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Biomedical subjects

B Wiedenmann

Publications and source records attributed to B Wiedenmann.

At least 127 records · Page 7Linked to original sources
PubMed1996

Endoscopic ultrasonography and somatostatin receptor scintigraphy in the preoperative localisation of insulinomas and gastrinomas.

BACKGROUND: Endoscopic ultrasonography (EUS) and somatostatin receptor scintigraphy (SRS) can detect a high percentage of gastroenteropancreatic neuroendocrine tumours especially in the upper gastrointestinal tract. The ability of these procedures to localise primary tumour lesions and metastases of gastrinomas and insulinomas was evaluated in comparison with transabdominal ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI). PATIENTS AND METHODS: In a prospective trial, patients with gastrinomas (n = 10) and insulinomas (n = 10) diagnosed by clinical signs and laboratory tests were assessed by EUS, SRS, US, CT and MRI. RESULTS: In 10 patients with gastrinoma and 10 patients with insulinoma, a total of 14 separate primary tumour lesions were histologically confirmed for each of the tumour entities. The mean diameter was 2.1 cm for gastrinomas and 1.5 cm for insulinomas. All insulinomas and nine gastrinoma lesions were located in the pancreas. Three gastrinomas were found in the duodenal wall, one in a periduodenal lymph node, and one in the liver, For gastrinomas, sensitivities were 79% with EUS, 86% with SRS and 29% with CT, US, and MRI. For insulinomas, sensitivities were 93% with EUS, 14% with SRS, 21% with CT and 7% with US and MRI. CONCLUSIONS: EUS is of high value for localising primary lesions of both tumour entities. SRS is a very sensitive procedure for diagnosing of gastrinomas but not insulinomas. CT, US and MRI are primarily useful for visualising metastases.

Adolescent↗
PubMed1996

Synaptobrevin is essential for secretion but not for the development of synaptic processes.

The formation of small synaptic vesicles represents a hallmark during synaptogenesis. The small synaptic vesicle protein synaptophysin is considered as a marker protein for synapses during neuronal development. Another small synaptic vesicle protein, synaptobrevin, is now well accepted to play an important role for the function of synapses in being a key component of exocytosis. Its role during synaptogenesis is not known. Tetanus toxin which exclusively proteolysis synaptobrevin thereby inhibiting secretion from all types of neurons was used to investigate consequences of inactivating synaptobrevin for the formation of small synaptic vesicles and synaptic contacts. In primary cultures of mouse hypothalamic and cerebellar neurons cultivated for 3 to 4 days, synaptobrevin appears earlier on small synaptic vesicles and in synaptic contacts than synaptophysin. Upon longer cultivation up to 12 to 14 days in vitro both proteins associated equally with small synaptic vesicles. Interestingly, GABA secretion stimulated by 50 mM potassium or 500 PM alpha-latrotoxin, did not vary during cultivation time. Tetanus toxin added to neuronal cultures at day 2 in vitro cleaved synaptobrevin and inhibited regulated GABA secretion during the whole cultivation time. Despite the impaired function of synaptobrevin other synaptic proteins such as synaptophysin, synaptotagmin, rab 3A, protein SV2, SNAP-25 and syntaxin were found in processes and synaptic contacts comparable to untreated cultures. The expression of various synaptic proteins was also followed in vivo. In mouse brains taken at different embryonic days, synaptobrevin, synaptotagmin, rab 6 and the membrane protein SNAP-25 were expressed earlier than synaptophysin and protein SV2. We conclude that synaptobrevin represents a marker for early events in synaptogenesis. Its proteolysis by tetanus toxin, however, does not interfere with the formation of synaptic contacts and neuronal differentiation.

Animals↗
PubMed1996

[Gastric hamartoma and thyroid gland carcinoma with follicular and neuroendocrine differentiation in Cowden syndrome].

A 40-year old male patient presented with a history of subtotal strumectomy, excision of multiple cutaneous lesions at the upper trunk and gastrointestinal polyposis of unknown origin. The patient was admitted for weight loss and intermittent diarrhea. Physical examination revealed craniomegaly, papillomatosis of the oral mucosa and epigastric tenderness. Endoscopically, multiple polyps were seen in the stomach, the duodenum, the terminal ileum, the distal colon and the rectum. Histologically, these lesions were classified as hamartomatous and hyperplastic polyps. In the punctate of the relapsed nodular goitre, neoplastic follicular cells were found. These findings led to the diagnosis of Cowden's disease. A complete thyroidectomy was performed. The histology verified a follicular thyroid carcinoma and showed a combined expression of thyroglobulin and of the neuroendocrine marker synaptophysin (appr. 50% of all tumor cells). Chromogranin A (a neuroendocrine tumor marker) was also elevated in the serum of the patient. Postoperatively, a radioiodine therapy was performed and the clinical condition of the patient has improved ever since. The presented case of Cowden's disease is the first male patient with thyroid carcinoma. Early consideration of Cowden's disease is substantial as multiple malignant neoplasms may occur in this disorder in increased incidence.

Adenocarcinoma, Follicular↗
PubMed1996

[Interstitial laser hyperthermia of gastrinoma liver metastases in a child].

Ultrasound-guided, laser-induced thermocoagulation with Nd:YAG laser (1064 nm) was performed in a child with metastatic gastrinoma disease. The emitted laser energy to coagulate a radius of 15-20 mm of metastatic liver tissue was 4 W with a duration time of 300 s. Marked reduction of gastrin was observed after interstitial laser hyperthermia.

Biomarkers, Tumor↗
PubMed1995

Nerve growth factor stimulates clonal growth of human lung cancer cell lines and a human glioblastoma cell line expressing high-affinity nerve growth factor binding sites involving tyrosine kinase signaling.

The growth of a panel of 22 different human tumor, leukemia, and lymphoma cell lines was examined in a human tumor cloning assay in agar or methylcellulose and a tritiated thymidine uptake assay. The cultures were performed in the absence or presence of increasing concentrations (0.5-500 ng/ml) of nerve growth factor (NGF). The growth of 17 of the 22 cell lines was not significantly and reproducibly affected by NGF. There was minor (1.2-fold) but reproducible stimulation of clonal growth in one glioblastoma cell line (86-HG-39) by NGF, but in this cell line NGF induced no growth modulation in a tritiated thymidine uptake assay. However, clonal growth of another glioblastoma cell line (87-HG-31) and all three lung cancer cell lines tested (HTB 119, HTB 120, CCL 185) could be stimulated up to 3-fold by NGF with a dose-response relationship for the growth factor. Growth stimulation by NGF could be completely reversed by neutralizing anti-NGF antibody and by the tyrosine kinase inhibitor genistein. Evaluation of secondary plating efficiency revealed the stimulation of colony formation as representing self-renewal and not terminal differentiation. Reverse transcriptase-PCR experiments in the five responding cell lines showed expression of both low-affinity NGF receptor (glycoprotein 75) and c-trk transcripts on the mRNA level. Of the five responding cell lines, only 86-HG-39, the cell line with the lowest responsiveness, revealed low-affinity NGF receptor on the protein level; the other four cell lines with high responsiveness, including the three lung cancer cell lines, expressed no low-affinity NGF receptor as shown by fluorescence-activated cell sorter analysis and immunoprecipitation using the ME 20.4 antibody. Immunoprecipitation using anti-trk antibodies was negative in all five responding cell lines. However, binding studies with iodinated NGF showed only low-affinity binding on the 86-HG-39 cell line and only high-affinity binding on the high-responder cell lines CCL 185 and 87-HG-31. In summary, our data suggest that NGF can be operative in stimulation of clonal growth of malignant tumor cells. High-affinity but not low-affinity binding sites mediate signal transduction for clonal growth and signaling involves tyrosine kinase activity.

Base Sequence↗
PubMed1995

[Somatostatin receptor scintigraphy and endoscopic ultrasound for the diagnosis of insulinoma and gastrinoma].

In a prospective study of 13 patients (three males and 10 females; mean age 53 [8-82] years) the value of somatostatin receptor scintigraphy (SRS) and endoscopic ultrasonography (EUS) was compared with transabdominal ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) in the diagnosis of insulinoma (six patients) or gastrinoma (seven patients). There were ten separate primary lesions of each tumour type, proven histologically. For insulinoma the sensitivity of EUS was 90%, SRS 10% and CT, US and MRI together 20%. For gastrinoma the sensitivity of EUS was 90%, SRS 100%, and 30% for the other three methods together. Thus EUS had a high diagnostic localizing sensitivity for both tumours, while SRS was highly sensitive only in the diagnosis of gastrinoma, not insulinoma. The value of CT, MRI and conventional ultrasonography lies in their ability to visualize distant metastases.

Adolescent↗
PubMed1995

Transport route for synaptobrevin via a novel pathway of insertion into the endoplasmic reticulum membrane.

Synaptobrevin/vesicle-associated membrane protein is one of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. It is proposed to provide specificity for the targeting and fusion of vesicles with the plasma membrane. It belongs to a class of membrane proteins which lack a signal sequence and contain a single hydrophobic segment close to their C-terminus, leaving most of the polypeptide chain in the cytoplasm (tail-anchored). We show that in neuroendocrine PC12 cells, synaptobrevin is not directly incorporated into the target organelle, synaptic-like vesicles. Rather, it is first inserted into the endoplasmic reticulum (ER) membrane and is then transported via the Golgi apparatus. Its insertion into the ER membrane in vitro occurs post-translationally, is dependent on ATP and results in a trans-membrane orientation of the hydrophobic tail. Membrane integration requires ER protein(s) different from the translocation components needed for proteins with signal sequences, thus suggesting a novel mechanism of insertion.

Adenosine Triphosphate↗
PubMed1995

Somatostatin receptor subtypes in neuroendocrine tumor cell lines and tumor tissues.

Somatostatin receptor scintigraphy (SRS) is positive in approximately 80% of all patients who have been found to have neuroendocrine (NE) gastroenteropancreatic (GEP) tumors. The reasons for negative results are unclear. The aim of the present study was identification of the specific somatostatin receptor (SSTR) subtypes that are responsible for the in vivo binding of the widely used somatostatin (SST) analogues octreotide and lanreotide in human neuroendocrine gastroenteropancreatic tumors. Ten patients were subjected to SRS with radiolabeled octreotide. Following surgical resection, tumor tissues were analyzed for SSTR subtype mRNA expression by the reverse transcription-polymerase chain reaction (RT-PCR). In addition, SSTR subtype transcripts were investigated by Northern blot analysis and RT-PCR in neuroendocrine tumor cell lines. Expression of SSTR at the protein level was studied by chemical cross-linking experiments. Three patients were negative by SRS. However, RT-PCR revealed most prominently SSTR 2 expression in all tumor specimens. In addition, all tumor tissues analyzed by chemical crosslinking exhibited SST-14 binding sites, indicating that at least some NE tumors were false-negative on SRS.

Animals↗
PubMed1995

Expression of functional GABAA receptors in neuroendocrine gastropancreatic cells.

Gastropancreatic neuroendocrine cells synthesize large amounts of gamma-aminobutyric acid (GABA). This amino acid neurotransmitter appears to be stored in and released from, vesicles similar to small synaptic vesicles. So far, the function of GABA in gastropancreatic, neuroendocrine cells has not been clarified. Previous work suggested that only pancreatic, glucagon-producing alpha 2 cells contain functional GABAA receptors. Using subunit-specific antibodies in sections of human antral mucosa, a human gastrinoma and rat pancreas, we show that expression of GABAA receptors is abundant in gastropancreatic, neuroendocrine cells. Using the patch-clamp technique in the whole-cell mode we demonstrate that both the rat insulinoma cell line RIN 38 and the amphicrine cell line AR42J express functional GABAA receptors, which are characterized by a relatively low benzodiazepine and Zn2+ sensitivity and by an insensitivity to the inverse benzodiazepine agonist 6,7-alpha-methoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). In contrast to neurons, activation of GABAA receptors leads to a membrane depolarization. This depolarization presumably activates voltage-gated Ca2+ channels, resulting in an increase in cytosolic Ca2+ concentration, [Ca2+]i, as shown with the fluorimetric dye fura-2. The combination of GABA release, GABAA receptor activation and the [Ca2+]i increase could constitute an autocrine mechanism, modulating the release of hormones such as gastrin, insulin and somatostatin.

Animals↗
PubMed1995

Retinoids: effects on growth, differentiation, and nuclear receptor expression in human pancreatic carcinoma cell lines.

BACKGROUND & AIMS: Advanced pancreatic carcinoma has a dismal prognosis despite extensive chemotherapeutic trials. The aim of this study was to evaluate the role of retinoids as an experimental therapeutic approach for pancreatic cancer. METHODS: Four ductal and one acinar pancreatic tumor cell lines were investigated. Growth was determined by cell number and a human tumor clonogenic assay. In vivo growth was assessed by xenografts transplanted into nude mice. Differentiation was characterized by immunofluorescence microscopy and carbonic anhydrase II gene expression. Retinoid receptors were characterized by Northern blotting and reverse-transcriptase polymerase chain reaction. RESULTS: Retinoid treatment results in a time- and dose-dependent growth inhibition in vitro and in vivo of ductal but not acinar pancreatic tumor cells. Retinoid treatment induces a more differentiated phenotype in ductal tumor cells as shown by morphological criteria and increased expression of carbonic anhydrase II. All pancreatic tumor cell lines expressed a broad panel of cellular retinoid binding proteins and nuclear retinoid receptors. Retinoic acid receptor gamma and cellular retinoic acid binding protein II were found in all retinoid-sensitive ductal tumor cell lines but not in the retinoid-resistant acinar cell lines. CONCLUSIONS: Detailed knowledge of nuclear retinoid receptor expression may provide rational strategies for retinoid treatment of pancreatic cancer.

Animals↗
PubMed1995

Differentiation of pluripotent embryonic stem cells into the neuronal lineage in vitro gives rise to mature inhibitory and excitatory neurons.

Embryonic stem (ES) cells represent a suitable model to analyze cell differentiation processes in vitro. Here, we report that pluripotent ES cells of the line BLC 6 differentiate in vitro into neuronal cells possessing the complex electrophysiological and immunocytochemical properties of postmitotic nerve cells. In the course of differentiation BLC 6-derived neurons differentially express voltage-dependent (K+, Na+, Ca2+) and receptor-operated (GABAA, glycine, AMPA, NMDA receptors) ionic channels. They generate fast Na(+)-driven action potentials and are functionally coupled by inhibitory (GABAergic) and excitatory (glutamatergic) synapses as revealed by measurements of postsynaptic currents. Moreover, BLC 6-derived neurons express neuron-specific cytoskeletal, cell adhesion and synaptic vesicle proteins and exhibit a Ca(2+)-dependent GABA secretion. Thus, the ES cell model enables the investigation of cell lineage determination and signaling mechanisms in the developing nervous system from a pluripotential stem cell to a differentiated postmitotic neuron. The in vitro differentiation of neurons from ES cells may be an excellent approach to study by targeted gene disruption a variety of neuronal functions.

Action Potentials↗
PubMed1995

[Imaging methods in diagnosis of neuroendocrine tumors of the gastrointestinal tract].

Neuroendocrine tumors of the gastroenteropancreatic system represent a group of tumors with various diagnostic problems. Especially detection of primary tumor lesions is often difficult. Endoscopic ultrasonography is a relatively new imaging procedure localizing insulinomas preoperatively in about 90% of cases. Thus, previously used invasive preoperative imaging methods are usually unnecessary. The combination of endoscopic ultrasonography and somatostatin receptor scintigraphy allows visualization of gastrinomas in 90% of cases. Somatostatin receptor scintigraphy can also visualize metastatic lesions of gastrinomas and carcinoids in the whole body with high accuracy. In surgical management of a gastrinoma, duodenal transillumination and intraoperative ultrasound should be performed in all cases to exclude small duodenal or periduodenal, extrapancreatic tumors. US, CT, and MRI should be mainly used to exclude local and distant metastases. Angiography is helpful in detecting anatomical variations of abdominal vessels preoperatively. Due to the excellent results of endoscopic ultrasonography and somatostatin receptor scintigraphy in localizing insulinomas and gastrinomas, transhepatic portal venous sampling appears to be obsolete.

Carcinoid Tumor↗
PubMed1994

Requirements for exocytosis in permeabilized neuroendocrine cells. Possible involvement of heterotrimeric G proteins associated with secretory vesicles.

Exocytosis in neuroendocrine cells, such as chromaffin cells, is under the regulatory control of heterotrimeric G proteins. LDCV from bovine adrenal medulla contains alpha o-, beta-, and gamma-subunits of G-protein heterotrimers. Probably G proteins associated with the secretory vesicles control the final steps of secretion. G(o), associated with LDCV, could be the pertussis toxin-sensitive G protein that either inhibits exocytosis in PC12 cells or activates it in chromaffin cells. So far, it is unclear whether the other effects of GTP analogues are mediated by heterotrimeric G proteins or by small GTP-binding proteins. The other type of secretory vesicle, SSV from rat brain, also possesses functional sets of G-protein heterotrimers, each consisting of an alpha-, a beta- and a gamma-subunit. In addition to alpha o-subunits, however, alpha i-subunits were found on SSV. Their functional role remains to be determined. Thus, two types of secretory vesicles of the regulated pathway possess functional sets of G-protein heterotrimers. Besides exocytosis, heterotrimeric G proteins on secretory vesicles may control their maturation, transmitter storage, and endocytotic retrieval. So far, it is unclear whether the pattern of G proteins on LDCV and SSV analogues differs within various types of neuroendocrine cells and whether it will change after neoplastic transformation. An altered G-protein setup, not only at the plasma membrane but also on secretory vesicles, may play a role in pathophysiological processes occurring in neuroendocrine cells and tumors derived from them. Such changes might explain the altered secretion observed in neuroendocrine tumor diseases.

Adrenal Medulla↗
PubMed1994

Electrical activity and calcium channels in neuroendocrine cells.

Similar to neuronal cells, neuroendocrine cells express voltage-dependent ion channels and fire action potentials. Ca2+ influx through voltage-dependent Ca2+ channels couples changes in membrane potential to Ca(2+)-dependent cellular processes, such as hormone release. Using the patch-clamp technique, we studied the spontaneous electrical activity as well as voltage-dependent Ca2+ channels in cholecystokinin-producing pancreatic cells (RIN 1056E cell line), in prolactin-secreting pituitary cells (GH3 cell line), and in calcitonin-secreting cells of the thyroid (rMTC 44-2 cell line). All three cell types displayed spontaneous electrical activity, that is, they spontaneously produced action potentials. RIN 1056E cells, GH3 cells, and rMTC cells exhibited (various types of) voltage-dependent Ca2+ channels that were regulated by various neurotransmitters and hormones, such as somatostatin.

Action Potentials↗