Biomedical subjects
Publications and source records attributed to R Schmidt.
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Poststenotic flow patterns were analyzed in a flow phantom with a 1.5-T magnetic resonance (MR) imager, with use of different MR imaging and MR angiographic pulse sequences. Spin-echo, fast field-echo, two-dimensional inflow (multiple single-section technique), and flow-adjusted-gradient sequences were applied. For the spin-echo sequences, modulus and phase images were reconstructed from each data set. The length of the region of poststenotic changes in signal amplitude and phase measured at a constant flow rate increased with stenosis grade. Likewise, the length of the region of poststenotic changes measured at a constant stenosis grade increased with flow rate. Moreover, the results depended on the alignment of the flow direction with the readout gradient. Comparison of modulus and phase images allowed discrimination of turbulent and nonturbulent flow, which yields additional information on stenosis grade in clinical MR angiography.
Magnetic resonance (MR) flow measurements were obtained in six healthy volunteers and 30 patients with arteriosclerotic disease with a 1.5-T imager and a pulse sequence for flow quantification based on flow-induced phase shifts. The iliac arteries were investigated in eight and the femoral arteries in 28 subjects. A trigger pulse, followed by the acquisition of 30 evenly distributed data sets, was applied every second heartbeat, thus eliminating any acquisition gap in a full heart cycle. For quantitative analysis, flow velocity was plotted as a function of time. Systolic acceleration, postsystolic deceleration, and pulsatility of flow were calculated and compared with stenosis grades determined from recent intraarterial digital subtraction angiograms. The flattening of the temporal flow patterns correlated with local severity of vascular occlusive disease.
The purpose of this study was to investigate the function of transplant kidneys in situ, and to detect pathologic changes, using volume-selective phosphorous NMR spectroscopy (31P MRS). Localized 31P MR spectra were obtained from 37 patients using a whole-body MR scanner with a combination of surface coils, adiabatic excitation pulses, and a modified image-selected in vivo spectroscopy (ISIS) sequence. Seventeen patients with pathologic changes after renal transplant were compared with a control group of 20 patients with no evidence of transplant dysfunction. The transplant kidneys with rejection reaction showed higher ratios of inorganic phosphate (P2i) to adenosine triphosphate-alpha (ATP-alpha) than the normal control group (.4 +/- .16 compared with .22 +/- .11, P = .01) and reduced pH. The spectra of transplant kidneys with tubular necrosis had lower phosphomonoester (PME)/phosphodiester (PDE) ratios than the control group (.65 +/- .35 compared with .96 +/- .5, P = .04). The pathologies of rejection and tubular necrosis could be differentiated from each other by pH (6.93 +/- .1 in rejection versus 7.14 +/- .19 in tubular necrosis, P = .04). Preliminary results indicate that localized image-guided 31P MR spectroscopy of transplant kidneys in situ can detect rejection reactions and acute tubular necrosis noninvasively, providing an incentive for further research.
The yeast Repressor Activator Protein 1 (RAP1) binds a 13-bp consensus found in many transcriptional regulatory regions, in silencer elements, and in telomeric repeat DNA of Saccharomyces cerevisiae. Gel retardation assays suggest that RAP1 bends DNA as it binds, with the vertex of the angle located 5' of the consensus. We show that removal of 230 aa in the N-terminus of RAP1 reduces the aberrant electrophoretic mobility of the protein-DNA complex, while removal of a C-terminal domain of RAP1 causes even greater distortion. To demonstrate that the aberrant electrophoretic mobility is really due to a bend in the double helix, the RAP1-DNA complex was analyzed by Scanning Tunnelling Microscopy (STM). The efficiency and accuracy of binding is checked in parallel by standard Transmission Electron Microscopy (TEM). Due to the use of high-angle shadowing of freeze-dried samples at low temperatures, the STM images allow us to confirm that RAP1 binding induces a DNA bend > 50 degrees, while the binding of the minimal DNA-binding domain shows significantly less distortion of the DNA helix.
One of the aims of modern microscopy is to quantify two-, three-, or even four-dimensional phenomena in biology, medicine, and material sciences. The requirements imposed on software by such data processing are exemplified by the design considerations of the IMAGIC-5 software system. This system includes facilities for multivariate statistical analysis of large data sets, for correlation averaging of two-dimensional crystals, and for three-dimensional reconstruction of macromolecular structures. The molecules may be arranged as two-dimensional crystals, as helices, or as single particles with arbitrary pointgroup symmetry. IMAGIC's novel angular reconstitution approach allows for the rapid determination of three-dimensional structures of uncrystallized molecules to high resolution. The general organization, user interaction strategy, file structure, and extendibility of IMAGIC are discussed and illustrated with some practical examples.
Pharmacokinetic gender-dependent differences in cytochrome P450-mediated drug metabolism, especially CYP3A4, and their clinical implications are increasingly apparent. CYP3A4 seems to be the most important CYP isoform in both bioactivation and N-dechloroethylation of the alkylating prodrug ifosfamide, but informations about possible gender-related differences are lacking. Therefore we compared in 10 male and 10 female liver microsomal preparations the contents and activities of specific isoenzymes, involved in both metabolic pathways, especially CYP3A4, further CYP2A6, CYP2C9 and CYP2B6 and measured the in vitro activities of these microsomes in the ifosfamide 4-hydroxylation and N-dechloroethylation using high-sensitive HPLC/MS and -UV detection methods. Statistically significant differences between male and female livers were found in the mean CYP3A4 contents and activities. These differences had no consequences on the ifosfamide 4-hydroxylation activities of liver microsomes in vitro. In contrast, in the ifosfamide N-dechloroethylation reaction we found a statistically significant difference between the liver microsomes of male and female patients (0.13 +/- 0.05 nmol/min nmol P450 vs. 0.28 +/- 0.13 nmol/min x nmolP450, respectively). In conclusion, we firstly demonstrated such gender-related difference in the ifosfamide N-dechloroethylation, which could result in a higher risk of partly severe neurotoxic side effects in female patients.
Cyclic analogues of the beta-casein-derived opioid peptide beta-casomorphin-5 (H-Tyr-Pro-Phe-Pro-Gly-OH) were prepared through substitution of the Pro2 residue with various alpha,omega-diamino acid residues (lysine, ornithine, 2,4-diaminobutyric acid) and cyclization of the omega-amino group to the C-terminal carboxyl function. Compounds of this type, with D-configuration at the 2-position residue, showed high opioid receptor affinity with some preference for mu receptors over delta receptors, high potency in the guinea pig ileum assay and considerable activity in the mouse vas deferens assay. Configurational inversion at the 4-position in these cyclic analogues resulted in enhanced affinity for both mu and delta receptors, whereas N-methylation of the Phe3 residue produced a potency decrease.
We investigated the antinociceptive efficacy of casomorphin (CM) derivatives using the vocalization test. Male Wistar rats received chronic microcannulae into the right lateral ventricle. One week later we examined the analgesic effect of CM derivatives 10, 30, 60, and 90 min after intraventricular injection (5 microliters). The analgesic effect was calculated as the individual percent increase in the pain threshold and was compared to controls (saline treatment). The substitution of D-lysine and D-ornithine in position 2 in connection with a cyclization through ring closure of the 2 position side chain amino group to the C-terminal glycine-COOH group resulted in high analgesic potency. The substitution of D-Pro4 was without any effect in the ineffective linear derivatives and decreased the effectiveness in the highly effective cyclic derivatives. The cyclic [D-Orn2]CM-5 and the cyclic [D-Lys2]CM-5 are the CM derivatives with the highest antinociceptive activity. The cyclic [D-Orn2]CM-5 is greater than 1000 times more effective than morphine. We conclude, on the basis of studies of receptor binding and in vitro investigations, that mu receptor activity alone is not responsible for the analgesic activity. The delta receptor and possibly also the kappa receptor could modulate the nociceptive effectiveness.
In this paper, we describe an approach to utilize case-based reasoning methods for trend prognoses for the monitoring of the kidney function in an Intensive Care Unit (ICU) setting. Since using conventional methods for reasoning over time does not fit for course predictions with poor medical knowledge of typical course patterns, we have developed abstraction methods suitable for integration into our case-based reasoning system ICONS. These methods combine medical experience with prognoses of multiparametric courses. On the ICU, the monitoring system NIMON provides a daily report based on current measured and calculated kidney function parameters. Subsequently, we generate course-characteristic trend descriptions of the renal function over the course of time. Using case-based reasoning retrieval methods, we search in the case base for courses similar to the current trend descriptions. Finally, we present the current course together with similar courses as comparisons and as probable prognoses to the user. We applied case-based reasoning methods in a domain which seemed reserved for statistical methods and conventional temporal reasoning.