Biomedical subjects

K Nicolay

Publications and source records attributed to K Nicolay.

At least 19 recordsLinked to original sources

PubMed2002

Characterization of the normal cardiac myofiber field in goat measured with MR-diffusion tensor imaging.

Cardiac myofiber orientation is a crucial determinant of the distribution of myocardial wall stress. Myofiber orientation is commonly quantified by helix and transverse angles. Accuracy of reported helix angles is limited. Reported transverse angle data are incomplete. We measured cardiac myofiber orientation postmortem in five healthy goat hearts using magnetic resonance-diffusion tensor imaging. A novel local wall-bound coordinate system was derived from the characteristics of the fiber field. The transmural course of the helix angle corresponded to data reported in literature. The mean midwall transverse angle ranged from -12 +/- 4 degrees near the apex to +9.0 +/- 4 degrees near the base of the left ventricle, which is in agreement with the course predicted by Rijcken et al. (18) using a uniform load hypothesis. The divergence of the myofiber field was computed, which is a measure for the extent to which wall stress is transmitted through the myofiber alone. It appeared to be <0.07 mm(-1) throughout the myocardial walls except for the fusion sites between the left and right ventricles and the insertion sites of the papillary muscles.

Animals↗

PubMed2001

Exogenous anandamide protects rat brain against acute neuronal injury in vivo.

The endocannabinoid anandamide [N-arachidonoylethanolamine (AEA)] is thought to function as an endogenous protective factor of the brain against acute neuronal damage. However, this has never been tested in an in vivo model of acute brain injury. Here, we show in a longitudinal pharmacological magnetic resonance imaging study that exogenously administered AEA dose-dependently reduced neuronal damage in neonatal rats injected intracerebrally with the Na(+)/K(+)-ATPase inhibitor ouabain. At 15 min after injury, AEA (10 mg/kg) administered 30 min before ouabain injection reduced the volume of cytotoxic edema by 43 +/- 15% in a manner insensitive to the cannabinoid CB(1) receptor antagonist SR141716A. At 7 d after ouabain treatment, 64 +/- 24% less neuronal damage was observed in AEA-treated (10 mg/kg) rats compared with control animals. Coadministration of SR141716A prevented the neuroprotective actions of AEA at this end point. In addition, (1) no increase in AEA and 2-arachidonoylglycerol levels was detected at 2, 8, or 24 hr after ouabain injection; (2) application of SR141716A alone did not increase the lesion volume at days 0 and 7; and (3) the AEA-uptake inhibitor, VDM11, did not affect the lesion volume. These data indicate that there was no endogenous endocannabinoid tone controlling the acute neuronal damage induced by ouabain. Although our data seem to question a possible role of the endogenous cannabinoid system in establishing a brain defense system in our model, AEA may be used as a structural template to develop neuroprotective agents.

Animals↗

PubMed2001

Neuroprotection by Delta9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity.

Excitotoxicity is a paradigm used to explain the biochemical events in both acute neuronal damage and in slowly progressive, neurodegenerative diseases. Here, we show in a longitudinal magnetic resonance imaging study that Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the main active compound in marijuana, reduces neuronal injury in neonatal rats injected intracerebrally with the Na(+)/K(+)-ATPase inhibitor ouabain to elicit excitotoxicity. In the acute phase Delta(9)-THC reduced the volume of cytotoxic edema by 22%. After 7 d, 36% less neuronal damage was observed in treated rats compared with control animals. Coadministration of the CB(1) cannabinoid receptor antagonist SR141716 prevented the neuroprotective actions of Delta(9)-THC, indicating that Delta(9)-THC afforded protection to neurons via the CB(1) receptor. In Delta(9)-THC-treated rats the volume of astrogliotic tissue was 36% smaller. The CB(1) receptor antagonist did not block this effect. These results provide evidence that the cannabinoid system can serve to protect the brain against neurodegeneration.

Acute Disease↗

PubMed2001

Application of magnetic resonance to animal models of cerebral ischemia.

The present review has been compiled to highlight the role of magnetic resonance imaging (MRI) and MR spectroscopy (MRS) for the investigation of cerebral ischemia in the animal experimental field of basic research. We have focused on stroke investigations analyzing the pathomechanisms of the disease evolution and on new advances in both nuclear MR (NMR) methodology or genetic engineering of transgenic animals for the study of complex molecular relationships and causes of the disease. Furthermore, we have tried to include metabolic and genetic aspects, as well as the application of functional imaging, for the investigation of the disturbance or restitution of functional brain activation under pathological conditions as relates to controlled animal experiments.

Animals↗

PubMed2001

Single-shot diffusion trace (1)H NMR spectroscopy.

Ignoring diffusion anisotropy can severely hamper the quantitative determination of water and metabolite diffusion in complex tissues. The measurement of the trace of the diffusion tensor provides unambiguous and rotationally invariant ADC values, but usually requires three separate experiments. A single-shot technique developed earlier, originally designed for diffusion trace MR imaging (Mori and van Zijl, Magn Reson Med 1995;33:41-52), was improved and adapted for diffusion trace MR spectroscopy. A double spin-echo pulse sequence was incorporated with four pairs of bipolar gradients with specific predetermined relative signs in each of the three orthogonal directions. The combination of gradient directions leads to cancellation of all off-diagonal tensor elements while constructively adding the diagonal elements. Furthermore, the pulse scheme provides complete compensation for cross-terms between static magnetic field gradients and the applied diffusion gradients, while simultaneously avoiding cross-terms with localization gradients. The sequence was tested at 4.7 T in vivo on rat brain for MRI and on rat skeletal muscle and brain for MRS. It is shown that the average ADC as determined from the measurement of the ADCs in the three orthogonal directions is in close agreement with the ADC obtained along the trace of the diffusion tensor in a single acquisition, for both water and metabolite diffusion. The large differences in water and metabolite diffusion coefficients as measured in the individual orthogonal directions illustrate the need for diffusion trace measurements when accurate and rotationally invariant diffusion quantitation is required. The pulse scheme presented here may be applied for such purposes in MRS and MRI studies.

Algorithms↗

PubMed2001

Magnetic coupling between water and creatine protons in human brain and skeletal muscle, as measured using inversion transfer (1)H-MRS.

Using the inversion transfer technique, the possible magnetic coupling between water protons and the protons of low-molecular weight metabolites was investigated in human brain and skeletal muscle at 1.5 T. The localized (1)H-MR spectra were recorded at different times after selective inversion of the water resonance. Water inversion led to a significant transient reduction in the signal intensity of the methyl protons of creatine/phosphocreatine, in both tissues. This is indicative of magnetic coupling between the protons of water and those of creatine/phosphocreatine. Neither the choline and N-acetylaspartate protons in brain nor the protons of the trimethylammonium pool in skeletal muscle showed a significant magnetic coupling to mobile water.

Brain Chemistry↗

PubMed2001

Diffusion NMR spectroscopy.

MR offers unique tools for measuring molecular diffusion. This review focuses on the use of diffusion-weighted MR spectroscopy (DW-MRS) to non-invasively quantitate the translational displacement of endogenous metabolites in intact mammalian tissues. Most of the metabolites that are observed by in vivo MRS are predominantly located in the intracellular compartment. DW-MRS is of fundamental interest because it enables one to probe the in situ status of the intracellular space from the diffusion characteristics of the metabolites, while at the same time providing information on the intrinsic diffusion properties of the metabolites themselves. Alternative techniques require the introduction of exogenous probe molecules, which involves invasive procedures, and are also unable to measure molecular diffusion in and throughout intact tissues. The length scale of the process(es) probed by MR is in the micrometer range which is of the same order as the dimensions of many intracellular entities. DW-MRS has been used to estimate the dimensions of the cellular elements that restrict intracellular metabolite diffusion in muscle and nerve tissue. In addition, it has been shown that DW-MRS can provide novel information on the cellular response to pathophysiological changes in relation to a range of disorders, including ischemia and excitotoxicity of the brain and cancer.

Animals↗

PubMed2001

On the importance of exchangeable NH protons in creatine for the magnetic coupling of creatine methyl protons in skeletal muscle.

The methyl protons of creatine in skeletal muscle exhibit a strong off-resonance magnetization transfer effect. The mechanism of this process is unknown. We previously hypothesized that the exchangeable amide/amino protons of creatine might be involved. To test this the characteristics of the creatine magnetization transfer effect were investigated in excised rat hindleg skeletal muscle that was equilibrated in either H2O or D2O solutions containing creatine. The efficiency of off-resonance magnetization transfer to the protons of mobile creatine in excised muscle was similar to that previously reported in intact muscle in vivo. Equilibrating the isolated muscle in D2O solution had no effect on the magnetic coupling to the immobile protons. It is concluded that exchangeable protons play a negligible role in the magnetic coupling of creatine methyl protons in muscle.

Animals↗

PubMed2001

Two-voxel localization sequence for in vivo two-dimensional homonuclear correlation spectroscopy.

The combination of localized 2D 1H MR correlation spectroscopy and Hadamard encoding allows the simultaneous acquisition of multiple volumes of interest without an increase in the experimental duration, compared to single-voxel acquisition. In the present study, 2D correlation spectra were acquired simultaneously within 20 to 40 min in two voxels located in each hemisphere of the rat brain. An intervoxel distance of 20% of the voxel size was sufficient to limit spatial contamination. The following cerebral metabolites gave detectable crosspeaks: N-acetylaspartate, the glutamate/glutamine pool, aspartate, phosphoethanolamine, glucose, glutathione, taurine, myo-inositols, lactate, threonine, gamma-aminobutyric acid, and alanine. Most of the metabolites were measured without contamination of other resonances.

Animals↗

PubMed2001

Cerebral metabolism in streptozotocin-diabetic rats: an in vivo magnetic resonance spectroscopy study.

AIMS/HYPOTHESIS: It is increasingly evident that the brain is another site of diabetic end-organ damage. The pathogenesis has not been fully explained, but seems to involve an interplay between aberrant glucose metabolism and vascular changes. Vascular changes, such as deficits in cerebral blood flow, could compromise cerebral energy metabolism. We therefore examined cerebral metabolism in streptozotocin-diabetic rats in vivo by means of localised 31P and 1H magnetic resonance spectroscopy. METHODS: Rats were examined 2 weeks and 4 and 8 months after diabetes induction. A non-diabetic group was examined at baseline and after 8 months. RESULTS: In 31P spectra the phosphocreatine:ATP, phosphocreatine:inorganic phosphate and ATP:inorganic phosphate ratios and intracellular pH in diabetic rats were similar to controls at all time points. In 1H spectra a lactate resonance was detected as frequently in controls as in diabetic rats. Compared with baseline and 8-month controls 1H spectra did, however, show a statistically significant decrease in N-acetylaspartate:total creatine (-14% and -23%) and N-acetylaspartate:choline (-21% and -17%) ratios after 2 weeks and 8 months of diabetes, respectively. CONCLUSION/INTERPRETATION: No statistically significant alterations in cerebral energy metabolism were observed after up to 8 months of streptozotocin-diabetes. These findings indicate that cerebral blood flow disturbances in diabetic rats do not compromise the energy status of the brain to a level detectable by magnetic resonance spectroscopy. Reductions in N-acetylaspartate levels in the brain of STZ-diabetic rats were shown by 1H spectroscopy, which could present a marker for early metabolic or functional abnormalities in cerebral neurones in diabetes.

Adenosine Triphosphate↗

PubMed2001

Losartan versus enalapril on cerebral edema and proteinuria in stroke-prone hypertensive rats.

Stroke-prone spontaneously hypertensive rats (SHRSP), subjected to high NaCl, show severe hypertension, organ damage, and early death. Preventive treatment with angiotensin II type 1 (AT1) receptor antagonists is known to be effective. Previously, we found that angiotensin converting enzyme (ACE) inhibition could reduce cerebral edema when treatment was started after manifestation of either proteinuria or cerebral edema. In this study AT1 receptor blockade was started at the same time points to evaluate whether this had an effect superior to ACE inhibition. SHRSP drank 1% NaCl. Group 1 served as controls. Group 2 and 3 rats were started on losartan and enalapril after proteinuria exceeded 40 mg/day. Group 4 and 5 rats were started on losartan and enalapril after the first observation of cerebral edema with T2-weighted magnetic resonance imaging scans. In controls, median survival was 54 days (range, 35 to 80 days) after the start of salt loading. With early-onset losartan and enalapril, survival increased to 305 days (range, 184 to 422 days) and 320 days (range, 134 to 368 days) (both P < .01 v group 1). Cerebral edema formation was prevented in all but two rats, one from each treatment modality. Development of proteinuria was markedly reduced. With late-onset treatment with losartan and enalapril, survival was 290 days (range, 120 to 367 days) and 264 days (range, 154 to 319 days) (both P < .01). Both losartan and enalapril decreased cerebral edema to baseline levels. Ultimately cerebral edema reoccurred, despite continued treatment, in 75% of the rats. Systolic blood pressure did not decrease after losartan treatment, but, similarly to early-onset treatment, decreased transiently after enalapril treatment. Cerebral edema and proteinuria were prevented and reduced in SHRSP treated with either an AT1 receptor antagonist or an ACE inhibitor. Survival was markedly and similarly prolonged by both treatments, whether initiated directly before or after development of cerebral edema. In rats where treatment was initiated after manifestation of cerebral edema, both cerebral edema and proteinuria reappeared despite continued treatment. Apparently, when hypertension is sustained, reappearance of target organ damage may not be entirely dependent on angiotensin.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2001

Post-mortem high-resolution MRI of the spinal cord in multiple sclerosis: a correlative study with conventional MRI, histopathology and clinical phenotype.

We used high-resolution MRI to study the post-mortem appearance of spinal cord multiple sclerosis in relation to histopathology and low-resolution images. Fifty-nine 3 cm long formalin-fixed spinal cord specimens from 19 multiple sclerosis patients and three controls were studied. Clinical characteristics of each patient were reviewed. High-field MRI consisted of proton-density weighted spin-echo imaging with an in-plane resolution of 80 microm. Specimens were also imaged at 1.0 T, with 1 mm pixel resolution. After MRI, the specimens were cut at 5 mm intervals and stained for myelin (Luxol fast blue/cresyl violet) and axons (Bodian method). Two observers scored the MRIs for abnormalities and divided them into (i) well-delineated areas of high signal intensity (SI) and (ii) poorly defined areas of mildly increased SI. Abnormalities were scored semiquantitatively, white matter and grey matter separately. In 81 sections the total area of abnormalities per section was measured on both histopathology sections and on matched high-field MRIs. Abnormalities ranged from just a few abnormal areas to complete involvement of the spinal cord specimen. Patients with an aggressive disease course had more abnormalities than patients with a mild or intermediate disease course. Areas of mildly increased SI were seen in all specimens, and were often found around focal high-SI lesions. However, in six patients, areas of mildly increased SI were the predominant finding on the MRIs, correlating with a primary progressive disease course. Histopathologically, high-SI areas correlated with complete demyelination, while mildly increased SI corresponded with partial demyelination. All areas scored as abnormal by the neuropathologist were also found on the MRIs, and sizes measured using both methods correlated well (r = 0.85, P<0.01). On conventional MRIs, abnormalities could be recognized fairly well. However, better differentiation could be made between high-SI and mildly increased SI abnormalities on the 4.7 T images. In conclusion, high-resolution MRI revealed a great range of abnormalities in spinal cord multiple sclerosis, which related to disease course during life. Furthermore, we found very good correlation between the extent of abnormalities shown by histopathology and the SI changes on proton-density MRIs, mainly relating to demyelination revealed histopathologically.

Adult↗

PubMed2000

Myelin/oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis in common marmosets: the encephalitogenic T cell epitope pMOG24-36 is presented by a monomorphic MHC class II molecule.

Immunization of common marmosets (Callithrix jacchus) with a single dose of human myelin in CFA, without administration of Bordetella pertussis, induces a form of autoimmune encephalomyelitis (EAE) resembling in its clinical and pathological expression multiple sclerosis in humans. The EAE incidence in our outbred marmoset colony is 100%. This study was undertaken to assess the genetic and immunological basis of the high EAE susceptibility. To this end, we determined the separate contributions of immune reactions to myelin/oligodendrocyte glycoprotein (MOG) and myelin basic protein to the EAE induction. Essentially all pathological features of myelin-induced EAE were also found in animals immunized with MOG in CFA, whereas in animals immunized with myelin basic protein in CFA clinical and pathological signs of EAE were lacking. The epitope recognition by anti-MOG Abs and T cells were assessed. Evidence is provided that the initiation of EAE is based on T and B cell activation by the encephalitogenic phMOG14-36 peptide in the context of monomorphic Caja-DRB*W1201 molecules.

Animals↗

PubMed2000

Direct evidence for the control of mitochondrial respiration by mitochondrial creatine kinase in oxidative muscle cells in situ.

The efficiency of stimulation of mitochondrial respiration in permeabilized muscle cells by ADP produced at different intracellular sites, e.g. cytosolic or mitochondrial intermembrane space, was evaluated in wild-type and creatine kinase (CK)-deficient mice. To activate respiration by endogenous production of ADP in permeabilized cells, ATP was added either alone or together with creatine. In cardiac fibers, while ATP alone activated respiration to half of the maximal rate, creatine plus ATP increased the respiratory rate up to its maximum. To find out whether the stimulation by creatine is a consequence of extramitochondrial [ADP] increase, or whether it directly correlates with ADP generation by mitochondrial CK in the mitochondrial intermembrane space, an exogenous ADP-trap system was added to rephosphorylate all cytosolic ADP. Under these conditions, creatine plus ATP still increased the respiration rate by 2.5 times, compared with ATP alone, for the same extramitochondrial [ADP] of 14 microM. Moreover, this stimulatory effect of creatine, observed in wild-type cardiac fibers disappeared in mitochondrial CK deficient, but not in cytosolic CK-deficient muscle. It is concluded that respiration rates can be dissociated from cytosolic [ADP], and ADP generated by mitochondrial CK is an important regulator of oxidative phosphorylation.

Adenosine Diphosphate↗

PubMed2000

In vivo glucose detection by homonuclear spectral editing.

A frequency-selective multiple-quantum-coherence spectral editing pulse sequence, Ssel-MQC, was implemented for the detection of the betaH1-glucose resonance at 4.63 ppm in rat brain in vivo. Unwanted signal suppression and glucose coherence transfer pathway selection were performed with magnetic field gradients. To optimize sensitivity, the sequence was executed with surface coil signal reception and adiabatic RF pulse transmission. The glucose editing capabilities of Ssel-MQC were first evaluated in vitro. Ssel-MQC achieved excellent water suppression (suppression factor >10(5)), at the expense of an approximately 60% loss of the glucose signal due to incomplete coherence transfer pathway selection. Next, the sequence was used for in vivo glucose detection in normal rat brain during D-glucose infusion and in the brain of diabetic rats prior to and following insulin infusion.

Animals↗

PubMed2000

1H and (31)P magnetization transfer studies of hindleg muscle in wild-type and creatine kinase-deficient mice.

The authors addressed the hypothesis that interactions with creatine kinase (CK) play a role in the off-resonance magnetization transfer (MT) effect of creatine in skeletal muscle. Toward that aim, (1)H MT studies were done on hindleg muscle in wild-type mice and in transgenic mice, lacking cytoplasmic CK and/or mitochondrial CK. The (1)H MT effect was essentially identical in wild-type muscle and the two single CK knock-out muscles, while moderately decreased in tissue lacking both CK isoforms. (31)P-NMR showed no off-resonance (31)P MT effect in skeletal muscle for PCr in any of the mice, while the enzymatic CK reaction flux was circa 0.2-0.3 sec(-1) in the wild-type muscle and in muscle deficient in mitochondrial CK. The CK enzyme flux was negligible in the other two CK knock-outs. These data suggest that CK plays a minor role in the (1)H MT effect of creatine. Irrespective of the underlying mechanism the creatine MT phenomenon probably has no significant consequences for the thermodynamic availability of total creatine to the CK reaction.

Animals↗

PubMed2000

Monitoring water content in deforming intervertebral disc tissue by finite element analysis of MRI data.

Mechanical loading, occurring during normal daily life, causes fluid to be expelled from intervertebral discs. Excessive fluid loss during heavy loading might make the disc more vulnerable to damage. In this study, fluid loss was investigated in vitro through monitoring the loss of MRI signal intensity in four bovine coccygeal intervertebral discs, compressed at 2000 N during 1.5 hr. The MRI signals were analyzed with the aid of finite element models to account for the deformation of the tissue. A gradual signal loss over time was found during loading, the most pronounced loss occurring in the central disc region. Initial patterns of signal distribution were quite variable between specimens but repeatable within specimens.

Animals↗

PubMed2000

In vivo (31)P-NMR diffusion spectroscopy of ATP and phosphocreatine in rat skeletal muscle.

The aim of this study was to measure the diffusion of ATP and phosphocreatine (PCr) in intact rat skeletal muscle, using (31)P-NMR. The acquisition of the diffusion-sensitized spectra was optimized in terms of the signal-to-noise ratio for ATP by using a frequency-selective stimulated echo sequence in combination with adiabatic radio-frequency pulses and surface coil signal excitation and reception. Diffusion restriction was studied by measuring the apparent diffusion coefficients of ATP and PCr as a function of the diffusion time. Orientation effects were eliminated by determining the trace of the diffusion tensor. The data were fitted to a cylindrical restriction model to estimate the unbounded diffusion coefficient and the radial dimensions of the restricting compartment. The unbounded diffusion coefficients of ATP and PCr were approximately 90% of their in vitro values at 37 degrees C. The diameters of the cylindrical restriction compartment were approximately 16 and approximately 22 microm for ATP and PCr, respectively. The diameters of rat skeletal muscle fibers are known to range from 60 to 80 microm. The modelling therefore suggests that the in vivo restriction of ATP and PCr diffusion is not imposed by the sarcolemma but by other, intracellular structures with an overall cylindrical orientation.

Adenosine Triphosphate↗