Biomedical subjects

G Adler

Publications and source records attributed to G Adler.

At least 73 records · Page 4Linked to original sources

PubMed2001

Verbal perseveration after right-unilateral ECT.

After electroconvulsive therapy (ECT), many patients experience a decrement in their mnestic capacity. We studied episodic memory in eight severely depressed patients treated with a course of right-unilateral ECT. For this purpose, a testing instrument was constructed by the authors. It was made of paper cards that held four pieces of information, namely a word, a number, a figure, and the color of the card. One of the cards was presented to the patients and the respective information was asked for on the subsequent day. Patients were tested every morning during the first two weeks of the ECT course. About half of the responses were correct. Patients did best in recalling the color; they did worst in recalling the number. Seven of the patients showed verbal perseverations. This is in accordance with the literature on perseveration in patients with neurologic deficits, especially in proactive-inhibitory tasks. Perseveration may be attributed to a deficit in selective attention, producing an arousal of irrelevant cues.

Adult↗

PubMed2001

Inhibition of nitric oxide synthesis by aminoguanidine increases intestinal damage in the acute phase of rat TNB-colitis.

The role of nitric oxide (NO) in the pathophysiology of inflammatory bowel diseases (IBD) is controversially discussed. The aim of the present study was to investigate the role of NO inhibition in the acute phase of rat 2,4,6-trinitrobenzenesulphonic acid (TNB)-colitis. To inhibit NO synthesis we used aminoguanidine (AG) as a selective inhibitor of inducible nitric oxide synthase (iNOS). TNB-colitis was induced in rats with and without pretreatment with AG (200 mg kg-1 body weight in the drinking water). The severity of colitis was observed over a period of 7 days. On days 1 and 2, AG reduced concentrations of plasma nitrate and nitrite as well as of portal 6-keto-prostaglandin 1alpha. AG pretreatment increased colonic damage and inflammatory response, assessed by colonic myeloperoxidase and serum lactate dehydrogenase activity, macroscopic damage score, tumour necrosis factor-alpha concentration in stool and colonic glutathione content. The AG-treated group showed a higher and prolonged nuclear factor kappaB (NF-kappaB)/Rel binding activity in the colon. We conclude that NOS inhibition by AG is not beneficial in acute intestinal inflammation. With regard to appropriate therapeutic strategies, NF-kappaB/Rel activation might be a more suitable target.

Acute Disease↗

PubMed2001

Phospholipase C activity of Helicobacter pylori is not associated with the presence of the cagA gene.

BACKGROUND: Knowledge about the possible role of phospholipase C (PLC) activity of microbial pathogens in the development of disease is increasing. Recently attention has focused on investigating PLC activity elaborated by Helicobacter pylori, but the role of this enzyme in H. pylori pathogenesis is still unknown. The aim of this study was to correlate PLC-activity of H. pylori on the basis of the cagA status with the clinical diagnosis of the patients. MATERIALS AND METHODS: Helicobacter pylori was isolated from patients with gastritis (G; n = 38), duodenal ulcer (DU; n = 15), gastric ulcer (GU; n = 11) and gastric cancer (GC; n = 12). Polymerase chain reaction primers DZ3/R009 which amplified a 1350-bp fragment were used to detect the cagA gene. PLC activity was determined using p-nitrophenylphosphorylcholine as substrate. RESULTS: Of the strains, 60% were cagA(+) and 40% were cagA(-). All strains showed PLC activity (2.20 +/- 0.91 U mg(-1) protein). PLC activity showed no association with the cagA status: cagA(+) (2.21 +/- 1.03 U mg(-1) protein), cagA(-) (2.18 +/- 0.79 U mg(-1) protein). Patients with GU had the highest PLC activity (2.77 +/- 1.26 U mg(-1) protein) and patients with GC had the lowest activity (1.8 +/- 0.57 U mg(-1) protein). CONCLUSIONS: Although PLC activity was present in all strains tested, it may only have pathological importance in patients with GU. However, the extent of PLC activity was independent of the presence of the cagA gene.

Adenocarcinoma↗

PubMed2001

Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin.

BACKGROUND & AIMS: Recently, several members of the claudin family have been identified as integral constituents of tight junctions. Using expression profiling, we previously found claudin-4 to be overexpressed in pancreatic cancer. Because claudin-4 has been described as a receptor for the cytotoxic Clostridium perfringens enterotoxin (CPE), we investigated the effect of CPE on pancreatic cancer cells. METHODS: Expression of claudin-4 was analyzed by Northern blots. In vitro toxicity of CPE was determined by trypan blue exclusion and the (86)Rb-release assay. The in vivo effect of CPE was studied in claudin-4-expressing nude mouse xenografts of the Panc-1 cell line. RESULTS: Expression analyses showed that claudin-4 was overexpressed in most pancreatic cancer tissues and cell lines and several other gastrointestinal tumors. CPE led to an acute dose-dependent cytotoxic effect, restricted to claudin-4-expressing cells and dependent on claudin-4 expression levels. Furthermore, transforming growth factor beta was identified as a negative modulator of both claudin-4 expression and susceptibility to CPE. In vivo, intratumoral injections of CPE in Panc-1 xenografts led to large areas of tumor cell necrosis and significant reduction of tumor growth. CONCLUSIONS: Our findings suggest that targeting claudin-4-expressing tumors with CPE represents a promising new treatment modality for pancreatic cancer and other solid tumors.

Adenocarcinoma↗

PubMed2001

Biglycan is overexpressed in pancreatic cancer and induces G1-arrest in pancreatic cancer cell lines.

BACKGROUND & AIMS: Biglycan (PG-I), a component of the extracellular matrix (ECM), is overexpressed in pancreatic cancer. To determine possible matrix-tumor interactions, we investigated the effects of PG-I on pancreatic cancer. METHODS: PG-I expression in cell lines and tissue samples was examined by Northern blot and immunofluorescence. The effect of PG-I on proliferation was determined by measuring activity of Ras, ERK, Rb, [(3)H]-thymidine incorporation, and cell cycle analysis. Expression of cyclin A, B1, D1, E1, G1, PCNA, p21, and p27 was analyzed by Northern and Western blots. RESULTS: PG-I was overexpressed in the ECM of pancreatic cancer samples compared with normal pancreas or chronic pancreatitis tissues. Addition of transforming growth factor (TGF)-beta induced PG-I expression in HFL and HFFF2 fibroblasts as well as in the pancreatic cancer cell line PANC-1. PG-I inhibited growth of both TGF-beta-responsive and TGF-beta-unresponsive pancreatic cancer cells by inducing G1-arrest, which is accompanied by an increase of p27 and reduction of cyclin A and proliferating cell nuclear antigen. Furthermore, endogenous Ras and ERK activation was partly reduced by PG-I in vitro. CONCLUSIONS: The ECM protein PG-I inhibits growth by arresting pancreatic cancer cells in G1 and may be part of a host defense mechanism aimed at slowing down pancreatic tumor progression.

Adult↗

PubMed2001

Oxidized low-density lipoproteins bind to the scavenger receptor, CD36, of hepatic stellate cells and stimulate extracellular matrix synthesis.

Cumulating evidence suggests that oxidative stress resulting in lipid peroxidation and protein modification is involved in the pathogenesis of chronic liver injury and fibrogenesis. We investigated the effects of oxidized low-density lipoproteins (oxLDL) on collagen and fibronectin synthesis of cultured human and rat hepatic stellate cells (HSC). As shown on protein and mRNA levels, oxLDL dose-dependently stimulated the synthesis of collagen types I and III and fibronectin of cultured HSC. The effect was biphasic, with a maximum between 5 and 25 microg/mL oxLDL (c-fibronectin concentration in HSC supernatants increased 3.9-fold; collagen type I increased 4-fold). Higher oxLDL concentrations were cytotoxic. LDL modified with malondialdehyde (MDA) was not toxic, but stimulated extracellular matrix synthesis as well. As demonstrated by immunofluorescence microscopy (double staining of CD36 and iso-alpha-smooth muscle actin [iso-alpha-sm actin]), immunoblot, and reverse-transcription polymerase chain reaction (RT-PCR), respectively, cultured human HSC express the oxLDL receptor, CD36 (glycoprotein IIIb). Colocalization of CD36 and iso-alpha-sm actin on sinusoidal lining cells was further demonstrated using sections of human fibrotic liver. Preincubation of cultured human HSC with the monoclonal antibody, OKM5, known to block CD36-mediated oxLDL uptake, resulted in a reduction of the oxLDL-stimulated collagen type I synthesis by 56%. In summary, our results demonstrate that low concentrations of modified lipoproteins (oxLDL and MDA-LDL) represent fibrogenic mediators that bind to CD36 and stimulate matrix synthesis of HSC.

Blotting, Northern↗

PubMed2001

[Treatment courses and therapeutic effectiveness of a psychogeriatric day hospital].

Since 1976, 37 psychogeriatric day hospitals have been set up in Germany. As only few empirical studies on the effectiveness of this day hospital system are available even 25 years on, the treatment course of 58 patients attending the psychogeriatric day hospital run by the Department of Psychiatry, University of Tübingen was evaluated. The course analysis was based on a series of tests comprising the following questionnaires: Social Situation Scale, Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), Munich Quality of Life Dimension List (MLDL), Mini Mental Status (MMS), Hamilton Depression Scale, and Cumulative Illness Rating Scale (CIRS). Women accounted for three-quarters of the sample, and men for one-quarter. The average age was 72 years. The fact that only 16% of the patients had been transferred from psychiatric hospitals and that more than half had been referred directly by their local doctors underlines the acute-psychiatric nature of the institution. More than 80% of the patients were discharged to their previous place of residence. A highly significant improvement in affective state was verified by the Hamilton Depression Scale. Significant improvements were also registered in the following items: general satisfaction with life, state of health, physical and mental performance, and scope for personal development. The quality of life, measured with the Munich Quality of Life Dimension List (MLDL), improved in nine of the nineteen items covered, with correction of the significance level alpha taken into account. The treatment outcomes confirmed the therapeutic effectiveness of this type of psychogeriatric institution from aspects of acute psychiatry too and should encourage the continued expansion of partial hospitalization facilities for the elderly.

Activities of Daily Living↗

PubMed2001

Acute pancreatitis.

The pathophysiologic concept of acute pancreatitis focuses on early events inside acinar cells such as activation of trypsin. Despite significant progress in the understanding of molecular events in experimental pancreatitis, knowledge of these mechanisms has not yet been translated into therapeutic strategies useful in humans. A single morphologic or laboratory marker reliably predicting the individual course of acute pancreatitis still awaits discovery. The clinical outcome of acute pancreatitis is dependent on the presence of necrosis and systemic complications. The extent of the systemic inflammatory response to local pancreatitis seems to be the rate-limiting step. Several mechanisms shed light on the interconnectivity between intra-acinar protease activation and immunoregulatory processes. Deciphering these cell biologic connections has already had an impact on the clinical management of patients and the identification of prognostic markers in human disease. However, further investigations of pancreatic pathophysiology are needed to initiate novel therapeutic strategies.

Journal Article↗

PubMed2001

Alcohol as a gastric disinfectant? The complex relationship between alcohol consumption and current Helicobacter pylori infection.

Alcoholic beverages have antimicrobial effects against Helicobacter pylori in vitro. To elucidate the relation between alcohol consumption and current infection with H. pylori in vivo, we carried out a pooled analysis of three recent studies from Southern Germany, comprising 1410 adults age 15 to 69. Detailed information on consumption of various alcoholic beverages was collected through standardized questionnaires. Helicobacter pylori infection was measured by 15C-urea breath test. Overall, prevalence of current H. pylori infection was lower among subjects who consumed alcohol (34.9%) than among nondrinkers (38.0%). The adjusted odds ratio was 0.79, with a 95% confidence interval of 0.58-1.08. Furthermore, alcohol consumption showed a strong inverse relation to the result of the 13C-urea breath test, a semiquantitative measure of the bacterial load, among infected subjects. The inverse association between alcohol consumption and H. pylori infection was not monotonic, however. Odds of infection were lowest at moderate levels of alcohol consumption and increased at higher levels of alcohol consumption, regardless of the type of alcoholic beverages consumed. These results support the hypothesis that moderate alcohol consumption may favor suppression and eventual elimination of H. pylori infection. At higher levels of alcohol consumption, the antimicrobial effects of alcoholic beverages may be opposed by adverse systemic effects of drinking, such as adverse effects on the immune defense.

Adolescent↗

PubMed2001

Integrin-mediated differentiation of a pancreatic carcinoma cell line is independent of FAK or MAPK activation levels.

INTRODUCTION: The extracellular matrix (ECM) plays a salient role for proliferation and differentiation of epithelial cells. It was demonstrated that cell-ECM interactions mediated through integrins control gene expression and the tissue phenotype even in malignant tumors. Alterations of the ECM are a key feature of ductal adenocarcinoma of the pancreas. AIMS: To examine the role of integrins and related signaling events for differentiation. METHODOLOGY AND RESULTS: We established an in vitro model for ECM-induced differentiation of poorly differentiated pancreatic carcinoma cells and found that a specific pattern of ECM proteins resembling basal laminas (matrigel) induces differentiation of the PaTu-II pancreatic carcinoma cell line to a ductal phenotype. Both beta1- and beta4-integrins are required for cellular differentiation. Integrin-associated signaling events include activation of pp125 focal adhesion kinase (FAK) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs). However, beta1- and beta4-integrin-mediated differentiation of PaTu-II cells was independent from FAK, ERK, and JNK activation levels. Inhibition of MAPK kinases by PD98059 led to a reduction of proliferation but did not interfere with cellular differentiation of PaTu-II cells on matrigel. CONCLUSION: The integrin-mediated differentiation of PaTu-II cells is regulated and maintained through FAK- and MAPK-independent signal transduction pathways.

Antigens, CD↗

PubMed2001

p300 acts as a transcriptional coactivator for mammalian Notch-1.

Notch-1 belongs to a family of transmembrane receptor proteins that direct the decisions as to various cell fates. After ligand binding, a proteolytic cleavage step occurs and the intracellular part of Notch-1, Notch-1-IC, translocates into the nucleus, where it targets the DNA binding protein RBP-J kappa/CBF1. RBP-J kappa mediates repression through recruitment of a histone deacetylase-containing complex. The Notch-1-IC/RBP-J kappa complex overcomes repression and activates the transcription of Notch target genes. We have identified a novel domain in Notch-1-IC, the EP domain, which is indispensable for full transcriptional activation. This transactivation domain is localized adjacent to the ankyrin repeats of Notch-1-IC. In cotransfection experiments, Notch-1-IC-mediated transcriptional activation was inhibited by E1A12S and p53, two proteins, which interfere with the function of the common coactivator p300. Protein-protein interaction assays demonstrated the association of Notch-1-IC and the CH3 region of p300. In addition, the interaction of mammalian Notch-1-IC with p300 was destabilized after deletion of the EP domain of Notch-1-IC. Based on physical interaction with Notch-1-IC and coactivator functions of p300, we propose a model for Notch-1-mediated gene regulation via p300.

Adenovirus E1A Proteins↗

PubMed2001

Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells.

The aim of this study was to identify fibrogenic mediators stimulating activation, proliferation, and/or matrix synthesis of rat pancreatic stellate cells (PSC). PSC were isolated from the pancreas of normal Wistar rats and from rats with cerulein pancreatitis. Cell activation was demonstrated by immunofluorescence microscopy of smooth muscle alpha-actin (SMA) and real-time quantitative RT-PCR of SMA, fibronectin, and transforming growth factor (TGF)-beta(1). Proliferation was measured by bromodeoxyuridine incorporation. Matrix synthesis was demonstrated on the protein and mRNA level. Within a few days in primary culture, PSC changed their phenotype from fat-storing to SMA-positive myofibroblast-like cells expressing platelet-derived growth factor (PDGF) alpha- and PDGF beta-receptors. TGF-beta(1) and tumor necrosis factor (TNF)-alpha accelerated the change in the cells' phenotype. Addition of 50 ng/ml PDGF and 5 ng/ml basic fibroblast growth factor (bFGF) to cultured PSC significantly stimulated cell proliferation (4.37 +/- 0.49- and 2.96 +/- 0.39-fold of control). Fibronectin synthesis calculated on the basis of DNA was stimulated by 5 ng/ml bFGF (3.44 +/- 1.13-fold), 5 ng/ml TGF-beta(1) (2.46 +/- 0.89-fold), 20 ng/ml PDGF (2.27 +/- 0.68-fold), and 50 ng/ml TGF-alpha (1.87 +/- 0.19-fold). As shown by RT-PCR, PSC express predominantly the splice variant EIII-A of fibronectin. Immunofluorescence microscopy and Northern blot confirmed that in particular bFGF and TGF-beta(1) stimulated the synthesis of fibronectin and collagens type I and III. In conclusion, our data demonstrate that 1) TGF-beta(1) and TNF-alpha accelerate the change in the cell phenotype, 2) PDGF represents the most effective mitogen, and 3) bFGF, TGF-beta(1), PDGF, and, to a lesser extent, TGF-alpha stimulate extracellular matrix synthesis of cultured rat PSC.

Animals↗

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↗

PubMed2001

Lack of association between Gly460Trp polymorphism of alpha-adducin gene and salt sensitivity of blood pressure in Polish hypertensives.

BACKGROUND: Previous studies have suggested that alpha-adducin (alpha-ADD) polymorphism may identify patients with a salt-sensitive form of hypertension. AIM: To investigate the association between Gly460Trp polymorphism of alpha-ADD and the pattern of blood pressure response to subacute (1 week) salt loading and depletion in young adult thin Polish hypertensives. METHODS: The study group consisted of 44 subjects with salt-sensitive hypertension (SS) and 24 subjects with non-salt-sensitive hypertension (SR). Genomic DNA isolated from peripheral blood leukocytes was amplified by PCR method with primers flanking the polymorphic region. The mismatch near to 3'-end of the upstream primer was introduced to create a Nla III restriction site in Trp 460 allele. In addition, excreted fraction of filtered sodium (FENa), plasma renin activity (PRA) and plasma concentrations of aldosterone (ALDO) were determined on normal, low and high salt diets. RESULTS: FENa on normal or high salt diets were significantly lower in the SS hypertensives as compared with the SR patients. PRA in SS group was also significantly lower as compared with results in SR group, but only on high salt diet. No significant difference was detected in frequencies of genotypes and alleles of alpha-ADD gene between SS and SR subjects. An additional analysis with regard to genotype (Gly/Gly vs. Gly/Trp+Trp/Trp) showed no significant difference in changes of blood pressure as well as in results of laboratory investigations. CONCLUSION: Our results suggest lack of association between Gly460Trp polymorphism of alpha-adducin gene and salt sensitivity of blood pressure in Polish hypertensives.

Adult↗

PubMed2001

Short-term rivastigmine treatment reduces EEG slow-wave power in Alzheimer patients.

The effects of a 5-day treatment with rivastigmine on the resting EEG power spectrum were studied in 15 mildly to moderately ill Alzheimer patients. In these patients, beta power was positively correlated with cognitive performance and negatively correlated with functional impairment. Rivastigmine produced a decrease in delta and theta power with no effect of hemisphere and electrode position. Delta power decrease reflects the cerebral cholinergic action of rivastigmine and may thus allow a quantitative assessment of its CNS effects.

Aged↗

PubMed2001

From acinar cell damage to systemic inflammatory response: current concepts in pancreatitis.

Acute pancreatitis represents a local inflammatory disorder with severe systemic consequences. Significant progress in understanding the pathophysiology of acute pancreatitis has been achieved in recent years. However, there is no clear concept about initialization and propagation of the disease both in experimental models and in humans. Furthermore, reliable strategies to evaluate prognosis and perform therapy are still missing. The review focuses on mechanisms originating from acinar cells leading to a systemic inflammatory response in experimental pancreatitis.

Animals↗

PubMed2001

TGF alpha transgenic mice. A model of pancreatic cancer development.

Pancreatic cancer is a devastating disease with a fatal prognosis due to late diagnosis and resistance to radiation and chemotherapy. The average survival after diagnosis is still 3 to 8 months. In the last few years genetic alterations in cancer-causing genes have been identified in tumors and putative premalignant lesions using microdissection techniques. However, the functional consequence of these genetic alterations for pancreatic growth and differentiation is unknown. TGF alpha overexpressed in the pancreas causes the development of tubular structures and fibrosis. Mice older than one year develop ductal pancreatic cancer. Crossbreeding these mice with p53 knockout mice dramatically accelerated tumor development. Moreover, tumors developing in these mice show frequently biallelic deletion of the Ink4a locus or LOH of SMAD4. These mice represent the first model of pancreatic adenocarcinomas with genetic alterations as well as growth characteristics similar to the human disease.

Animals↗

PubMed2001

Use of DNA arrays/microarrays in pancreatic research.

In recent years, enormous technical advances in experimental protocols as well as robotic and bioinformatic techniques have allowed DNA array/microarray technology to emerge as the leading technology in the field of functional, disease-related genome analysis. Multiple applications exist for DNA arrays/microarrays including comparative genomic analysis to identify chromosomal imbalances (Matrix-CGH), the study of mutations and genetic polymorphisms, and the study of gene expression (expression profiling). Expression profiling is the most widely used application of DNA array/microarray technology and allows to measure gene expression of thousands of genes simultaneously. The present review describes the basic principles of expression profiling analyses and outlines some applications in pancreatic cancer research.

Humans↗