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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

AimTo gather data regarding factors predicting responsiveness to pasireotide in acromegaly.Patients and methodsSSTR2a, SSTR3, SSTR5, AIP, Ki-67 and the adenoma subtype were evaluated in somatotroph adenomas from 39 patients treated post-operatively with somatostatin analogues (SSAs). A standardized SSTR scoring system was applied (scores 0–3). All patients received first-generation SSAs, and 11 resistant patients were subsequently treated with pasireotide LAR.ResultsNone of the patients with negative or cytoplasmic-only SSTR2a expression (scores 0–1) were responsive to first-generation SSAs, as opposed to 20% (score 2) and 50% of patients with a score of 3 (P=0.04). None of the patients with an SSTR5 score of 0–1 were responsive to pasireotide, as opposed to 5/7 cases with a score of 2 or 3 (P=0.02). SSTR3 expression did not influence first-generation SSAs or pasireotide responsiveness. Tumours with low AIP were resistant to first-generation SSAs (100 vs 60%; P=0.02), while they had similar responsiveness to pasireotide compared to tumours with conserved AIP expression (50 vs 40%; P=0.74). Tumours with low AIP displayed reduced SSTR2 (SSTR2a scores 0–1 44.4 vs 6.7%; P=0.006) while no difference was seen in SSTR5 (SSTR5 scores 0–1 33.3 vs 23.3%; P=0.55). Sparsely granulated adenomas responded better to pasireotide compared to densely granulated ones (80 vs 16.7%; P=0.04).ConclusionThe expression of SSTR5 might predict responsiveness to pasireotide in acromegaly. AIP deficient and sparsely granulated adenomas may benefit from pasireotide treatment. These results need to be confirmed in larger series of pasireotide-treated patients.

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 membrane and intracellular steps of thiamin (T) uptake were studied in rat isolated enterocytes. The membrane step was investigated by using enterocytes deenergized with 25 μM rotenone and a short (30 s) incubation time, while the intracellular metabolic step was assessed by using nor-moenergized (normal) cells incubated for a longer (30 min) time. Evaluation of Km, Jmax and KD (apparent passive permeability coefficient) values, at 30 s incubation, indicated that deenergization slightly reduced both the affinity and the capacity of the saturable component of T uptake, as well as the capacity of the non-saturable component. At 30 min incubation, deenergization suppressed completely the saturable component, without affecting the non-saturable component. Comparison of the Km and Jmax values of the saturable components in nor-moenergized enterocytes at 30 s and 30 min indicated that intracellular metabolic phosphorylation is probably the event responsible for the active process involved in T uptake.

Gastro-oesophageal reflux disease has a chronic course, and often requires long-term treatment. Proton pump inhibitors are the treatment of choice for both acute and maintenance treatment, but little is known from randomized controlled trials of their effects beyond 1 year.To compare the efficacy and safety of two doses of rabeprazole with 20 mg omeprazole in the maintenance treatment of erosive gastro-oesophageal reflux disease over 5 years.Two hundred and forty-three patients who had previously responded to acute treatment for erosive gastro-oesophageal reflux disease were prospectively randomized to receive 5 years of treatment with rabeprazole (10 or 20 mg daily) or omeprazole (20 mg daily). The primary outcome measure was endoscopically confirmed relapse of erosive gastro-oesophageal reflux disease.One hundred and twenty-three patients (51%) completed all 5 years of the study, with similar completion rates in the three groups. Relapses occurred in nine of 78 (11.5%), eight of 82 (9.8%) and 11 of 83 (13.3%) patients in the rabeprazole 20 mg, rabeprazole 10 mg and omeprazole 20 mg groups, respectively. Gastric biopsy showed no evidence of any harmful effects. All treatments were well tolerated.Rabeprazole 10 mg, rabeprazole 20 mg and omeprazole 20 mg all had similar efficacy in the maintenance treatment of gastro-oesophageal reflux disease. All three were safe and well tolerated during 5 years of treatment.

The endocrine tumors of the pancreas and the gastrointestinal tract may be of difficult interpretation. The recent histopathological classification of the endocrine tumors by the World Health Organization (W.H.O.) introduced new criteria for their interpretation, classification and diagnosis. The present paper aims at defining simple guidelines for the practical, routine approach to the histopathological diagnosis of the endocrine tumors of the digestive system according to the new W.H.O. criteria.

The effects of chemical (CD) and surgical (SD) deafferentation of the cerebellum on thiamine pyrophosphate (ThPP)- dependent enzymes (transketolase, TK; pyruvate-, PDH, and alpha-ketoglutarate, alphaKGDH, dehydrogenases) and thiamine (Th) metabolizing enzymes (thiamine pyrophosphokinase, ThPK; thiamine mono-, ThMPase, and pyrophosphatases, ThPPase) were evaluated in vitro in rats in steady state conditions. The enzymes were also determined in the intact cerebral cortex of the same animals. CD was carried out by i.p. injection of 3-acetylpyridine, followed by harmaline and niacinamide. SD was carried out by complete dissection of the peduncles of the left cerebellar hemisphere. Chemical and surgical cerebellar deafferentations significantly lowered the contents of both Th-metabolizing and ThPP-dependent enzymes in the cerebellum without modifying those of the cerebral cortex. ThPK and TK, which are particularly concentrated in neurons, were the most affected enzymes. The decrease in ThPP-dependent enzymes shown here is associated with the slowing down of the Th phosphorylation-dephosphorylation cycle and with no modification in the ThPP content in the cerebellum, both of which were found in a previous study. Cerebellar deafferentation seems to only affect the apoenzyme moiety of the enzymes.

The aim of this prospective research was to compare, in a seven-year follow-up, the clinical outcome of ulcerative pancolitis with that of non-progressive ulcerative colitis. The activity of the disease was evaluated by a Clinical Activity Index and an Endoscopic Index. Of 112 cases of ulcerative colitis observed, 95 showed no change in extent and were studied as examples of non-progressive UC, and in this group the extension of the disease was: pancolitis in 19%, left-sided colitis in 39%, proctosigmoiditis in 17% and proctitis in 25%. A colectomy had to be performed in 5%. None of the enrolled cases developed a cancer during the follow-up. The patients with ulcerative pancolitis or left-sided colitis were treated with 5-ASA 1.6 g/day in a delayed-release formulation, while the cases with proctosigmoiditis or proctitis were treated with 5-ASA enemas 4 g/day. The cases with more than one relapse/year were 39%. The proportion of patients with only one relapse/year was 53%. The patients with steady remission for all the seven years of the trial were only 8%, but with a statistically significant difference between the groups with initial diagnosis of proctosigmoiditis or proctitis and the group with initial diagnosis of pancolitis or left-sided colitis (12% versus 5%). Among the cases with continuous remission, 37% showed colonic alterations, with an endoscopic score higher than 4 but a clinical score less than 6. Side-effects were observed in 6% patients but without treatment withdrawal. Non-progressive ulcerative colitis throughout the colon has a relatively good prognosis which seems to be independent of the location of the disease, even if we have found a statistically significant higher percentage of cases with steady remission among the patients with more distal disease.

The major clinicopathologic aspects of 55 gastric neuroendocrine tumors were analyzed. Forty-six of 55 cases were well-differentiated tumors and 9 were poorly differentiated gastric neuroendocrine carcinomas. Well-differentiated gastric neuroendocrine tumors comprised 1 gastrinoma and 45 enterochromaffin-like (ECL)-cell tumors. ECL tumors were grouped depending on their clinical background. Type 1, associated with chronic atrophic gastritis of the acidopeptic mucosa (A-CAG), included 28 cases with tumor growths mainly restricted to the mucosa and submucosa, with no metastasis. Type 2, associated with hypertrophic gastropathy, included seven cases, six of which were associated with Zollinger-Ellison syndrome (ZES) and multiple endocrine neoplasia type 1 (MEN-1), including two cases with local metastasis. Type 3, not associated with any significant clinicopathologic condition (sporadic), included 10 cases, 7 of which were deeply invasive and 5 metastatic. The nine gastric neuroendocrine carcinomas were highly aggressive metastatic tumors. At follow-up, no tumor-related death was observed for type 1 and type 2 ECL tumors. Type 3 (sporadic) ECL tumors were fatal in 3 of 10 cases, and 6 of 9 patients with gastric neuroendocrine carcinomas died of their tumor disease. It is concluded that type 1 and type 2 well-differentiated ECL tumors are benign or low-grade tumors, whereas type 3 well-differentiated ECL tumors and the poorly differentiated neuroendocrine carcinomas are malignant neoplasms.

The effects of acute ethanol administration on different steps of thiamine (T), thiamine monophosphate (TMP) and pyrosphosphate (TPP) metabolism were determined in vivo in nervous tissues (cerebral cortex, cerebellum, brain stem and sciatic nerve) and in other tissues (small intestinal mucosa, kidney, heart, skeletal muscle and liver) of rats. The radioactivity of T and its phosphoesters in plasma and tissues was determined under steady-state conditions and at fixed time intervals (0.25-24 hr) after an i.p. injection of Thiazole-[2-14C]-thiamine (30 micrograms: 1.25 microCi) in the presence of a constant plasma ethanol concentration (37 mM; 1.75 g.l-1) produced by repeated intragastric administration of ethanol. Control animals received water intragastrically. Ethanol-treated rats and controls were starved, with water ad libitum during the 24 hr study period. Data were evaluated by using appropriate compartmental models, which allowed calculation of fractional rate constants, turnover rates and turnover times. In nervous tissues ethanol enhanced TMP entry (without affecting T entry or T and TMP release), reduced turnover time of total T and TPP, caused an almost general enhancement of TPP dephosphorylation without affecting T pyrophosphorylation, and increased markedly T content in the mixture released by tissues. Overall, ethanol appeared to enhance exchanges of T compounds in nervous tissues. In other tissues, the effects of ethanol were less consistent. Ethanol increased T uptake in kidney and liver and T release in liver and heart, but had no effect on T exchanges in the small intestinal mucosa and in skeletal muscle. In the presence of ethanol, TMP uptake increased in heart and skeletal muscle and decreased in the small intestinal mucosa, while TMP release decreased in heart and remained unchanged in all other organs. Turnover times tended to increase for total T and to decrease for TPP. T pyrophosphorylation was generally reduced, and T phosphates dephosphorylation generally enhanced. T became the most abundant component in the mixture released from all tissues.

Tumours producing regulatory peptides or amines common to the nervous and endocrine systems are called neuroendocrine tumours [1, 2]. They are composed of variably differentiated cells that share a number of morphologic markers normally expressed by neurons and endocrine cells [3, 4]. In laboratory animals, the occurrence of neuroendocrine tumours, which is virtually null in young animals, shows an extraordinary increase with age [5, 6]. The reasons for this phenomenon are still poorly understood; however it has been hypothesised that neuroendocrine tissues become particularly susceptible to transformation following age-related endocrinological imbalances [5–7].

The aim of this study was evaluating the correlation between intra-abdominal pressure (IAP) and Sequential Organ Failure Assessment (SOFA) [1] in critically ill patients admitted to our ICU.

The need for standards in the management of patients with endocrine tumors of the digestive system prompted the European Neuroendocrine Tumor Society (ENETS) to organize a first Consensus Conference, which was held in Frascati (Rome) and was based on the recently published ENETS guidelines on the diagnosis and treatment of digestive neuroendocrine tumors (NET). Here, we report the tumor-node-metastasis proposal for foregut NETs of the stomach, duodenum, and pancreas that was designed, discussed, and consensually approved at this conference. In addition, we report the proposal for a working formulation for the grading of digestive NETs based on mitotic count and Ki-67 index. This proposal, which needs to be validated, is meant to help clinicians in the stratification, treatment, and follow-up of patients. © Springer-Verlag 2006.

Ventricular myocardial cell action potentials were measuredin situ by means of intracellular microelectrodes in the heart of pyridoxine-deficient rats both at spontaneous frequency and at frequencies increased to higher levels. Pyridoxine deficiency lowered the rates of depolarization and repolarization phases of ventricular action potentials thus lengthening their duration. A noticeable bradycardia seemed to be induced by pyridoxine deficiency.

Ventricular cell action potentials were measured in situ using intracellular microelectrodes in the hearts of vitamin A-deficient rats, both at the spontaneous heart rate and at rates increased to various higher levels. The changes found indicate that a lack of vitamin A in the tissue may modify the ion permeability underlying cardiac electrogenesis, without affecting cardiac energetic metabolism. Results are discussed in the light of recent theories that vitamin A may stabilize the structure of cell membranes and control their permeability.

1. A method for the chromatographic separation of thiamine and its mono-, di- and tri- phosphoric esters on Dowex columns I, X-8 (200-400 mesh) was studied, pure solutions being used. 2. The use of two columns containing the resin in borate and acetate form respectively proved to be particularly suitable for the preliminary separation of T and TMP from TDP and TTP. 3. The succesive use of 0.03 M H3BO3 and 0.1 M NaCl in 0.1 M HCl allowed the elution of T and TMP, respectively, from the first column, while the elution of TDP and TTP was achieved by using 0.02 M Na acetate in 0.04 M acetic acid and 0.1 M HCl respectively. 4. The recoveries of the added substances amounted to 91–97%.

The myocardial fibre cell action potentials of rats, made thiamine deficient by a synthetic diet or by antivitamin treatment (pyrithiamine or oxythiamine), have been measured in Situ by means of fluctuating microelectrodes. Although the amplitude of the action potential was unchanged, its duration was distinctly increased, owing to a lessened repolarization. Bradycardia, which was also found in thiamine deficiency, was viewed essentially as a consequence of the slowed cellular membrane recovery processes.

A total of 60 patients with endoscopically diagnosed duodenal ulcer were treated with pirenzepine or cimetidine for 8-10 weeks until endoscopic healing of the ulcer. After ulcer healing 20 random patients received 50 mg pirenzepine per os daily for 6 months, 20 received 400 mg cimetidine per os daily for 6 months, and the remaining 20 received topic antacids for 6 months whenever they complained of pyrosis and/or epigastric pain. Endoscopic checks were repeated after 6 months (or earlier, if clinical picture was consistent with relapsing ulcer). Relapsing duodenal ulcer or erosive duodenitis was observed in 5 patients treated with pirenzepine (25%), in 4 patients treated with cimetidine (20%), and in 13 patients treated with occasional antacids (65%). Differences were significant between the antacid-treated patients and each of the other two groups, but not significant between pirenzepine-treated and cimetidine-treated groups.

In different animal species, including man, thiamin is absorbed in vivo from the small intestine by means of two mechanism: at low intraluminal concentrations (less than 1.5 microM), absorption shows a saturation kinetics; at higher concentrations, passive transport (diffusion) takes place. The absorption is maximal in the duodenum, its rate decreasing caudally along the small intestine. In vitro at low concentrations, the transcellular transport system of thiamin shows the following general features: it takes place against a chemical concentration gradient, is easily saturable (Km = 0.16-0.63 microM; Vmax = 5.2 mumol X g-1 X h-1), is blocked by cellular metabolic inhibitors, anoxia, low temperature and thiamin structural analogues. It is Na+-dependent and operates mainly from mucosa to serosa. In contrast, distinctive features of the thiamin transfer are the following: entry in the enterocyte in the free form (sodium-independent); pyrophosphorylation by means of a cytoplasm thiamin-pyrophosphokinase; the dephosphorylation of thiamin-pyrophosphate by means of particulate intracellular phosphatases; the cellular exit mainly in the free form, through the action of the controluminal Na-K activated ATPase. A working scheme for thiamin intestinal transport is proposed and discussed.

A total of 110 subjects with duodenal ulcer healed with cimetidine (C) (50 patients), ranitidine (R) (40 patients) or pirenzepine (20 patients) was randomly divided in 3 groups. The first group (40 patients) was treated with R (150 mg nightly); the second group (40 patients) with C (400 mg nightly) and the third group with antacids as needed for symptomatic relief. The presence of the ulcer and its healing were established by endoscopy, which was repeated after 6 and 12 months of treatment, or previously if symptoms suggested recurrence. At the end of the year's follow-up, no recurrence of ulcers was observed in 75% of the R group, in 77.5% of the C group and in 40% of the antacids group. Some erosive duodenitis developed in the first and second groups (17.5% and 20% respectively), but none in the antacids group. Most of the ulcers that recurred did so in the first 6 months of treatment. No relevant side-effects were observed with the treatments described. Although no significant difference was detected between C and R treatments, both appeared to be clearly more effective than antacids. The usefulness of adequate prophylactic treatment against the tendency of duodenal ulcer to recur is stressed.

30 patients submitted to partial gastrectomy (Billroth II) who later suffered digestive complaints (pain, "heartburn", bilious vomiting) showed gastric hyperemia, oedema and some erosions of the gastric stump when examined by endoscopy, the presence of cancer having been excluded by biopsy. These patients were randomly allocated into 2 groups of 15, one of which was treated with sucralfate (1 g 4 times), and the other with carbenoxolone (50 mg 4 times), daily for 8 weeks. After sucralfate the endoscopic finding showed a clear improvement in the gastric wall, accompanied by the almost complete disappearance of the complaint symptoms, in 13 cases (86.6%). After carbenoxolone the same improvement was observed at the endoscopy in 12 cases (80%), with similar recovery from symptoms. Nevertheless, no histological changes that could be attributed to the treatments were observed. In those patients whose endoscopic pattern remained unchanged by either drug, the complaints did not show any relief. No side-effects were detected during either of these drug treatments, each of which showed a similar therapeutic efficacy.

Starting from mucosal cells, isolated from rat small intestine, subcellular fractionation was carried out. Four fractions were prepared and characterized by marker enzymes and electron microscopic examination: nuclei plus microvilli, mitochondria, microsomes and supernatant. Thiamine-pyrophosphokinase activity was localized mainly in the supernatant fraction, with minor amount in mitchondria and microsomes. On the contrary thiamine-pyrophosphatase activity was present only in the particulate fractions (especially in microsomes), being completely absent from the supernatant.