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U Schmidt

Publications and source records attributed to U Schmidt.

At least 109 records · Page 6Linked to original sources
PubMed1999

Human heart failure: cAMP stimulation of SR Ca(2+)-ATPase activity and phosphorylation level of phospholamban.

Failing human myocardium has been associated with decreased sarcoplasmic reticulum (SR) Ca(2+)-ATPase activity. There remains controversy as to whether the regulation of SR Ca(2+)-ATPase activity is altered in heart failure or whether decreased SR Ca(2+)-ATPase activity is due to changes in SR Ca(2+)-ATPase or phospholamban expression. We therefore investigated whether alterations in cAMP-dependent phosphorylation of phospholamban may be responsible for the reduced SR Ca(2+)-ATPase activity in human heart failure. Protein levels of phospholamban and SR Ca(2+)-ATPase, detected by Western blot, were unchanged in failing compared with nonfailing human myocardium. There was decreased responsiveness to the direct activation of the SR Ca(2+)-ATPase activity by either cAMP (0.01-100 micromol/l) or protein kinase A (1-30 microgram) in failing myocardium. Using the backphosphorylation technique, we observed a decrease of the cAMP-dependent phosphorylation level of phospholamban by 20 +/- 2%. It is concluded that the impaired SR function in human end-stage heart failure may be due, in part, to a reduced cAMP-dependent phosphorylation of phospholamban.

Adult↗
PubMed1999

Results of immunochemotherapy with interleukin-2, interferon-alpha2 and 5-fluorouracil in the treatment of metastatic renal cell cancer.

OBJECTIVE: In patients with advanced metastatic renal cell carcinoma (RCC) seen at a single institution, the toxicity and long-term clinical effects of a combination therapy with recombinant interleukin-2 (rIL-2), recombinant interferon-alpha2 (rIFN-alpha2) and 5-fluorouracil (5-FU) were evaluated. METHOD: From August 1992 through August 1997, 47 consecutive patients (38 men) with metastatic RCC were treated using rIL-2 and rIFN-alpha2 subcutaneously in combination with intravenous 5-FU. An average of 2. 4 cycles/patient (range 1-9) was administered. RESULTS: Toxicity grades II and III (World Health Organization) were observed in 24 and 17 patients, respectively. We achieved 9 major responses (7 complete responses (CR) and 2 partial responses (PR)) for an objective response rate of 19.1% (95% confidence interval 9.1-33.3%). A further 13 patients (27.7%) had a stabilization of disease. After a mean follow-up of 17.9 (2-53) months, 4 patients are alive with no evidence of disease. The 1- and 3-year survival probability was 70 and 37%, respectively. In an univariate analysis, two prognostic factors were correlated with disease outcome: Karnofsky performance index (p = 0.01) and the presence of bone metastases (p = 0.023). CONCLUSION: This triple-drug combination therapy was effective in the treatment of progressive RCC in almost every fifth patient.

Antineoplastic Agents↗
PubMed1999

Site-specific fluorescence labelling of recombinant polyomavirus-like particles.

For the development of gene therapy protocols based on polyomavirus-like particles, we describe a method for fluorescence labelling of virions in order to study virus-cell interactions preceding gene delivery. Site-specific fluorescence labelling of polyomavirus-like particles is achieved via a single cysteine residue and maleimide conjugates of fluorescence dyes (fluorescein, Texas Red). Polyomavirus-like particles can be assembled in vitro from recombinant capsomers produced in E. coli. Since the assembly process is independent of disulfide bond formation, all cysteine residues of the wild-type protein were replaced by serines, and a new unique cysteine residue was introduced for the attachment of the fluorescence marker.

Animals↗
PubMed1998

Time course of enzyme induction in liver and kidneys and absorption, distribution and elimination of 1,4-dichlorobenzene in rats.

Time course of enzyme induction was measured in Fischer344 rats treated daily at 150 and 600 mg 1,4-dichlorobenzene (1.4-DCB)/kg p.o. up to 28 days. The monoxygenases 7-ethoxycoumarin O-deethylase (ECOD), 7-ethoxyresorufin O-deethylase (EROD) and aldrin epoxidase (ALD) as well as the phase II enzymes; epoxide hydrolase (EH), glutathione S-transferase (GS-T) and glucuronyl transferase (GLU-T) were dose-dependently induced in the liver of males and females. A pronounced induction in the kidneys was measured at 600 mg/kg only for ECOD. After single oral administration of 100 and 1000 mg/kg bw and feeding of 100 and 1000 ppm (corresponding to approximately 10 and 100 mg/kg bw) to male Wistar rats for 28 days, the time course of 1,4-DCB and 2,5-DCP concentrations was investigated in plasma, adipose, hepatic and renal tissue. In addition, total urinary excretion of 2,5-DCP was determined. After single application, 1,4-DCB and 2,5-DCP were rapidly eliminated from the plasma and tissues, 40-60% of the dose administered was excreted as 2,5-DCP in the urine. There were no indications of cumulative effects after a feeding period of 28 days. The concentrations decreased in all tissues until the 7th day of study. Thereafter, there seems to be a steady state until the 28th day. A total of 7 days after the end of exposure, no more residues could be detected. Following long-term inhalation (450 and 3000 mg/m3) 1,4-DCB concentrations were highest in adipose tissues at 6 months followed by a marked decline at 18 months. 1,4-DCB and 2,5-DCP concentrations in plasma and liver were much lower but again with a peak at 6 months. When compared with published human data on measurements in plasma, urine, liver and adipose tissue the results suggest that there should be no hazard for the general population.

Absorption↗
PubMed1998

Mutant alleles of the MRS2 gene of yeast nuclear DNA suppress mutations in the catalytic core of a mitochondrial group II intron.

Previous studies show that some yeast strains carrying point mutations of domain 5 that block splicing of a mitochondrial group II intron yield spontaneous revertants in which splicing is partially restored by dominant mutations of nuclear genes. Here we cloned and sequenced the suppressor allele of one such gene, and found it to be a missense mutation of the MRS2 gene (MRS2-L232F). The MRS2 gene was first implicated in group II intron splicing by the finding that overexpression of the wild-type gene weakly suppresses the splicing defect of a mutation of another intron. Tetrad analysis showed that independently isolated suppressors of two other domain 5 mutations are also allelles of the MRS2 gene and DNA sequencing identified a new missense mutation in each strain (MRS2-T230I and MRS2-L213M). All three suppressor mutations cause a temperature-sensitive respiration defect that is dominant negative in heterozygous diploids, but those strains splice the mutant intron at the elevated temperature. The three mutations are in a domain of the protein that is likely to be a helix-turn-helix region, so that effects of the mutations on protein-protein interactions may contribute to these phenotypes. These mutations suppress the splicing defect of many, but not all, of the available splicing defective mutations of aI5gamma, including mutations of several intron domains. Protein and RNA blot experiments show that the level of the protein encoded by the MRS2 gene, but not the mRNA, is elevated by these mutations. Interestingly, overexpression of the wild-type protein restores much lower levels of splicing than were obtained with similar elevated levels of the mutated Mrs2 proteins. The splicing phenotypes of these strains suggest a direct role for Mrs2 protein on group II intron splicing, but an indirect effect is not yet ruled out.

Alleles↗
PubMed1998

Expression of the extracellular matrix signaling molecule Cyr61 is downregulated in prostate cancer.

BACKGROUND: Prostate cancer (CaP) is one of the most common neoplasms in the USA and Europe. We used differential display PCR (DD-PCR) to identify genes related to the development of prostate cancer. METHODS: The RNA of 4 patients with untreated CaP was analyzed for differentially expressed genes. Using DD-PCR, we identified a downregulated cDNA-fragment in these prostate cancer cells. This fragment (N7) was cloned and further analyzed by CMRT-PCR, Northern-blot analysis, and in situ hybridization. RESULTS: Sequence analysis revealed that N7 is identical to the 3'-untranslated region of the recently described immediate early gene Cyr61. Comparative multiplex RT-PCR with sequence specific primers showed that Cyr61 is downregulated in the tumor tissue of 7 out of 13 patients. By in situ hybridization we could demonstrate that the expression of Cyr61 is restricted to the epithelium of the prostate. Immunohistochemical analysis showed that Cyr61 protein could be found in the epithelium of normal prostatic tissue, whereas prostate cancer tissue showed a marked decrease of Cyr61 protein expression. CONCLUSIONS: Cyr61 is a member of the emerging family of extracellular signaling proteins and enhances the effect of bFGF. The changed pattern of expression Cyr61 might therefore contribute to the altered interactions between epithelial and stromal cells in prostate carcinoma.

Animals↗
PubMed1998

Modulation of ventricular function through gene transfer in vivo.

We used a catheter-based technique to achieve generalized cardiac gene transfer in vivo and to alter cardiac function by overexpressing phospholamban (PL) which regulates the activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). By using this approach, rat hearts were transduced in vivo with 5 x 10(9) pfu of recombinant adenoviral vectors carrying cDNA for either PL, beta-galactosidase (beta-gal), or modified green fluorescent protein (EGFP). Western blot analysis of ventricles obtained from rats transduced by Ad.PL showed a 2.8-fold increase in PL compared with hearts transduced by Ad.betagal. Two days after infection, rat hearts transduced with Ad.PL had lower peak left ventricular pressure (58.3 +/- 12.9 mmHg, n = 8) compared with uninfected hearts (92.5 +/- 3.5 mmHg, n = 6) or hearts infected with Ad.betagal (92.6 +/- 5.9 mmHg, n = 6). Both peak rate of pressure rise and pressure fall (+3, 210 +/- 298 mmHg/s, -2, 117 +/- 178 mmHg/s, n = 8) were decreased in hearts overexpressing PL compared with uninfected hearts (+5, 225 +/- 136 mmHg/s, -3, 805 +/- 97 mmHg/s, n = 6) or hearts infected with Ad.betagal (+5, 108 +/- 167 mmHg/s, -3, 765 +/- 121 mmHg/s, n = 6). The time constant of left ventricular relaxation increased significantly in hearts overexpressing PL (33.4 +/- 3.2 ms, n = 8) compared with uninfected hearts (18.5 +/- 1.0 ms, n = 6) or hearts infected with Ad.betagal (20.8 +/- 2.1 ms, n = 6). These differences in ventricular function were maintained 7 days after infection. These studies open the prospect of using somatic gene transfer to modulate overall cardiac function in vivo for either experimental or therapeutic applications.

Adenoviruses, Human↗
PubMed1998

Contribution of abnormal sarcoplasmic reticulum ATPase activity to systolic and diastolic dysfunction in human heart failure.

Two of the most significant characteristics of failing human myocardium are an increased diastolic [Ca2+]i and a prolonged diastolic relaxation. These abnormalities are more pronounced at higher frequencies of stimulation and may be caused by an altered Ca2+ resequestration into the sarcoplasmic reticulum (SR). The force-frequency relationship was determined in multicellular preparations obtained from non-failing (n=6) and failing human myocardium (n=11). The active force in non-failing tissue increased as a function of the frequency of stimulation. In failing myocardium, an increase in frequency of stimulation (>1 Hz) was accompanied by a decrease in active force. Changes in the frequency of stimulation and active force were also associated with changes in intracellular calcium concentrations. The diastolic force in failing myocardium was augmented following an increase in frequency of stimulation, whereas in non-failing tissue, no increase in diastolic force was observed. Associated with the increase in diastolic force was an increase in intracellular diastolic calcium concentrations. The SR Ca2+ ATPase activity was reduced in failing compared to non-failing myocardium. SR Ca2+ ATPase was positively correlated with diastolic force in non-failing myocardium. The relationship between Ca2+ ATPase activity at 1 micromol/l [Ca2+] and active force between 0.5 and 2.0 Hz was different between failing and non-failing myocardium. The diastolic force demonstrate an inverse relationship with the SR Ca2+ ATPase activity in failing myocardium. These data suggest that a reduction in SR Ca2+ ATPase activity contributes to the impairment in both systolic and diastolic function of failing human hearts.

Adenosine Triphosphatases↗
PubMed1998

A Measurement of the Certainty Effect.

In order to measure the certainty effect, the present paper tries to develop an axiomatic model of decision under risk which can accommodate the certainty effect and is, apart from this property, equivalent to expected utility. This leads to a new concept denoted by certainty preference which implies that a higher utility index is assigned to a consequence in the case of certainty than to the same consequence in the presence of risk. Now, a notion of comparative certainty preference can be obtained which will be characterized in terms of properties of the derived utility representation and allows for a generalization of the Arrow-Pratt measure of absolute risk aversion. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

Differentiative effects of dopamine on striatal neurons involve stimulation of the cAMP/PKA pathway.

The neurotransmitter dopamine (DA) stimulates neurite outgrowth and growth cone formation in cultures of embryonic rat striatum through activation of D1 but not D2 receptors. We show here that neurite outgrowth could be stimulated to a similar extent by elevating cellular cAMP levels. Second, the neuritotrophic effect of DA was completely abolished by inhibiting adenylate cyclase or protein kinase A (PKA) but not protein kinase C (PKC). Third, double staining of cultures with antibodies against growth-associated protein-43 (GAP-43) and the phosphorylated form of the cAMP response element binding protein (pCREB) showed that pCREB was nearly exclusively associated with GAP-43-positive, i.e., actively growing, neurons. Again, this effect depended on D1 receptor and PKA activation. Although cross-talk with other signaling pathways needs to be studied further, we conclude that DA promotes the differentiation of striatal neurons via stimulation of D1 receptors and the cAMP/PKA signal transduction pathway.

Animals↗
PubMed1998

[Must the accident victim be protected from the emergency physician?].

Quality control in preclinical medical care has become a matter of concern in recent years. In order to evaluate the quality of treatment one has to set standards. Most of the current standards were defined by different preclinical care organisations and are also accepted in the unique emergency medical care protocol used in the Federal Republic of Germany. Considering these standards, we retrospectively analyzed the preclinical treatment of all multiple trauma patients admitted to our department between 1985 and 1996. The major issues of this analysis were the diagnoses, the indications for invasive measures and the performance. Regarding the triage, for example, it was noted that 28% of patients who should have been admitted to a level I trauma center considering the severity of their injury were first admitted to a level III hospital and needed to be transferred later. In 7% of patients two additional mistakes and in 4% of patients more than two mistakes in the triage were noted. On the other hand, there are records of patients who were considered to be only slightly injured but received invasive treatment. Preclinical intubation and mechanical ventilation was not performed in 16.5% although the severity of injury clearly demanded it. A thoracic drain tube was not positioned in 38% of patients suffering from severe thoracic trauma (AISThorax > or = 4). Insufficient application of resuscitation volume (< 2500 ml on admission) was evident in 17% of all documented patients. According to our results, the initial evaluation of severity of injury is still a major problem and leads to wrong decisions for treatment. Although the qualification of ambulance physicians has been standardized for some years, there are still clear deficits in the preclinical management of trauma patients that need to be targeted.

Adult↗
PubMed1998

[How effective and acceptable is a self-treatment manual with concomitant brief therapy in bulimia nervosa].

We compared 8 fortnightly sessions plus a self-care manual (guided self change, GSC) with 16 weekly individual sessions of cognitive behaviour therapy (CBT). There were 31 sufferers of DSM-III-R-bulimia nervosa (BN) in each group. Both treatments resulted in significant improvements regarding self and interviewer based measures of bulimia nervosa as well as depression, self-esteem, quality of life and knowledge about nutrition, weight and shape. There were no significant differences between therapies regarding drop-out rate, compliance with follow-up, and the number of patients receiving additional treatment. At none of the assessments was there a significant difference between GSC and CBT regarding severity of BN, Beck Depression Inventory-score, self-esteem, and quality of life. A significantly higher percentage of CBT-patients were abstinent from bingeing for at least one week at the end of treatment. Three months later, the GSC-group had caught up in this respect and knew more about nutition, weight and shape. Only the sum-scores on a BN self-rating scale were worse for GSC than CBT at the end of therapy and at follow-up. There were no significant differences between the two groups in general treatment satisfaction and judgement about the usefulness of the therapies. Thus, guided self change with a selfcare manual can save therapist time without impinging significantly on treatment satisfaction and effectiveness.

Adult↗
PubMed1998

Merkel cell carcinoma of the eyelid: histological and immunohistochemical features with special respect to differential diagnosis.

BACKGROUND: Merkel cell carcinomas (MCC) not infrequently involve the periorbital region and the eyelids. Clinically, they are relatively characteristic but often unsuspected. Histologically, MCC are often misdiagnosed as lymphoma, melanoma, or metastatic small cell carcinoma of the lung (SCCL). METHODS: We present clinical, histological, and immunohistochemical data on six eyelid cases (all females; age 63-102 years; one with concomitant CLL) from our files of 77 MCC with special respect to differential diagnosis. For comparison, 22 SCCL were analyzed. Immunohistochemistry was done with antibodies against pan-cytokeratin (pan-CK), cytokeratin-20 (CK-20), neurofilament protein (NF), neuron-specific enolase (NSE), chromogranin (CHR), and S100 protein (S100). RESULTS: Morphologically, five of six MCC were prototypic, one was of the small cell variant. Immunohistochemically, dot-like positivities for pan-CK and CK-20 were seen in all six MCC, and for NF in five tumors. None of the 22 SCCL stained positively for CK-20 or NF but 21/22 cases were positive for pan-CK. Only 1/21 SCCL showed dot-like patterns for pan-CK; 20/21 reacted diffusely. All MCC and 13/22 SCCL displayed CHR-positive cells. All MCC and all SCCL were positive for NSE and negative for S100. CONCLUSIONS: Dot-like positivities for CK-20 or NF are important to prove MCC and to exclude SCCL in clinically and morphologically doubtful cases. Dot-like positivities for pan-CK favor MCC, but do not always exclude SCCL. NSE and CHR are of no value for the differential diagnosis of MCC and SCCL. Melanoma and lymphoma are ruled out by negativity for S100 and pan-CK, respectively.

Aged↗
PubMed1998

Mapping of D1 dopamine receptor mRNA by non-radioactive in situ hybridization.

In order to improve the identification and characterization of dopaminoceptive neurons, the rat brain was mapped for D1 dopamine receptor mRNA by non-radioactive in situ hybridization (ISH) with a 45mer digoxigenin-labeled oligonucleotide probe. The specificity of the results was controlled with the help of a 396-bp D1 receptor riboprobe. Labeled hybrids were visualized with an alkaline phosphatase-coupled anti-digoxigenin antibody. The high resolution obtained permitted individual labeled cells to be identified and to distinction between cell bodies and processes. D1 mRNA was largely confined to neurons. With the exception of ependymal cells, glial cells were not distinctly labeled. Subcellularly, D1 mRNA was localized to perikarya but not to dendrites or axons. D1 receptor-expressing neurons were present in all of the known terminal fields of mesencephalic or diencephalic dopaminergic neurons. However, D1 message was also detected in brain areas which are not known to contain D1 ligand binding sites or in which the presence or the cellular source of this receptor subtype had previously not been unequivocally established, such as the hippocampus or cerebellar cortex. Moreover, labeled neurons were present in regions not known to receive dopaminergic projections, such as the thalamic and some brainstem nuclei. We conclude that this ISH technique provides a considerable gain in sensitivity and resolution with regard to neurotransmitter receptor mapping.

Animals↗
PubMed1998

The protein family of RNA helicases.

RNA helicases represent a large family of proteins that have been detected in almost all biological systems where RNA plays a central role. They are ubiquitously distributed over a wide range of organisms and are involved in nuclear and mitochondrial splicing processes, RNA editing, rRNA processing, translation initiation, nuclear mRNA export, and mRNA degradation. RNA helicases are described as essential factors in cell development and differentiation, and some of them play a role in transcription and replication of viral single-stranded RNA genomes. Comparisons of the conserved sequences reveal a close relationship between them and suggest that these proteins might be derived from a common ancestor. Biochemical studies have revealed a strong dependence of the unwinding activity on ATP hydrolysis. Although RNA helicase activity has only been demonstrated for a few examples yet, it is generally believed that all members of the largest subgroups, the DEAD and DEAH box proteins, exhibit this activity.

Amino Acid Sequence↗
PubMed1998

Cytokeratin and neurofilament protein staining in Merkel cell carcinoma of the small cell type and small cell carcinoma of the lung.

Merkel cell carcinoma (MCC) has a small cell variant, indistinguishable in hematoxylin-eosin sections from metastatic small cell carcinoma of the lung (SCCL). To investigate whether intermediate filament expression is helpful in this distinction, 17 MCCs of the small cell type were examined for cytokeratin, as well as neurofilament protein immunostaining, and compared with 59 intermediate-type MCCs and 22 SCCL. With a pan-cytokeratin cocktail (cytokeratin 1-8, 10, 13-16, 19), most (39 of 55) intermediate-type tumors and, more important, 11 of 16 cases of the small cell variant exhibited focal paranuclear staining with dot-like positivity, crescentic positivity, or both. A combined focal (dot-like/crescentic) and diffuse cytoplasmic pan-cytokeratin staining was seen in additional 8 of 55 intermediate and 4 of 16 small cell MCCs. Cytokeratin 20 also evoked focal cytoplasmic staining and occasionally focal and diffuse positivity in the MCCs, irrespective of the subtype. Exclusively diffuse cytokeratin 20 patterns did not occur. Conversely, most SCCL showed a diffuse expression of pancytokeratin, and all cases remained cytokeratin 20 negative. When neurofilament protein was applied, approximately half of the MCCs (25 of 40), including 7 of 11 of the small cell variant, were positive, whereas all SCCL were negative. In conclusion, the cytokeratin and neurofilament protein patterns of small cell MCCs are identical to the pattern of intermediate MCCs but differ from the profile of SCCL, which may help in the differential diagnosis.

Adult↗
PubMed1998

Chest tube decompression of blunt chest injuries by physicians in the field: effectiveness and complications.

OBJECTIVE: Recent literature suggests that patients who undergo emergent tube thoracostomy in the field are at increased risks for complications. This study evaluates indications, complications, and effectiveness of field placement of chest tubes by an aeromedical service. METHODS: In a prospective study, 624 consecutive patients with chest injuries (Abbreviated Injury Scale score 1-6) were included. All patients were treated at the scene by a physician-staffed aeromedical service and transported by air to a Level I trauma center. Indications, clinical findings before and after chest tube insertion, and subsequent radiologic diagnosis by chest roentgenography were documented prospectively. RESULTS: Seventy-six chest tubes (50 unilateral, 13 bilateral) were inserted laterally in 63 patients (10%) by blunt dissection. Clinical findings included pneumothorax in 30 patients and hemothorax in 18 patients. In 15 patients receiving field chest tubes, neither pneumothorax nor hemothorax was confirmed. Six patients (<1%) arrived at the trauma center with unsuspected pneumothoraces and required chest tube insertion. No tension pneumothoraces escaped field detection and treatment. Four chest tubes placed in the field required repositioning in the hospital because of malfunction or malpositioning. Radiologic findings excluded intraparenchymal tube placements in all patients. No pleural infections were observed in these 63 patients during their hospital stay. No antibiotics were administered as a result of prehospital chest tube placement. CONCLUSION: Prehospital chest tube thoracostomy is safe, effective, and associated with low morbidity. Nontherapeutic chest tube placements occurred in 15 of 624 patients (2.4%); missed pneumothoraces occurred in 6 of 624 patients (<1%). Aggressive prehospital physician management of blunt chest trauma leads to an earlier treatment of potentially life-threatening injuries. Significant morbidity can be avoided by prompt pleural decompression using proper techniques.

Abbreviated Injury Scale↗