodies to serotonin (5-HT) raised in rabbits. Ultrathin sections from paraformaldehyde fixed plastic embedded tissues were directly labelled with the 5-HT antiserum, using the protein A-gold technique to visualize the immunoreaction. The 5-HT immunoreactivity (5-HT-IR) in the rat gastrointestinal mucosa was exclusively localized to epithelial EC cells with a low background over other epithelial non-enterochromaffin cells. Quantitative evaluation of the immunoreaction revealed that most of the 5-HT-IR in the cytoplasm of EC cells (60%) was located over the dense cores of the secretory granules. However, a significant part of the cytoplasmic 5-HT-IR (40%) was located outside the dense cores of the secretory granules which suggests that different forms of 5-HT storage may exist.

Two hundred thirty-four patients with extensive ulcerative colitis from the city of Göteborg, Sweden have been followed up and the cumulative risk of development of cancer of the large bowel was estimated. These patients constitute all persons in this region who developed an extensive ulcerative colitis between 1951 and 1974. All patients were followed up until December 1975. The mean observation time was 8.5 years, median value six years. Fifteen patients developed carcinoma of the large bowel. Five of the 15 patients were still alive in December 1975. The expected number of colorectal carcinomas in a matched reference group was 0.49. The cumulative incidence of carcinoma 25 years after the onset of colitis for the whole group of patients was 34% and for those who developed the disease before 25 years of age it was 43%.

This review comprises an analysis of the treatment alternatives for pancreatic tumours of the MEN 1 syndrome presently in use at the Surgical Endocrine Unit of Sahlgrenska Hospital, GoUteborg, Sweden. Patients with pancreatic tumours localized by imaging studies are offered surgical excision. Otherwise the therapy is individualized. Some patients with Zollinger-Ellison syndromes are managed with medical antiulcer treatment, others are treated with total gastrectomy. MEN 1 patients with other syndromes, e.g. insulinomas, glucagonomas and VIPomas, are offered surgery with the aim of tumour excision. Even noncurative excision might benefit the management of these cases and possibly prolong life. Asymptomatic patients with raised hormonal tumour markers in whom imaging studies have failed to reveal any tumours, are continuously followed without treatment. The malignant behaviour of the pancreatic tumours varies between different MEN 1 families. MEN 1 patients are considered for total pancreatectomy if they ha...

This review comprises an analysis of the treatment alternatives for pancreatic tumours of the MEN 1 syndrome presently in use at the Surgical Endocrine Unit of Sahlgrenska Hospital, Göteborg, Sweden. Patients with pancreatic tumours localized by imaging studies are offered surgical excision. Otherwise the therapy is individualized. Some patients with Zollinger-Ellison syndromes are managed with medical antiulcer treatment, others are treated with total gastrectomy. MEN 1 patients with other syndromes, e.g. insulinomas, glucagonomas and VIPomas, are offered surgery with the aim of tumour excision. Even noncurative excision might benefit the management of these cases and possibly prolong life. Asymptomatic patients with raised hormonal tumour markers in whom imaging studies have failed to reveal any tumours, are continuously followed without treatment. The malignant behaviour of the pancreatic tumours varies between different MEN 1 families. MEN 1 patients are considered for total pancreatectomy if they have multiple malignant pancreatic tumours and if the pancreatic disease has caused high morbidity and mortality in the family.

The volume flow in the calves was measured by means of plethysmography in 14 patients who had a cholecystectomy and in 3 patients who had a wedge biopsy of the breast. The blood flow increased 100% during abdominal surgery, while no change was observed during the extraabdominal operation. When the legs were placed horizontally during cholecystectomy clear signs of venous pooling were observed. Venous pooling in the calves increased when pillows were placed in the popliteal fossae to prevent over-stretching of the knees. Elevation of the legs 20 degrees in the hip joints decreased the venous stasis considerably. Except for intermittent effects on the circulation caused by strong retraction of the intestines, no clear-cut change in the degree of venous stasis was observed during the course of a cholecystectomy.

Serotonin-like immunoreactivity (5-HT-LI) has been localized at the ultrastructural level in enterochromaffin (EC) cells of rat gastrointestinal tract. Ultra-thin sections of tissues embedded in epoxy resin were incubated with 5-HT antisera and antibody binding sites were visualized with protein A-gold. Three different antisera were compared and were shown to require different fixation regimens for optimal preservation of 5-HT-LI. For one antiserum, tissues fixed in glutaraldehyde and osmium tetroxide could be used to demonstrate 5-HT-LI in EC cells. Immunocytochemical localization of 5-HT can thus be performed with good ultrastructural preservation of tissues. Quantitative evaluation of the intracellular distribution of 5-HT-LI was performed on EC cells from antrum, duodenum, and proximal colon, fixed in glutaraldehyde only. In all three locations, the majority of the gold particles (90%) in EC cells were localized over the dense core of the secretory granules, while a minor fraction (10%) were localized in parts of the cytoplasm devoid of granules. In EC cells fixed in glutaraldehyde and post-fixed in osmium tetroxide, 5-HT-LI was reduced by about 85%, although intracellular distribution was essentially the same as in cells fixed in glutaraldehyde alone. The results indicate that 5-HT in EC cells is stored mainly in secretory granules, with a small fraction of 5-HT being localized outside the granules.