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T Tatlisumak

Publications and source records attributed to T Tatlisumak.

At least 19 recordsLinked to original sources
PubMed2000

Stanniocalcin: A molecular guard of neurons during cerebral ischemia.

Stanniocalcin (STC) is a glycoprotein hormone originally found in bony fish, in which it regulates calcium/phosphate homeostasis and protects against hypercalcemia. The recently characterized human STC shows about 70% homology with fish STC. We previously reported a constitutive expression of STC in terminally differentiated neurons. Here, we show that exposure of human neural-crest-derived cell line Paju to hypercalcemic culture medium induced expression of STC. Treatment of Paju cells with recombinant human STC increased their uptake of inorganic phosphate. Paju cells expressing STC by cDNA transfection displayed increased resistance to ischemic challenge and to elevated intracellular free calcium induced by treatment with thapsigargin. An up-regulated and redistributed expression of STC was observed in neurons surrounding the core of acute infarcts in human and rat brains. Given that mobilization and influx of calcium is considered a main neurotoxic mechanism following ischemia, our results suggest that the altered expression of STC contributes to the protection of cerebral neurons against hypoxic/ischemic damage. Manipulation of the STC expression may therefore offer a therapeutic approach to limit the injury after ischemic brain insults.

Adolescent↗
PubMed2000

The future of stroke treatment.

The concept of the therapeutic window of opportunity in ischemic neuronal injury and understanding the necessity of well organized stroke services revolutionized the management of acute ischemic stroke during the last years of the second millennium. Thrombolysis with IV rt-PA within 3 hours from the onset of symptoms is an established therapy for selected patients. The challenge of stroke therapy at the outset of this millennium is how to translate basic pathophysiologic evidence of ischemic neuronal injury into novel neuroprotective therapies either independently or combined with thrombolysis. Great hopes are placed in identification of pivotal molecular events in ischemic brain tissue and design of effective pharmacological interventions to target them. Aggressive, invasive procedures are also being developed and therapies such as intra-arterial clot lysis, hemicraniectomy and mild hypothermia may improve the bleakest outcomes associated with the most severe forms of ischemic stroke, but their role must be rigorously evaluated. There is, however, no need to wait for future breakthroughs. The existing evidence strongly implies that good care of patients with stroke starts with organization of the entire stroke chain; from the prehospital scene, through the emergency room, to the stroke unit. Without structured stroke services no pharmacological or intervening therapy is likely to improve the outcome of the patient with a stroke.

Animals↗
PubMed2000

Plasma endothelin-1 levels neither increase nor correlate with neurological scores, stroke risk factors, or outcome in patients with ischemic stroke.

BACKGROUND AND PURPOSE: Endothelins (ETs) are potent vasoconstrictors and may play a role in the pathophysiology of several diseases. Limited and controversial data exist on their role in human ischemic stroke. We planned a prospective, observational, and longitudinal clinical study to test whether ET-1 levels increase in various phases of ischemic stroke and whether the ET-1 levels correlate with neurological scores, stroke etiology, stroke risk factors, or final outcome. METHODS: We measured plasma ET-1 levels with a sandwich-enzyme immunoassay method in 101 consecutive patients with ischemic stroke on admission and 1 week, 1 month, and 3 months after stroke and in 101 sex- and age-matched control subjects. At each sampling, the patients underwent a complete neurological evaluation. All stroke risk factors were recorded, an array of laboratory tests were performed, and the subtype of ischemic stroke was determined. The patients were contacted 3 years later for prognostic determination. RESULTS: ET-1 levels in patients (2.4+/-1.3 pg/mL on admission, 2.2+/-1.4 pg/mL at 1 week, 2.1+/-1.4 pg/mL at 1 month, and 2.1+/-1.2 pg/mL at 3 months) were not different from those of the control subjects (2.2+/-0.9 pg/mL) at any time point. No correlation was found between the ET-1 levels and stroke etiology, stroke risk factors, stroke recurrence risk, age, sex, or neurological scores, except that ET-1 levels correlated with the use of warfarin and with body mass index. CONCLUSIONS: Plasma ET-1 levels were normal in patients with ischemic stroke. Our findings cannot exclude a role of ETs in the pathophysiology of ischemic stroke because plasma levels might not accurately reflect intracerebral concentrations, but they also do not support the occurrence of a major plasma ET-1 level increase at any phase of stroke. Our patient population is the largest ever reported in whom ET-1 levels were measured, but it consisted of mild and moderately ill patients with stroke due to the study design, of which the aim was long-term observation, which excludes severely ill patients.

Adult↗
PubMed1999

Neuroprotective effects of a novel broad-spectrum cation channel blocker, LOE 908 MS, on experimental focal ischemia: a multispectral study.

Thirty-four rats undergoing 90 minutes of temporary middle cerebral artery occlusion were randomly and blindly assigned to vehicle or (RS)-(3,4-dihydro-6, 7-dimethoxyisoquinoline-1-gamma1)-2-phenyl-N,N-di-2-(2, 3, 4-trimethoxyphenyl)ethyl acetamide (LOE 908 MS; 0.5 mg/kg) i.v. bolus at 30 minutes after arterial occlusion followed by a 5 mg/kg/hr i.v. infusion for 3.8 hours (n =17/group). Perfusion-, diffusion- and T(2)-weighted magnetic resonance imaging was performed before treatment and repeatedly after treatment. Multispectral analysis was used to define ischemic abnormalities. The size of the ischemic abnormalities, including the ischemic core and penumbra, was not different between the two groups before treatment. However, a significant difference in ischemic lesion size was detected beginning 1.5 hours after treatment. The size of the ischemic core was significantly smaller in the treatment group, while the size of the ischemic penumbra was similar in the two groups at 85 minutes after arterial occlusion. Postmortem infarct size at 24 hours was significantly smaller in the drug-treated group than in the placebo group. These results demonstrate that LOE 908 MS can reduce ischemic lesion size, which is probably attributable to inhibition of expansion of the ischemic core. J. Magn. Reson. Imaging 1999;10:138-145.

Acetamides↗
PubMed1999

Reversal of acute apparent diffusion coefficient abnormalities and delayed neuronal death following transient focal cerebral ischemia in rats.

Twenty-two rats were subjected to 8, 15, 30, or 60 minutes of temporary middle cerebral artery occlusion (n = 5 per group) or sham occlusion (n = 2) in the magnetic resonance imaging unit. Diffusion-, perfusion-, and T2-weighted imaging were acquired before and during occlusion, and after reperfusion. A coregistration method was used to correlate the acute changes of the average apparent diffusion coefficient (ADCav) with the histology after 72 hours at the same topographic sites. The initially reduced ADCav values recovered completely in both the lateral caudoputamen and upper frontoparietal cortex in the 8-, 15-, and 30-minute groups, partially in the cortex, and not at all in the caudoputamen in the 60-minute group. The histology showed that the caudoputamen was either normal or had mild neuronal injury in the 8-minute group and invariably had some degree of neuronal death in the 15-, 30-, and 60-minute groups, whereas the cortex was either normal or had varying degrees of neuronal injury in all groups. No histological abnormalities were seen in the sham-operated rats. Our data suggest that acute ADCav reversal does not always predict tissue recovery from ischemic injury and that temporary focal ischemia for even 8-minute duration can cause delayed neuronal death that is more severe in the caudoputamen where the initial ADCav decline was greater than in the cortex.

Animals↗
PubMed1999

Bilateral sphenoid wing metastases of prostate cancer presenting with extensive brain edema.

A 76-year-old man insidiously developed diffuse neurological symptoms: cognitive decline, dysphagia, dysphasia and mental disturbance. Computed tomography of the cranium revealed widespread bilateral brain edema and symmetrical bilateral sphenoid wing hyperostosis. Adjacent to the hyperostosis that resembled skull base meningiomas, two separate parenchymatous temporal lobe lesions enhancing with contrast medium were observed. The patient had earlier been diagnosed to have prostatic carcinoma. Dexamethasone therapy resulted in discontinuation of the neurological symptoms. The diagnosis of metastasized adenocarcinoma of the prostate was confirmed histologically on autopsy after a sudden death from pneumonia. Intracranial metastases of prostate cancer may have a predilection site at the sphenoid wing, and can mimic a skull base meningioma. Intracranial spread of prostatic adenocarcinoma should be considered in elderly men as a treatable cause of gradual neurological deterioration, especially if cranial malignancy or hyperostosis is found.

Adenocarcinoma↗
PubMed1998

A glycine site antagonist, ZD9379, reduces number of spreading depressions and infarct size in rats with permanent middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: Spreading depressions (SDs) occur in experimental focal ischemia and contribute to lesion evolution. N-Methyl-D-aspartate (NMDA) antagonists inhibit SDs and reduce infarct size. The glycine site on the NMDA receptor complex offers a therapeutic target for acute focal ischemia, potentially devoid of many side effects associated with competitive and noncompetitive NMDA antagonists. We evaluated the effect of the glycine antagonist ZD9379 on SDs and brain infarction. METHODS: Male Sprague-Dawley rats (n = 18) weighing 290 to 340 g undergoing permanent middle cerebral artery occlusion (MCAO) were randomly and blindly assigned to receive drug or placebo: group 1 (pre-MCAO treatment group; n=5), a 5-mg/kg bolus of ZD9379 over 5 minutes followed by 5 mg/kg per hour drug infusion for 4 hours beginning 30 minutes before MCAO; group 2 (post-MCAO treatment group; n=7), a 5-mg/kg bolus of ZD9379 30 minutes after MCAO followed by 5 mg/kg per hour drug infusion for 4 hours; and group 3 (control group; n=6), vehicle for 5 hours beginning 30 minutes before MCAO. SDs were monitored electrophysiologically for 4.5 hours after MCAO by continuous recording of cortical DC potentials and electrocorticogram. Infarct volume was measured 24 hours after MCAO by 2,3,5-triphenyltetrazolium chloride staining. RESULTS: Corrected infarct volume was 90+/-72 mm3 (mean+/-standard deviation) in group 1, 105+/-46 mm3 in group 2, and 226+/-40 mm3 in group 3 (P<.001). The corresponding numbers of SDs in the three groups were 8.2+/-5.8, 8.1+/-2.5, and 16.0+/-5.1, respectively (P<.01). When all animals (n=18) were analyzed, infarct volumes and the number of SDs were significantly correlated (r=.68, P=.002). CONCLUSIONS: This study demonstrated that ZD9379 initiated before or after MCAO significantly reduced the number of SDs and infarct volume in a permanent focal ischemia model, implying that ZD9379 is neuroprotective and its neuroprotective effect may be related to inhibiting ischemia-related SDs.

Analysis of Variance↗
PubMed1998

Dichotomized efficacy end points and global end-point analysis applied to the ECASS intention-to-treat data set: post hoc analysis of ECASS I.

BACKGROUND AND PURPOSE: It is not yet known which end points are the most suitable for evaluation of the effects of acute stroke intervention. The European Cooperative Acute Stroke Study (ECASS) I study used 2 primary end points. The study was powered to detect a 15% improvement of the median of each primary end point. The study failed to show this effect and was negative in the intention-to-treat analysis. The National Institute of Neurological Disorders and Stroke (NINDS) study used 4 dichotomized end points and applied a global end-point analysis. This study was positive and led to FDA approval of thrombolytic therapy for acute ischemic stroke. This study was undertaken to answer the question of whether a different statistical design may have shown a positive results of the ECASS I trial. METHODS: We performed a retrospective analysis of the ECASS I intention-to-treat data set (615 randomized and treated patients, rtPA treatment versus placebo) and post hoc application of the NINDS trial statistical methodology (global end-point analysis). The scores of the modified Rankin Scale (mRS), Barthel Index (BI), and the National Institutes of Health Stroke Scale (NIHSS) were dichotomized according to the criteria used in the NINDS trial. Favorable outcome was defined as a score of 0 or 1 on mRS, a score of 95 or 100 on BI, and a score of 0 or 1 on NIHSS. RESULTS: The number of patients reaching favorable outcome were higher in all 3 end points in the rtPA-treated group. The effect sizes were 8% for mRS, 6% for BI, and 14% for NIHSS, respectively. The differences are statistically significant for the mRS (P=0.044; odds ratio [OR], 1. 4; 95% confidence interval [CI], 1.0 to 2.0) and the NIHSS (P=0.001; OR, 1.9; 95% CI, 1.4 to 2.8), while for the BI significance was missed (P=0.102; OR, 1.3; 95% CI, 0.9 to 1.8). The global end-point statistics, however, shows a significant increase (P=0.008; OR, 1.5; 95% CI, 1.1 to 2.0) of favorable outcome in the rtPA-treated patient group. CONCLUSIONS: Using the global end-point analysis, ECASS is positive in the intention-to-treat analysis. This may indicate that the time window for thrombolysis may be as long as 6 hours. Looking at the 3 dichotomized end points, the effect sizes for 2 end points, mRS and BI, are smaller in the ECASS 6-hour intention-to-treat population compared with the NINDS trial, whereas the effect size for the NIHSS is larger. While in the NINDS trial all 3 end points reveal statistically significant results, in ECASS only 2 of the 3 corresponding end points, mRS and NIHSS, were statistically significant. This finding underlines an important difference of a global end-point approach: it may show a positive overall result although one of the end points is not positive.

Cerebrovascular Disorders↗
PubMed1998

A novel endothelin antagonist, A-127722, attenuates ischemic lesion size in rats with temporary middle cerebral artery occlusion: a diffusion and perfusion MRI study.

BACKGROUND AND PURPOSE: Endothelins (ETs) are potent vasoconstrictors. Plasma ET levels increase during acute brain ischemia and may worsen the ischemic damage. Diffusion-weighted MRI (DWI) and perfusion imaging (PI) are powerful tools for evaluation of acute cerebral ischemia. We studied the effects of A-127722, a novel ET(A)-selective ET antagonist, on cerebral ischemic lesion size using 2,3,5-triphenyltetrazolium chloride (TTC) staining postmortem, on acute ischemic lesion development with DWI, and on the cerebral circulation using PI. METHODS: Twenty male Sprague-Dawley rats received either 5 mg/kg of A-127722 or vehicle (n=10 per group) intravenously 30 minutes and subcutaneously 4 hours after middle cerebral artery occlusion (MCAO). Whole-brain DWI and single-slice PI were done before initiation of treatment and repeated frequently thereafter up to 4 hours after MCAO. The animals were reperfused in the MRI scanner 90 minutes after the onset of MCAO. At 24 hours the animals were killed, and the brains were cut into six 2-mm-thick slices and stained with 2% TTC. Percent hemispheric lesion volume (%HLV) was calculated for each animal. RESULTS: Physiological parameters, body weight, neurological scores, and premature mortality (2 versus 2) did not differ between the two groups. No hypotension, abnormal behavior, or other adverse effects were seen. TTC-derived %HLV was 25.3+/-5.6% for controls and 16.2+/-9.6% for treated animals (36% reduction, P<.02). Six animals in each group had successful reperfusion as shown by PI. Among these animals, %HLV was 23.2+/-3.1% for controls and 9.3+/-4.4% for treated animals (60% reduction, P=.0001). The beneficial effect of A-127722 was limited to animals in which successful reperfusion was demonstrated. No difference in PI-detected perfusion deficit size was observed between the groups. DWI did not demonstrate significant in vivo lesion size differences. CONCLUSIONS: A-127722 significantly reduced ischemic lesion size in rats without observable adverse effects. It is not clear whether the effect was due to vasodilatation of collateral arterioles not detectable by PI or whether A-127722 has neuroprotective properties that are independent of vascular effects.

Acute Disease↗
PubMed1998

A new method to improve in-bore middle cerebral artery occlusion in rats: demonstration with diffusion- and perfusion-weighted imaging.

BACKGROUND AND PURPOSE: In-bore middle cerebral artery occlusion (MCAO) enables investigators to acquire preischemic MRI data and to image ischemic changes immediately after occlusion. We have developed a highly successful in-bore MCAO method. This study describes the methods and pertinent techniques. METHODS: Sixty-seven Sprague-Dawley rats were subjected to temporary (n=36) or permanent (n=31) MCAO. The occluding device consisted of a supporting tubing, a driving line, and a silicone-coated 4-0 nylon suture occluder. Outside the magnet, the occluder was positioned in the carotid canal. MCAO was achieved in the magnet bore by remotely advancing the driving line until resistance was felt. Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) were acquired before and immediately after occlusion and were used to document the presence of MCAO. RESULTS: Fifty-nine (88.1%) rats were successfully occluded, demonstrating hyperintensity on DWI, perfusion deficits on PWI, and no subarachnoid hemorrhage at postmortem examination. The average values of the apparent diffusion coefficient in both the frontoparietal cortex and the lateral caudoputamen significantly decreased as early as 3 minutes after the onset of ischemia. The failures included preocclusion damage (1/67), sliding out of the occluder during occlusion (1/67), no occlusion (2/67), and arterial perforation (4/67). CONCLUSIONS: Our in-bore MCAO method is easily performed and is as successful as MCAO induced outside the magnet.

Animals↗
PubMed1998

Delayed treatment with an adenosine kinase inhibitor, GP683, attenuates infarct size in rats with temporary middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: Brain ischemia is associated with a marked increase in extracellular adenosine levels. This results in activation of cell surface adenosine receptors and some degree of neuroprotection. Adenosine kinase is a key enzyme controlling adenosine metabolism. Inhibition of this enzyme enhances the levels of endogenous brain adenosine already elevated as a result of the ischemic episode. We studied a novel adenosine kinase inhibitor (AKI), GP683, in a rat focal ischemia model. METHODS: Four groups of 10 adult Sprague-Dawley rats were exposed to 90 minutes of temporary middle cerebral artery (MCA) occlusion. Animals were injected intraperitoneally with vehicle, 0.5 mg/kg, 1.0 mg/kg, or 2.0 mg/kg of GP683 30, 150, and 270 minutes after the induction of ischemia by a researcher blinded to treatment group. The animals were euthanatized 24 hours after MCA occlusion, and brains were stained with 2,3,5-triphenyltetrazolium chloride. We measured brain temperatures in a separate group of 6 rats before and after administration of 1.0 mg/kg GP683. RESULTS: All treated groups showed a reduction in infarct volumes, but a significant effect was observed only in the 1.0 mg/kg-dose group (44% reduction, P=0.0077). Body weight, physiological parameters, neurological scores, and mortality did not differ among the 4 groups. No apparent behavioral side effects were observed. Brain temperatures did not change after drug injection. CONCLUSIONS: Our results indicate that the use of AKIs offers therapeutic potential and may represent a novel approach to the treatment of acute brain ischemia. The therapeutic effect observed was not caused by a decrease in brain temperature.

Adenosine Kinase↗
PubMed1998

Efficacy of intra-arterial and intravenous prourokinase in an embolic stroke model evaluated by diffusion-perfusion magnetic resonance imaging.

OBJECTIVE: To explore the utility of intravenous (i.v.) prourokinase treatment, we compared intra-arterial (i.a.) and i.v. delivery in a rat embolic stroke model, using diffusion (DWI) and perfusion (PI) magnetic resonance imaging to assess in vivo effects on ischemic lesion evolution and reperfusion. BACKGROUND: Thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA) for acute ischemic stroke is useful during the initial hours after onset. Prourokinase is a novel thrombolytic agent with potential safety advantages in comparison to rt-PA. METHODS: Twenty-four male Sprague-Dawley rats were embolized with autologous blood clots into the middle cerebral artery territory and then randomly assigned at 30 minutes after embolization to a 2-hour bolus infusion with i.a. prourokinase, i.v. prourokinase, or vehicle. DWI and PI were performed before treatment and repeated during and at the end of the treatment. RESULTS: PI demonstrated that both i.a. and i.v. significantly improved the percentage of the ischemic hemisphere that was normally perfused when the 20-minute, pretreatment, and 145-minute after embolization time points were compared; in the control group, the hypoperfused volume increased over time. DWI disclosed that the ischemic lesion evolution slightly decreased in the i.a. group, remained stable in the i.v. group, and increased over time in the control group. Infarct volume by triphenyltetrazolium chloride (TTC) staining was significantly smaller in both treatment groups than controls. CONCLUSIONS: These results demonstrate that i.a. and i.v. therapy with prourokinase are equally effective in promoting reperfusion and inhibiting the development of focal ischemic injury in this rat embolic stroke model.

Animals↗
PubMed1997

Reproducibility and reliability of middle cerebral artery occlusion using a silicone-coated suture (Koizumi) in rats.

The best technical approach to rat middle cerebral artery occlusion (MCAO) using a nylon-monofilament suture remains unsettled, regarding the usefulness of coated or uncoated sutures. Three investigators with different degrees of experience: A, well skilled; B, 2 years of experience; C, a novice with 6 months of experience, each subjected 10 Sprague-Dawley rats to permanent MCAO using low-viscosity silicone-coated sutures with a mean diameter 0.468+/-0.013 mm (mean+/-S.D.) at the tip and 0.361+/-0.013 mm in the body. Post-mortem corrected infarct size 24 h after MCAO was similar among the three investigators: A, 204.7+/-33.2 mm3; B, 212.6+/-42.8, and C, 195.9+/-44.4. The coefficient of variation was 16.2% to 22.7%, and 19.4% for the three investigators. This study suggests that experimental stroke with silicone-coated sutures (Koizumi's method) provides good reproducibility and reliability, among investigators of varying experience.

Animals↗
PubMed1997

Synergistic effects of citicoline and MK-801 in temporary experimental focal ischemia in rats.

BACKGROUND AND PURPOSE: Citicoline, a naturally occurring precursor of phosphatidylcholine, is neuroprotective and is currently being assessed in clinical trials. To evaluate potential synergistic neuroprotective effects of prolonged citicoline treatment and early N-methyl-D-aspartate (NMDA) antagonist therapy, suboptimal treatment regimens of citicoline and MK-801 were tested alone and in combination in a rat model of temporary focal ischemia. METHODS: Four groups of Sprague-Dawley rats (n = 12 per group) underwent 90 minutes of temporary middle cerebral artery occlusion (MCAO) with the suture model. Animals were randomly and blindly assigned to one of four treatment groups: (1) saline, vehicle; (2) MK-801, 0.5 mg/kg IV bolus at 60 minutes after MCAO followed by saline 1 mL/kg IP daily for 7 days; (3) saline IV at 60 minutes after MCAO followed by citicoline 250 mg/kg IP daily for 7 days; or (4) both MK-801 and citicoline (daily for 7 days) active treatment. Triphenyltetrazolium chloride staining was used to assess postmortem infarct volume. Neurological scores were determined daily. RESULTS: Premature mortality between days 2 and 4 was 33.3% in group 1, 41.7% in groups 2 and 3, and 25.0% in group 4. Mean corrected infarct volume was significantly reduced in group 4 compared with the others (175.2 +/- 89.3 mm3 in group 1, 179.1 +/- 78.5 mm3 in group 2, 163.9 +/- 73.7 mm3 in group 3, and 84.7 +/- 56.8 mm3 in group 4 [P < .02, ANOVA and P < .05, Scheffé's test for group 1 versus group 4]). Mean infarct volume in animals dying prematurely was significantly (P < .05, Student's t test) larger in group 1 than those surviving for 7 days (247.2 +/- 89.5 versus 139.2 +/- 68.2 mm3), but there was no significant difference in infarct volume in groups 2, 3, and 4 between animals dying prematurely and those surviving for 7 days. CONCLUSIONS: These results demonstrate synergistic neuroprotective effects of citicoline and an NMDA antagonist in temporary experimental focal ischemia.

Animals↗
PubMed1997

Glycine site antagonist attenuates infarct size in experimental focal ischemia. Postmortem and diffusion mapping studies.

BACKGROUND AND PURPOSE: The glycine site on the N-methyl-D-aspartate (NMDA) receptor complex offers a therapeutic target for acute focal ischemia, potentially devoid of most side effects associated with competitive and noncompetitive NMDA antagonists. METHODS: A novel glycine receptor antagonist, ZD9379, was studied in 70 Sprague-Dawley rats using the suture occlusion model of permanent middle cerebral artery occlusion (MCAO). In the first experiment, 20 rats received an initial bolus of vehicle or 10 mg/kg ZD9379 (n = 10 in each group) 30 minutes after MCAO, followed by a continuous infusion of the same dose per hour for 4 hours. Diffusion-weighted MRI with echo-planar acquisition was used to generate maps of the apparent diffusion coefficient (ADC) of water. In a second experiment, 50 rats were assigned to five groups: vehicle and 10, 5, 2.5, and 1 mg/kg ZD9379 (n = 10 in each group) with the same dosing protocol but no imaging. In both experiments, infarct volume was determined by 2,3,5-triphenyltetrazolium chloride staining. RESULTS: In the first experiment, before therapy was begun, there was no significant difference in ADC-derived ischemic lesion volume between the two groups. Over time, the 10-mg/kg ZD9379-treated rats had a significant delayed regional recovery of reduced ADC values in the peripheral parietal cortex (P = .0156). Postmortem corrected infarct volume at 24 hours after MCAO was significantly smaller in the group treated with 10 mg/kg ZD9379 than in the vehicle group (119.2 +/- 52.2 versus 211.2 +/- 50.0 mm3 [mean +/- SD]; P = .0008; a reduction of 43.6%). In the second experiment, postmortem corrected infarct volumes in rats receiving 10, 5, and 2.5 mg/kg ZD9379 were significantly smaller than in those receiving vehicle, a reduction of 42.6%, 51.4%, and 42.9%, respectively (P = .0001). CONCLUSIONS: This study demonstrates that 2.5- to 10-mg/kg doses of ZD9379 initiated 30 minutes after MCAO significantly reduced infarct size. Diffusion mapping disclosed a delayed treatment effect of this glycine antagonist in focal ischemia, confirmed by the postmortem study.

Animals↗
PubMed1996

Hematologic disorders associated with ischemic stroke.

Hematological disorders underlie a small proportion of all ischemic strokes. The association of these coagulation abnormalities with ischemic stroke is not always clear. The etiology of stroke still remains uncertain in a large number of cases and proper screening for coagulation abnormalities and the discovery of new coagulation disorders will probably increase the rate of strokes attributable to these causes. Since large case-control studies with unselected and consecutive stroke patients from different ethnic origins have not yet been performed to determine the role of coagulation abnormalities in ischemic stroke, our knowledge is dependent on case reports and small series of mostly younger patients. Extensive hematologic evaluation of unselected stroke patients will likely yield little useful information and be too expensive. Every stroke patients needs a careful evaluation, and in selected cases, this should include coagulation parameters. Patients with unexplained strokes after a careful evaluation, previous thrombotic episodes, or a positive family history for thrombosis, are good candidates for further coagulation studies. As long as the hypercoagulable state persists, both arterial and venous thromboembolic recurrences can be expected. Many of these patients may benefit from anticoagulants. In patients with hereditary coagulation disorders, studies should be extended to close relatives. Since some coagulation tests are fairly expensive, provide only equivocal data, and are not widely available, we advise a step-by-step approach starting with the patient and family history.

Anemia, Sickle Cell↗
PubMed1996

Effect of basic fibroblast growth factor on experimental focal ischemia studied by diffusion-weighted and perfusion imaging.

BACKGROUND AND PURPOSE: Basic fibroblast growth factor (bFGF) has documented neuroprotective properties. This study was performed to evaluate the effects of bFGF on infarct size when administered 30 minutes after induction of focal cerebral ischemia in rats. Diffusion-weighted and perfusion MRI were used during the drug infusion. METHODS: We blindly randomized 20 Sprague-Dawley rats to receive either drug (n = 10) or vehicle (n = 10). The animals underwent middle cerebral artery (MCA) occlusion using the suture model. Diffusion-weighted MRI was initiated 30 minutes after induction of ischemia and repeated frequently for 3.5 hours. Drug (45 micrograms/kg per hour) or vehicle (saline) infusion began 30 minutes after MCA occlusion and continued for 3 hours. Perfusion images were made at 25, 90, and 150 minutes after MCA occlusion. The animals were killed after 24 hours of permanent MCA occlusion, and brains were stained with 2,3,5-triphenyltetrazolium chloride (TTC). RESULTS: The TTC-derived, corrected infarct volume postmortem in the bFGF-treated group was significantly smaller than that in controls (126.6 +/- 51.9 versus 180.2 +/- 54.9 mm3, mean +/- SD, P = .038). Diffusion imaging showed essentially equal lesion volumes 3 hours after MCA occlusion (195.4 +/- 61 mm3 in the drug-treated group and 194.4 +/- 65 mm3 in controls). At 4 hours, ischemic lesion size was 182.1 +/- 56.9 mm3 in treated animals and 222.9 +/- 88.7 mm3 in the controls (P = .24, NS). Perfusion imaging did not show a change of cerebral perfusion within ischemic brain regions in the bFGF group during the infusion. No behavioral or physiological side effects were observed. CONCLUSIONS: bFGF is a safe and effective treatment for focal cerebral ischemia in rats. We observed a modest delayed difference of ischemic lesion size in vivo with diffusion MRI. The diffusion-weighted MRI findings suggest a potential delayed therapeutic effect of bFGF, and the perfusion imaging findings imply that the effect is not due to increased blood flow to the ischemic region.

Animals↗