Gut inflammation modulated by the enteric nervous system and neurotrophic factors.
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Animals↗
Biomedical subjects
G Adler
Publications and source records attributed to G Adler.
In vivo alpha(1)-adrenergic lipolytic activity in subcutaneous adipose tissue of obese subjects.
The role of alpha(1)-adrenoceptors in lipid mobilization and blood flow was investigated in situ using microdialysis of subcutaneous adipose tissue in severely obese subjects. The lipolysis rate was assessed by determination of interstitial glycerol concentration. The alpha(1)-adrenoceptor agonist norfenefrine caused an increase in glycerol level in adipose tissue that was similar to that observed with the physiologic alpha(1,2)-beta(1)-adrenoceptor agonist norepinephrine, whereas the alpha(1)-adrenoceptor antagonist urapidil showed no effect on basal lipolysis rate. However, the enhanced glycerol concentration due to norfenefrine and norepinephrine was suppressed in the presence of urapidil. The beta-adrenoceptor antagonist propranolol showed no effect on norfenefrine-stimulated glycerol outflow. Blood flow was assessed using the ethanol escape technique. Perfusion with norfenefrine decreased blood flow, whereas urapidil enhanced blood flow significantly. Despite the increase in blood flow, the basal interstitial glycerol concentration remained unchanged. Although norfenefrine at high concentrations could inhibit the urapidil-induced increase in blood flow, the norfenefrine-induced glycerol output was not affected. These results demonstrate that alpha(1)-adrenoceptors are involved in regulation of lipolysis rate and microcirculation of adipose tissue. However, the observed changes in local blood flow were not related to glycerol output.
Adipose Tissue↗
High prevalence of osteoporotic vertebral fractures in patients with Crohn's disease.
BACKGROUND AND AIMS: Osteopenia and osteoporosis are frequent in Crohn's disease. However, there are few data on related vertebral fractures. Therefore, we evaluated prospectively the prevalence of osteoporotic vertebral fractures in these patients. METHODS: A total of 293 patients were screened with dual energy x ray absorptiometry of the lumbar spine (L1-L4) and proximal right femur. In 156 patients with lumbar osteopenia or osteoporosis (T score <-1), x ray examinations of the thoracic and lumbar spine were performed. Assessment of fractures included visual reading of x rays and quantitative morphometry of the vertebral bodies (T4-L4), analogous to the criteria of the European Vertebral Osteoporosis Study. RESULTS: In 34 (21.8%; 18 female) of 156 Crohn's disease patients with reduced bone mineral density, 63 osteoporotic vertebral fractures (50 fx. (osteoporotic fracture with visible fracture line running into the vertebral body and/or change of outer shape) and 13 fxd. (osteoporotic fracture with change of outer shape but without visible fracture line)) were found, 50 fx. in 25 (16%, 15 female) patients and 13 fxd. in nine (5.8%, three female) patients. In four patients the fractures were clinically evident and associated with severe back pain. Approximately one third of patients with fractures were younger than 30 years. Lumbar bone mineral density was significantly reduced in patients with fractures compared with those without (T score -2.50 (0.88) v -2.07 (0.66); p<0.025) but not at the hip (-2.0 (1.1) v -1.81 (0.87); p=0.38). In subgroups analyses, no significant differences were observed. CONCLUSIONS: In patients with Crohn's disease and reduced bone mineral density, the prevalence of vertebral fractures-that is, manifest osteoporosis-was strikingly high at 22%, even in those aged less than 30 years, a problem deserving further clinical attention.
Absorptiometry, Photon↗
Phenylalanine kinetics in healthy volunteers and liver cirrhotics: implications for the phenylalanine breath test.
Expired 13CO2 recovery from an oral l-[1-13C]phenylalanine ([13C]Phe) dose has been used to quantify liver function. This parameter, however, does not depend solely on liver function but also on total CO2 production, Phe turnover, and initial tracer distribution. Therefore, we evaluated the impact of these factors on breath test values. Nine ethyl-toxic cirrhotic patients and nine control subjects received intravenously 2 mg/kg of [13C]Phe, and breath and blood samples were collected over 4 h. CO2 production was measured by indirect calorimetry. The exhaled 13CO2 enrichments were analyzed by isotope ratio mass spectrometry and the [13C]Phe and l-[1-13C]tyrosine enrichments by gas chromatography-mass spectrometry. The cumulative 13CO2 recovery was significantly lower in cirrhotic patients (7 vs. 12%; P < 0.01), in part due to lower total CO2 production rates. Phe turnover in cirrhotic patients was significantly lower (33 vs. 44 micro mol. kg(-1). h(-1); P < 0.05). When these extrahepatic factors were considered in the calculation of the Phe oxidation rate, the intergroup differences were even more pronounced (3 vs. 7 micro mol. kg(-1). h(-1)) than those for 13CO2 recovery data. Also, the Phe-to-Tyr conversion rate, another indicator of Phe oxidation, was significantly reduced (0.7 vs. 3.0 micro mol. kg(-1). h(-1)).
Adult↗
Ultrasound and magnetic resonance imaging in Crohn's disease: a comparison.
The objective of this retrospective study was to compare MRI of the abdomen with ultrasound of the abdomen and gastrointestinal tract in patients with Crohn's disease. Forty-six patients were included in the study. We analyzed the localization of Crohn's lesions, the number of affected bowel segments, the number of stenoses, and the presence of abscesses, fistulae, and any additional findings. Findings were verified by means of one or more of the following: enteroclysis; surgical findings; and colonoscopy. The results show that MRI is superior to ultrasound in the localization of affected bowel segments (sensitivity: MRI 97.5%; US 76%) and in recognizing fistulae (sensitivity: MRI 87%; US 31%), stenoses (sensitivity: MRI 100%; US 58%) and abscesses (sensitivity: MRI 100%; US 89%). Magnetic resonance imaging of the abdomen should be obtained to clarify discrepant clinical and sonographic findings. In addition, despite its higher cost, MRI of the abdomen is justified in patients in whom Crohn's lesions are known or suspected in anatomic areas proximal to the terminal or neoterminal ileum and in cases with suspicion of fistulae and abscesses.
Abdomen↗
TGF-beta-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system.
TGF-beta strongly promotes local tumor progression in advanced epithelial tumors, though the underlying mechanisms are poorly understood. In the present study, we demonstrate the potential of TGF-beta to increase the invasiveness of the pancreatic cancer cell lines PANC-1 and IMIM-PC1. TGF-beta-induced tumor cell invasion occurred in a time-dependent manner, started after 12 hr and continued to increase even 48 hr after a single application of the growth factor. Blocking of secreted TGF-beta1 by application of neutralizing antibodies 24 hr after TGF-beta treatment completely prevented the sustained effects of TGF-beta on tumor cell invasion. Together with our previous observation that TGF-beta1 up-regulates its own expression in both cell lines, our data suggest that TGF-beta1 acts in an autocrine manner to maintain tumor cell invasion. As measured by Northern blot hybridization and zymography, TGF-beta treatment of PANC-1 and IMIM-PC1 cells resulted in strong up-regulation of expression and activity of both matrix metalloproteinase-2 (MMP-2) and the urokinase plasminogen activator (uPA) system. Treatment with MMP inhibitors or inhibitors of the uPA system caused significant reduction of TGF-beta-induced invasiveness in both cell lines. In contrast, expression and activity of MMP-2 and uPA as well as tumor cell invasiveness remained unaffected in cell lines with defects of the TGF-beta type II receptor (MiaPaca2) or the Smad4 gene (IMIM-PC2 and CAPAN-1). In these cell lines, TGF-beta also failed to auto-induce its own expression. In conclusion, our results suggest that TGF-beta1 is a strong promotor of pancreatic cancer progression. TGF-beta thereby acts in an autocrine manner to induce tumor cell invasion, which is mediated by MMP-2 and the uPA system.
Enzyme Activation↗
Nuclear factor-kappaB is constitutively active in C-cell carcinoma and required for RET-induced transformation.
Specific point mutations of the RET proto-oncogene have been demonstrated to be responsible for multiple endocrine neoplasia (MEN) types 2A and 2B, for familial medullary thyroid carcinoma (MTC) syndromes, as well as for sporadic MTC. Here we show that nuclear factor (NF)-kappaB is activated in RET-associated C-cell carcinoma specimens. TT cells, a human MTC cell line expressing MEN 2A type RET, display transcriptionally active RelA(p65) in the nucleus. NF-kappaB activity in these cells is attributable to constitutive IkappaB kinase (IKK) activity and high turn over of IkappaBalpha. RET harboring the mutations C634R (MEN 2A) or M918T (MEN 2B), in contrast to wild-type RET, activates a NF-kappaB-dependent reporter construct upon transient transfection in HeLa cells. We show that the prototype RET mutation C634R enhances phosphorylation of IkappaBalpha by IKKbeta but not by IKKalpha. RET-induced NF-kappaB and IKKbeta activity requires Ras function but does neither involve the classical mitogen-activated protein kinase kinase/extracellular signal-regulated kinase nor the phosphoinositide 3-kinase/Akt pathways. In contrast, RET-induced NF-kappaB activity is dependent on Raf and MEKK1. Inhibition of constitutive NF-kappaB activity results in cell death of TT cells and blocks focus formation induced by oncogenic forms of RET in NIH 3T3 cells. These results suggest that RET-mediated carcinogenesis critically depends on IKK activity and subsequent NF-kappaB activation.
3T3 Cells↗
Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation.
The aim of this study was to examine the effects of transforming growth factor (TGF) beta1 on the phenotype and the biological behavior of pancreatic cancer cell lines with and without mutations in the TGF-beta signaling pathway and to elucidate whether the Ras signaling cascade participates in mediating these effects of TGF-beta1. TGF-beta-responsive (PANC-1, COLO-357, and IMIM-PC1) and nonresponsive (CAPAN1 and IMIM-PC2) pancreatic cancer cell lines with activating mutations of the Ki-Ras oncogene were treated with 10 ng/ml TGF-beta1 over time. Phenotypic alterations were studied by electron and phase contrast microscopy and by immunohistochemistry and expression analyses of differentiation markers. The influence of TGF-beta on tumor cell scattering, migration, and invasion was determined. The role of the Ras-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) cascade in mediating TGF-beta-induced morphological and functional effects were studied by pretreatment with the MEK1 inhibitor PD 98059 and by measuring ERK2 activation using immune complex kinase assays. TGF-beta1 led to a reversible and time-dependent epithelial-mesenchymal transdifferentiation (EMT) in TGF-beta-responsive pancreatic cancer cell lines, characterized by a fibroblastoid morphology and an up-regulation of mesenchymal markers and a down-regulation of epithelial markers. EMT was associated with an increase in tumor cell migration, invasion, and scattering. In the responsive cell lines, TGF-beta1 induced a moderate but sustained activation of ERK2. EMT, the concomitant changes in gene expression, and the invasive and migratory potential were reduced or abolished by pretreatment with the selective MEK1 inhibitor. Thus, in TGF-beta-responsive pancreatic cancer cells with activating Ki-Ras mutations, TGF-beta1 treatment caused an EMT associated with a more invasive phenotype. Cross-talk with the Ras-MEK-ERK-signaling cascade appears to be essential for mediating these effects of TGF-beta1.
Cell Differentiation↗
Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines.
E-cadherin-mediated cell-cell adhesion is reduced in epithelial tumors, which is thought to be a prerequisite to acquire invasive properties. We observed that several pancreatic carcinoma cell lines with high metastatic potential expressed normal levels of E-cadherin and possessed functional E-cadherin/catenin adhesion complexes. When the cell lines PANC-1, BxPC-3, and PaTu8988s were cultured either on type I or type III collagen, E-cadherin gene expression was repressed, and E-cadherin and catenin protein concentrations were reduced. In contrast, growth on fibronectin and collagen type IV had no influence. Collagen type I- or type III-dependent reduction of E-cadherin expression led to decreased cell-cell adhesion, increased proliferation, and migratory activity as well as morphological transformation. Overexpression of activated c-Src in PANC-1 cells mimicked collagen-induced E-cadherin down-regulation and changed the elevated cell proliferation and migration. Conversely, treatment of cells with the Src-inhibitors PP1 or herbimycin A resulted in complete suppression of collagen type I-induced E-cadherin decrease. Our data demonstrate that specific collagens are able to promote metastatic behavior by down-regulation of E-cadherin gene expression in a Src-kinase-dependent manner. This points toward a novel mechanism for substrate-dependent signaling and underlines the significance of extracellular matrix environment for tumor growth and invasiveness.
Antigens, CD↗
Post-dexamethasone cortisol level and memory performance in elderly depressed patients.
Depressed patients frequently show non-suppression in the dexamethasone suppression test, i.e. elevated post-dexamethasone cortisol levels. Elevated cortisol levels have been suggested to cause memory impairment through toxic effects on hippocampal neurons. In order to test this hypothesis, we studied the relationships between post-dexamethasone cortisol level and memory impairment in a group of 27 elderly depressive patients. In contrary to the expected, we found a positive correlation between post-dexamethasone cortisol level and memory performance. Thus, a dose-effect relationship between cortisol and memory impairment could not be ascertained. In some patients in early stages of Alzheimer's disease, cortisol may even have protective effects on memory performance through its anti-inflammatory action.
Aged↗
A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease.
This study describes a tumor progression model for ductal pancreatic cancer in mice overexpressing TGF-alpha. Activation of Ras and Erk causes induction of cyclin D1-Cdk4 without increase of cyclin E or PCNA in ductal lesions. Thus, TGF-alpha is able to promote progression throughout G1, but not S phase. Crossbreeding with p53 null mice accelerates tumor development in TGF-alpha transgenic mice dramatically. In tumors developing in these mice, biallelic deletion of Ink4a/Arf or LOH of the Smad4 locus is found suggesting that loci in addition to p53 are involved in antitumor activities. We conclude that these genetic events are critical for pancreatic tumor formation in mice. This model recapitulates pathomorphological features and genetic alterations of the human disease.
Animals↗
Day-clinic treatment of late-life depression.
BACKGROUND: There are few studies evaluating treatment in gerontopsychiatric day-clinics. In this paper, data are presented on the outcome of day-clinic treatment in late-life depression. METHOD: Forty-four depressed elderly patients (mean Hamilton Depression Score: 17.6) were examined at admission and discharge for psychopathology, functioning in daily living, social situation, burden with medical disease and quality of life. RESULTS: At discharge, the patients showed a significant reduction in depressive symptoms, improvements in cognitive performance, social activities and contacts. However, a more detailed analysis revealed that only patients responding to treatment (n=20) improved in the respective parameters. Patients, who did not recover fully from depression (n=24), did not improve in any of these parameters. At admission, responders and nonresponders did not differ concerning quality of life. At discharge, responders were significantly more satisfied in 11 of 20 domains of life quality. A shorter life time duration of depressive disease and male sex were predictive for a remission of depression. Thus, it could be shown that a considerable number of patients suffering from late-life depression may be successfully treated in a gerontopsychiatric day-clinic and 45.5% fully recover from depression. CONCLUSIONS: The day-clinic setting meets the specific needs of patients suffering from late-life depression by maintaining them in the community, supporting their abilities for self-care and promoting social contacts. Treatment in a day-clinic may be recommended for many elderly depressed patients.
Activities of Daily Living↗
[Chemotherapy of colorectal carcinoma].
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Administration, Oral↗
Association analysis of HTR6 and HTR2A polymorphisms in sporadic Alzheimer's disease.
In order to identify gene variants related to the serotonergic neurotransmitter system that possibly represent a hereditary risk factor for sporadic Alzheimer's disease (AD), patients suffering from AD and non-demented psychiatric inpatients without symptoms of dementia were genotyped for polymorphisms of HTR6 (267C/T) and HTR2A (-1438G/A). Although there was a tendency toward an increased number of the genotype TT of the 5-HT6 receptor polymorphism in AD patients when compared to controls (2.8% vs. 1.3%), neither this nor the 5-HT2A promoter polymorphism showed significant differences in their genotypic or allelic distribution among patients and controls. These polymorphisms probably do not represent major genetic risk factors of AD. However, further studies including other genetic variants of the serotonergic neurotransmitter system are needed in order to elucidate their role in AD.
Alleles↗
Pancreatic function tests: when to choose, what to use.
Although techniques for high-resolution imaging of the pancreas are constantly being improved, the evaluation of pancreatic function remains crucial for the workup of pancreatic diseases. More than 20 direct and indirect tests are available for the assessment of pancreatic function. Measurement of fecal elastase-1 is recommended as the most suitable test for the initial assessment of pancreatic function. Among other techniques, the pancreolauryl test, and alternatively the BT-PABA (N-benzoyl-L-tyrosyl-p-aminobenzoic acid) or the (13)C-mixed-triglyceride test, yield the best sensitivity and specificity. Nevertheless, all indirect tests are of limited value in patients with mild to moderate impairment of pancreatic function. In these patients, the secretin-caerulein test remains the gold standard.
Ceruletide↗
Is a preoperative multidiagnostic approach to predict surgical resectability of periampullary tumors still effective?
BACKGROUND: Multimodality staging is recommended in patients with periampullary tumors to optimize preoperative determination of resectability. We investigated the potency of currently used diagnostic procedures in order to determine resectability. METHODS: Ninety-five consecutive patients with periampullary tumors prehospitally staged resectable underwent preoperative diagnostic tests: helical-computed tomography (CT) with maximum intensity projection of arterial vessels (MIP), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreaticography (MRCP), endoscopic ultrasonography (EUS), endoscopic retrograde cholangiopancreaticography (ERCP), digital subtraction angiography (DSA), and positron emission tomography (PET). Diagnoses were verified by surgery and histopathology. RESULTS: In 45 patients with benign and 50 patients with malignant periampullary tumors sensitivity for tumor diagnosis was 89% to 96% in CT, MRI, EUS, and PET. Small tumors were best diagnosed by EUS (100%). Diagnosis of malignancy was made with 85% (EUS), 83% (CT), 82% (PET), and 72% (MRI) accuracy. Arterial vessel infiltration was best predicted by CT/MIP with an accuracy of 85%. For venous vessel infiltration MRI reached 85% accuracy. Accuracy rates for local nonresectability were 93% (EUS), 92% (MRI), and 90% (CT). Two and 4 of 8 patients with distant metastases were identified by CT and PET, respectively. The correct diagnosis of malignancy and determination of resectability was made by CT in 71% and by MRI in 70%. Biliary stenting reduced accuracy of CT diagnosis of malignancy from 88% to 73%. CONCLUSIONS: CT obtained before stenting was the single most useful test, providing correct diagnosis in 88% and resectability in 71% of patients. If no tumor is depicted in CT, EUS should be added. Uncertain venous vessel infiltration can be verified by MRI or EUS. Angiography should no longer be a routine diagnostic procedure. Equivocal tumors or possible metastasis may be further examined with PET.
Ampulla of Vater↗
Small cell lung cancer is not associated with the presence of anti-fucosyl-GM1 ganglioside autoantibodies reactive in immunoenzymatic test.
The characteristic feature of small cell lung cancer carcinoma (SCLC) is the aberrant expression and abundant presentation of fucosyl-GM1 ganglioside (FucGM1). In the present study we searched for the presence of anti-FucGM1 ganglioside, as well as anti-GM1, GM2 and GD3 ganglioside autoantibodies in the sera of patients with SCLC and as a control, in sera of patients with renal cell cancer (RC) and healthy blood donors. The autoantibodies against FucGM1 were present at low titer in only three of 36 SCLC patients, and with similar titer in two of 36 RC patients and four of 36 healthy controls. Likewise, the autoantibodies against GM2 and GM3 gangliosides were found only sporadically and with the same titer and frequency in cancer patients as in healthy persons. Anti-GD3 autoantibodies could not be detected in any of the screened sera.
Autoantibodies↗
Norepinephrine-induced glycerol release from adipose tissue: influence of age and body mass index in obese people.
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Adipose Tissue↗