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Biomedical subjects

M Rudin

Publications and source records attributed to M Rudin.

At least 37 records · Page 2Linked to original sources
PubMed2000

Regional brain activation by bicuculline visualized by functional magnetic resonance imaging. Time-resolved assessment of bicuculline-induced changes in local cerebral blood volume using an intravascular contrast agent.

Functional magnetic resonance imaging (fMRI) has been applied to study rat focal brain activation induced by intravenous administration of the GABA(A) antagonist bicuculline. Using magnetite nanoparticles as a blood pool contrast agent, local changes in cerebral blood volume (CBV) were assessed with high temporal (10 s) and spatial (0.35 x 0.6 mm(2)) resolutions. Upon infusion of the bicuculline region-specific increases in CBV have been observed, suggesting CBV to reflect brain activity. During the first 2 min, the signal increases were predominant in the cortex, followed by increases in other brain areas, such as the caudate putamen, thalamus and cerebellum. Ten minutes after the start of infusion, a dominant response was observed in the thalamus, while in the caudate putamen a biphasic response pattern was seen. The magnitude of the signal responses in all brain regions was dependent on the dose of bicuculline and, in general, matched the known distribution of GABA(A) binding sites. This study suggests that pharmacological fMRI, displaying brain function at the highly specific level of drug-receptor interaction, should foster our understanding of normal and pathological brain function.

Animals↗
PubMed2000

The role of magnetic resonance imaging and spectroscopy in transplantation: from animal models to man.

Critical success factors in solid organ and vascular transplantation are the assessment of graft status/viability as well as stringent monitoring of transplant recipients, preferentially using noninvasive techniques. This review addresses the application of magnetic resonance imaging (MRI) and spectroscopy (MRS) in the field of transplantation. The first section is devoted to the description of the main MR techniques used for monitoring the status of the graft noninvasively. Subsequently, the role of MRI/MRS in the analysis of the viability of organs for transplantation is discussed. Since chronic rejection remains a major difficulty, development of new therapies is still ongoing. Thus, the third part is devoted to the use of MRI/MRS for monitoring graft rejection in animal models of transplantation. This is followed by a discussion of clinical studies of transplantation involving MRI/MRS. Finally, a general appraisal is made on available imaging techniques for the non-invasive characterization of grafts in situ, highlighting the role of MR methods in the field of transplantation.

Animals↗
PubMed2000

Cytoprotection does not preserve brain functionality in rats during the acute post-stroke phase despite evidence of non-infarction provided by MRI.

In animal models of stroke the promise of a therapy is commonly judged from infarct size measurements, assuming that a reduction in infarct size results in reduction of the functional deficits. We have evaluated the validity of the concept that structural integrity translates into functional integrity during the acute post-stroke period (24 h). Unilateral permanent middle cerebral artery occlusion (pMCAO) in Fischer F344 rats leads to infarcts comprising the ipsilateral striatum and cortical structures, including the somatosensory cortex. Infarct volumes were assessed using magnetic resonance imaging (MRI) methods (T(2), diffusion, perfusion MRI). The functional integrity of the somatosensory cortex was assessed by functional MRI (fMRI) measuring changes in local cerebral blood volume, and by assessing the forelimb grip strength and the beam-walking performance of the animals. Treatment with the calcium antagonist isradipine (2.5 mg/kg injected s.c. immediately after pMCAO) reduced the total infarct size by more than 40% compared to vehicle-injected controls. In particular, the ipsilateral somatosensory cortex appeared normal in diffusion- and T(2)-weighted MRI images. In sham-operated rats simultaneous electrical stimulation of both forepaws led to similar activation of both somatosensory cortices, while in pMCAO animals given vehicle only the contralateral cortex showed an fMRI response. Similarly, in pMCAO rats treated with isradipine, functional activation following bilateral electrical stimulation was only detected in the contralateral somatosensory cortex despite the normal appearance of the ipsilateral cortex in MRI images. Furthermore, fMRI responses to pharmacological stimulation with bicuculline were virtually absent in the ipsilateral somatosensory cortices both in vehicle- and isradipine-treated rats. Finally there was no significant difference between vehicle- and isradipine-treated animals upon the performance of beam-walking test or in forelimb grip strength. It is concluded that during the acute (24 h) post-occlusion period, structural integrity in the somatosensory cortex revealed by MRI does not translate into preservation of function.

Adenosine Triphosphate↗
PubMed2000

Glial cell proliferation in the spinal cord after dorsal rhizotomy or sciatic nerve transection in the adult rat.

Proliferation of glial cells is one of the hallmarks of CNS responses to neural injury. These responses are likely to play important roles in neuronal survival and functional recovery after central or peripheral injury. The boundary between the peripheral nervous system (PNS) and CNS in the dorsal roots, the dorsal root transitional zone (DRTZ), marks a distinct barrier for growth by injured dorsal root axons. Regeneration occurs successfully in the PNS environment, but ceases at the PNS-CNS junction. In order to understand the role of different glial cells in this process, we analysed the proliferation pattern of glial cells in central (CNS) and peripheral (PNS) parts of the dorsal root and the segmental white and grey spinal cord matter after dorsal rhizotomy or sciatic nerve transection in adult rats 1-7 days after injury. Monoclonal antibody MIB-5 or antibodies to bromodeoxyuridine were used to identify proliferating cells. Polyclonal antibodies to laminin were used to distinguish the PNS and CNS compartments of the dorsal root. Dorsal root lesion induced glial cell proliferation in the CNS as well as PNS beginning at 1 day, with peaks from 2 to 4 days postoperatively. After sciatic nerve injury, cell proliferation occurred only in the CNS, was minimal at 1 day, and peaked from 2 to 4 days postoperatively. Double immunostaining with specific glial cell markers showed that after dorsal root transection 60% of the proliferating cells throughout the postoperative period examined were microglia, 30% astrocytes and 10% unidentified in the CNS, while in the PNS 40% were Schwann cells, 40% macrophages and 20% unidentified. After sciatic nerve injury virtually all proliferating cells were microglia. These findings indicate that non-neuronal cells in the CNS and PNS are extremely sensitive to the initial changes which occur in the degenerating dorsal root axons, and that extensive axonal degeneration is a prerequisite for astroglial and Schwann cell, but not microglial cell, proliferation.

Age Factors↗
PubMed2000

Quantitative assessment of rat kidney function by measuring the clearance of the contrast agent Gd(DOTA) using dynamic MRI.

Magnetic resonance imaging (MRI) has been applied to assess kidney function in normal rats by monitoring the passage of the extracellular contrast agent GdDOTA. High-resolution images have been obtained using either the rapid acquisition with relaxation enhancement (RARE) or the snapshot pulse sequence. The latter was superior in anatomic definition due to the shorter echo delays used. The GdDOTA induced signal enhancements in the various renal structures were theoretically modeled and the results of the regression analysis then used to estimate local tissue concentrations in renal cortex, inner medulla and outer medulla/pelvis. The concentration-time curves in vena cava and renal cortex were similar and distinctly different from the ones in medulla and pelvis. This is reflected in the time-to-peak (TTP) values, which were TTP (blood) = 0.18 +/- 0.03 < TTP (cortex) = 0.26 +/- 0.05 < TTP (outer medulla) = 0.62 +/- 0.03 < TTP (inner medulla/pelvis) = 0.92 +/- 0.16 min. The initial tracer uptake rates depended linearly on the dose of GdDOTA administered, the value of the uptake rate in the cortex being significantly higher than those in the outer and inner medulla, which were identical within error limits. The initial medullar tracer uptake followed a first-order kinetics. The rate constant k(cl) = (dc[medulla]/dt)/c[cortex] = 3.4 +/- 0.5 min(-1) for the transition from cortex (predominantly blood signal) to medulla (predominantly urine) was considered a measure for the renal clearance. Intravenous administration of furosemide at doses 2.5, 5, and 10 mg/kg led to a dose-dependent decrease of k(cl). This reflects the inhibitory effect of the diuretic furosemide on medullary water resorption and thus the dilution of the GdDOTA in urine.

Animals↗
PubMed2000

Analysis of input functions from different arterial branches with gamma variate functions and cluster analysis for quantitative blood volume measurements.

Regional cerebral blood volume (rCBV) provides valuable information about the nature and progress of diseases of the central nervous system. While relative rCBV maps can be derived directly from dynamic susceptibility contrast data, the arterial input function (AIF) has to be measured for absolute rCBV quantification. For determination of the AIF pixels located completely within a feeding artery must be selected. However, by using a region-of-interest (ROI) based selection some confounding effects can occur, especially if single shot echo planar imaging (EPI) with low spatial resolution is used. In this study we analyzed the influence of partial volume effects and spatial misregistration due to frequency shifts induced by paramagnetic contrast agents. We analyzed AIFs from the internal carotid artery (ICA), the vertebral artery (VA) and the middle cerebral artery (MCA) using gamma variate function based parameterization. The concentration time curves (CTC) of several pixels which were selected on the basis of strong signal drop appeared distorted during the bolus passage. Moreover, the amplitudes of input functions derived from the MCA were smaller by a factor of three as compared to those of the ICA and VA. Simulations revealed that these effects can be attributed to a spatial shift of the vessel along phase-encoding direction during the passage of the bolus. We therefore developed a procedure for a pixel selection based on cluster analysis which classifies pixels according to the parameters of the fitted gamma variate functions. This approach accounted for misregistration of the vessel and yielded very consistent results for a group of normal subjects.

Brain↗
PubMed1999

In vivo magnetic resonance methods in pharmaceutical research: current status and perspectives.

In the last decade, in vivo MR methods have become established tools in the drug discovery and development process. In this review, several successful and potential applications of MRI and MRS in stroke, rheumatoid and osteo-arthritis, oncology and cardiovascular disorders are dealt with in detail. The versatility of the MR approach, allowing the study of various pathophysiological aspects in these disorders, is emphasized. New indication areas, for the characterization of which MR methods have hardly been used up to now, such as respiratory, gastro-intestinal and skin diseases, are outlined in a subsequent section. A strength of MRI, being a non-invasive imaging modality, is the ability to provide functional, i.e. physiological, readouts. Functional MRI examples discussed are the analysis of heart wall motion, perfusion MRI, tracer uptake and clearance studies, and neuronal activation studies. Functional information may also be derived from experiments using target-specific contrast agents, which will become important tools in future MRI applications. Finally the role of MRI and MRS for characterization of transgenic and knock-out animals, which have become a key technology in modern pharmaceutical research, is discussed. The advantages of MRI and MRS are versatility, allowing a comprehensive characterization of a diseased state and of the drug intervention, and non-invasiveness, which is of relevance from a statistical, economical and animal welfare point of view. Successful applications in drug discovery exploit one or several of these aspects. In addition, the link between preclinical and clinical studies makes in vivo MR methods highly attractive methods for pharmaceutical research.

Animals↗
PubMed1999

Magnetic resonance angiography of the rat cerebrovascular system without the use of contrast agents.

We describe and discuss the application of three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiography (MRA) to visualize non-invasively the cerebral vasculature of the rat. MR angiograms of healthy spontaneously hypertensive rats were obtained without the use of contrast agents. Total imaging time ranged from 1 to 50 min for a 3D data set. The influences of the data matrix and the inflow delay on the image quality and the total imaging time are assessed and discussed. Varying the inflow delay yielded in addition semiquantitative information on hemodynamics. The method was applied to obtain angiograms in rat models of permanent and temporal middle cerebral artery occlusion. Occlusion and reopening of the vessel could easily be verified by MRA. However, after reperfusion a slight reduction in blood flow was observed.

Animals↗
PubMed1999

Effect of gamma radiation on native endolithic microorganisms from a radioactive waste deposit site.

A time-course experiment was conducted to evaluate the effects of gamma radiation on the indigenous microbiota present in rock obtained from Yucca Mountain, Nevada Test Site. Microcosms were constructed by placing pulverized Yucca Mountain rock in polystyrene cylinders. Continuous exposure (96 h) at a dose rate of 1.63 Gy/min was used to mimic the near-field environment surrounding waste canisters. The expected maximum surface dose rate from one unbreached canister designed to contain spent nuclear fuels is 0.06 Gy/min. Considering the current repository packing design, multiple canisters within one vault, the cumulative dose rate may well approach that used in this experiment. The microbial communities were characterized after receiving cumulative doses of 0, 0.098, 0. 58, 2.33, 4.67, 7.01 and 9.34 kGy. Radiation-resistant microorganisms in the pulverized rock became viable but nonculturable (VBNC) after a cumulative dose of 2.33 kGy. VBNC microorganisms lose the ability to grow on media on which they have routinely been cultured in response to the environmental stress imposed (i.e. radiation) but can be detected throughout the time course using direct fluorescence microscopy techniques. Two representative exopolysaccharide-producing isolates from Yucca Mountain were exposed to the same radiation regimen in sand microcosms. One isolate was much more radiation-resistant than the other, but both had greater resistance than the general microbial community based on culturable counts. However, when respiring cell counts (VBNC) were compared after irradiation, the results would indicate much more radiation resistance of the individual isolates and the microbial community in general. These results have significant implications for underground storage of nuclear waste as they indicate that indigenous microorganisms are capable of surviving gamma irradiation in a VBNC state.

Bacteria↗
PubMed1999

Resuscitation of microorganisms after gamma irradiation.

Microbiological analysis of rock exposed to gamma-radiation doses between 0 and 9.34 kGy indicated that some microorganisms became viable but nonculturable (VBNC) and lost metabolic capacity as measured by BIOLOG microtiter plates. To investigate this phenomenon, portions of irradiated rock were placed at 4 degrees C for 2 months in an attempt to resuscitate the microbes to a culturable state. Culturable heterotrophs were enumerated and BIOLOG plates were used to determine the metabolic capability of the microbial community. Culturable bacteria that had previously been nonculturable were found at all doses. The number of colony types decreased from 26 in the nonirradiated control rock to between 9 and 10 in rock irradiated at doses ranging from 2.34 to 9.34 kGy. BIOLOG plates indicated partial recovery of metabolic capacity in all the samples tested. Fatty acid methyl ester analysis of the recovered isolates using the MIDI system (Microbial ID, Inc.) yielded three distinct groups of related bacteria. All resuscitated isolates clustered with the original nonirradiated isolates at the genus level, and 92% of them clustered at the species level. These results indicate that microbes were likely resuscitated from a VBNC state.

Bacteria↗
PubMed1999

Calcineurin inhibitors FK506 and SDZ ASM 981 alleviate the outcome of focal cerebral ischemic/reperfusion injury.

The neuroprotective properties of drugs binding to FKBP12, with and without subsequent inhibition of calcineurin, were investigated in rat models of ischemic embolic stroke. Drug effects on brain infarct volumes evoked by transient middle cerebral artery occlusion (MCAO) and by permanent MCAO were determined in vivo by T2-weighted magnetic resonance imaging and post mortem by triphenyltetrazolium chloride staining and histology. Drugs binding to FKBP12 and inhibiting calcineurin, such as FK506 and SDZ ASM 981, dose dependently reduced the infarct volumes, determined 48 h after MCAO by both magnetic resonance imaging and triphenyltetrazolium chloride staining but only in the transient MCAO model. In vivo potencies to reduce brain infarcts paralleled the in vitro potencies to inhibit calcineurin. Histological staining after 6 days of survival showed that the neuroprotective effects were permanent. Rapamycin, known to bind with similar affinity to FKBP12 but not to inhibit calcineurin, was not neuroprotective but abolished the neuroprotective effects of FK506 when coadministered. In the permanent MCAO models, FK506 showed no effect when injected before and little effect when injected after MCAO. Measurements of core temperatures after MCAO in controls and drug-treated rats do not support hypothermia being the mechanism responsible for neuroprotection. We conclude that drugs inhibiting calcineurin activity are neuroprotective in focal cerebral ischemia/reperfusion but not in permanent ischemia models, possibly by preventing reperfusion injury.

Animals↗
PubMed1998

Phylogeography of the West Indian manatee (Trichechus manatus): how many populations and how many taxa?

To resolve the population genetic structure and phylogeography of the West Indian manatee (Trichechus manatus), mitochondrial (mt) DNA control region sequences were compared among eight locations across the western Atlantic region. Fifteen haplotypes were identified among 86 individuals from Florida, Puerto Rico, the Dominican Republic, Mexico, Columbia, Venezuela, Guyana and Brazil. Despite the manatee's ability to move thousands of kilometers along continental margins, strong population separations between most locations were demonstrated with significant haplotype frequency shifts. These findings are consistent with tagging studies which indicate that stretches of open water and unsuitable coastal habitats constitute substantial barriers to gene flow and colonization. Low levels of genetic diversity within Florida and Brazilian samples might be explained by recent colonization into high latitudes or bottleneck effects. Three distinctive mtDNA lineages were observed in an intraspecific phylogeny of T. manatus, corresponding approximately to: (i) Florida and the West Indies; (ii) the Gulf of Mexico to the Caribbean rivers of South America; and (iii) the northeast Atlantic coast of South America. These lineages, which are not concordant with previous subspecies designations, are separated by sequence divergence estimates of d = 0.04-0.07, approximately the same level of divergence observed between T. manatus and the Amazonian manatee (T. inunguis, n = 16). Three individuals from Guyana, identified as T. manatus, had mtDNA haplotypes which are affiliated with the endemic Amazon form T. inunguis. The three primary T. manatus lineages and the T. inunguis lineage may represent relatively deep phylogeographic partitions which have been bridged recently due to changes in habitat availability (after the Wisconsin glacial period, 10 000 B P), natural colonization, and human-mediated transplantation.

Animals↗
PubMed1998

Susceptibility to cerebral infarction in the stroke-prone spontaneously hypertensive rat is inherited as a dominant trait.

BACKGROUND AND PURPOSE: Susceptibility to cerebral infarction was compared in stroke-prone spontaneously hypertensive (SHRSP), normotensive Wistar-Kyoto (WKY) rats, and F1 hybrids derived from a SHRSP/WKY cross. METHODS: The proximal left middle cerebral artery (MCA) was occluded under anesthesia and infarct volume assessed 24 hours later by magnetic resonance imaging and confirmed 5 days later by quantitative histopathology. Total hemispheric infarct volume was expressed as a percentage of the total brain volume. RESULTS: Infarct volumes measured by MRI in adult SHRSP (19.5 +/- 2.0%) and F1 hybrid rats (19.4 +/- 1.9%) were significantly greater than in WKY (11.1 +/- 2.4; CI [6.07, 10.76]) and (5.93, 10.52), respectively, P<.001). Sensitivity to an ischemic insult was unrelated to blood pressure: although systolic blood pressures differed between young versus adult male SHRSP and between female versus male SHRSP and F1 hybrids, infarct volumes were equal. A close correlation was found between infarct volumes measured by MRI and histology (r=.92, P<.0001). CONCLUSIONS: Outcome to MCA occlusion (MCAO) measured with MRI provides a reproducible and nonterminal quantitative phenotypic marker of stroke susceptibility in the SHRSP. This is the first study to employ MCAO with MRI to quantify stroke susceptibility in F1 hybrid rats and indicates a dominant mode of inheritance for this phenotype.

Animals↗