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Biomedical subjects

R Arnold

Publications and source records attributed to R Arnold.

At least 199 records · Page 11Linked to original sources
PubMed1996

[Molecular biology, pharmacology and signal transduction of 5 cloned human somatostatin receptors].

Somatostatin is a hormone with inhibitory properties, which is expressed in several tissues including the gastrointestinal tract. Actually, somatostatin and somatostatin-analogues are used for the treatment of neuroendocrine tumors and esophageal varices. Somatostatin acts via specific receptors. So far, five somatostatin receptor subtypes have been isolated and cloned. They are characterized by a high degree of sequence homology. The different receptor subtypes recognize the naturally occurring and the pharmaceutically developed ligands with different affinities. The receptor subtypes are expressed in a tissue-specific manner and in different tissues they couple to different signal-transduction pathways. The somatostatin receptors are also expressed in several malignant tissues. But the expression pattern varies from tumor to tumor. The availability of the receptors and their cDNAs allows the characterization of somatostatin's molecular action in greater detail. The design of even more potent somatostatin anlogues seems possible as well as the development of new therapeutical strategies.

Amino Acid Sequence↗
PubMed1995

A fraction enriched in a novel glucocorticoid receptor-interacting protein stimulates receptor-dependent transcription in vitro.

Glucocorticoids influence numerous cell functions by regulating gene activity. The glucocorticoid receptor (GR) is a ligand-activated transcription factor and, like any other transcription factor, does not modulate gene activity just by binding to DNA. Interaction with other proteins is probably required to enhance the establishment of a functional transcription initiation complex. To identify such proteins, we analyzed the in vitro interaction of the glucocorticoid receptor bound to a double glucocorticoid response element with nuclear proteins and describe here three interacting proteins with different molecular weights. One of them, which we named GRIP 170 (GR-interacting protein), was purified and microsequenced, and it turned out to be an unknown protein. When tested in a cell-free transcription assay, the fraction highly enriched for GRIP 170 does not influence basal promoter activity but does enhance GR induction.

Carrier Proteins↗
PubMed1995

[Metastasizing pancreatic vipoma. Its diagnosis and therapy with the somatostatin analog octreotide].

HISTORY: An 82-year-old woman was hospitalized for anaemia of 4.8 g/dl after having suffered for about one year from watery treatment-resistant diarrhoea, causing a weight loss of ca. 10 kg. FINDINGS: Computed tomography, magnetic resonance imaging and endosonography revealed a 2.5 x 2.0 cm space-occupying mass in the body of the pancreas. Taking into account electrolyte abnormalities (potassium 2.7 mmol/l), marked metabolic acidosis (pH 7.16, base excess -20.3 mmol/l) and achlorhydria, an increased serum concentration of vasoactive peptide (VIP) of 548.5 pmol/l confirmed a VIPoma. Somatostatin-receptor scintigraphy also demonstrated a metastasis, 1.8 cm in diameter, in the region of the right ovary. TREATMENT AND COURSE: Under administration of somatostatin analogue octreotide (150 micrograms three times daily subcutaneously) the symptoms quickly disappeared and the stools as well as electrolyte and acid-base balances became normalized. After 5 months of treatment the levels of VIP, pancreatic enzymes and gastrin were within normal limits or clearly suppressed. There has been no recent evidence of tumour progression. CONCLUSION: This case demonstrates so far successful suppression of a metastasizing VIPoma with the somatostatin analogue octreotide, the metastasis having been revealed first by somatostatin-receptor scintigraphy.

Aged↗
PubMed1995

Emergence of CD52-, phosphatidylinositolglycan-anchor-deficient T lymphocytes after in vivo application of Campath-1H for refractory B-cell non-Hodgkin lymphoma.

CD52 is a phosphatidylinositolglycan (PIG)-anchored glycoprotein (PIG-AP) expressed on normal T and B lymphocytes, monocytes, and the majority of B-cell non-Hodgkin lymphomas. We observed the emergence of CD52- T cells in 3 patients after intravenous treatment with the humanized anti-CD52 monoclonal antibody Campath-1H for refractory B-cell lymphoma and could identify the underlaying mechanism. In addition to the absence of CD52, the PIG-AP CD48 and CD59 were not detectable on the CD52- T cells in 2 patients. PIG-AP-deficient T-cell clones from both patients were established. Analysis of the mRNA of the PIG-A gene showed an abnormal size in the T-cell clones from 1 of these patients, suggesting that a mutation in the PIG-A gene was the cause of the expression defect of PIG-AP. An escape from an immune attack directed against PIG-AP+ hematopoiesis has been hypothesized as the cause of the occurrence of PIG-AP-deficient cells in paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia. Our results support the hypothesis that an attack against the PIG-AP CD52 might lead to the expansion of a PIG-anchor-deficient cell population with the phenotypic and molecular characteristics of PNH cells.

Antibodies, Monoclonal↗
PubMed1995

Shoe, scimitar or sequestration: a shifting spectrum.

Congenital abnormalities of the tracheobronchial tree are rare causes of recurrent chest infections in childhood. A case is described which shows some typical features of horseshoe lung. More detailed imaging revealed complete separation of the right and left pleural cavities and the malformation represents part of the sequestration spectrum. The case emphasises the need for careful evaluation of the pulmonary arteries, veins, bronchi and oesophagus, particularly prior to surgery.

Adolescent↗
PubMed1995

Pathophysiological effects of long-term acid suppression in man.

A critical evaluation has been made of the available evidence in man of the effects of prolonged low acid states on the structure and function of the stomach. Various human models have been examined. 1. Ageing does not affect acid output from the normal male stomach, and there may be an increase in women. With progressive atrophy of the corpus mucosa, which is more frequent and rapid in patients with gastric ulcer, there is an associated loss of secretory function. Chronic gastritis and atrophy are the most important age-related changes, which in many cultures are hypothesized to develop via a prior Helicobacter pylori-related gastritis. However, H. pylori colonization of the mucosa decreases with increasing grades of gastric atrophy probably because intestinal metaplasia provides a hostile environment. Atrophy and intestinal metaplasia are associated with precancerous lesions and gastric cancer. Apparent hyperplasia of the gastric argyrophil endocrine cells is a common and spontaneous phenomenon in patients with atrophic gastritis, which in part may be related to the preferential loss of nonendocrine cells. 2. Pernicious anemia is associated with a complete lack of acid production, marked hypergastrinemia, and endocrine cell hyperplasia in the majority of patients. ECL-cell carcinoids and gastric cancer occur with a prevalence of 3-7%, and endoscopic surveillance in routine clinical practice is not warranted. 3. Gastric ECL-cell carcinoids are rare events that have been described in association with two diseases in man, pernicious anemia and Zollinger-Ellison syndrome as part of multiple endocrine neoplasia syndrome type I, and usually relate to marked hypergastrinemia and the presence of chronic atrophic gastritis with gastric antibodies or a genetic defect rather than the presence or absence of acid. Regression or disappearance of ECL-cell carcinoids, either spontaneously or after removal of the gastrin drive, has been recorded. Lymph node, and rarely hepatic, metastases are documented but death in these cases has been anecdotal. 4. Therapy with H2 antagonists may result in up to a twofold rise in serum gastrin levels but in man no endocrine cell hyperplasia has been recorded. However, the data for H2 antagonists on these aspects are very limited. There is no drug-related risk of gastric or esophageal cancer, although the incidence of the latter may be raised. Long-term treatment with omeprazole is associated with a two- to fourfold increase in gastrin levels over baseline values in one third of patients and apparent endocrine cell hyperplasia in 7% of cases overall.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1995

Gastrointestinal motor and secretory responses to cholinergic stimulation in humans. Differential modulation by muscarinic and cholecystokinin receptor blockade.

The present study investigated how a cholinergic agonist modifies interdigestive motility and secretion of the upper gastrointestinal tract and how muscarinic and cholecystokinin receptor blockade interfere with this direct cholinergic stimulation. In eight healthy volunteers, gastrointestinal motor and secretory responses to bethanechol (12.5, 25, and 50 micrograms kg-1 h-1) with and without a background of atropine (5 micrograms kg-1 h-1) or loxiglumide (10 mg kg-1 h-1) were studied. Stepdoses of bethanechol caused a parallel stimulation of antroduodenal motility and gastropancreatic secretion (P < 0.01) without inducing a fed pattern. However, duration of phase I was shortened (P < 0.05). Only high doses of bethanechol enhanced gastrin (P < 0.05), cholecystokinin (P < 0.05), and pancreatic polypeptide (P < 0.01) release. Atropine completely antagonized motor and secretory responses to cholinergic stimulation. Loxiglumide left cholinergically stimulated motility and pancreatic enzyme secretion unaltered. With co-infusion of bethanechol and loxiglumide, PP release dropped by 63% (P < 0.01); gastric acid output, gastrin and CCK release increased by 56%, 16%, and 25%, respectively (P < 0.05). We conclude that stimulation by a cholinergic agonist preserves the interdigestive pattern. Low dose muscarinic receptor blockade abolishes cholinergic stimulation over the full dose range. Inhibition of somatostatin release would explain stimulation of gastrin release and gastric acid secretion with co-infusion of bethanechol and loxiglumide. Endogenous CCK appears to interact with direct cholinergic stimulation at the pancreatic PP cell and the gastric D-cell but not at pancreatic acinar and antroduodenal smooth muscle cells.

Adult↗
PubMed1995

Circulating and tissue guanylin immunoreactivity in intestinal secretory diarrhoea.

Guanylin is a recently discovered peptide hormone that activates intestinal guanylate cyclase (GC-C) and thereby stimulates intestinal chloride secretion. Immunohistochemistry showed its presence in enterochromaffin (EC) cells of the gut. In vitro studies suggested that guanylin plays an important role in the endogenous modulation of intestinal salt and water secretion. In the present study the concentration of circulating immunoreactive (IR)-guanylin in plasma of patients with intestinal diarrhoea due to chronic bowel inflammation and patients with carcinoid tumours were measured with a specific radioimmunoassay. In 22 patients with Crohn's disease and eight patients with ulcerative colitis, plasma concentrations of IR-guanylin were 44 +/- 3 and 42 +/- 4 fmol mL-1, respectively. Levels were not different from that in 44 healthy volunteers suggesting that the circulating hormone is not involved in diarrhoea of these patients. In 17 patients with symptomatic carcinoid tumors the median concentration of circulating IR-guanylin was significantly enhanced (94 +/- 16 fmol mL-1, range 37-312 fmol mL-1). Immunohistochemistry revealed the presence of immunoreactive guanylin in carcinoid tissues, suggesting that these tumours co-release guanylin along with their usual resident hormone, serotonin. Enhanced local secretion of guanylin may play a causal role in diarrhoea of these patients and its elevation in plasma may be of diagnostic value in this type of endocrine tumours.

Adult↗
PubMed1995

Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients.

The nutrient-dependent glucagon-like peptide-1 (7-36) amide (GLP-1) release was studied in comparison to the glucose-dependent insulin-releasing polypeptide (GIP) response in 10 healthy volunteers each undergoing various protocols. Plasma samples were saved up to 120 min after challenges by oral, intravenous or intraduodenal administration of nutrients. Basal plasma-GLP-1 concentrations ranged between 0.4 and 1.4 pM, maximal postprandial GLP-1 levels peaked between 10 and 12 pM. Intravenous glucose (25 g i.v.) did not change basal GLP-1 levels. Oral administration of glucose (50 g) induced a biphasic GLP-1 release peaking at 30-60 min and a biphasic GIP release peaking at 5 and 45 min. This increase paralleled the secretion of insulin. Oral galactose (100 g) and amino acids (25 g) also induced a rapid plasma GLP-1 response. After fat (67 g corn oil) a strong and long-lasting (> 120 min) increase of GLP-1 plasma levels occurred. When a mixed liquid meal was given (6 g soybean oil, 5 g casein, 13 g glucose) immunoreactive (IR)-GLP-1 rapidly increased and peaked after 5 min with declining levels after 30 min. In response to an intraduodenal infusion of a small glucose load (5.34 g within 120 min) a rapid, short-lasting GLP-1 response occurred whereas plasma GIP and insulin levels remained unaltered. Luminal perfusion of an isolated vascularly perfused rat ileum with a polydiet induced a rapid rise of portally released IR-GLP-1 which was followed by a sustained release. Glucose evoked sodium-dependently a sharp increase of IR-GLP-1 levels followed by a plateau release. The intraluminal infusion of a mixture of amino acids or fat was without any effect on IR-GLP-1. We hypothesize that in contrast to GIP the GLP-1 release from L cells is triggered by nervous reflexes, by putative humoral factor(s) being released from the upper small intestine in addition to nutrient stimuli acting at the luminal surface of the gut.

Adult↗
PubMed1995

Cisapride stimulates human esophageal motility.

The potency of cisapride to stimulate esophageal motility is still a matter of conjecture. This double-blind placebo-controlled study assessed the effect of repeated oral doses of cisapride at 10 and 20 mg on interdigestive esophageal motility in 10 healthy male volunteers. In each experiment, esophageal motility was recorded continuously for 60 min with a sleeve sensor straddling the lower esophageal sphincter and four series of 10 wet swallows being performed. Analysis of motor events was computer assisted. Plasma cisapride levels amounted to 72.3 +/- 6.1 ng/ml with 10 mg cisapride and 142.5 +/- 11.9 ng/ml with 20 mg cisapride (p < 0.001 vs. 10 mg). Lower esophageal sphincter pressure increased from 20.6 +/- 2.3 mm Hg (placebo) to 28.9 +/- 2.3 mm Hg with 10 mg cisapride (p < 0.0001 vs. placebo) and to 26.8 +/- 1.8 mm Hg with 20 mg cisapride (p < 0.001 vs. placebo). Cisapride increased amplitude, duration, and area but not contractility and peristaltic velocity of esophageal contraction waves. Cisapride caused a maximum rise in amplitude of 22.4%, in area of 19.4%, and in duration of 9.6%. Its effects were greatest in the proximal and middle smooth muscle segments and more pronounced with 10 than with 20 mg. We conclude that cisapride clearly increases lower esophageal sphincter pressure and, to a lesser extent, raises amplitude and prolongs duration of esophageal contraction waves. Effects on contraction waves seem to correlate with the density of cholinergic innervation. Increasing the dose above 10 mg in the steady state does not further enhance the effect in healthy subjects.

Administration, Oral↗
PubMed1995

Voglibose (AO-128) is an efficient alpha-glucosidase inhibitor and mobilizes the endogenous GLP-1 reserve.

The alpha-glucosidase inhibitor voglibose (AO-128) was designed to prevent rapid postprandial blood glucose rises in non-insulin-dependent diabetics. We analyzed its effect on the entero-insular axis in 72 healthy volunteers in a double-blind study design before, after the 1st dose, and on the 7th day of a 7-day treatment protocol (3 daily loads). Six parallel groups of 12 volunteers received voglibose (0.5, 1.0, 2.0, or 5.0 mg) or placebo (two groups). Blood was drawn at regular intervals up to 180 min after a standardized breakfast to analyze the levels of glucose, insulin, C peptide, gastric inhibitory polypeptide, and glucagon-like peptide 1 (GLP-1). As expected, after ingestion of voglibose, slight to moderate gastro-intestinal discomfort but no severe side-effects were reported. In a dose-dependent manner, voglibose significantly reduced postprandial increases of blood glucose, insulin, and C peptide. At the lower loads (0.5 and 1 mg voglibose three times daily), these effects were more pronounced after 7 days. The postprandial increase of gastric inhibitory polypeptide was already reduced after the first load of 2 and 5 mg voglibose. In comparison to the placebo group, this inhibition became also significant for the lower loads after 7 days. Interestingly, GLP-1, originating from the lower intestines, was increasingly released under voglibose treatment. The first administration of 1 mg voglibose enhanced GLP-1 secretion > 80% above controls. Treatment with 1 mg voglibose three times daily over 7 days revealed a maximal mobilizing effect on endogenous GLP-1 (> 90% above controls) which was not further increased by 2- or 5-mg loads. We conclude that voglibose treatment effectively inhibits intestinal disaccharidases and thereby mobilizes the endogenous pool of insulinotropic GLP-1.

Adolescent↗
PubMed1995

Effect of gastrin receptor blockade on gastrin and histidine decarboxylase gene expression in rats during achlorhydria.

BACKGROUND: Gastrin stimulates histidine decarboxylase (HDC) activity and proliferation of enterochromaffin-like (ECL) cells. Furthermore, it has been suggested that gastrin controls HDC gene expression. We therefore analysed the effect of gastrin receptor blockade by PD 136 450 (CAM 1189) on HDC gene expression. The influence of PD 136 450 on gastrin, somatostatin, and chromogranin A was also evaluated. METHODS: Gene expression of HDC, gastrin, somatostatin, and chromogranin A (CgA) was analysed by Northern blot analyses after 14 days' application of the proton pump inhibitor BY 308 and/or the gastrin/cholecystokinin B receptor antagonist PD 136 450. RESULTS: PD 136 450 had no significant effect on gastrin mRNA or somatostatin mRNA in controls and during proton pump inhibition. BY 308 treatment resulted in a marked induction of HDC and CgA mRNA, whereas concomitant PD 136 450 in a concentration previously shown to suppress maximal pentagastrin-induced gastric acid secretion and to prevent BY 308-induced ECL cell proliferation did not result in significant alteration. PD 136 450 increased HDC significantly and CgA mRNA to a lesser extent in normogastrinaemic rats, whereas previous work showed a decreased ECL cell labelling index. CONCLUSIONS: These data suggest that there are independent regulatory pathways for ECL cell proliferation and gene expression. Other factors besides gastrin may act through PD 136 450-insensitive pathways to control HDC and CgA gene expression.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1995

The role of stable chromosome aberrations as biological indicators of radiation effect: studies in patients after total body irradiation and bone marrow transplantation.

The so-called unstable aberrations measured primarily as dicentrics and ring chromosomes are very useful as indicators of human radiation exposure. The role of stable chromosomal aberrations as indicators of radiation effects is not yet known. Stable chromosome aberrations persist longer in radiation-exposed individuals because cells with monocentric aberrations (= stable) have a higher probability of survival after cell division than multicentric or acentric aberrations (= unstable). Aberrations were investigated in 89 patients with chronic myelogenous leukemia undergoing total body irradiation (TBI) for bone marrow transplantation (BMT). Serial follow-up investigations were performed in 31 patients by analyzing lymphocytes of the peripheral blood. Patients had TBI of 10 to 12 Gy as conditioning therapy for BMT. Stable anomalies were investigated by Giemsa-banding and karyotyping in addition to standard analysis. A very high number of cells with stable aberrations was found up to five years after TBI. Investigations of the blood showed that a considerable number of cells with stable aberrations derive from radiation-damaged and clonally expanded hemopoietic precursor cells. We conclude that stable aberrations are useful as indicators of radiation effects in human beings. Clonal stable aberrations represent cellular radiation effects conserved at the stem cell level. Stable aberrations should be analyzed not only by the use of fluorescence in situ hybridization with chromosome painting probes, but also by karyotyping. The latter is necessary to detect stem cell effects by proving the clonal expansion of chromosomal aberrations, and should be performed with the assistance of an automatic chromosome analysis system.

Blood Cells↗