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Biomedical subjects

G Adler

Publications and source records attributed to G Adler.

At least 19 recordsLinked to original sources
PubMed2001

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↗
PubMed2001

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↗
PubMed2001

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↗
PubMed2001

Effects of fibrogenic mediators on the development of pancreatic fibrosis in a TGF-beta1 transgenic mouse model.

The pancreas morphology of transgenic mice that overexpress transforming growth factor-beta1 (TGF-beta1) in the pancreas resembles partially morphological features of chronic pancreatitis, such as progressive accumulation of extracellular matrix (ECM). Using this transgenic mouse model, we characterized the composition of pancreatic fibrosis and involved fibrogenic mediators. On day 14 after birth, fibrotic tissue was mainly composed of collagen type I and III. At this time, mRNA levels of TGF-beta1 were increased. On day 70, the ECM composition was expanded by increased deposition of fibronectin, whereas connective tissue growth factor, fibroblast growth factor (FGF)-1, and FGF-2 mRNA expression levels were elevated in addition to TGF-beta1. In parallel, the number of pancreatic stellate cells (PSC) increased over time. In vitro, TGF-beta1 stimulated collagen type I expression but not fibronectin expression in PSC, in contrast to FGF-2, which stimulated both. This confirms that TGF-beta1 mediates pancreatic fibrosis through activation of PSC and deposition of collagen type I and III at early time points. Furthermore, this points to an indirect mechanism in which TGF-beta regulates pancreatic ECM assembly by induction of additional growth factors.

Animals↗
PubMed2000

Promoter polymorphism of the 5-HT transporter and Alzheimer's disease.

The role of the deletion/insertion polymorphism within the promoter region of the serotonin transporter gene (5-HTT) is under discussion as a potential genetic risk factor for Alzheimers's disease (AD). Here we report significant differences in the allelic distribution of this polymorphism with a higher frequency of the short variant allele in AD patients when compared to controls. This difference was independent of the apolipoproteinE genotype. Thus, our study supports the notion that genetic alterations in the serontonergic neurotransmitter system may be involved in the etiopathogenesis of AD. However, given the reported negative findings, we are presently trying to identify diagnostic subgroups for which the 5-HTT promoter polymorphism represents a susceptibility locus.

Alleles↗
PubMed2000

Molecular cloning and characterization of the human protein kinase D2. A novel member of the protein kinase D family of serine threonine kinases.

We have isolated the full-length cDNA of a novel human serine threonine protein kinase gene. The deduced protein sequence contains two cysteine-rich motifs at the N terminus, a pleckstrin homology domain, and a catalytic domain containing all the characteristic sequence motifs of serine protein kinases. It exhibits the strongest homology to the serine threonine protein kinases PKD/PKCmicro and PKCnu, particularly in the duplex zinc finger-like cysteine-rich motif, in the pleckstrin homology domain and in the protein kinase domain. In contrast, it shows only a low degree of sequence similarity to other members of the PKC family. Therefore, the new protein has been termed protein kinase D2 (PKD2). The mRNA of PKD2 is widely expressed in human and murine tissues. It encodes a protein with a molecular mass of 105 kDa in SDS-polyacrylamide gel electrophoresis, which is expressed in various human cell lines, including HL60 cells, which do not express PKCmicro. In vivo phorbol ester binding studies demonstrated a concentration-dependent binding of [(3)H]phorbol 12,13-dibutyrate to PKD2. The addition of phorbol 12,13-dibutyrate in the presence of dioleoylphosphatidylserine stimulated the autophosphorylation of PKD2 in a synergistic fashion. Phorbol esters also stimulated autophosphorylation of PKD2 in intact cells. PKD2 activated by phorbol esters efficiently phosphorylated the exogenous substrate histone H1. In addition, we could identify the C-terminal Ser(876) residue as an in vivo phosphorylation site within PKD2. Phosphorylation of Ser(876) of PKD2 correlated with the activation status of the kinase. Finally, gastrin was found to be a physiological activator of PKD2 in human AGS-B cells stably transfected with the CCK(B)/gastrin receptor. Thus, PKD2 is a novel phorbol ester- and growth factor-stimulated protein kinase.

Amino Acid Sequence↗
PubMed2000

TGFbeta1 represses proliferation of pancreatic carcinoma cells which correlates with Smad4-independent inhibition of ERK activation.

Transforming growth factor beta (TGFbeta) is a tumor suppressor acting as inhibitor of cell cycle progression of epithelial cells. We show that treatment of the pancreatic carcinoma cell lines PANC-1 and BxPC-3 with TGFbeta1 inhibits both growth factor-induced activation of the extracellular signal-regulated kinase 2 (ERK2) and translocation of the kinase to the nucleus. TGFbeta1 causes a concentration-dependent reduction of cell proliferation in both cell lines. By measuring ERK activation, we can show that TGFbeta1 is able to repress ERK activation induced by mitogenic stimuli such as EGF. This inhibitory effect of TGFbeta1 is not mediated by suppression of Ras or c-Raf-1 activation, but mediated by TGFbeta1-induced activation of a serine-threonine phosphatase, as demonstrated by inhibition of phosphatases by treatment with okadaic acid. Results obtained in the Smad4-deficient pancreatic carcinoma cell line BxPC-3, demonstrate that TGFbeta1-induced growth inhibition is mediated by a Smad4-independent prevention of ERK2 activation. In contrast to the effects of TGFbeta1 on epithelial cells, mesenchymal NIH3T3 fibroblasts exhibit elevated ERK2 activation and increased cell proliferation in response to TGFbeta1 treatment. Smad4-independent phosphatase-mediated inhibition of mitogen-activated ERK2 represents a novel effector pathway contributing to suppression of epithelial pancreatic carcinoma cell proliferation by TGFbeta1, in addition to the well-known Smad-induced tumor suppressor activity of TGFbeta. Oncogene (2000) 19, 4531 - 4541.

3T3 Cells↗
PubMed2000

Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells.

Carcinoid tumors are predominantly found in the gastrointestinal tract and are characterized by hypersecretion of various substances, including bioamines and neuropeptides, leading to functional tumor disease. Here, we demonstrate that human BON carcinoid tumor cells express functionally active insulin-like growth factor-I (IGF-I) receptors and secrete IGF-I, suggesting an autocrine action of this growth factor. The IGF-I receptor was functionally active. IGF-I stimulated phosphatidylinositol 3-kinase (PI3-kinase), p70 S6 kinase (p70s6k), and extracellular signal-regulated kinase 2 activity in BON cells. Furthermore, immunoneutralization of endogenously released IGF-I markedly reduced the high basal activity of p70s6k and extracellular signal-regulated kinase 2 in serum-starved BON cells. Exogenously added IGF-I induced a marked increase in chromogranin A secretion, a marker protein for neuroendocrine secretion, by a process that was largely dependent on PI3-kinase activity. In addition, immunoneutralization of endogenously released IGF-I markedly reduced basal chromogranin A release by BON cells. Thus, the autocrine IGF-I loop regulates basal neuroendocrine secretion in BON cells. Next, we investigated the role of IGF-I as a growth promoting agent for BON cells. Our data demonstrate that IGF-I stimulates anchorage-dependent and anchorage-independent growth of BON cells by a pathway that involves PI3-kinase, mammalian target of rapamycin/p70s6k, and mitogen-activated protein kinase kinase 1 activity. Interestingly, mitogen-activated protein kinase kinase 1 activity was less important for anchorage-independent growth of BON cells. Endogenously released IGF-I was found to be largely responsible for autonomous growth of BON cells in serum-free medium and for the constitutive expression of cyclin D1 in these cells. In conclusion, IGF-I is a major autocrine regulator of neuroendocrine secretion and growth of human BON neuroendocrine tumor cells. Because our data also demonstrate that a significant proportion of neuroendocrine tumors express the IGF-I receptor and its ligand, interference with this pathway could be useful in the treatment of hypersecretion syndromes and growth of human neuroendocrine tumors.

Carcinoid Tumor↗
PubMed2000

Smad1 and Smad4 are components of the bone morphogenetic protein-4 (BMP-4)-induced transcription complex of the Xvent-2B promoter.

To study the mechanism of transcriptional activation of the Xenopus homeobox gene Xvent-2B, we have delineated the bone morphogenetic protein-4 (BMP-4)-responsive region between -275/-152 in the proximal promoter. Consistent with the BMP-4 inductive nature of this region, this element exhibits transcriptional activation upon ectopic expression of Smad1 and Smad4. Electrophoretic mobility shift assays with total cellular extracts demonstrated that a DNA fragment encompassing this region was competent in the formation of a BMP-4-induced protein-DNA complex containing Smad1. Two different Smad binding regions were localized, a distal binding region for Smad1 containing two GCAT motifs and proximal AGNC binding sites for Smad4, the latter being conserved in other transforming growth factor-beta-responsive elements. Mutation of the Smad4 binding motif completely abolished transcriptional activation, whereas mutation or deletion of the Smad1 recognition sequence inhibited Smad1/Smad4 responsiveness. These results provide a functional characterization and identification of a vertebrate Smad1/Smad4 DNA response element induced by BMP-4 signaling and offers insight into the transcriptional regulation of a component essential for dorsoventral patterning in Xenopus embryos.

Animals↗
PubMed2000

A novel transmembrane serine protease (TMPRSS3) overexpressed in pancreatic cancer.

We report the characterization of a novel serine protease of the chymotrypsin family, recently isolated by cDNA-representational difference analysis, as a gene overexpressed in pancreatic cancer. The 2.3-kb mRNA of the gene, named TMPRSS3, is strongly expressed in a subset of pancreatic cancer and various other cancer tissues, and its expression correlates with the metastatic potential of the clonal SUIT-2 pancreatic cancer cell lines. The deduced polypeptide sequence consists of 437 amino acids and exhibits all of the structural features characteristic of serine proteases with trypsin-like activity. TMPRSS3 is membrane bound with a NH2-terminal signal-anchor sequence and a glycosylated extracellular region containing the serine protease domain. Thus, TMPRSS3 is a novel membrane-bound serine protease overexpressed in cancer, which may be of importance for processes involved in metastasis formation and tumor invasion.

Amino Acid Sequence↗
PubMed2000

Fibrinogen fractions in the third trimester of pregnancy and in puerperium.

The concentration of fibrinogen, its fractions, and the concentration of C-reactive protein were determined in 45 healthy pregnant women before and after vaginal (27) or caesarean section 18 delivery. The control group consisted of 33 blood donors. In pregnancy, increased concentration of total fibrinogen and its fractions and a normal concentration of C-reactive protein were noted. Three days after vaginal delivery the concentration of total and high molecular weight fibrinogen fraction decreased slightly and the ratio of high to low molecular weight fibrinogen increased. After caesarean section both total and high molecular weight fibrinogen and the ratio of high to low molecular weight fibrinogen increased. The C-reactive protein concentration increased after either type of delivery. The degree of augmentation, however, was ten times as strong after caesarean section. In all women at the end of puerperium the concentrations of the compounds studied returned to normal values. The results suggest that the mechanisms leading to the increase of fibrinogen during pregnancy and after delivery are different. The increase of all fibrinogen fractions in pregnancy may depend first of all on hormones, whereas the increased proportion of high molecular weight to low molecular weight fibrinogen after delivery depends on the acute phase reaction. The degree of this reaction depends on the type of delivery.

Adult↗
PubMed2000

Role of MT-MMPs and MMP-2 in pancreatic cancer progression.

Activation of matrix metalloproteinase-2 (MMP-2) by the membrane-type matrix metalloproteinases (MT-MMPs) has been associated with tumor progression. In the present study, we examined the role of MMP-2 and its activators MT1-MMP, MT2-MMP and MT3-MMP in pancreatic tumor cell invasion and the development of the desmoplastic reaction characteristic of pancreatic cancer tissues. Northern blot analyses revealed that transcript levels of MT1-MMP and MT2-MMP, but not MT3-MMP, were enhanced in pancreatic cancer tissues (n = 18) compared with both chronic pancreatitis (n = 9) and healthy pancreas (n = 9). A good correlation was found between MT1-MMP and both MMP-2 expression (p < 0.01) and activity in pancreatic cancer tissues. In addition, expression and activation of MMP-2 were strongly associated with the extent of the desmoplastic reaction in pancreatic cancer tissues. Invasion assays showed a good correlation between MMP-2 expression and activity and the invasive potential of pancreatic cancer cell lines. In cell lines with high levels of MMP-2 expression and activity, the MMP inhibitor Batimastat led to significant reduction of the number of invading cells. Our results suggest that MT1-MMP is involved in the progression of pancreatic cancer via activation of MMP-2. MMP-2 itself plays an important role in tumor cell invasion and appears to be associated with the development of the characteristic desmoplastic reaction in pancreatic cancer.

Adenocarcinoma↗
PubMed2000

MRI in the diagnosis of small bowel disease: use of positive and negative oral contrast media in combination with enteroclysis.

The aim of the study was to evaluate the additional findings of MRI following small bowel enteroclysis and to compare the efficacy of negative and positive intraluminal contrast agents. Fifty patients with inflammatory or tumorous small bowel disease were investigated by small bowel enteroclysis and consecutive MRI using breathhold protocol (T1-weighted fast low-angle shot, T2-weighted turbo spin echo). Patients were randomly assigned to either receiving a positive oral (Magnevist, Schering, Berlin, Germany) or a negative oral MR contrast media (Abdoscan, Nycomed, Oslo, Norway). The pattern of contrast distribution, the contrast effect, presence of artifacts, as well as bowel wall and extraluminal changes, were determined and compared between the contrast type using Fischer's exact test. Sensitivity, specificity, and diagnostic accuracy for MRI and enteroclysis were calculated. Twenty-seven patients had clinically proven Crohn's disease and two patients surgically proven small bowel tumours. Magnetic resonance imaging had important additional findings as abscesses and fistulae in 20 patients. Surgically compared sensitivities were 100 and 0% for MRI and enteroclysis, for the detection of abscesses, and 83.3 and 17 % for the diagnosis of fistulae, respectively. Bowel wall thickening was more reliably detected with use of positive oral contrast media without intravenous enhancement (p < 0.001), whereas postcontrast negative oral contrast media allow for a superior detection (p < 0.001). T2-weighted sequences were necessary with use of negative oral contrast media, because loop abscesses may be masked. Magnetic resonance imaging should be performed in all patients with suspicion of extraintestinal complications, because the complications are more reliably detected by MRI. Negative oral contrast media show advantages with the use of intravenous contrast but can mask loop abscesses using only T1-weighted imaging.

Abscess↗
PubMed2000

Diagnostic imaging in Crohn's disease: comparison of magnetic resonance imaging and conventional imaging methods.

Conventional enteroclysis remains the method of choice in the diagnosis of inflammatory small bowel disease. The reported sensitivity rates, however, for the diagnosis of extraintestinal processes, such as fistulae and abscesses, are moderate. Computed tomography (CT) is the method of choice for the diagnosis of extraintestinal complications. The anatomical designation of the affected bowel segment may, however, prove difficult due to axial slices, and the applied radiation dose is high. The use of magnetic resonance imaging (MRI) in the diagnosis of inflammatory small bowel disease is a relatively new indication for the method; prerequisites were the development of breathhold sequences and phased array coils. Optimized magnetic resonance tomographic imaging requires a combined method of enteroclysis and MRI, which guarantees an optimal filling and distension of the small bowel. The high filling volume leads to a secondary paralysis of the small bowel and avoids motion artifacts. In a trial of 84 patients with histological and endoscopic correlation the sensitivity in diagnosing inflammatory bowel disease was 85.4% for enteroclysis and 95.2% for MRI, and the specificity was 76.9% for enteroclysis and 92.6% for MRI. As none of the abscesses was diagnosed with enteroclysis, the sensitivity was 0% for enteroclysis, but 77.8% for MRI. The sensitivity in diagnosing fistulae was 17.7% for enteroclysis and 70.6% for MRI. In summary, MRI can detect the most relevant findings in patients with inflammatory small bowel disease with an accuracy superior to that of enteroclysis.

Contrast Media↗
PubMed2000

[Social status and life satisfaction of the elderly].

A rating instrument suited for a standardized evaluation of the social situation within a geriatric assessment is presented. The social dimensions "activities", "contacts", "living" and "finances" are screened by means of four to ten items and reflected by respective scores. The instrument was applied in a study group of 60 elderly persons of the general population and evaluated by means of life satisfaction measures. Positive correlations between the dimensions of the social situation and the respective domains of life satisfaction were found. Cut-offs, allowing the identification of patients, whose social situation is indicative for a low life satisfaction, are proposed.

Activities of Daily Living↗
PubMed2000

Disturbed bile secretion and cytochrome P450 function during the acute state of experimental colitis in rats.

BACKGROUND/AIMS: A variety of hepatobiliary abnormalities has been described in patients with inflammatory bowel diseases. However, the pathophysiological mechanisms leading to these liver alterations are poorly understood. The aim of the present study was to investigate parameters of liver function in a trinitrobenzenesulfonic acid (TNB)-induced rat colitis model. METHODS: Glucose output, bile acid secretion, bile acid uptake, and the cytochrome P-450 metabolic capacity during TNB-colitis were studied in the perfused liver model. Furthermore, hepatic bile acid- and glycogen content was measured. To evaluate the inflammatory response in the colon and liver, NF-kappaB/Rel was quantified by electrophoretic mobility shift assays. As an NF-kappaB/Rel regulated gene the inducible NO-synthase (NOS2) was evaluated by Western blot analysis. As possible mediators released from the inflamed colon into the portal vein, endotoxin and the stable metabolite of prostaglandin I2 (6-keto-prostaglandin-F1alpha) were determined. RESULTS: Glucose output, bile acid secretion, bile acid uptake, and cytochrome P-450 metabolic capacity decreased on the first and second day of TNB-colitis. Hepatic bile acid content increased at day 14 of colitis. Glycogen content was reduced, most likely due to an inadequate chow intake of these animals. A low level of portal endotoxin was detectable during the first 2 days of colitis. In addition, 6-keto-prostaglandin-F1alpha was clearly increased in portal blood. NF-kappaB/Rel binding activity and inducible NOS2 were strongly positive in the colon during colitis. Although low levels of portal endotoxin were measured during the first 2 days of colitis, no significant NF-kappaB/Rel activity and NOS2 induction were detected in the liver. CONCLUSION: Our results indicate that during the acute state of the TNB-colitis, bile acid secretion and cytochrome P-450 function are disturbed in the absence of distinct inflammatory changes in the liver.

Animals↗