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M Schwab

Publications and source records attributed to M Schwab.

At least 37 records · Page 2Linked to original sources
PubMed2002

["Off-label" prescribing of drugs in the ambulatory care of children and adolescents].

BACKGROUND AND OBJECTIVE: Hospitalised children receive up to 90 % of their drug prescriptions without ("unlicensed use") or outside ("off-label use") the terms of their product license. As no data are available for pediatric outpatients in Germany, we determined "off-label" use in a representative cohort of children and adolescents. PATIENTS AND METHODS: We analyzed 1.74 million prescriptions, written from January 1 st through March 31 st, 1999, to 455 661 children and adolescents aged 0 to 16 years by 6886 specialists in pediatric, general or internal medicine. All prescriptions were covered by the public health insurance, Allgemeine Ortskrankenkasse, (AOK) Baden-Wuerttemberg. License status of 1 592 006 identifiable prescriptions comprising more than 10 000 differently branded drugs was determined in 5 age groups and in different groups of the Anatomical Therapeutical Chemical Classification (ATC). As reference documents for licensing status we used the "Fachinformation" (summary of product characteristics), the "Rote" and "Gelbe" Liste, respectively. RESULTS: 13.2 %, i. e. 210 528 of the 1.59 million prescriptions, were "off-label". 75 % of these "off-label" prescriptions were due to a lack of information on pediatric use in the summary of product characteristics. The highest "off-label" fractions were found in drugs topically used in eyes and ears (78.6 %), dermatological (57.9 %), cardiovascular drugs (55.2 %), drugs für musculoskeletal (45.2 %) and urogenital disorders (48.5 %) and antidepressants (36.6 %). CONCLUSION: "Off-label" prescribing in outpatient children is less frequent than in pediatric inpatients. Considering the high absolute number of prescriptions however, 13.2 % cannot be neglected. Doctors prescribing drugs for children and adolescents should be aware of their actual licensing status because of its medical and legal consequences.

Adolescent↗
PubMed2002

[Evaluation of CHILI teleradiology network 4 years after clinical implementation].

The CHILI teleradiology network has more than 60 installations in Germany and the USA. Radiological images and cardiological multiframe series are exchanged in clinical routine. This article investigates in what way and how often the system is used. This is done by means of accounting files that are produced automatically by the system. User functions, transmission protocols, data quantity, frequencies and time of data transmission and teleconferences are evaluated and discussed in this paper. Different application scenarios have been identified and are described and analyzed as well. An important result is, that the system is not merely an emergency system. Instead, it is used in daily routine as a multifunctional, multimodality workstation with advanced features for teleradiology and telecardiology.

Computer Communication Networks↗
PubMed2001

Neuroblastoma tumor cell-binding peptides identified through random peptide phage display.

Random peptide phage display libraries have been employed widely to identify protein-protein interactions, using as targets either purified proteins, intact cells, or organs. To isolate peptides that bind to human neuroblastoma cells, we have used a phage display approach with the neuroblastoma cell line WAC 2 as the target. In particular, two bacteriophages, t147 and t160, displaying peptides p147 and p160, respectively, were isolated by repeated display cycles. Binding of t147 and t160 to WAC 2 cells was abrogated by pretreatment with the peptides p147 and p160, respectively, which strongly support that cellular binding of both phages is dictated by their displayed peptides. Immunofluorescence analysis by confocal light microscopy revealed that the major proportion of t147 remains on the surface of WAC 2 cells and that only a fraction is taken up into the cells. In contrast, the vast majority of t160 is internalized. K(+) depletion reduced the number of the phages internalized by the cells to approximately 20% for t160 and to 10% for t147, indicating that the phage internalization was through receptor-mediated endocytosis. Phage t147 appears to bind to a range of tumor cell lines, including neuroblastoma, breast cancer, glioblastoma and C-cell carcinoma, but less so to non-tumor lines, such as erythrocytes, lymphocytes, monocytes and epithelial cells. Phage t160 bound to a range of neuroblastoma cell lines and a breast cancer cell line, but not to other tested cell lines. While neither of the displayed peptides conferred a narrow tissue specific binding ability, they do provide a basis for targeted drug delivery in selected experimental or natural tumor systems.

Amino Acid Sequence↗
PubMed2001

Yeast Hct1 recognizes the mitotic cyclin Clb2 and other substrates of the ubiquitin ligase APC.

Ubiquitin-mediated proteolysis has emerged as a key mechanism of regulation in eukaryotic cells. During cell division, a multi-subunit ubiquitin ligase termed the anaphase promoting complex (APC) targets critical regulatory proteins such as securin and mitotic cyclins, and thereby triggers chromosome separation and exit from mitosis. Previous studies in the yeast Saccharomyces cerevisiae identified the conserved WD40 proteins Cdc20 and Hct1 (Cdh1) as substrate-specific activators of the APC, but their precise mechanism of action has remained unclear. This study provides evidence that Hct1 functions as a substrate receptor that recognizes target proteins and recruits them to the APC for ubiquitylation and subsequent proteolysis. By co-immunoprecipitation, we found that Hct1 interacted with the mitotic cyclins Clb2 and Clb3 and the polo-related kinase Cdc5, whereas Cdc20 interacted with the securin Pds1. Failure to interact with Hct1 resulted in stabilization of Clb2. Analysis of Hct1 derivatives identified the C-box, a motif required for APC association of Hct1 and conserved among Cdc20-related proteins. We propose that proteins of the Cdc20 family are substrate recognition subunits of the ubiquitin ligase APC.

Amino Acid Motifs↗
PubMed2001

Functional interaction of Yaf2 with the central region of MycN.

MYCN is often amplified in advanced-stage neuroblastomas with the consequence of enhanced MycN protein expression. By employing the yeast two-hybrid system we found that Yaf2 binds to the central region of MycN. Binding was also seen in vitro and in vivo. Ectopically expressed Yaf2, like MycN, is localized in the nuclei of neuroblastoma cells. Endogenous Yaf2 is expressed in all three tested neuroblastoma cell lines, all of which also express MycN. Yaf2 was able to enhance MycN-mediated transactivation from an E-box promoter, deletion of the Yaf2 binding region in MycN abrogates this effect. Thus, the binding of Yaf2 to the central region of MycN is functional in mammalian cells.

3T3 Cells↗
PubMed2001

Frequency of C3435T polymorphism of MDR1 gene in African people.

The variability of P-glycoprotein expression between individuals is linked to a C3435T polymorphism of the human MDR1 gene. Concentration of P-glycoprotein in intestinal epithelial cells and in a subset of lymphoid cells is substantially lower in people with the T/T genotype than those with the C/C genotype. We compared allele frequencies of the C3435T polymorphism in random samples of west African, African American, white, and Japanese people. We recorded a significantly higher frequency of the C/C genotype in West Africans and African Americans (142 of 172 [83%] and 25 of 41 [61%], respectively), than in white people (139 of 537 [26%]) (p<0.0001). These findings could affect use of drugs that are P-glycoprotein substrates (such as HIV-1 protease inhibitors and ciclosporin) in African populations.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Constitutional genomic instability with inversions, duplications, and amplifications in 9p23-24 in BRCA2 mutation carriers.

Germ-line mutations of the BRCA2 gene (13q12-13) account for a large proportion of familial breast cancer cases in females and the majority of familial breast cancers in males. Recent studies provide evidence for a role of the BRCA2 protein in the maintenance of genomic integrity by involvement in DNA repair and recombination. In pursuit of identifying in humans genetic damage resulting from mutated BRCA2, we have analyzed constitutional karyotypes of BRCA2 mutation carriers. The present study establishes that constitutional distal 9p rearrangements without obvious additional gross chromosomal alterations are a recurrent feature of independently ascertained families. From our cytogenetic analyses we have no indication of additional gross rearrangements, but we cannot exclude more subtle recombinations in other genomic regions. We also show that the topography of the 9p rearrangements can differ among family members, even within an individual that can have cell populations with different 9p rearrangements. Collectively these results raise point to an association of mutant BRCA2 with genomic instability and gene alteration in 9p23-24 in at least a subset of BRCA2 mutation carriers.

Adult↗
PubMed2001

Amplification of oncogenes revisited: from expression profiling to clinical application.

Regulatory or structural alterations of cellular oncogenes have been implicated in the causation of cancers. Amplification represents one of the major molecular pathways by which gene expression is constitutively enhanced above the level of physiologically normal variation. Consequently, the significance of oncogene amplification in tumorigenesis originally had emerged from expression profiling of tumor cells by oncogene arrays. Amplified oncogenes have been found associated with more aggressive tumor variants and in selected settings are clinical markers to determine patient prognosis.

Breast Neoplasms↗
PubMed2001

N-myc enhances the expression of a large set of genes functioning in ribosome biogenesis and protein synthesis.

The myc oncogenes are frequently activated in human tumors, but there is no comprehensive insight into the target genes and downstream cellular pathways of these transcription factors. We applied serial analysis of gene expression (SAGE) to identify targets of N-myc in neuroblastomas. Analysis of 42,000 mRNA transcript tags in SAGE libraries of N-myc- transfected and control neuroblastoma cells revealed 114 up-regulated genes. The majority of these genes have a role in ribosome assembly and activity. Northern blot analysis confirmed up-regulation of all tested transcripts. Induction was complete within 4 h after N-myc expression. The large majority of the ribosomal proteins were induced, as well as genes controlling rRNA maturation. Cellular rRNA content was 45% induced. SAGE libraries and northern blot analysis confirmed up-regulation of many of these genes in N-myc-amplified neuroblastomas. As N-myc can functionally replace c-myc, we analyzed whether N-myc targets were induced by c-myc as well. Approximately 40% of these N-myc targets were up-regulated in a c-myc-transfected melanoma cell line. These data suggest that myc genes function as major regulators of the protein synthesis machinery.

Gene Expression Profiling↗
PubMed2001

Non-linear changes of electrocortical activity after antenatal betamethasone treatment in fetal sheep.

We determined the effects of betamethasone on the fetal sheep electrocorticogram (ECoG) using linear (power spectral) and non-linear analysis. For non-linear analysis we used an algorithm based on the Wolf algorithm for the estimation of the leading Lyapunov exponent which calculates a prediction error based on the course of the time series in the phase space. A high prediction error stands for low predictibility or low regularity and vice versa. After 48 h of baseline recordings, vehicle (n = 6) or betamethasone (n = 7) at 10 microg h(-1) was infused over 48 h to the sheep fetus at 128 days gestational age (0.87 of gestation). ECoG spectral analysis revealed no difference in power spectrum between vehicle- and betamethasone-treated fetuses. The prediction error of the ECoG during REM sleep was higher than during non-REM or quiet sleep in both groups (P < 0.0001) revealing lower causality of brain activity during REM sleep. During REM sleep, prediction error significantly decreased 18-24 h after onset of betamethasone treatment (P < 0.05) and returned to baseline values within the following 24 h of continued betamethasone treatment. No ECoG changes were found during quiet sleep. Non-linear ECoG changes during metabolically active REM sleep accompanied the previously described decrease in cerebral blood flow. These results suggest that betamethasone in doses used in perinatal medicine acutely alters complex neuronal activity.

Algorithms↗
PubMed2001

Hypoxia promotes apoptosis of human neuroblastoma cell lines with enhanced N-myc expression.

We have examined the effect of hypoxia and nutrient depletion on the growth of human neuroblastoma cells with normal or enhanced expression of the N-myc oncogene. The combination of both conditions reduced the growth of neuroblastoma cells with normal N-myc expression. However, this effect was much more pronounced in neuroblastoma cells with enhanced N-myc expression and eventually resulted in apoptosis, presumably by the up-regulation of CD95. Our data suggest that therapeutic induction of tumor hypoxia and nutrient depletion (for example, by anti-angiogenesis) could help to improve the outcome of patients with neuroblastomas carrying the prognostically unfavourable N-myc amplification.

Apoptosis↗
PubMed2001

Effect of antenatal betamethasone treatment on microtubule-associated proteins MAP1B and MAP2 in fetal sheep.

Betamethasone has been used extensively to accelerate fetal lung maturation, yet little is known of its effects on neuronal morphogenesis in the developing fetus. Microtubule-associated proteins (MAPs) are a diverse family of cytoskeletal proteins that are important for brain development and the maintenance of neuroarchitecture. Vehicle (n = 7) or betamethasone (10 ug h-1, n = 7) was infused I.V. to fetal sheep over 48 h beginning at 0.87 of gestation (128 days of gestation), producing fetal plasma betamethasone concentrations resembling those to which the human fetus is exposed during antenatal glucocorticoid therapy. Paraffin sections of the left hemisphere were stained with monoclonal antibodies against MAP1B and the MAP2 isoforms MAP2a,b,c and MAP2a,b. The level of the juvenile isoform MAP2c was determined by comparison of the two MAP2 immunostainings. We were able to detect MAP1B and MAP2 immunoreactivity (IR) in the fetal sheep brain. MAP2c was the major MAP2, constituting 90.2 % of the total MAPBetamethasone exposure diminished MAP1B IR in the frontal cortex and caudate putamen (P < 0.05) but not in the hippocampus. A decrease of MAP2 IR was found in the frontal cortex, hippocampus and caudate putamen (P < 0.05). Loss of MAP2 IR was mainly due to the loss of MAP2c IR. Haematoxylin-eosin staining did not demonstrate irreversible neuronal damage. Regional cerebral blood flow determined using coloured microspheres was significantly decreased by 28 % in the frontal cortex and by 36 % in the caudate putamen but not in the hippocampus 24 h after the onset of betamethasone exposure (P < 0.05). The loss of MAP1B and MAP2a,b,c IR showed a significant correlation to the cerebral blood flow decrease only in the frontal cortex (P < 0.05). These data suggest that mechanisms other than metabolic insufficiency caused by the decreased cerebral blood flow may contribute to the loss of MAPs. The results suggest that clinical doses of betamethasone may have acute effects on cytoskeletal proteins in the fetal brain.

Animals↗
PubMed2001

DAP-5 is involved in MycN/IFNgamma-induced apoptosis in human neuroblastoma cells.

Death associated protein-5 (DAP-5) is a ubiquitously expressed member of the translation initiation factor eIF4G family that lacks the eIF4E binding site. A dominant negative fragment of DAP-5 protects HeLa cells from IFNgamma-induced cell death. By employing a functional approach we examined the role of DAP-5 in human neuroblastoma cells that are sensitized for IFNgamma-induced apoptosis by tetracycline controlled MYCN expression. DAP-5 fragment transcribed at high levels and translated into a functional miniprotein of 28 kDa protected neuroblastoma cells from IFNgamma-induced apoptosis. Reduced serum levels were toxic to cells constitutively expressing DAP-5 fragment suggesting that DAP-5 protein is essential for both viability and death of human neuroblastoma cells.

Antineoplastic Agents↗
PubMed2001

Prognostic value of codon 918 (ATG-->ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma.

We have determined the frequency of 918 RET proto-oncogene mutations (ATG-->ACG) in primary MTC tumors and metastases and correlated the presence or absence of this mutation with the clinical outcome of patients suffering from sporadic medullary thyroid carcinoma (MTC). A total of 197 samples, consisting of both primary tumors and lymph node metastases from 34 patients with sporadic MTC, were collected for PCR analysis of the RET 918 mutation. In 75 of the samples (38%), codon 918 (ATG-->ACG) mutations could be detected. The mutations showed a heterogeneous distribution: 21/34 patients (62%) had mutations in at least 1 tumor sample, and in 13 patients (38%) the mutation was present in all examined samples. Patients were considered 918mt when at least 1 tumor sample showed the RET 918 mutation. These 918mt and 918 wild-type (918wt) patients did not differ significantly concerning sex, age at diagnosis, TNM stage at diagnosis, number of examined tumor samples or follow-up time. However, 918mt patients showed more aggressive development of distant metastases during follow-up (p = 0.032, Fisher's exact test) with decreased metastases-free survival (p < 0.005, log-rank test). Furthermore, 918mt patients had a significantly lower survival rate than 918wt patients (p = 0.048, log-rank test). These data show that the RET codon 918 mutation has a prognostic impact on patients with sporadic MTC which may influence follow-up treatment.

Adult↗
PubMed2001

Antenatal betamethasone treatment reduces synaptophysin immunoreactivity in presynaptic terminals in the fetal sheep brain.

Knowledge of morphofunctional effects on the fetal brain induced by exogenous glucocorticoids is limited. Recently, we reported alterations of both the neuronal cytoskeleton and electrocortical function in the ovine fetal brain after antenatal betamethasone treatment in doses used in perinatal medicine. In the present study we examined whether these changes are accompanied by morphological alterations of synapses. Chronically instrumented fetal sheep at 0.87 of gestation were treated either with isotonic saline (n=7) or 10 microg/h betamethasone (n=7) over 48 h administered directly to the fetal jugular vein. Paraffin sections of the frontal neocortex, caudate putamen and hippocampus were stained with a monoclonal antibody against synaptophysin, a specific membrane protein of presynaptic vesicles and quantified morphometrically. Synaptophysin-like immunoreactivity (synaptophysin-LI) showed a widespread granular pattern in the neuropil. Betamethasone exposure reduced synaptophysin-LI in the frontal neocortex, caudate putamen and hippocampus by 46.9, 41.0 and 55.4%, respectively, (P<0.05) that was not accompanied by irreversible neuronal damage. These results suggest that clinical doses of betamethasone have acute effects on presynaptic terminals in the fetal sheep brain that could contribute to the altered complexity of electrocortical function that we have shown previously to occur following fetal exposure to betamethasone.

Animals↗
PubMed2001

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Journal Article↗