Cereb Blood Flow Research Articles

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Temporal relation between the ADC and DC potential responses to transient focal ischemia in the rat: a Markov chain Monte Carlo simulation analysis.

Markov chain Monte Carlo simulation was used in a reanalysis of the longitudinal data obtained by Harris et al. (J Cereb Blood Flow Metab 20:28-36) in a study of the direct current (DC) potential and apparent diffusion coefficient (ADC) responses to focal ischemia. The main purpose was to provide a formal analysis of the temporal relationship between the ADC and DC responses, to explore the possible involvement of a common latent (driving) process. A Bayesian nonlinear hierarchical random coefficients model was adopted. DC and ADC transition parameter posterior probability distributions were generated using three parallel Markov chains created using the Metropolis algorithm. Particular attention was paid to the within-subject differences between the DC and ADC time course characteristics. The results show that the DC response is biphasic, whereas the ADC exhibits monophasic behavior, and that the two DC components are each distinguishable from the ADC response in their time dependencies. The DC and ADC changes are not, therefore, driven by a common latent process. This work demonstrates a general analytical approach to the multivariate, longitudinal data-processing problem that commonly arises in stroke and other biomedical research.

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The acidosis paradox: asphyxial brain injury without coincident acidemia

The acidosis paradox: asphyxial brain injury without coincident acidemia

The aerobic brain: lactate decrease at the onset of neural activity

The metabolic events of neuronal energetics during functional activity are still partially unexplained. In particular, lactate (and not glucose) was recently proposed as the main substrate for neurons during activity [Proc Natl Acad Sci USA 91 (1994) 10625]. By means of proton magnetic resonance spectroscopy, lactate was reported to increase during the first minutes of prolonged stimulation [Proc Natl Acad Sci USA 88 (1991) 5829; J Cereb Blood Flow Metab 12 (1992) 584; Magn Reson Med 35 (1996) 143], but the studies reported thus far suffered from low temporal resolution. In the present study we used a time-resolved proton magnetic resonance spectroscopy strategy in order to analyse the evolution of lactate during the early seconds following a brief visual stimulation (event-related design). A significant decrease in lactate concentration was observed 5 s after the stimulation, while a recovering of the baseline was observed at 12 s.

DIFFUSION WEIGHTED MAGNETIC RESONANCE IMAGING OF RAT TESTES: A METHOD FOR EARLY DETECTION OF ISCHEMIA

We investigated the feasibility of diffusion weighted magnetic resonance imaging (MRI) for the early detection of ischemia in the testis. Circulation to the right testis in Wistar rats was occluded by surgical ligation of the right funicle. The left side was sham operated and served as a control. The diffusion and T2-weighted MRI images of the 2 testes was performed postoperatively by a 1.5 Tesla MRI unit using a knee coil. On apparent diffusion coefficient images and T2-weighted images the region of interest values in the 2 testes were measured and statistically compared. At 1 hour after testicular funicle ligation the apparent diffusion coefficient was 18% lower in the ischemic than in the sham operated testis (p <0.0098). At 2 hours the difference was 20% (p <0.0017). In the signal-to-noise ratio on T2-weighted images there was no difference in the left and right testes. Altered diffusion occurs in an ischemic testis, which can be measured on MRI at 1.5 Tesla. Thus, diffusion-weighted MRI may be a helpful method for the differential diagnosis of acute testicular torsion.

Nonparametric permutation tests for functional neuroimaging: A primer with examples

Requiring only minimal assumptions for validity, nonparametric permutation testing provides a flexible and intuitive methodology for the statistical analysis of data from functional neuroimaging experiments, at some computational expense. Introduced into the functional neuroimaging literature by Holmes et al. ([1996]: J Cereb Blood Flow Metab 16:7-22), the permutation approach readily accounts for the multiple comparisons problem implicit in the standard voxel-by-voxel hypothesis testing framework. When the appropriate assumptions hold, the nonparametric permutation approach gives results similar to those obtained from a comparable Statistical Parametric Mapping approach using a general linear model with multiple comparisons corrections derived from random field theory. For analyses with low degrees of freedom, such as single subject PET/SPECT experiments or multi-subject PET/SPECT or fMRI designs assessed for population effects, the nonparametric approach employing a locally pooled (smoothed) variance estimate can outperform the comparable Statistical Parametric Mapping approach. Thus, these nonparametric techniques can be used to verify the validity of less computationally expensive parametric approaches. Although the theory and relative advantages of permutation approaches have been discussed by various authors, there has been no accessible explication of the method, and no freely distributed software implementing it. Consequently, there have been few practical applications of the technique. This article, and the accompanying MATLAB software, attempts to address these issues. The standard nonparametric randomization and permutation testing ideas are developed at an accessible level, using practical examples from functional neuroimaging, and the extensions for multiple comparisons described. Three worked examples from PET and fMRI are presented, with discussion, and comparisons with standard parametric approaches made where appropriate. Practical considerations are given throughout, and relevant statistical concepts are expounded in appendices.

An Update on Estrogen: Higher Cognitive Function, Receptor Mapping, Neurotrophic Effects

An Update on Estrogen: Higher Cognitive Function, Receptor Mapping, Neurotrophic Effects

Measurement of tissue oxygen extraction ratios from venous blood T(2): increased precision and validation of principle.

It has recently been shown that parenchymal oxygen extraction ratios (OERs) can be quantified using the absolute T(2) of venous blood draining from this tissue (Oja et al., J Cereb Blood Flow Metab 1999;19:1289-1295). Here, a modified Carr-Purcell-Meiboom-Gill (CPMG) multiecho experiment was used to increase the efficiency and precision of this approach and to test the applicability of the two-compartment exchange model for spin-echo BOLD effects in pure venous blood. Relaxation measurements on bovine blood as a function of CPMG interecho spacing, oxygen saturation, and hematocrit provided the baseline relaxation and susceptibility shift parameters necessary to directly relate OER to T(2) of venous blood in vivo. Using an interecho spacing of 25 ms, the results on visual activation studies in eight volunteers showed T(2)(CPMG) values increasing from 128 +/- 9 ms to 174 +/- 18 ms upon activation, corresponding to local OER values of 0.38 +/- 0.04 and 0.18 +/- 0.05 during baseline activity and visual stimulation, respectively. These OER values are in good agreement with literature data on venous oxygenation and numbers determined previously using a single-echo approach, while the measured T(2)s are about 20-40 ms longer.

The neuroprotective efficacy of NXY-059 in permanent MCAo in the rat: Dose response and therapeutic window

P78 Introduction. NXY-059 (disodium 4-[(tert-butylimino)methyl] benzene-1,3-disulfonate N-oxide) is a nitrone with free radical trapping properties and is being developed for the treatment of acute ischemic stroke. NXY-059 possesses proven neuroprotective efficacy in rat transient models of middle cerebral artery occlusion (MCAo) (J Cereb Blood Flow Metab 1999;19:778–87), however its efficacy in permanent models of focal cerebral ischemia has not been as extensively tested. In the present study we have examined the efficacy of NXY-059 at three doses and further examined the therapeutic window of the mid-range dose. Methods. Adult male Wistar rats (300–330g) were given a unilateral permanent MCAo using an intraluminal suture technique. To assess efficacy of three doses of NXY-059, vehicle or NXY-059 (30, 50 or 70 mg/kg/h) was infused using minipumps for 24 hours. Dosing began 5 minutes after the MCAo with a bolus injection of vehicle or NXY-059 (30, 50 or 70 mg/kg). To assess the therapeutic window, treatment with 50 mg/kg (loading dose) and 50 mg/kg/h (over 24 hours) NXY-059 was commenced at 5, 30, 60, 120 and 240 minutes after MCAo. For both assessments, brains were removed 24 hours after commencing treatment and volume of damage was calculated from 5 x 2mm sections stained with triphenyl tetrazolium chloride. Results. NXY-059 (30, 50 and 70 mg/kg/h) reduced the volume of damage by 23%, 57% and 81% respectively (p&lt;0.05). Treatment with NXY-059 (50 mg/kg/h) beginning at 5, 30, 60, 120 and 240 minutes after permanent MCAo reduced the volumes of damage by 52%, 45%, 50%, 43% and 35% respectively (p&lt;0.05). Conclusions. In rats given a permanent MCA occlusion, NXY-059 at doses of 30–70 mg/kg/h given for 24 hours significantly (p&lt;0.05) reduced the volume of cerebral damage, and significant protection was seen when treatment was delayed for as long as 4 hours after permanent MCAo.

The neuroprotective efficacy of NXY-059 in permanent MCAo in the rat: Dose response and therapeutic window

P78 Introduction. NXY-059 (disodium 4-[(tert-butylimino)methyl] benzene-1,3-disulfonate N-oxide) is a nitrone with free radical trapping properties and is being developed for the treatment of acute ischemic stroke. NXY-059 possesses proven neuroprotective efficacy in rat transient models of middle cerebral artery occlusion (MCAo) (J Cereb Blood Flow Metab 1999;19:778–87), however its efficacy in permanent models of focal cerebral ischemia has not been as extensively tested. In the present study we have examined the efficacy of NXY-059 at three doses and further examined the therapeutic window of the mid-range dose. Methods. Adult male Wistar rats (300–330g) were given a unilateral permanent MCAo using an intraluminal suture technique. To assess efficacy of three doses of NXY-059, vehicle or NXY-059 (30, 50 or 70 mg/kg/h) was infused using minipumps for 24 hours. Dosing began 5 minutes after the MCAo with a bolus injection of vehicle or NXY-059 (30, 50 or 70 mg/kg). To assess the therapeutic window, treatment with 50 mg/kg (loading dose) and 50 mg/kg/h (over 24 hours) NXY-059 was commenced at 5, 30, 60, 120 and 240 minutes after MCAo. For both assessments, brains were removed 24 hours after commencing treatment and volume of damage was calculated from 5 x 2mm sections stained with triphenyl tetrazolium chloride. Results. NXY-059 (30, 50 and 70 mg/kg/h) reduced the volume of damage by 23%, 57% and 81% respectively (p Conclusions. In rats given a permanent MCA occlusion, NXY-059 at doses of 30–70 mg/kg/h given for 24 hours significantly (p

Treatment of pediatric traumatic brain injury: A broad path to a narrow gate

Treatment of pediatric traumatic brain injury: A broad path to a narrow gate

The Effect of the Dendritic Growth Factor BMP-7 on Local Cerebral Glucose Utilization and Blood Flow in Reversible Middle Cerebral Artery Occlusion in Rats

P79 Bone morphogenetic protein-7 (BMP-7) (=osteogenic protein-1, OP-1) has been shown to enhance dendritic growth and improve functional recovery after experimental stroke. In this study, we examined the effect of BMP-7 on local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu) following transient middle cerebral artery occlusion. Sprague Dawley rats (n=29) were anesthetized with halothane/nitrous oxide and received 2-h middle cerebral artery occlusion (MCAo) by poly-L-lysine coated intraluminal suture (1). Rectal and cranial (left temporalis muscle) temperatures were regulated at 37–37.5 o C. BMP-7 or vehicle (volume, 25μl) was administered intracisternally in blinded fashion at 24h after MCAo. Neurological status was evaluated during occlusion (60 min) and daily for 2 days after MCAo; a grading scale of 0–12 was employed (1). LCMRglu was measured autoradiographically with 14 C-2 deoxyglucose (2-DG) and LCBF with 14 C-iodoantipyrine 48 h after MCAo. Four animals groups were studied: LCMRglu series (BMP-7, n=7; vehicle, n=8); LCBF series (BMP-7, n=6; vehicle, n=8). Average three-dimensional image data sets were constructed for each group and were compared by pixel-based statistical methods (2). Rectal and cranial temperatures, MABP, plasma glucose and blood gases were similar among groups. BMP-7 significantly improved the neurological score compared to vehicle at 48 after MCAo (7.3 ± 0.4 vs. 9.0 ± 0.2, respectively; p&lt;0.0003). Compared to vehicle-rats, BMP-7 significantly increased LCMRglu in ipsilateral basal ganglia, improved LCBF in ipsilateral subthalamus, and decreased LCBF and LCMRglu in contralateral cortical regions. The improved glucose metabolism in ipsilateral basal ganglia of BMP-7 rats is compatible with its salutary influence on neurological recovery. Supported by Creative BioMolecules, Inc., Hopkinton, MA, and by NIH Grant NS 05820. (1)Belayev L, Alonso OF, Busto R, Zhao W, Ginsberg MD: Stroke 27:1616–1623,1996. (2)Zhao W, Belayev L, Ginsberg MD: J Cereb Blood Flow Metab 17:1281–1290,1997.

BLADDER EPITHELIAL CELLS FROM PATIENTS WITH INTERSTITIAL CYSTITIS PRODUCE AN INHIBITOR OF HEPARIN-BINDING EPIDERMAL GROWTH FACTOR-LIKE GROWTH FACTOR PRODUCTION

The etiology of interstitial cystitis is unknown. We previously identified an interstitial cystitis urine factor, antiproliferative factor, that inhibits proliferation of bladder epithelial cells in vitro and complex changes in epithelial growth factor levels, including profound decreases in heparin-binding epidermal growth factor-like growth factor (HB-EGF). Bladder and renal pelvic catheterization of patients with interstitial cystitis indicated that the antiproliferative factor is made and/or activated in the distal ureter or bladder. Therefore, we determined whether bladder epithelial cells from interstitial cystitis cases produced the antiproliferative factor and whether purified antiproliferative factor could alter production of growth factors known to be abnormal in interstitial cystitis. Antiproliferative factor activity was determined by 3H-thymidine incorporation into primary bladder epithelial cells. The antiproliferative factor was purified by size fractionation followed by sequential chromatography involving ion exchange, hydrophobic interaction and high performance liquid chromatography. HB-EGF, epidermal growth factor, insulin-like growth factor and insulin-like growth factor binding protein 3 levels were determined by enzyme-linked immunosorbent assay. Bladder epithelial cells from patients with interstitial cystitis produced a single antiproliferative factor with the same purification profile as that purified from interstitial cystitis urine. Purified antiproliferative factor specifically inhibited HB-EGF production by bladder epithelial cells in vitro, and the effect of interstitial cystitis urine or purified antiproliferative factor on bladder cell proliferation was inhibited by recombinant human HB-EGF in a dose dependent manner. Similar to urine HB-EGF, serum HB-EGF was also significantly lower in interstitial cystitis cases than in controls. Bladder epithelial abnormalities in interstitial cystitis may be caused by a negative autocrine growth factor that inhibits cell proliferation by down-regulating HB-EGF production. Furthermore, decreased levels of urine and serum HB-EGF indicate that interstitial cystitis may be a urinary tract manifestation of a systemic disorder.

Abstracts of literature

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The Effect of the Dendritic Growth Factor BMP-7 on Local Cerebral Glucose Utilization and Blood Flow in Reversible Middle Cerebral Artery Occlusion in Rats

P79 Bone morphogenetic protein-7 (BMP-7) (=osteogenic protein-1, OP-1) has been shown to enhance dendritic growth and improve functional recovery after experimental stroke. In this study, we examined the effect of BMP-7 on local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu) following transient middle cerebral artery occlusion. Sprague Dawley rats (n=29) were anesthetized with halothane/nitrous oxide and received 2-h middle cerebral artery occlusion (MCAo) by poly-L-lysine coated intraluminal suture (1). Rectal and cranial (left temporalis muscle) temperatures were regulated at 37–37.5oC. BMP-7 or vehicle (volume, 25μl) was administered intracisternally in blinded fashion at 24h after MCAo. Neurological status was evaluated during occlusion (60 min) and daily for 2 days after MCAo; a grading scale of 0–12 was employed (1). LCMRglu was measured autoradiographically with 14C-2 deoxyglucose (2-DG) and LCBF with 14C-iodoantipyrine 48 h after MCAo. Four animals groups were studied: LCMRglu series (BMP-7, n=7; vehicle, n=8); LCBF series (BMP-7, n=6; vehicle, n=8). Average three-dimensional image data sets were constructed for each group and were compared by pixel-based statistical methods (2). Rectal and cranial temperatures, MABP, plasma glucose and blood gases were similar among groups. BMP-7 significantly improved the neurological score compared to vehicle at 48 after MCAo (7.3 ± 0.4 vs. 9.0 ± 0.2, respectively; p<0.0003). Compared to vehicle-rats, BMP-7 significantly increased LCMRglu in ipsilateral basal ganglia, improved LCBF in ipsilateral subthalamus, and decreased LCBF and LCMRglu in contralateral cortical regions. The improved glucose metabolism in ipsilateral basal ganglia of BMP-7 rats is compatible with its salutary influence on neurological recovery. Supported by Creative BioMolecules, Inc., Hopkinton, MA, and by NIH Grant NS 05820. (1)Belayev L, Alonso OF, Busto R, Zhao W, Ginsberg MD: Stroke 27:1616–1623,1996. (2)Zhao W, Belayev L, Ginsberg MD: J Cereb Blood Flow Metab 17:1281–1290,1997.