Sodium iodide symporter (NIS)-mediated radiovirotherapy of hepatocellular cancer using a conditionally replicating adenovirus.

In this study, we determined the in vitro and in vivo efficacy of sodium iodide symporter (NIS) gene transfer and the therapeutic potential of oncolytic virotherapy combined with radioiodine therapy using a conditionally replicating oncolytic adenovirus. For this purpose, we used a replication-selective adenovirus in which the E1a gene is driven by the mouse alpha-fetoprotein (AFP) promoter and the human NIS gene is inserted in the E3 region (Ad5-E1/AFP-E3/NIS). Human hepatocellular carcinoma cells (HuH7) infected with Ad5-E1/AFP-E3/NIS concentrated radioiodine at a level that was sufficiently high for a therapeutic effect in vitro. In vivo experiments demonstrated that 3 days after intratumoral (i.t.) injection of Ad5-E1/AFP-E3/NIS HuH7 xenograft tumors accumulated approximately 25% ID g(-1) (percentage of the injected dose per gram tumor tissue) (123)I as shown by (123)I gamma camera imaging. A single i.t. injection of Ad5-E1/AFP-E3/NIS (virotherapy) resulted in a significant reduction of tumor growth and prolonged survival, as compared with injection of saline. Combination of oncolytic virotherapy with radioiodine treatment (radiovirotherapy) led to an additional reduction of tumor growth that resulted in markedly improved survival as compared with virotherapy alone. In conclusion, local in vivo NIS gene transfer using a replication-selective oncolytic adenovirus is able to induce a significant therapeutic effect, which can be enhanced by additional (131)I application.

[Diseases in gastroenterology]. / Gastroenterologische Krankeitsbilder.

Autoimmune diseases of gastrointestinal organs require a timely diagnosis to facilitate appropriate treatment. It is an important challenge to differentiate autoimmune pancreatitis (AIP) from pancreatic carcinoma. This is hampered by the occurrence of focal changes in the pancreatic parenchyma in AIP. Additionally, lymphadenopathy and duct obstruction are present. Autoimmune hepatitis (AIH) results in liver cirrhosis and organ failure if not discovered in time. In 40 % of patients with AIH the initial diagnosis is not achieved at an early stage. Intestinal tuberculosis must be differentiated from Crohn's disease, especially if modern biotherapies employing antibodies are planned.

[Medicinal therapy of metastasized neuroendocrine tumors of the gastroenteropancreatic system.] / Medikamentöse Therapie bei metastasierten neuroendokrinen Tumoren des gastroenteropankreatischen Systems.

Neuroendocrine neoplasms of the gastroenteropancreatic system are classified according to the WHO classification system 2010 into neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC). The proliferation index Ki-67 and the grading of NETs is essential for the prognosis and therapy plan. Also NET tumor biology and therapeutic options may differ depending on the primary NET tumor location. Palliative therapy of inoperable NETs involves local ablative methods in cases of primary liver metastasis, peptide receptor radionuclide therapy (PRRT) in NETs expressing somatostatin receptors and different options for medicinal therapy. This manuscript reviews the current role of biotherapy with somatostatin analogues and interferon-alpha for symptom and tumor control. In addition conventional chemotherapy regimens and novel molecular targeted therapeutic options, such as sunitinib or everolimus in NET of the pancreas are reviewed. Possible therapeutic algorithms are discussed.

Reduced proliferation and a high apoptotic frequency of pancreatic beta cells contribute to genetically-determined diabetes susceptibility of db/db BKS mice.

Leptin receptor-deficient db/db mice are a commonly used research model and it is known that the genetic background, on which the mutation is bred, modulates the phenotype. While diabetes-resistant strains sustain near normal glycemia and hyperinsulinemia, susceptible backgrounds develop overt hyperglycemia and islet involution. We hypothesized that genetically-determined differences in the proliferative capacity and the apoptotic frequency of pancreatic beta cells contribute to this phenotypic disparity. We studied C57BLKS/J (BKS; diabetes-susceptible) and C57BL/6 (B6; diabetes-resistant) db/db mice and heterozygous controls from 5 to 12 weeks of age. Body weight, fasting blood glucose, plasma insulin, HOMA-IR, alpha cell mass, beta cell mass, proliferation and apoptosis were measured. Comparable insulin resistance developed in the 2 db/db strains, which was well compensated for on both genetic backgrounds until 7 weeks of age. As expected, the BKS mice became hyperglycemic at 9 weeks. Beta cell proliferation was initially increased in both db/db strains but decreased rapidly in the BKS mice with advancing age. The rate of beta cell apoptosis was already higher in prediabetic BKS mice than in their B6 counterparts. Beta cell mass increased continuously in the B6 strain until 12 weeks of age, but declined from 7 weeks onwards in BKS. An age-dependent decline of beta cell proliferation and an increased rate of beta cell apoptosis already in the prediabetic state probably contribute to the diabetes susceptibility of db/db BKS mice. These factors could also play a role in the genetic predisposition for type 2 diabetes in humans.

Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, trypsin activation, and acinar cell apoptosis while increasing secretion in rat pancreatic acini.

Endoplasmic reticulum (ER) stress leads to accumulation of un- or misfolded proteins inside the ER and initiates the unfolded protein response (UPR). Several UPR components are physiologically involved in pancreatic development and are pathophysiologically activated during acute pancreatitis. However, the exact role of ER stress in exocrine pancreatic acini is mainly unclear. The present study examined the effects of tauroursodeoxycholic acid (TUDCA), a known ER chaperone, on acinar function and UPR components. Isolated rat pancreatic acini were stimulated by increasing concentrations of cholecystokinin (CCK-8) with or without preincubation of TUDCA. UPR components were analyzed, including chaperone binding protein (BiP), protein kinase-like ER kinase (PERK), X-box binding protein (XBP)-1, c-Jun NH(2)-terminal kinase (JNK), CCAAT/enhancer binding protein homologues protein (CHOP), caspase 3 activation, and apoptosis. In addition, TUDCA effects were measured on amylase secretion, calcium signaling, trypsin, and cathepsin B activation. TUDCA preincubation led to a significant increase in amylase secretion after CCK-8 stimulation, a 50% reduction of intracellular trypsin activation, and reduced cathepsin B activity, although the effects for cathepsin B were not statistical significant. Furthermore, TUDCA prevented the CCK-8-induced BiP upregulation, diminished PERK and JNK phosphorylation, and prohibited the expression of CHOP, caspase 3 activation and apoptosis. XBP-1 splicing was not altered. ER stress response mechanisms are activated in pancreatic inflammation. Chemical chaperones enhance enzyme secretion of pancreatic acini, reduce ER stress responses, and attenuate ER stress-associated apoptosis. These data hint new perspectives for an employment of chemical chaperones in the therapy of acute pancreatitis.

Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial.

AIM: To assess the efficacy and safety of saxagliptin vs. glipizide as add-on therapy to metformin in patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone. METHODS AND PATIENTS: A total of 858 patients [age ≥ 18 years; glycated haemoglobin (HbA(1c) ) > 6.5 - 10.0%; on stable metformin doses ≥ 1500 mg/day] were randomised 1 : 1 to saxagliptin 5 mg/day or glipizide up-titrated as needed from 5 to 20 mg/day for 52 weeks. The primary objective was to assess if the change from baseline HbA(1c) achieved with saxagliptin plus metformin was non-inferior to glipizide plus metformin. RESULTS: The per-protocol analysis demonstrated non-inferiority of saxagliptin vs. glipizide; adjusted mean changes from baseline HbA(1c) were -0.74% vs. -0.80%, respectively; the between-group difference was 0.06% (95% CI, -0.05% to 0.16%). Treatment with saxagliptin vs. glipizide was associated with a significantly smaller proportion of patients with hypoglycaemic events (3.0% vs. 36.3%; p < 0.0001) and a divergent impact on body weight (adjusted mean change from baseline -1.1 kg with saxagliptin vs. 1.1 kg with glipizide; p < 0.0001). There was a significantly smaller rise in HbA(1c) (%/week) from week 24 to 52 with saxagliptin vs. glipizide (0.001% vs. 0.004%; p = 0.04) indicating a sustained glycaemic effect beyond week 24. Excluding hypoglycaemic events, the proportion of patients experiencing adverse events (AEs) was similar (60.0% saxagliptin vs. 56.7% glipizide); treatment-related AEs were less common with saxagliptin vs. glipizide (9.8% vs. 31.2%), attributable to the higher frequency of hypoglycaemia in glipizide patients. Discontinuation rates resulting from AEs were similar (∼4%). CONCLUSION: Saxagliptin plus metformin was well tolerated, provided a sustained HbA(1c) reduction over 52 weeks, and was non-inferior to glipizide plus metformin, with reduced body weight and a significantly lower risk of hypoglycaemia.

Oesophageal ulceration after selective internal radiation therapy in a patient with carcinoma of unknown primary.

BACKGROUND: Cancer of unknown primary (CUP) is defined as histologically confirmed metastases in the absence of an identifiable primary tumor. Patients with solely liver metastases from adenocarinomas represent the most frequent subgroup with an unfavourable prognosis. The medium survival averages 6 to 9 months. No chemotherapheutic standard has been established. CASE: We present a patient with hepatic CUP. After cycles of chemotherapy and hemihepatectomy the tumor returned and showed hepatic progression. The patient was evaluated for selective internal radiation therapy (SIRT). Three years after diagnosis she is still alive and tumorfree. Despite a good result and disease control our patient suffered radiation-induced ulceration in the oesophagus, stomach, and duodenum. This side effect appears in up to 12 % of patients, often very late after treatment, is refractory to pharmacotherapy and persistent over a long time. CONCLUSIONS: SIRT is a new, effective treatment in patients with hepatic CUP. Because of the anticipated increase of this therapy, adverse side effects such as ulcerations in the upper-GI tract secondary to ectopic implantation of microspheres may be seen more commonly. Awareness of this and the recognition of microspheres in biopsies is cardinal for appropriate management and maintenance of the patient's quality of life.

[Progressive dyspnoea in two patients with carcinoid syndrome]. / Progrediente Dyspnoe bei Karzinoidsyndrom.

In patients with carcinoid syndrome, there has always to be considered cardiac impairment. We report about two patients with hepatic and bone metastases of a neuroendocrine tumor of the midgut, who suffered from progressive dyspnea. This was caused in both cases by a right-to-left atrial shunt, in case 1 based on a patent foramen ovale (PFO), in case 2 based on a secundum atrial septal defect. Symptoms were significantly reduced by percutaneous closure of PFO and ASD, respectively. Right-to-left atrial shunt was facilitated by right-sided carcinoid induced endocardial fibrosis with the consequence of severe tricuspid regurgitation, leading to an increase of right atrial pressure.

The role of the novel Th17 cytokine IL-26 in intestinal inflammation.

BACKGROUND AND AIMS: Interleukin 26 (IL-26), a novel IL-10-like cytokine without a murine homologue, is expressed in T helper 1 (Th1) and Th17 cells. Currently, its function in human disease is completely unknown. The aim of this study was to analyse its role in intestinal inflammation. METHODS: Expression studies were performed by reverse transcription-PCR (RT-PCR), quantitative PCR, western blot and immunohistochemistry. Signal transduction was analysed by western blot experiments and ELISA. Cell proliferation was measured by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. IL-26 serum levels were determined by an immunoluminometric assay (ILMA). RESULTS: All examined intestinal epithelial cell (IEC) lines express both IL-26 receptor subunits IL-20R1 and IL-10R2. IL-26 activates extracellular signal-related kinase (ERK)-1/2 and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) mitogen-activated protein (MAP) kinases, Akt and signal transducers and activators of transcription (STAT) 1/3. IL-26 stimulation increases the mRNA expression of proinflammatory cytokines but decreases cell proliferation. In inflamed colonic lesions of patients with Crohn's disease, an elevated IL-26 mRNA expression was found that correlated highly with the IL-8 and IL-22 expression. Immunohistochemical analysis demonstrated IL-26 protein expression in colonic T cells including Th17 cells expressing the orphan nuclear receptor RORgammat, with an increased number of colonic IL-26-expressing cells in active Crohn's disease. CONCLUSION: Intestinal cells express the functional IL-26 receptor complex. IL-26 modulates IEC proliferation and proinflammatory gene expression and its expression is upregulated in active Crohn's disease, indicating a role for this cytokine system in the innate host cell response during intestinal inflammation. For the first time, IL-26 expression is demonstrated in colonic RORgammat-expressing Th17 cells in situ, supporting a role for this cell type in the pathogenesis of Crohn's disease.

JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand.

BACKGROUND: cJun terminal kinase (JNK) is constitutively activated in most hepatocellular carcinomas (HCCs), yet its exact role in carcinogenesis remains controversial. While tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a major mediator of acquired immune tumour surveillance, and is currently being tested in clinical trials as a novel cancer therapy, the resistance of many tumours to TRAIL and concerns about its toxicity in vivo represent obstacles to its clinical application. In this study we investigated whether JNK activity in HCC could contribute to the resistance to apoptosis in these tumours. METHODS: The effect of JNK/Jun inhibition on receptor-mediated apoptosis was analysed by pharmacological inhibition or RNA interference in cancer cells and non-tumour cells isolated from human liver or transgenic mice lacking a phosphorylation site for Jun. RESULTS: JNK inhibition caused cell cycle arrest, enhanced caspase recruitment, and greatly sensitised HCC cells but not normal hepatocytes to TRAIL. TRAIL-induced activation of JNK could be effectively interrupted by administration of the JNK inhibitor SP600125. CONCLUSIONS: Expression and TRAIL-dependent feedback activation of JNK likely represent a mechanism by which cancer cells escape TRAIL-mediated tumour surveillance. JNK inhibition might represent a novel strategy for specifically sensitising HCC cells to TRAIL thus opening promising therapeutic perspectives for safe and effective use of TRAIL in cancer treatment.

Comparison of CT colonography, colonoscopy, sigmoidoscopy and faecal occult blood tests for the detection of advanced adenoma in an average risk population.

BACKGROUND AND AIMS: This prospective trial was designed to compare the performance characteristics of five different screening tests in parallel for the detection of advanced colonic neoplasia: CT colonography (CTC), colonoscopy (OC), flexible sigmoidoscopy (FS), faecal immunochemical stool testing (FIT) and faecal occult blood testing (FOBT). METHODS: Average risk adults provided stool specimens for FOBT and FIT, and underwent same-day low-dose 64-multidetector row CTC and OC using segmentally unblinded OC as the standard of reference. Sensitivities and specificities were calculated for each single test, and for combinations of FS and stool tests. CTC radiation exposure was measured, and patient comfort levels and preferences were assessed by questionnaire. RESULTS: 221 adenomas were detected in 307 subjects who completed CTC (mean radiation dose, 4.5 mSv) and OC; 269 patients provided stool samples for both FOBT and FIT. Sensitivities of OC, CTC, FS, FIT and FOBT for advanced colonic neoplasia were 100% (95% CI 88.4% to 100%), 96.7% (82.8% to 99.9%), 83.3% (95% CI 65.3% to 94.4%), 32% (95% CI 14.9% to 53.5) and 20% (95% CI 6.8% to 40.7%), respectively. Combination of FS with FOBT or FIT led to no relevant increase in sensitivity. 12 of 45 advanced adenomas were smaller than 10 mm. 46% of patients preferred CTC and 37% preferred OC (p<0.001). CONCLUSIONS: High-resolution and low-dose CTC is feasible for colorectal cancer screening and reaches sensitivities comparable with OC for polyps >5 mm. For patients who refuse full bowel preparation and OC or CTC, FS should be preferred over stool tests. However, in cases where stool tests are performed, FIT should be recommended rather than FOBT.

[Diabetes mellitus - perioperative management]. / Perioperatives Management bei Diabetes mellitus.

The prevalence of diabetes in hospitalized adults is conservatively estimated at 12-25% and rising. Poor glucose control and presence of diabetes complications (e.g. diabetic nephropathy, diabetic neuropathy, atherosclerosis) are commonly regarded as risk factors for perioperative morbidity and mortality. Thus it is crucial to determine diabetes comorbidities preoperatively in order to avoid perioperative renal and cardiovascular complications. Perioperative glycemic control is challenging due to preoperative changes in diabetes treatment and the effects of surgery-associated stress hyperglycemia. For patients in general surgical units, evidence for specific glycemic goals is based on epidemiologic and physiologic data rather than clinical trials. According to guidelines of the German Society of Nutrition, the approximation of normoglycemia is reasonable as long as hypoglycemia is avoided (suggested range for plasma glucose 80-145 mg/dL).

Alpha-fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma.

Due to limited treatment options the prognosis of patients with advanced hepatocellular cancer (HCC) has remained poor. To investigate an alternative therapeutic approach, we examined the feasibility of radioiodine therapy of HCC following human sodium iodide symporter (NIS) gene transfer using a mouse alpha-fetoprotein (AFP) promoter construct to target NIS expression to HCC cells. For this purpose, the murine Hepa 1-6 and the human HepG2 hepatoma cell lines were stably transfected with NIS cDNA under the control of the tumor-specific AFP promoter. The stably transfected Hepa 1-6 cell line showed a 10-fold increase in iodide accumulation, while HepG2 cells accumulated (125)I approximately 60-fold. Tumor-specific NIS expression was confirmed on mRNA level by northern blot analysis, and on protein level by immunostaining, that revealed primarily membrane-associated NIS-specific immunoreactivity. In an in vitro clonogenic assay up to 78% of NIS-transfected Hepa 1-6 and 93% of HepG2 cells were killed by (131)I exposure, while up to 96% of control cells survived. In vivo NIS-transfected HepG2 xenografts accumulated 15% of the total (123)I administered per gram tumor with a biological half-life of 8.38 h, resulting in a tumor absorbed dose of 171 mGy MBq(-1) (131)I. After administration of a therapeutic (131)I dose (55.5 MBq) tumor growth of NIS expressing HepG2 xenografts was significantly inhibited. In conclusion, tumor-specific iodide accumulation was induced in HCC cells by AFP promoter-directed NIS expression in vitro and in vivo, which was sufficiently high to allow a therapeutic effect of (131)I. This study demonstrates the potential of tumor-specific NIS gene therapy as an innovative treatment strategy for HCC.

The effect of the availability of inhaled insulin on glycaemic control in patients with Type 2 diabetes failing on oral therapy: the evaluation of Exubera as a therapeutic option on insulin initiation and improvement in glycaemic control in clinical practice (EXPERIENCE) trial.

AIM: To examine the impact of inhaled human insulin (Exubera, EXU) on patient or physician willingness to adopt insulin after oral glucose-lowering agent failure. METHODS: During a randomized controlled trial in primary, secondary and tertiary care in Europe and North America, 739 patients using >or= 2 oral glucose-lowering agents with glycated haemoglobin (HbA(1c)) >or= 8.0% were assigned to two treatment groups: Group 1 (standard care with the option of EXU) or Group 2 (standard care only). Standard care included adjusting oral therapy (optimizing current regimen or adding/omitting agents) and/or initiating subcutaneous (s.c.) insulin. The primary endpoint was difference in HbA(1c) between randomized groups at 26 weeks. Secondary outcomes included differences in the rate of uptake of insulin therapy, proportion achieving satisfactory glycaemic control, treatment satisfaction and safety outcomes. RESULTS: At baseline, insulin was initiated by more [odds ratio 6.0; 95% confidence interval (CI) 4.2 to 8.8; P < 0.0001] patients in Group 1 (86.2%; 76.7% EXU plus 9.5% s.c.) than Group 2 (50.7%; s.c. insulin only). At 26 weeks, mean (sd) changes in HbA(1c) from baseline were -2.0% (1.2%) and -1.7% (1.3%) in Groups 1 and 2, respectively, a difference of -0.2% (95% CI: -0.1% to -0.4%; P = 0.004). In Group 1, 45% of patients achieved an HbA(1c)

Do we need gastric acid?

Evidence from comparative anatomy and physiology studies indicates that gastric acid secretion developed during the evolution of vertebrates approximately 350 million years ago. The cellular mechanisms that produce gastric acid have been conserved over the millennia and therefore proton pump inhibitors have pharmacological effects in almost all relevant species. These observations suggest that gastric acid provides an important selective advantage; however, in modern-day humans the need for gastric acid can be questioned in light of the widespread use of safe and effective pharmacologic acid suppression. The Kandahar Working Group addressed questions concerning the need, production and effects of gastric acid, specifically: (1) motility in the upper gastrointestinal (GI) tract; (2) neuroendocrine factors; (3) digestive and mucosal processes; (4) microbiology, and (5) central processes and psychological involvement. We addressed each topic with the individual models available to answer our questions including animal versus human studies, pharmacologic, surgical as well as pathophysiologic states of acid suppression.

Islet cell function: alpha and beta cells--partners towards normoglycaemia.

Under normal conditions, insulin and glucagon are counter-regulatory hormones whose balanced action exhibits a relationship that ensures normoglycaemia. Elevated glucose levels following a meal stimulate pancreatic islet beta cells to secrete insulin and islet alpha cells to downregulate production of glucagon. With declining glucose and insulin levels, alpha-cell production of glucagon is increased to stimulate hepatic glucose production, preventing fasting hypoglycaemia. In type 2 diabetes mellitus (T2DM), beta-cell insulin response to glucose is blunted, including absence of early acute response, and alpha-cell response to glucose is impaired, resulting in absolute or relative hyperglucagonaemia and inappropriate hepatic glucose output that contributes to fasting hyperglycaemia. These changes are associated with structural and functional changes in pancreatic islets, including reduced beta-cell mass and reduced beta-cell:alpha-cell ratio. The role of the incretin hormone glucagon-like peptide-1 (GLP-1) in regulating glucose-dependent beta-cell insulin production and glucose-dependent alpha-cell glucagon production has been used to develop GLP-1-based therapies. These therapies may reduce the imbalances among insulin and glucagon that characterise T2DM, resulting in improved glycaemic control.

Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans.

The gastrointestinal hormone, glucagon-like peptide-1(7-36)amide (GLP-1) is released after a meal. The potency of synthetic GLP-1 in stimulating insulin secretion and in inhibiting glucagon secretion indicates the putative physiological function of GLP-1. In vitro, the nonmammalian peptide, exendin(9-39)amide [ex(9-39)NH2], is a specific and competitive antagonist of GLP-1. This in vivo study examined the efficacy of ex(9-39)NH2 as an antagonist of exogenous GLP-1 and the physiological role of endogenous GLP-1. Six healthy volunteers underwent 10 experiments in random order. In each experiment, a 30-min period of euglycemia was followed by an intravenous infusion of glucose for 150 min that established a stable hyperglycemia of 8 mmol/liter. There was a concomitant intravenous infusion of one of the following: (1) saline, (2) GLP-1 (for 60 min at 0.3 pmol . kg-1 . min-1 that established physiological postprandial plasma levels, and for another 60 min at 0.9 pmol . kg-1 . min-1 to induce supraphysiological plasma levels), (3-5) ex(9-39)NH2 at 30, 60, or 300 pmol . kg-1 . min-1 + GLP-1, (6-8) ex(9-39)NH2 at 30, 60, or 300 pmol . kg-1 . min-1 + saline, (9 and 10) GIP (glucose-dependent insulinotropic peptide; for 60 min at 0.8 pmol . kg-1 . min-1, with saline or ex(9-39)NH2 at 300 pmol . kg-1 . min-1). Each volunteer received each of these concomitant infusions on separate days. ex(9-39)NH2 dose-dependently reduced the insulinotropic action of GLP-1 with the inhibitory effect declining with increasing doses of GLP-1. ex(9-39)NH2 at 300 pmol . kg-1 . min-1 blocked the insulinotropic effect of physiological doses of GLP-1 and completely antagonized the glucagonostatic effect at both doses of GLP-1. Given alone, this load of ex(9-39)NH2 increased plasma glucagon levels during euglycemia and hyperglycemia. It had no effect on plasma levels of insulin during euglycemia but decreased plasma insulin during hyperglycemia. ex(9-39)NH2 did not alter GIP-stimulated insulin secretion. These data indicate that in humans, ex(9-39)NH2 is a potent GLP-1 antagonist without any agonistic properties. The pancreatic A cell is under a tonic inhibitory control of GLP-1. At hyperglycemia, the B cell is under a tonic stimulatory control of GLP-1.

Gastric emptying and release of incretin hormones after glucose ingestion in humans.

This study investigated in eight healthy male volunteers (a) the gastric emptying pattern of 50 and 100 grams of glucose; (b) its relation to the phase of interdigestive motility (phase I or II) existing when glucose was ingested; and (c) the interplay between gastric emptying or duodenal perfusion of glucose (1.1 and 2.2 kcal/min; identical total glucose loads as orally given) and release of glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1(7-36)amide (GLP-1), C-peptide, insulin, and plasma glucose. The phase of interdigestive motility existing at the time of glucose ingestion did not affect gastric emptying or any metabolic parameter. Gastric emptying of glucose displayed a power exponential pattern with a short initial lag period. Duodenal delivery of glucose was not constant but exponentially declined over time. Increasing the glucose load reduced the rate of gastric emptying by 27.5% (P < 0.05) but increased the fractional duodenal delivery of glucose. Both glucose loads induced a fed motor pattern which was terminated by an antral phase III when approximately 95% of the meal had emptied. Plasma GLP-1 rose from basal levels of approximately 1 pmol/liter of peaks of 3.2 +/- 0.6 pmol/liter with 50 grams of glucose and of 7.2 +/- 1.6 pmol/liter with 100 grams of glucose. These peaks occurred 20 min after glucose intake irrespective of the load. A duodenal delivery of glucose exceeding 1.4 kcal/min was required to maintain GLP-1 release in contrast to ongoing GIP release with negligibly low emptying of glucose. Oral administration of glucose yielded higher GLP-1 and insulin releases but an equal GIP release compared with the isocaloric duodenal perfusion. We conclude that (a) gastric emptying of glucose displays a power exponential pattern with duodenal delivery exponentially declining over time and (b) a threshold rate of gastric emptying of glucose must be exceeded to release GLP-1, whereas GIP release is not controlled by gastric emptying.

Adalimumab in patients with Crohn's disease--safety and efficacy in an open-label single centre study.

AIM: To evaluate the efficacy and safety of adalimumab, a human antitumour necrosis factor-alpha antibody, in induction and maintenance of remission in patients with Crohn's disease either refractory or intolerant to infliximab in a single centre cohort. METHODS: Sixteen Crohn's disease patients received 160 mg adalimumab subcutaneously in week 0, followed by 80 mg every other week. Clinical response was assessed based on Crohn's disease activity index and laboratory parameters (leukocyte count, C-reactive protein). In all patients genotyping for CARD15 variants and the +1059G/C polymorphism in the C-reactive protein gene was performed. RESULTS: In 10 of 16 patients (63%) treated with adalimumab, remission (CDAI score <150) was induced for at least 8 weeks independent of CARD15 or +1059G/C CRP status. In six of these 10 patients ongoing remission is observed now for more than 24 weeks. Adalimumab significantly decreased C-reactive protein serum levels and Crohn's disease activity index. There was one serious complication (fungal pneumonia). Six patients intermittently developed minor dermatological problems resolving after topical therapy. Otherwise, treatment was generally well tolerated. CONCLUSION: Adalimumab can induce and maintain remission in patients with moderate to severe Crohn's disease intolerant or refractory to infliximab. Further experience from larger cohorts is required to evaluate dose regimen and safety profiles in Crohn's disease therapy.

Cannabinoid type 1 receptor modulates intestinal propulsion by an attenuation of intestinal motor responses within the myenteric part of the peristaltic reflex.

Cannabinoid-1 (CB1) receptor activation affects gastrointestinal propulsion in vivo. It was our aim to further characterize the involved myenteric mechanisms in vivo and in vitro. In CB1(-/-) mice and wild-type littermates we performed in vivo transit experiments by charcoal feeding and in vitro electrophysiological recordings in mouse small intestinal smooth muscle. Ascending neuronal contraction (ANC) following electrical field stimulation was studied in rat ileum in a partitioned organ bath separating the aboral stimulation site from the oral recording site. The knockout animals displayed an accelerated upper gastrointestinal transit compared to control animals. The CB1 receptor antagonist AM251 stimulated the force of the ANC in a concentration dependent manner when added in the oral chamber. Anandamide significantly inhibited the ANC when added in the oral chamber. Neither AM251 nor anandamide had an influence on the contraction latency. No effects were observed when drugs were added in the aboral chamber, proving a CB1 mediated action on the neuromuscular junction. Resting membrane potentials and neuronal induced inhibitory junction potentials in CB1(-/-) mice were unchanged as compared to wild type. However, the electrophysiological slow waves were more sensitive to blockade of Ca(2+) channels in CB1(-/-) mice. Our data strongly suggest a physiological involvement of the CB-1 receptor in the regulation of small intestinal motility. Therefore, CB1 receptors are a promising target for the treatment of motility disorders.