Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage. We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm³) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments. Among 1000 participants with a mean (±SD) systolic blood pressure of 200.6±27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group than in the standard-treatment group (9.0% vs. 4.0%, P=0.002). The treatment of participants with intracerebral hemorrhage to achieve a target systolic blood pressure of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg. (Funded by the National Institute of Neurological Disorders and Stroke and the National Cerebral and Cardiovascular Center; ATACH-2 ClinicalTrials.gov number, NCT01176565.)

Zinc is present in presynaptic nerve terminals throughout the mammalian central nervous system and likely serves as an endogenous signaling substance. However, excessive exposure to extracellular zinc can damage central neurons. After transient forebrain ischemia in rats, chelatable zinc accumulated specifically in degenerating neurons in the hippocampal hilus and CA1, as well as in the cerebral cortex, thalamus, striatum, and amygdala. This accumulation preceded neurodegeneration, which could be prevented by the intraventricular injection of a zinc chelating agent. The toxic influx of zinc may be a key mechanism underlying selective neuronal death after transient global ischemic insults.

Infarct volume is one of the common indexes for assessing the extent of ischemic brain injury following focal cerebral ischemia. Accuracy in the measurement of infarct volume is compounded by postischemic brain edema that may increase brain volume in the infarcted region. We evaluated the effect of brain edema on infarct volume determined by triphenyltetrazolium chloride and hematoxylin and eosin stains in a focal cerebral ischemia model in rats. In a middle cerebral artery occlusion model in rats, infarction is confined to the cerebral cortex. The infarct was delineated by triphenyltetrazolium chloride stain and, in selected samples, by hematoxylin and eosin stain. We determined infarct size at different times after the ischemic insult (6 hours to 7 days) in relation to the evolution of brain edema by the direct measurement of infarct volume. Indirect measurement to reduce the effect of edema on infarct volume was also conducted in the same brain samples. Direct measurement showed that infarct volume fluctuated with the evolution of brain edema (one-way analysis of variance, p < 0.0001). Infarct volume determined by indirect measurement was independent of the extent of brain edema and remained stable from 6 hours to 3 days after ischemia. There was a good correlation between triphenyltetrazolium chloride and hematoxylin and eosin stains in delineating infarct volume with both direct and indirect measurement. Traditional direct measurement of infarct volume is associated with an overestimation of infarct volume during the development of brain edema in the first 3 days after ischemia. This artifact can be reduced with indirect measurement, which is based on noninfarcted cortex volume.

The temporal evolution of cerebral infarction was examined in rats subjected to transient occlusion of both common carotid arteries and the right middle cerebral artery. After severe (90-min) ischemia, substantial right-sided cortical infarction was evident within 6 h and fully developed after 1 day. After mild (30-min) ischemia, no cortical infarction was present after 1 day. However, infarction developed after 3 days; by 2 weeks, infarction volume was as large as that induced by 90-min ischemia. These data suggest that infarction after mild focal ischemia can develop in a surprisingly delayed fashion. Some evidence of neuronal apoptosis was present after severe ischemia, but only to a limited degree. However, 3 days after mild ischemia, neurons bordering the maturing infarction exhibited prominent TUNEL staining, and DNA prepared from the periinfarct area of ischemic cortex showed internucleosomal fragmentation. Furthermore, pretreatment with 1 mg/kg cycloheximide markedly reduced infarction volume 2 weeks after mild ischemia. These data raise the possibility that apoptosis, dependent on active protein synthesis, contributes to the delayed infarction observed in rats subjected to mild transient focal cerebral ischemia.

In the search for a more reproducible focal ischemic stroke model in the rat, we systematically interrupted blood flow to the right middle cerebral artery territory by ligating the right middle cerebral artery, and the right and left common carotid arteries in succession. Using a laser-Doppler flowmeter, we found that the relative surface blood flow in cerebral cortex supplied by the right middle cerebral artery decreased to 62, 48, and 18% of baseline respectively after successive ligation of the right middle cerebral artery, and the right and left common carotid arteries. A focal infarct in the cerebral cortex supplied by the right middle cerebral artery was consistently noted after ligation of the right middle cerebral and the right common carotid arteries and temporary clip occlusion of the left common carotid artery for 60 min. The surface areas of infarction measured 100 +/- 6 mm2 and the maximal cross-sectional area of infarction was 10.4 +/- 1.1 mm2 (N = 10). The mortality rate was 7% (N = 70). The characteristic changes of ischemic necrosis were limited to the cortex with sparing of subcortical structures. No motor deficits occurred. Occlusion of the right middle cerebral artery alone or together with the right common carotid artery did not consistently cause gross infarction and the maximal cross-sectional area of infarction was smaller (the right middle cerebral artery, 1.7 +/- 0.8 mm2, N = 10; the right middle cerebral artery plus the right common carotid artery, 4.8 +/- 1.9 mm2, N = 10). Permanent ligation of the right middle cerebral artery and both common carotid arteries had a high mortality (60% in 3 days, N = 10).(ABSTRACT TRUNCATED AT 250 WORDS)

The Multicenter Animal Spinal Cord Injury Study (MASCIS) adopted a modified 21-point open field locomotor scale developed by Basso, Beattie, and Bresnahan (BBB) at Ohio State University (OSU) to measure motor recovery in spinal-injured rats. BBB scores categorize combinations of rat hindlimb movements, trunk position and stability, stepping, coordination, paw placement, toe clearance, and tail position, representing sequential recovery stages that rats attain after spinal cord injury. A total of 22 observers from 8 participating centers assessed 18 hindlimbs of 9 rats at 2–6 weeks after graded spinal cord injury. The observers were segregated into 10 teams. The teams were grouped into 3 cohorts (A, B, and C), consisting of one experienced team from OSU and two non-OSU teams. The cohorts evaluated the rats in three concurrent and sequential sessions. After viewing a rat for 4 min, individual observers first assigned scores without discussion. Members of each team then discussed and assigned a team score. Experience (OSU vs. non-OSU) and teamwork (individual vs. team) had no significant effect on mean scores although the mean scores of one cohort differed significantly from the others (p = 0.0002, ANOVA). However, experience and teamwork significantly influenced reliability of scoring. OSU team scores had a mean standard deviation or discordance of 0.59 points, significantly less than 1.31 points for non-OSU team scores (p = 0.003, ANOVA) and 1.30 points for non-OSU individual scores (p = 0.001, ANOVA). Discordances were greater at the upper and lower ends of the scale, exceeding 2.0 in the lower (15) ends of the scale but were <1.0 for scores between 4 and 16. Comparisons of non-OSU and OSU team scores indicated a high reliability coefficient of 0.892 and a correlation index (r²) of 0.894. These results indicate that inexperienced observers can learn quickly to assign consistent BBB scores that approach those given by experienced teams, that the scores are most consistent between 4 and 16, and that experience improves consistency of team scores.