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M C Schmidt

Publications and source records attributed to M C Schmidt.

At least 19 recordsLinked to original sources
PubMed2000

beta-subunits of Snf1 kinase are required for kinase function and substrate definition.

The Snf1 kinase and its mammalian homolog, the AMP-activated protein kinase, are heterotrimeric enzymes composed of a catalytic alpha-subunit, a regulatory gamma-subunit and a beta-subunit that mediates heterotrimer formation. Saccharomyces cerevisiae encodes three beta-subunit genes, SIP1, SIP2 and GAL83. Earlier studies suggested that these subunits may not be required for Snf1 kinase function. We show here that complete and precise deletion of all three beta-subunit genes inactivates the Snf1 kinase. The sip1Delta sip2Delta gal83Delta strain is unable to derepress invertase, grows poorly on alternative carbon sources and fails to direct the phosphorylation of the Mig1 and Sip4 proteins in vivo. The SIP1 sip2Delta gal83Delta strain manifests a subset of Snf phenotypes (Raf(+), Gly(-)) observed in the snf1Delta 10 strain (Raf(-), Gly(-)), suggesting that individual beta-subunits direct the Snf1 kinase to a subset of its targets in vivo. Indeed, deletion of individual beta-subunit genes causes distinct differences in the induction and phosphorylation of Sip4, strongly suggesting that the beta-subunits play an important role in substrate definition.

AMP-Activated Protein Kinases↗
PubMed2000

Validation of excised bovine nasal mucosa as in vitro model to study drug transport and metabolic pathways in nasal epithelium.

The present work aims at the validation of excised bovine nasal mucosa as an in vitro model to address transport and metabolism pathways relative to the nasal mucosal uptake of therapeutic peptides. Preservation of the viability of the excised tissue in the course of in vitro studies of up to 3 h was demonstrated by (i) positive viability staining, (ii) constant transepithelial electrical resistance (42 +/- 12 Omega cm(2)), (iii) constant rates of metabolic turnover, and (iv) linear permeation profiles of therapeutic peptides and (3)H-mannitol. Using 1-leucine-4-methoxy-2-naphthylamide as a model substrate, we observed no difference between bovine and human nasal aminopeptidase activity. By a series of therapeutic peptides, no direct correlation was found between their effective permeability coefficients (from 0. 1 x 10(-5) to 5 x 10(-5) cm s(-1)) and their respective molecular masses (from 417 to 3,432 Da), indicating that other factors dominate nasal permeability. For instance, the permeabilities of metabolically labile peptides were concentration dependent and saturable, as demonstrated for two short thymopoietin fragments, Arg-Lys-Asp (TP3) and Arg-Lys-Asp-Val (TP4). By permeation studies using gonadorelin and two gonadorelin derivatives, buserelin and Hoe 013, without and in the presence of the chemical enhancer bacitracin, we also verified the ability of the model to assess chemical enhancer effects and their reversibility. In conclusion, our work demonstrates the potential of the investigated in vitro model, excised bovine nasal mucosa, to explore mechanistic aspects of nasal transport and metabolism of therapeutic peptides.

Absorption↗
PubMed2000

Long-term survival of glioblastoma multiforme: importance of histopathological reevaluation.

The overall prognosis for patients with glioblastoma multiforme is extremely poor. However, a small proportion of patients enjoy prolonged survival. This study investigated retrospectively the extent to which erroneous histopathological classification may contribute to long-term survival of patients initially diagnosed with "glioblastoma multiforme." We compared two age- and gender-matched patient groups with different postoperative time to tumor progression (TTP), defined as "short-term" for TTP of less than 6 months (n = 54), and "long-term" for TTP of more than 12 months (n = 52). Histological specimens of the corresponding tumors, all primarily diagnosed as glioblastoma multiforme, were reevaluated according to the current World Health Organization (WHO) classification of central nervous system tumors, with the investigators being blinded to clinical outcome. Among the tumors from short-term TTP patients, one tumor (2%) was reclassified as anaplastic oligoastrocytoma (WHO grade III) while the remaining 53 were confirmed as glioblastoma multiforme. In contrast, 13 tumors (25%) from the long-term TTP patients were reclassified, mostly as anaplastic oligodendroglioma (WHO grade III; n = 7) or anaplastic oligoastrocytoma (WHO grade III, n = 2), respectively. In addition, three were reclassified as anaplastic astrocytoma (WHO grade III), and one was identified as anaplastic pilocytic astrocytoma (WHO grade III). Our data indicate that a sizable proportion of glioblastoma patients with long-term survival actually carry malignant gliomas with oligodendroglial features. The correct histopathological recognition of these tumors has not only prognostic but also therapeutic implications, since oligodendroglial tumors are more likely to respond favorably to chemotherapy.

Adult↗
PubMed2000

Nasal epithelial permeation of thymotrinan (TP3) versus thymocartin (TP4): competitive metabolism and self-enhancement.

PURPOSE: To investigate concentration dependent permeabilities and metabolism kinetics of thymotrinan (TP3) versus thymocartin (TP4) in nasal epithelium in vitro. METHODS: Excised bovine nasal mucosa was used as an in vitro model. Permeabilities were studied in a diffusion chamber, metabolism kinetics in a reflection kinetics set-up. Studies were performed at various TP3 and TP4 concentrations. The 3H-mannitol flux was measured to monitor junctional permeability. Potential Ca(2+)-complexation was investigated using a Ca(2+)-selective electrode. RESULTS: Permeability of TP3 was negligible at 0.1 and 0.2 mM and increased drastically above 0.4 mM up to -2 X 10(-5) cm s(-1). In the presence of 2 mM TP4 the TP3 permeabilites were significantly above (approximately 4 x 10(-5) cm s(-1)) the level of TP3 without TP4, and TP3 metabolism was totally inhibited. TP3 and TP4 showed a significant concentration dependent effect on the permeability of 3H-mannitol. A hyperosmolarity effect of the peptide solutions was excluded. Transepithelial electrical resistance (TEER; approximately 30 ohms cm2) was unchanged by either TP3 or TP4. At 1 mM TP3 the mucosal-to-serosal permeability was four times higher than serosal-to-mucosal, indicating enzyme polarization. In reflection kinetics studies, TP3 degradation was slightly higher on the mucosal than on the serosal side. TP3 and TP4 followed the same non-linear metabolism kinetics. CONCLUSIONS: Increase in permeability at high TP concentrations involves competitive enzyme saturation combined with self-enhanced paracellular permeation.

Adjuvants, Immunologic↗
PubMed2000

p0071, a member of the armadillo multigene family, is a constituent of sarcomeric I-bands in human skeletal muscle.

p0071 is a member of the armadillo gene family that is expressed in a wide variety of mammalian tissues and cell types with a prominent cell-cell contact association in epithelial cells. Here, we report the expression and localization patterns of p0071 in differentiating human skeletal muscle cells and in normal and diseased human skeletal muscle tissues. Northern blots revealed expression of p0071 mRNA in adult skeletal muscle tissue. RT-PCR analysis and Western blotting experiments identified two differentially spliced isoforms of p0071. The balance between these isoforms shifted during in vitro differentiation of isolated muscle cells from predominant expression of the short variant to a preponderance of the larger variant from day 6 onwards. Immunolocalization studies in mature skeletal muscle tissue revealed that p0071 is a constituent of myofibrils with a distinct localization at the level of sarcomeric N2-lines. During myofibrillogenesis, p0071 was not detected in non-striated nascent myofibrils, but became apparent shortly after the development of compact Z-discs in early myotubes. Furthermore, we studied the expression of p0071 in a wide variety of neuromuscular disorders by indirect immunofluorescence. Here, the myofibrillar staining of p0071 was preserved in all the disease entities included in our study. Our results provide the first evidence that a member of the armadillo multigene family is a constituent of the contractile apparatus in human skeletal muscle. The localization of p0071 at the level of I-bands and the timepoint of its integration into developing myofibrils suggest a possible role in the organization of thin filaments.

Age Factors↗
PubMed2000

Comprehensive allelotype and genetic anaysis of 466 human nervous system tumors.

Brain tumors pose a particular challenge to molecular oncology. Many different tumor entities develop in the nervous system and some of them appear to follow distinct pathogenic routes. Molecular genetic alterations have increasingly been reported in nervous system neoplasms. However, a considerable number of affected genes remain to be identified. We present here a comprehensive allelotype analysis of 466 nervous system tumors based on loss of heterozygosity (LOH) studies with 129 microsatellite markers that span the genome. Specific alterations of the EGFR, CDK4, CDKN2A, TP53, DMBT1, NF2, and PTEN genes were analyzed in addition. Our data point to several novel genetic loci associated with brain tumor development, demonstrate relationships between molecular changes and histopathological features, and further expand the concept of molecular tumor variants in neuro-oncology. This catalogue may provide a valuable framework for future studies to delineate molecular pathways in many types of human central nervous system tumors.

Alleles↗
PubMed1999

Analysis of the MEN1 gene in sporadic pituitary adenomas.

The MEN1 gene on chromosome 11q13 is mutated in patients afflicted with multiple endocrine neoplasia syndrome type 1 (MEN1). These patients develop endocrine tumours of the pancreas, the parathyroid, and the anterior pituitary. In order to determine the role of MEN1 in sporadic pituitary adenomas, 61 pituitary adenomas were analysed from patients without evidence of a familial tumour syndrome. Single strand conformation polymorphism (SSCP) analysis was performed for the entire coding sequence of MEN1. Fragments with aberrant migration patterns were sequenced bidirectionally. Only a single somatic mutation was detected in this series. In addition, several previously reported and three novel polymorphisms were observed. Loss of heterozygosity analysis with 12 polymorphic markers, however, identified 13 pituitary adenomas with allelic deletions on chromosome 11. Allelic losses occurred significantly more often in pituitary adenomas with hormone secretion than in non-functioning adenomas. These data suggest that MEN1 mutations are rare events in sporadic pituitary adenomas. However, the discrepancy of only 1/61 adenomas with MEN1 mutation but 13/61 (22 per cent) with allelic loss on chromosome 11 may suggest the presence of a yet unknown tumour suppressor gene, relevant to the pathogenesis of sporadic pituitary adenomas.

Adenoma↗
PubMed1999

Molecular genetic analysis as a tool for evaluating stereotactic biopsies of glioma specimens.

Over the last years, distinct genetic lesions have been associated with individual tumor entities. Stereotactic biopsy has become an essential diagnostic tool in surgical neuro-oncology. In order to evaluate the potential of molecular analyses in stereotactic biopsies, we examined a series of 156 human brain tumors from patients undergoing stereotactic biopsy for molecular alterations typically seen in astrocytic gliomas and compared those results with a control group of 268 astrocytic tumors obtained at open surgery. Stereotactic biopsies of astrocytomas with borderline histopathological features between the WHO grades II and III showed a higher rate of allelic losses on chromosome 10 than those of the WHO grade II from open surgery (p = 0.011). Stereotactic biopsies of astrocytomas with borderline histopathological features between the WHO grades III and IV showed a higher rate of allelic losses on chromosome 10 than those of the WHO grade III from open surgery (p = 0.013). This indicates that stereotactic biopsies with features intermediate between grades are likely to correspond to the higher malignancy grade. Our data demonstrate that molecular genetic approaches can be successfully applied to stereotactic glioma biopsies. The difference in the distribution of malignancy associated genetic alterations between a stereotactic and openly resected group of gliomas indicates that histopathology may underestimate the malignant potential in some stereotactic specimens. We propose to further evaluate the molecular analysis of stereotactic glioma biopsies as a useful adjunct to standard histopathological procedures.

Biopsy↗
PubMed1999

Std1 and Mth1 proteins interact with the glucose sensors to control glucose-regulated gene expression in Saccharomyces cerevisiae.

The Std1 protein modulates the expression of glucose-regulated genes, but its exact molecular role in this process is unclear. A two-hybrid screen for Std1-interacting proteins identified the hydrophilic C-terminal domains of the glucose sensors, Snf3 and Rgt2. The homologue of Std1, Mth1, behaves differently from Std1 in this assay by interacting with Snf3 but not Rgt2. Genetic interactions between STD1, MTH1, SNF3, and RGT2 suggest that the glucose signaling is mediated, at least in part, through interactions of the products of these four genes. Mutations in MTH1 can suppress the raffinose growth defect of a snf3 mutant as well as the glucose fermentation defect present in cells lacking both glucose sensors (snf3 rgt2). Genetic suppression by mutations in MTH1 is likely to be due to the increased and unregulated expression of hexose transporter genes. In media lacking glucose or with low levels of glucose, the hexose transporter genes are subject to repression by a mechanism that requires the Std1 and Mth1 proteins. An additional mechanism for glucose sensing must exist since a strain lacking all four genes (snf3 rgt2 std1 mth1) is still able to regulate SUC2 gene expression in response to changes in glucose concentration. Finally, studies with green fluorescent protein fusions indicate that Std1 is localized to the cell periphery and the cell nucleus, supporting the idea that it may transduce signals from the plasma membrane to the nucleus.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Translocation of human calcitonin in respiratory nasal epithelium is associated with self-assembly in lipid membrane.

We studied the mechanisms involved in the translocation of human calcitonin (hCT) through excised bovine nasal mucosa (net mucosal-to-serosal permeability approximately 10(-)5 cm s-1). To determine structural requirements for the suggested vesicular internalization two carboxyfluorescein-labeled (fl) hCT fragments, the C-terminal fragment [Nalpha-fl]hCT(9-32) and the N-terminal fragment [Lys(fl)18]hCT(1-24) were synthesized. In presence of the endocytosis inhibitor cytochalasin D mucosal-to-serosal and serosal-to-mucosal hCT permeabilities were equal. Pathway visualization by confocal laser scanning microscopy showed punctated fluorescence indicating vesicular internalization of both hCT and [Nalpha-fl]hCT(9-32). In contrast, the N-terminal fragment lacking the beta-sheet forming C-terminus (25-32) was not internalized. Circular dichroism showed that, when interacting with neutral and negatively charged liposomes, hCT adopts beta-sheet conformation. In a concentrated aqueous solution, beta-sheet formation induces hCT self-assembly and fibrillation. High partitioning of hCT into lipid bilayer membranes was reflected by an apparent partition coefficient log D(pH 7.4) = 2.5 (liposome-buffer equilibrium dialysis). We propose that the high lipid partitioning and beta-sheet formation result in C-terminus-restricted supramolecular self-assembly of hCT and [Nalpha-fl]hCT(9-32) in lipid membranes. Vesicular internalization is suggested to be associated with self-assembly induced perturbation of the lipid bilayer. Condensed hCT self-assemblies may explain the high capacity of net mucosal-to-serosal hCT permeation, which compares favorably with the low transport capacity of receptor-mediated endocytosis.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1998

Amino acid residues in Std1 protein required for induction of SUC2 transcription are also required for suppression of TBPDelta57 growth defect in Saccharomyces cerevisiae.

The STD1 gene of Saccharomyces cerevisiae was isolated independently as a multicopy suppressor of a dominant negative mutation in the TATA-binding protein and of a mutation in the Snf1/Snf4 kinase complex, suggesting that Std1 might couple the Snf1 kinase signaling pathway to the transcriptional machinery. In order to identify the protein domains that specify these activities of the Std1 protein, a plasmid library of randomly mutagenized STD1 genes was screened for loss of function alleles using complementation of the raffinose growth defect of a std1-, mth1- strain as an assay. One missense allele (P236S) with complete loss of function at 30 degreesC and four missense alleles (L173F, E225K, S269L and E274K) that conferred a temperature sensitive phenotype were identified. The C-terminal 20 residues of Std1 were essential for SUC2 derepression, whereas the deletion of the N-terminal 96 residues did not affect SUC2 gene induction. Std1 mutants that lost the ability to induce SUC2, were also unable to suppress the growth defect caused by the expression of the dominant negative TBPDelta57 protein, suggesting that these two genetic screens may be detecting the same biological activity.

Alleles↗
PubMed1998

An oligonucleotide inhibits oligomerization of a rolling circle initiator protein at the pT181 origin of replication.

A large number of plasmids have been shown to replicate by a rolling circle (RC) mechanism. The initiators encoded by these plasmids have origin-specific, nicking-closing activity that is required for the initiation and termination of RC replication. Since the initiators of many RC plasmids are rate-limiting for replication, these proteins are usually inactivated after supporting one round of replication. In the case of the pT181 plasmid, inactivation of the initiator RepC protein occurs by the attachment of an oligonucleotide to its active tyrosine residue. We have generated the inactivated form of RepC, termed RepC*, in vitro and investigated the effects of attachment of the oligonucleotide on its various biochemical activities. Our results demonstrate that while RepC* is inactive in nicking-closing and replication activities due to the blockage of its active tyrosine residue, it is competent in origin DNA binding and DNA religation activities. We have investigated the oligomeric state of RepC and RepC* and found that RepC exists as a dimer in solution and can oligomerize on the DNA. We have generated heterodimers in vitro between the wild-type and epitope-tagged RepC proteins. In electrophoretic mobility shift experiments, the initiator heterodimers generated a novel DNA-protein complex, demonstrating that it binds to DNA as a dimer. We have shown that a DNA binding mutant of RepC can be targeted to the origin in the presence of the wild-type protein primarily through a protein-protein interaction. Interestingly, RepC* is defective in its ability to oligomerize on the DNA. RepC* inhibited the DNA binding and replication activity of wild-type RepC to only a very limited extent, suggesting that it may play only a minor regulatory role in replication in vivo. Based on these and earlier results, we propose a model for the role of RepC during the initiation and termination of pT181 RC replication.

Bacterial Proteins↗
PubMed1998

Identification of cis-acting elements in the SUC2 promoter of Saccharomyces cerevisiae required for activation of transcription.

We analyzed the effects of site-directed mutations in the SUC2 promoter of Saccharomyces cerevisiae. Analyses were performed in wild-type as well as mig1 and tup1 mutant strains after the promoter mutants were reintroduced into the native SUC2 locus on the left arm of chromosome IX. Mutation of the two GC boxes revealed that these elements play two distinct roles: they are, as expected, required for Mig1-mediated repression but they are also necessary for activation of the SUC2 promoter in response to glucose limitation. The individual GC boxes are functionally redundant with regard to Mig1-mediated repression, however, only the upstream GC box is essential for high level expression of SUC2. Microccocal nuclease sensitivity of the SUC2 promoter in derepressed cells was reduced in the GC box mutant promoters, particularly in the vicinity of the TATA box. The difference in nuclease sensitivity between wild-type and GC box mutant promoters was not evident in tup1- cells. The formation of nuclease-resistant chromatin does not require the GC boxes, indicating that other cis-acting elements can serve to recruit the Ssn6-Tup1 co-repressor complex to the SUC2 promoter.

Base Sequence↗
PubMed1998

[Magnetic resonance tomography in diagnosis of cardiac space-occupying lesions].

Imaging of cardiac masses is technically highly demanding. Imaging techniques should fulfill the following requirements: excellent spatial and temporal resolution, short imaging time, broad availability, low cost. Diagnostic questions include: tumor origin, size, extension, tissue type, functional consequences of tumor involvement. Transthoracic echocardiography is the imaging technique of choice in most patients. If clinical questions remain, TEE, CT or MRI can be used as secondary imaging techniques. Advantages of MRI include: excellent spatial and temporal resolution, multiplanar capabilities, large field of view, lack of radiation. Pericardial and intracardiac as well as paracardiac masses are depicted in great detail and therapeutically relevant information is usually obtained in addition to what is known from echocardiography. Although tissue differentiation is possible, a histologic diagnosis cannot be obtained. Disadvantages of MRI are artifacts in patients with severe arrhythmias or dyspnoea.

Heart Neoplasms↗
PubMed1998

Permeation and pathways of human calcitonin (hCT) across excised bovine nasal mucosa.

In vitro permeation of human calcitonin (hCT), salmon calcitonin (sCT), and the somatostatin analog octreotide (SMS) through excised bovine nasal mucosa was studied applying donor/receiver experiments and confocal laser scanning microscopy. Permeabilities of gonadorelin, buserelin, Hoe013, and of thymopoietin fragments TP5 and TP4 were also included. Apparent permeability coefficients (Peff) ranged between 4 x 10(-5) (SMS) and 1.7 x 10(-5) cm s(-1) (TP4). Such Peff are typical for leaky-type airway epithelia. The order of permeabilities was: SMS >> hCT, sCT > buserelin, Hoe013 >> TP5 > TP4, LHRH. The relatively high permeability of hCT and sCT contrasted to their high molecular weight. At 37 degrees C, the permeability of hCT from mucosal to serosal (m-to-s) was found two-fold higher (p < 0.05) than from serosal to mucosal (s-to-m). Controls using 3H-mannitol showed equal permeabilities in both directions. At 4 degrees C, permeation of hCT was reduced but equal in both directions (m-to-s and s-to-m). As evaluated by confocal laser scanning microscopy, uptake studies with FITC-18-hCT revealed intracellular fluorescence in the epithelial cells, at 10 min/10 microM exposure in the form of fluorescent vesicles. By combination of these findings, an endocytotic pathway is suggested to contribute to the transport of hCT through nasal epithelium.

Animals↗
PubMed1998

Identification of a calcineurin-independent pathway required for sodium ion stress response in Saccharomyces cerevisiae.

The calcium-dependent protein phosphatase calcineurin plays an essential role in ion homeostasis in yeast. In this study, we identify a parallel ion stress response pathway that is independent of the calcineurin signaling pathway. Cells with null alleles in both STD1 and its homologue, MTH1, manifest numerous phenotypes observed in calcineurin mutants, including sodium, lithium, manganese, and hydroxyl ion sensitivity, as well as alpha factor toxicity. Furthermore, increased gene dosage of STD1 suppresses the ion stress phenotypes in calcineurin mutants and confers halotolerance in wild-type cells. However, Std1p functions in a calcineurin-independent ion stress response pathway, since a std1 mth1 mutant is FK506 sensitive under conditions of ion stress. Mutations in other genes known to regulate gene expression in response to changes in glucose concentration, including SNF3, RGT2, and SNF5, also affect cell growth under ion stress conditions. Gene expression studies indicate that the regulation of HAL1 and PMR2 expression is affected by STD1 gene dosage. Taken together, our data demonstrate that response to ion stress requires the participation of both calcineurin-dependent and -independent pathways.

Adaptation, Physiological↗
PubMed1997

Assessment of myocardial perfusion by magnetic resonance imaging.

Magnetic resonance imaging (MRI) has proven useful for anatomic and functional evaluation of the heart. However, until recently assessment of myocardial perfusion has not been possible by MRI. Using newly developed ultrafast imaging sequences, images can be acquired rapidly with a high temporal resolution, which is a prerequisite for imaging the initial passage of a bolus of MR-contrast medium through the myocardium. Only gadolinium chelates, which rapidly diffuse out of vascular space, are currently approved for clinical use. The first pass of a bolus of one of these agents through hypoperfused myocardium distal to a coronary artery stenosis enhances this area less as compared to normally perfused areas. This different myocardial enhancement is often visible when looking at the series of MR images. However, intensity differences are rapidly decreasing as MR-contrast media are diluted in the systemio circulation after the first pass and diffuse to the interstitium. Therefore, only the first pass is of interest for MR-perfusion imaging. Additional and often more precise information can be derived by measuring parameters of the signal intensity time curve such as mean transit time, maximum signal intensity increase, upslope, downslope, and delay before reaching maximum signal intensity. Temporal resolution is the crucial factor in MR-perfusion imaging because it takes only 20 to 60 seconds for the contrast medium to pass through the myocardium. Therefore, this dynamic process must be imaged with a high temporal resolution. Moreover, image acquisition must be fast enough to minimize motion artefacts and to maximize the spatial coverage of the ventricle. Ultrafast gradient echo techniques and echo planar imaging are in principle capable to fulfill these demands. While ultrafast gradient echo sequences enable one to acquire a maximum of 2 slices per heartbeat, echo planar sequences need only 30 to 50 msec to completely acquire one image and are thus able to image the entire ventricle within one heartbeat. However, they are also more susceptible to image artefacts. As gradients capable of producing high quality echo planar images are not widely available, ultrafast gradient echo techniques are commonly used for MR-perfusion imaging. A good correlation between quantitative estimates of myocardial perfusion by MRI after injection of an intravascular contrast agent and microsphere measurements has been shown in animal experiments but quantitative MR perfusion measurements have not yet been performed in humans. Clinical studies have until now focused on visual and parametric analysis of signal intensity time curves. From these studies, sensitivities and specifities in the range of 60 to 90% as compared to x-ray coronary angiography and scintigraphy were reported despite the fact that only parts of the left ventricular myocardium could be assessed. However, a generally accepted method of acquiring and analysing MR perfusion images does not yet exist. Therefore, future improvements of hardware and pulse-sequences as well as the development of new blood pool contrast agents are necessary before MR-perfusion imaging will become a widely accepted and clinically useful diagnostic procedure.

Artifacts↗