bluuebunny/crossref_metadata_2025 huggingface dataset:
Do Changes in Oxygen Metabolism in the Unaffected Cerebral Hemisphere Underlie Early Neurological Recovery After Stroke?
Authors: Iglesias S. , Marchal G. , Rioux P. , Beaudouin V. , Hauttement J.L. , de la Sayette V. , Le Doze F. , Derlon J.M. , Viader F. , Baron J.C.
Published: June 2011

Background and Purpose
Whether an initial depression of function in the unaffected hemisphere (“transcallosal diaschisis”) plays a role in early neurological recovery after acute stroke remains controversial. Previous studies were confounded by lack of acute-stage assessment with follow-up and by the problem of defining a suitable control group, since preexisting stroke risk factors may influence prestroke cerebral metabolism. We evaluated with positron emission tomography (PET) the relationships between unaffected-hemisphere (ie, contralateral) oxygen consumption (cCMRO
2
) and quantitative neurological assessments (and their respective evolution over time) after ischemic stroke.

Methods
Among 30 consecutive patients with first-ever middle cerebral artery ischemic stroke studied with the
15
O equilibrium method, we selected all survivors (n=19; mean age, 74.6 years) who were investigated both within the first 18 hours after stroke onset (PET
1
; mean, 11±4 hours) and 15 to 30 days later (PET
2
; mean, 24±10 days), with each patient serving as his/her own control. Neurological deficits were quantified using Orgogozo's middle cerebral artery scale (N score) at each PET session. Neurological changes were calculated as changes in the N score. A late CT scan coregistered with PET provided infarct topography and volume index.

Results
At PET
2
, we observed the overall expected neurological recovery. There was a nearly significant trend for a decrease in cCMRO
2
from PET
1
to PET
2
, especially for the neocortex (
P
=.08, F test); in a subgroup of eight patients with large infarcts, this CMRO
2
decline was significant (
P
<.05) in the mirror region to the infarct. There was no significant correlation (Spearman's tests) between acute-stage cCMRO
2
and same-day N scores or between changes in cCMRO
2
versus changes in N score from PET
1
to PET
2
(any region). There was a nearly significant trend for lower PET
2
cCMRO
2
in the subgroup of eight patients with large compared with small infarcts (
P
=.06).

Conclusions
We found no evidence for an influence of cCMRO
2
on acute-stage neurological deficit or for a role of the unaffected hemisphere in early recovery after acute MCA ischemic stroke. The decline in unaffected-hemisphere metabolism from the acute to the subacute stage in the face of overall clinical recovery appears clinically irrelevant. The fact that the neocortical cCMRO
2
at PET
2
tended to be lower, and declined significantly from PET
1
to PET
2
in the mirror region in the subgroup of patients with large infarcts, suggests that this delayed effect represents transcallosal fiber degeneration.
Felbamate Protects CA1 Neurons From Apoptosis in a Gerbil Model of Global Ischemia
Authors: Wasterlain Claude G. , Adams Lisa M. , Wichmann Joseph K. , Sofia R. Duane
Published: June 2011

Background and Purpose
Felbamate, a novel anticonvulsant that binds to the glycine site of the
N
-methyl-
d
-aspartate receptor, has been shown to have neuroprotective properties in vitro and in vivo. In a rat pup model of hypoxia-ischemia, felbamate selectively reduced delayed death in hippocampal granule cells. The present study explores its neuroprotective potential in a gerbil model of global ischemia, in which good evidence exists that ischemia triggers apoptosis of CA1.

Methods
Gerbils were subjected to bilateral carotid occlusion for 5 minutes and then treated with felbamate (100 or 200 mg/kg IV) or vehicle. They were killed 3 days later, and the numbers of live and dead neurons in the CA1 sector of the hippocampus were counted at stereotaxically defined levels.

Results
Felbamate (200 mg/kg IV) administered after the release of carotid clamping did not change brain temperature but reduced neuronal death in CA1 from 332±60 cells per section of dorsal hippocampus in unmedicated gerbils to 62±12 cells in felbamate-treated animals (
P
<.001). A lower dose of felbamate (100 mg/kg post hoc) showed only a nonsignificant reduction of neuronal death. In the 200-mg/kg group, felbamate serum concentrations peaked at 162 μg/mL and were above 100 μg/mL for at least 3 hours, and brain levels reached 150 μg/mL at 1 hour. In the 100-mg/kg group, blood serum levels were well below 100 μg/mL.

Conclusions
These results suggest that felbamate given post hoc is remarkably effective in preventing delayed apoptosis secondary to global ischemia but that effective neuroprotection requires doses higher than those used for anticonvulsant treatment.
Transvenous Hemodynamic Assessment of Experimental Arteriovenous Malformations
Authors: Murayama Yuichi , Massoud Tarik F. , Viñuela Fernando
Published: June 2011

Background and Purpose
A Doppler guidewire was used to monitor progressive changes in draining vein flow parameters during experimental embolotherapy in a swine arteriovenous malformation (AVM) model.

Methods
A microcatheter was positioned superselectively in the main arterial feeder and main draining vein in each of 10 AVM models in swine. With use of the Doppler guidewire, preembolization arterial and venous average peak velocities (APVs) and pulsatility indices were recorded. The device was left in the draining vein during transarterial particulate (in 8 swine) or liquid adhesive (in 2 swine) embolization, and continuous transvenous flow during and after treatment was monitored. Periembolization Doppler flow parameters were correlated qualitatively with angiographic changes in the nidus.

Results
Preembolization draining vein flow was pulsatile, with a mean APV of 38.9±13.7 cm/s. After embolization, this changed significantly to a less pulsatile or nonpulsatile pattern, with a lower mean APV of 9.2±4.9 cm/s (
P
=.0001). A novel expression, the maximum minus the minimum peak velocity (MxPV−MnPV), was used in evaluating the transvenous Doppler spectra. This was reduced significantly after embolization from a mean of 11.1±3.5 cm/s to 6.7±2.5 cm/s (
P
=.0025). Objective periembolization hemodynamic changes were detected in the draining veins earlier than the visually subjective angiographic changes within the nidus.

Conclusions
Transvenous Doppler guidewire assessment of two parameters, APV and MxPV−MnPV, is useful in the hemodynamic evaluation of experimental arteriovenous shunting and may be used for future objective and quantitative monitoring during endovascular AVM embolotherapy.
Temporal Correlation Mapping Analysis of the Hemodynamic Penumbra in Mutant Mice Deficient in Endothelial Nitric Oxide Synthase Gene Expression
Authors: Lo Eng H. , Hara Hideaki , Rogowska Jadwiga , Trocha Marek , Pierce Allen R. , Huang Paul L. , Fishman Mark C. , Wolf Gerald L. , Moskowitz Michael A.
Published: June 2011

Background and Purpose
Mice containing deletions in the genes encoding nitric oxide (NO) synthase have been useful to dissect the role of NO in cerebral ischemia. We recently reported that mice lacking expression of the endothelial isoform of NO synthase (eNOS) develop larger infarcts after middle cerebral artery occlusion. Because NO or a related product of NO synthase activity is important for relaxation of cerebral blood vessels, we examined for possible hemodynamic differences in the peri-ischemic zone of eNOS-deficient and wild-type mice after middle cerebral artery occlusion using functional CT scanning techniques.

Methods
Wild-type SV129 mice (n=10) and mice deficient in eNOS gene expression (n=10) were subjected to middle cerebral artery occlusion under halothane anesthesia. Thirty minutes after ischemia, functional CT scanning was performed with dynamic scanning protocols to measure the cerebral transit profiles of injected contrast agents. A temporal correlation mapping technique was used to analyze the pattern of hemodynamic perturbations based on alterations in the shape of the cerebral transit profiles. Statistical thresholds defined the hemodynamic core and penumbra.

Results
Hemodynamic deficits were more severe in the mutant than wild-type mouse. When expressed as a percentage of the total insult, core areas were significantly increased in mutant mice (39.8±3.7%) compared with wild types (28.8±3.4%). Conversely, areas of the hemodynamic penumbra were significantly smaller in mice deficient in eNOS activity (60.2±3.7%) than in wild-type mice (71.2±3.4%). Furthermore, the calculated relative perfusion index within the hemodynamic penumbra was significantly lower in the group with eNOS gene deletion (35.6±1.5% in mutants versus 43.0±2.4% in wild types).

Conclusions
These data indicate that mice lacking eNOS expression show a greater degree of hemodynamic compromise after middle cerebral artery occlusion and suggest that a product of eNOS activity (eg, NO) may protect brain after focal cerebral ischemia, possibly by improving blood flow within the penumbral zone.
Acute Changes in Intracranial Pressure and Pressure-Volume Index After Forebrain Ischemia in Normoglycemic and Hyperglycemic Rats
Authors: Morimoto Yuji , Morimoto Yoshiko , Warner David S. , Pearlstein Robert D.
Published: June 2011

Background and Purpose
Hyperglycemia enhances the deleterious effect of global cerebral ischemia. One possible explanation is that increased anaerobic glycolysis leads to exaggeration of intracellular acidosis and increased postischemic edema. To examine the importance of this edema on postischemic cerebral perfusion dynamics, we measured acute changes in intracranial pressure (ICP), specific gravity, and the pressure-volume index (PVI) after forebrain ischemia in normoglycemic and hyperglycemic rats.

Methods
Rats underwent 15 minutes of forebrain ischemia and 90 minutes of reperfusion. ICP and mean arterial pressure were continuously monitored. Before ischemia, rats received either saline or glucose intravenously. Ninety minutes after ischemia, the specific gravity of the neocortex was measured. In a second experiment, the PVI was measured at 20 and 60 minutes after ischemia.

Results
Preischemic ICP (mean±SD) was 7±1 mm Hg in both groups. A peak ICP (≈11 mm Hg) occurred within 15 to 20 minutes after ischemia in both groups. Between 25 and 80 minutes after ischemia, ICP was significantly but only slightly greater in hyperglycemic than in normoglycemic rats. Cerebral perfusion pressure was similar between groups and remained greater than 100 mm Hg. Specific gravity was also similar for both groups but was less than normal values. The PVI in hyperglycemic rats was lower than in normoglycemic rats, indicating reduced compliance.

Conclusions
These findings indicate that hyperglycemia-augmented intraischemic tissue acidosis does not contribute to worsened outcome by means of compromised cerebral perfusion pressure during the early stages of recovery. Nevertheless, evidence was found for decreased cerebral compliance, indicating an effect of hyperglycemia on intracranial volume compartments other than cortical parenchyma.
History of Parental Death From Stroke or Heart Trouble and the Risk of Stroke in Middle-aged Men
Authors: Wannamethee S. Goya , Shaper A. Gerald , Ebrahim Shah
Published: June 2011

Background and Purpose
The purpose of this study was to determine the effect of a history of parental death from stroke or heart trouble on the risk of major stroke events (fatal and nonfatal) in middle-aged British men.

Methods
A prospective study was undertaken of 7735 middle-aged men, drawn at random from general practices in 24 British towns, who were followed up for an average of 14.8 (range, 13.5 to 16.0) years.

Results
In the 7683 men providing information on at least one of their parents, there were 278 major stroke events and 947 major ischemic heart disease events. A history of death from stroke or heart trouble in mother or father was associated with a significantly increased risk of stroke independent of other risk factors, including hypertension. The association is due almost entirely to an increased risk of nonfatal stroke. In comparison with men whose parents were still alive or who had no history of parental death from either heart trouble or stroke, the adjusted relative risk of stroke in men with a history of parental stroke death was 1.4 (95% confidence interval [CI], 1.1 to 2.0;
P
=.02), and in men with parental heart trouble death, the relative risk was 1.3 (95% CI, 1.0 to 1.7;
P
=.04). The positive relationships were present whether the parental death occurred before or after 70 years of age. A parental death from stroke was not associated with increased risk of an ischemic heart disease event, although the latter was significantly associated with a history of parental death from heart trouble.

Conclusions
Although factors such as hypertension and smoking are of major importance in the etiology of stroke, there is a link between a history of parental death from cardiovascular disease (stroke or heart trouble) and the risk of stroke that appears to be independent of the established risk factors.
Multigated Doppler Ultrasound in the Detection of Emboli in a Flow Model and Embolic Signals in Patients
Authors: Molloy Jane , Markus Hugh S.
Published: June 2011

Background and Purpose
The ability to detect asymptomatic circulating cerebral emboli may contribute to the management of patients with stroke, but its clinical usefulness will depend on effective systems for automatically detecting embolic signals (ES) and differentiating them from artifact. A new method involves the use of a multidepth probe that allows recording from both distal and proximal sample volumes along the same vessel. Theoretically, an embolus should appear sequentially, with a time delay, between the two channels, whereas an artifact should appear simultaneously in the two channels.

Methods
We evaluated this method in an in vitro flow model and in patients. In an in vitro model, with a flow pattern mimicking intracerebral flow, 181 air bubbles and 193 thrombus emboli were compared with the signals resulting from 368 episodes of artifact; a sample volume of 5 mm and a channel separation of 10 mm were used. ES from two groups of patients—those with carotid artery stenosis (141 ES) and those with mechanical prosthetic cardiac valves (125 ES)—were studied and compared with 222 episodes of artifact produced in the same patients.

Results
In the model the mean (SD) time delay was 17.32 (9.94) ms for air emboli and 17.78 (10.66) ms for thrombus emboli compared with −0.01 (0.39) ms for artifact (air and thrombus emboli versus artifact,
P
<.0001). A sensitivity of 100% and specificity of 100% were obtained when a cutoff of >2 ms was used for an embolus. The method allowed equally good detection of those air emboli that resulted in receiver overload and aliasing. In patients the mean (SD) time delay was 29.6 (28.2) ms for valve ES and 14.9 (15.42) for carotid ES compared with 0.00 (0.46) for artifact (carotid and valve ES versus artifact,
P
<.0001). Considering only those signals that were visible in both Doppler time domains resulted in a sensitivity for valve ES of 98.9% and for carotid ES of 94.0%, with a specificity of 99.0%. However, in one patient in the valve group some ES were visible only in the proximal channel, possibly because of passage of emboli down branch vessels between the two sample volumes. In addition, for the less intense carotid ES some signals were unclear or absent in one or both of the time domain signals at either depth, although visible in the post–fast Fourier transform spectra. Including those ES visible in only one channel reduced the sensitivity to 75.2% for valve ES and 92.6% for carotid ES.

Conclusions
The multigated technique offers a new method of detecting ES and differentiating them from artifact and is the first reliable method for differentiating intense ES resulting in receiver overload from artifact. Occasionally its sensitivity is reduced when ES do not appear in the distal channel, probably because they pass down a side branch; this may be reduced by reducing gate separation. Some less intense carotid ES can be difficult to detect if the amplitude increase is small compared with the amplitude of the background Doppler signal.
Serial Measurement of Interleukin-6, Transforming Growth Factor-β, and S-100 Protein in Patients With Acute Stroke
Authors: Kim Jong S. , Yoon Sung S. , Kim Yang H. , Ryu Jin S.
Published: June 2011

Background and Purpose
Cytokine changes in patients with acute stroke have been insufficiently studied. The purpose of this study was to delineate the characteristics of serial changes of serum interleukin-6 (IL-6) and transforming growth factor-β (TGF-β) in patients with cerebral infarction and intracerebral hemorrhage.

Methods
We serially (within 24 hours, at day 3, and at day 7) measured the serum levels of IL-6 and TGF-β in 29 patients with acute stroke (10 with large cortical cerebral infarction, 9 with subcortical small infarction, and 10 with intracerebral hemorrhage). As an index of brain damage, S-100 protein was also measured. Twelve age-matched healthy subjects were tested as a control.

Results
S-100 protein was detected in only 11 patients with large infarction or intracerebral hemorrhage. Its level peaked at day 3 in patients with infarction, whereas it peaked within 24 hours in those with intracerebral hemorrhage. The level of IL-6 was most markedly elevated at day 1, which tended to decrease thereafter. However, its level remained significantly elevated compared with that of the control group even at day 7. The level of TGF-β was significantly decreased at day 1 and day 3 and tended to return toward the control value thereafter. The levels of both cytokines were not significantly different among the three different stroke subtypes and were not correlated with the number of blood leukocytes and platelets.

Conclusions
The alteration of IL-6 and TGF-β levels, which occurs rapidly after acute stroke regardless of the subtype, may reflect the changing immunological-inflammatory status of these patients and does not appear to reflect merely the consequence of the brain damage.
Potentiation of Oxygen-Glucose Deprivation–Induced Neuronal Death After Induction of iNOS
Authors: Hewett Sandra J. , Muir Judith K. , Lobner Doug , Symons Amy , Choi Dennis W.
Published: June 2011

Background and Purpose
Previous studies have shown that brain ischemia and other insults can induce a marked increase in inducible nitric oxide synthase (iNOS) expression in astrocytes and some immune cells, but the biological significance of this phenomenon has not been elucidated. The purpose of the present study was to determine whether this induction of astrocyte iNOS alters neuronal vulnerability to severe hypoxic insults.

Methods
Astrocytic iNOS was induced by exposure of murine cortical cultures to interferon gamma in combination with either interleukin-1β or lipopolysaccharide. Cultures were exposed to combined oxygen-glucose deprivation. The extracellular concentration of glutamate was measured by high-performance liquid chromatography.
N
-Methyl-
d
-aspartate (NMDA) receptor activity was assessed by measurement of
45
Ca
2+
influx; neuronal death was assessed by morphological examination and quantitated by measurement of lactate dehydrogenase efflux to the bathing medium.

Results
In murine neocortical cell cultures containing neurons and astrocytes, neuronal injury induced by combined oxygen-glucose deprivation was not reduced by the addition of the nitric oxide synthase inhibitors
N
G
-nitro-
l
-arginine or
L
G
-nitro-arginine methyl ester. However, after induction of astrocyte iNOS activity with interferon gamma plus lipopolysaccharide or interleukin-1β, oxygen-glucose deprivation–induced neuronal injury was markedly enhanced and nitric oxide synthase inhibitors became protective. This iNOS-mediated potentiation was associated with a large increase in both extracellular glutamate accumulation and
45
Ca
2+
influx into neurons. The potentiation could be blocked by MK-801 but not CNQX, suggesting critical involvement of NMDA receptor activation.

Conclusions
These results support the idea that nitric oxide production mediated by induced astrocytic iNOS can potentiate NMDA receptor–mediated neuronal death consequent to hypoxic-ischemic insults.
Effects of Preischemic Hyperglycemia on Brain Damage Incurred by Rats Subjected to 2.5 or5 Minutes of Forebrain Ischemia
Authors: Li Ping-An , Kristián Tibor , Shamloo Mehrdad , Siesjö Bo K.
Published: June 2011

Background and Purpose
The objective of this study was to explore whether preischemic hyperglycemia, which is known to aggravate brain damage due to transient global or forebrain ischemia of intermediate duration (10 to 20 minutes), increases the density of selective neuronal necrosis, as observed primarily in the CA1 sector of the hippocampus after brief periods of forebrain ischemia in rats (2.5 and 5 minutes).

Methods
Anesthetized rats were subjected to two-vessel forebrain ischemia of 2.5- or 5-minute duration. Normoglycemic or hyperglycemic rats were either allowed a recovery period of 7 days for histopathological evaluation of neuronal necrosis in the hippocampus, isocortex, thalamus, and substantia nigra or were used for recording of extracellular concentrations of Ca
2+
([Ca
2+
]
e
), K
+
, or H
+
, together with the direct current (DC) potential.

Results
Ischemia of 2.5- or 5-minute duration gave rise to similar damage in the CA1 sector of the hippocampus in normoglycemic and hyperglycemic groups (10% to 15% and 20% to 30% of the total population, respectively). However, in hyperglycemic animals subjected to 2.5 minutes of ischemia, CA1 neurons never depolarized and [Ca
2+
]
e
did not decrease. In the 5-minute groups, the total period of depolarization was 2 to 3 minutes shorter in hyperglycemic than in normoglycemic groups. This fact and results showing neocortical, thalamic, and substantia nigra damage in hyperglycemic animals after 5 minutes of ischemia demonstrate that although hyperglycemia delays the onset of ischemic depolarization and hastens repolarization and extrusion of Ca
2+
, it aggravates neuronal damage due to ischemia.

Conclusions
These results reinforce the concept that hyperglycemia exaggerates brain damage due to transient ischemia and prove that this exaggeration is observed at the neuronal level. The results also suggest that the concept of the duration of an ischemic transient should be qualified, particularly if ischemia is brief, ie, <10 minutes in duration.
TGF-β1 Protects Hippocampal Neurons Against Degeneration Caused by Transient Global Ischemia
Authors: Henrich-Noack P. , Prehn J.H.M. , Krieglstein J.
Published: June 2011

Background and Purpose
Transforming growth factor-β1 (TGF-β1) has been shown to rescue cultured neurons from excitotoxic and hypoxic cell death and to reduce infarct size after focal cerebral ischemia in mice and rabbits. The present study investigated the effects of TGF-β1 in a different pathophysiological setting and the delayed neuronal death of hippocampal pyramidal cells after transient global ischemia in rats, and evaluated the potential mechanisms of the neuroprotective activity of TGF-β1.

Methods
Transient forebrain ischemia was induced in male adult Wistar rats with bilateral occlusion of both common carotid arteries combined with systemic hypotension for 10 minutes. Seven days after ischemia, brains were perfusion-fixed and stained for histological evaluation. TGF-β1 or vehicle was injected intracerebroventricularly (ICV; 0.5, 4, and 50 ng) or intrahippocampally (4 ng) 1 hour before ischemia. For in vitro studies, hippocampal neurons were derived from E17 rat embryos and cultured for 10 to 14 days. Cells were exposed to (1)
S
-nitrosocysteine (SNOC; 30 μmol/L) to induce nitric oxide–induced oxidative injury and (2) staurosporine (0.03 μmol/L) to induce apoptotic cell death.

Results
Transient forebrain ischemia caused extensive degeneration of CA1 hippocampal pyramidal cells in vehicle-treated control animals. Ischemic injury was not significantly reduced after ICV administration of 0.5 ng TGF-β1 (71±7% damaged neurons versus 84±3% in vehicle-treated controls; n=9 and 11, respectively;
P
=.07, Mann-Whitney
U
test). Administration of 4 ng TGF-β1 reduced the percentage of damaged CA1 pyramidal cells from 71±10% in controls to 52±7% in TGF-β1–treated animals (n=11 and 12, respectively;
P
=.04). TGF-β1 (4 ng) also produced significant protection when injected directly into the hippocampal tissue. In contrast, ICV administration of 50 ng TGF-β1 failed to show a protective effect in two separate sets of experiments. In vitro, a 24-hour pretreatment of the cultured hippocampal neurons with TGF-β1 (0.1 to 10 ng/mL) significantly inhibited both nitric oxide and staurosporine neurotoxicity. Posttreatment with TGF-β1 (10 ng/mL) also inhibited staurosporine neurotoxicity but actually potentiated nitric oxide–induced neuronal injury.

Conclusions
We demonstrated that TGF-β1 in a surprisingly low dose range has the capacity to reduce injury to CA1 hippocampal neurons caused by transient global ischemia in rats. This protective action could well be associated with the antioxidative and antiapoptotic effects of TGF-β1 demonstrated in vitro.
Inhibitory Effect of MS-153 on Elevated Brain Glutamate Level Induced by Rat Middle Cerebral Artery Occlusion
Authors: Umemura Kazuo , Gemba Takefumi , Mizuno Atsuhiro , Nakashima Mitsuyoshi
Published: June 2011

Background and Purpose
In this study we investigated the effects of a novel compound, MS-153 ([
R
]-[−]-5-methyl-1-nicotinoyl-2-pyrazoline), on elevated brain glutamate concentrations and cerebral infarct volume induced by middle cerebral artery (MCA) occlusion in the rat.

Methods
The rat MCA was occluded by a thrombus induced by a photochemical reaction between green light and the photosensitizer dye rose bengal, which causes endothelial injury followed by formation of a platelet- and fibrin-rich thrombus at the site of photochemical reaction; this method is routinely used in our laboratory to produce arterial occlusion in experimental animals. Extracellular glutamate concentration at the ischemic border zone was determined by a microdialysis technique. The size of cerebral infarction was measured by a histochemical technique 24 hours after MCA occlusion. MS-153 was administered at various doses as a continuous infusion for 24 hours, beginning 0 to 2 hours after MCA occlusion.

Results
At the ischemic border zone, the concentration of glutamate in the extracellular fluid increased by 40-fold after ischemia. At 3.13 mg/kg per hour, MS-153 reduced glutamate concentration (
P
<.05) and also the size of ischemic cerebral infarction (
P
<.05). Furthermore, the glutamate uptake inhibitor
dl
-
threo
-β-hydroxyaspartate reversed the effect of MS-153 on glutamate concentration.

Conclusions
The reduction in the size of cerebral infarction by MS-153 may be attributable to the inhibition of glutamate release or an increase in cellular glutamate uptake.
Effect of Age in Rodent Models of Focal and Forebrain Ischemia
Authors: Sutherland Garnette R. , Dix Gary A. , Auer Roland N.
Published: June 2011

Background and Purpose
The majority of animal experiments examining the nature and treatment of stroke have used relatively young animals ranging in age from 2 to 6 months. However, significant morphological, neurochemical, and behavioral changes occur with aging in rodents, particularly during the first 24 months of age. This study examines the effect of age in two models of transient ischemia, a forebrain and a focal model, in male Wistar rats.

Methods
We induced forebrain ischemia of 12 minutes' duration by bilateral carotid artery occlusion with controlled hypotension at a mean blood pressure of 45 mmHg and, using an intraluminal filament technique, induced focal middle cerebral artery occlusion of 100 minutes' duration at a mean blood pressure of 60 mm Hg. Physiological parameters were monitored and maintained within normal limits. On day 7 after ischemia, the rats were perfusion-fixed and the brains removed for quantitative histopathology.

Results
After forebrain ischemia, older rats showed significantly less CA1 neuronal necrosis than the younger group (
P
<.003), whereas both striatal and neocortical injury were significantly greater in the older group (
P
<.05). Among animals subjected to focal ischemia, the volume of infarcted tissue and the number of necrotic neurons in the area adjacent to the infarction were both greater in older rats (
P
<.05).

Conclusions
This study emphasizes the importance of age in models of forebrain and focal ischemia. The interaction between age-related changes in morphology, neurochemistry, and behavior on the ischemic cascade complicates the interpretation of mechanistic data, and pharmacological effects observed in younger animals may not necessarily translate to an older population.
Prevalence of Asymptomatic Retinal Emboli in an Australian Urban Community
Authors: Mitchell Paul , Wang Jie Jin , Li Weining , Leeder Stephen R. , Smith Wayne
Published: June 2011

Background and Purpose
Because no population-based estimates are available for asymptomatic retinal emboli, we aimed to assess prevalence and associations of this sign in a defined older Australian urban population.

Methods
A total of 3654 persons aged 49 years or older, representing 82% of residents in an urban area west of Sydney, underwent a detailed eye examination that included medical history, stereo retinal photography, and fasting blood tests including lipids. Retinal emboli were diagnosed clinically and from photographic grading and classified as cholesterol, platelet-fibrin, or calcific in type.

Results
Asymptomatic retinal emboli were found in 51 participants (1.4%; 95% confidence interval [CI], 1.0% to 1.8%). The prevalence was 0.8% in persons aged <60 years, 1.4% for those aged 60 to 69 years, 2.1% for those aged 70 to 79 years, and 1.5% for those aged 80 years or older. Men had a significantly higher prevalence (2.2%) of retinal emboli than women (0.8%,
P
<.001) after adjustment for age (odds ratio [OR], 2.7; 95% CI, 1.5 to 4.8). Forty-one emboli (80%) were cholesterol type, 7 (14%) were platelet-fibrin, and 3 (6%) were calcific. Significant associations were found after age-sex adjustment, with hypertension (OR, 2.2; 95% CI, 1.2 to 3.8), a combined history of vascular disease (OR, 2.4; 95% CI, 1.3 to 4.4), past vascular surgery (OR, 3.5; 95% CI, 1.4 to 8.5), and current (OR, 2.2; 95% CI, 1.1 to 4.2) or any (OR, 2.6; 95% CI, 1.2 to 4.3) smoking history. These associations persisted after multivariate analysis. There were no significant associations with diabetes, obesity, or fasting blood test findings.

Conclusions
This study provides accurate prevalence rates for asymptomatic retinal emboli in the elderly and confirms associations with hypertension, smoking, and vascular disease.
Thromboembolism Prophylaxis in Chronic Atrial Fibrillation
Authors: Munschauer F.E. , Priore R.L. , Hens M. , Castilone A.
Published: June 2011

Background and Purpose
By 1992, several prospective trials established the efficacy of anticoagulation (AC) and to some extent antiplatelet (AP) agents in the prevention of stroke in the setting of atrial fibrillation (AF). The objective of this study was to determine whether practice patterns in AF stroke prophylaxis reflect the findings of clinical trials and whether stroke prophylaxis in AF differs between community hospitals and tertiary teaching hospitals.

Methods
Retrospectively, 1250 hospital charts were reviewed. After patients who had undergone recent surgery, received treatment for malignancy, or were not in chronic AF on discharge were eliminated, 651 remaining records were analyzed for the presence of 26 clinical factors influencing the selection of thromboembolism prophylaxis. Descriptive statistics and logistic regression were used to analyze the association between clinical and demographic factors and the decision to treat with AC, AP, or no specific antiembolic therapy.

Results
Of the 651 patients in AF, 273 (42%) received no emboli prophylaxis while 219 (34%) were treated with AC (warfarin), 146 (22%) were treated with AP, and 13 (2%) received both agents. Patients discharged in AF from community hospitals were significantly less likely to be treated with either AC or AP agents than patients discharged from tertiary centers. A strong bias against thromboembolism prophylaxis with either AC or AP agents in AF existed with age over 45 years. Multivariate logistic regression indicated that the decision to treat was associated only with the presence of prosthetic valve, history of prior stroke, mitral disease, and absence of a recent gastrointestinal bleed or occult blood in stool. Even after adjustment for these factors, a significant bias against treatment with either AC or AP agents with advancing age and discharge from community hospitals remained.

Conclusions
Thromboembolism prophylaxis with either AC or AP agents is underutilized in the setting of AF. Furthermore, factors known to increase the risk of embolization in AF such as age, hypertension, diabetes, and heart disease were not associated with decisions to treat with either AP or AC agents. This study suggests that the use of clinical guidelines suggested by trials of thromboembolism prophylaxis in AF could reduce the incidence of stroke.
Cerebral Aneurysms in the Elderly in Yamaguchi, Japan
Authors: Yamashita Katsuhiro , Kashiwagi Shiro , Kato Shoichi , Takasago Teiichi , Ito Haruhide
Published: June 2011

Background and Purpose
The number of elderly people is markedly increasing in Japan. We have investigated the epidemiology and management outcome of cerebral aneurysms in elderly patients aged ≥70 years.

Methods
A total of 3100 patients were enrolled in the Yamaguchi Data Bank of Cerebral Aneurysm between 1985 and 1995. Of these, 598 with ruptured cerebral aneurysms and 120 with unruptured cerebral aneurysms were elderly (ie, aged ≥70 years).

Results
The number of elderly patients with cerebral aneurysms has markedly increased since 1991, and in 1995 approximately 30% of all patients with cerebral aneurysms were elderly. In cases of ruptured cerebral aneurysms, the proportion of patients with severe neurological grade did not change and that with an unfavorable outcome did not decrease throughout the 11 years. The proportion of patients with severe neurological grade in the elderly group was higher than in the younger group (<70 years), and the management outcome of elderly patients for each neurological grade on admission was worse than that of younger patients (
P
<.01). However, the incidence rate of symptomatic cerebral vasospasm and rebleeding was the same for the two age groups. Eventually, 60.4% of all elderly patients with ruptured cerebral aneurysms had an unfavorable outcome. In cases of unruptured cerebral aneurysms, 63.3% of the selected elderly patients were surgically treated, and the surgical morbidity and mortality rates were 26.3% and 4.0%, respectively. These rates were nonsignificantly higher than those for younger patients.

Conclusions
The number of elderly patients with cerebral aneurysms has markedly increased in Yamaguchi. Because of the unsatisfactory management outcome of ruptured cerebral aneurysms and surgical outcome of unruptured cerebral aneurysms in elderly patients during the 11-year period, we propose the treatment of unruptured cerebral aneurysms at a younger age and the use of a screening system to detect these subjects.
Subcortical Hypoperfusion Associated With Asymptomatic White Matter Lesions on Magnetic Resonance Imaging
Authors: Hatazawa Jun , Shimosegawa Eku , Satoh Takao , Toyoshima Hideto , Okudera Toshio
Published: June 2011

Background and Purpose
We examined whether hemodynamic and metabolic abnormalities in the cerebral white matter, basal ganglia, and thalamus are associated with asymptomatic white matter lesions (WML) depicted on MR images.

Methods
A positron emission tomographic study with H
2
15
O, C
15
O, and
15
O
2
was performed in eight normal control subjects without any WML (mean±1 SD age, 68.5±10.2 years) and in 15 asymptomatic subjects with WML (71.3±8.5 years) to measure regional cerebral blood flow (CBF), cerebral blood volume, oxygen extraction fraction (OEF), and oxygen metabolic rate.

Results
In the cerebral white matter in the asymptomatic subjects with WML, significantly lower CBF (20.3±3.9 mL/100 mL per minute;
P
<.05) and significantly higher OEF (0.43±0.08;
P
<.05) were found compared with those for control subjects (23.5±2.6 mL/100 mL per minute and 0.37±0.06, respectively). The severity of WML was not related to the magnitude of hypoperfusion. In the basal ganglia, significantly lower CBF (44.9±6.9 mL/100 mL per minute;
P
<.01) and significantly higher OEF (0.54±0.08;
P
<.01) were found in the WML group than in control subjects (70.1±12.0 mL/100 mL/min and 0.39±0.03, respectively). In the thalamus, there was no significant difference in CBF and OEF between the control and WML groups.

Conclusions
Hypoperfusion of the cerebral white matter and basal ganglia in asymptomatic WML subjects may be induced by the arteriosclerosis of long penetrating medullary arteries and lenticulostriate arteries but may not be directly related to the production of WML. The role of hypoperfusion in the production of WML and acceleration of its development remains to be elucidated.
Activated Microglial Cells Are Colocalized With Perivascular Deposits of Amyloid-β Protein in Alzheimer’s Disease Brain
Authors: Uchihara Toshiki , Akiyama Haruhiko , Kondo Hiromi , Ikeda Kenji
Published: June 2011

Background and Purpose
Microglial cells are present in the center of senile plaques (SPs) in Alzheimer’s disease (AD) brain. Such a localization of microglial cells suggests that they are involved in the deposition or the clearance of amyloid-β protein (Aβ) in the brain. We examined their association with another type of parenchymal Aβ deposit, which is termed the perivascular deposits of Aβ (PAβ).

Methods
Thick sections from AD brain were stained with a three-color immunofluorescence method that labeled Aβ, activated microglial cells, and vascular endothelial cells simultaneously.

Results
Three-dimensional observation under a laser scanning microscope confirmed that perivascular aggregates of activated microglial cells were colocalized with PAβ.

Conclusions
Microglia occur in association with both SPs and PAβ, suggesting that they play important roles in the metabolism of Aβ in AD brain.
Cerebral Microembolic Signals During Cardiopulmonary Bypass Surgery
Authors: Brækken Sigrun K. , Russell David , Brucher Rainer , Abdelnoor Michel , Svennevig Jan L.
Published: June 2011

Background and Purpose
We sought to determine the number of cerebral microembolic signals (MES) and their time of occurrence during the two most frequent types of cardiopulmonary bypass (CPB) surgery: coronary artery bypass grafting (CABG) and cardiac valve replacement (VR). Furthermore, we sought to examine the association between MES, patient characteristics, and intraoperative parameters.

Methods
Forty-two patients were studied, 15 of whom had CABG and 27 VR. Cerebral MES were detected with the use of transcranial Doppler monitoring of the right middle cerebral artery.

Results
Cerebral MES were detected in all patients. The number was significantly higher during VR (median, 1048) than during CABG (median, 82) (
P
<.001). In VR patients, 85% of the MES were detected when the heart regained effective ejection. During CABG, the highest number was detected when the aorta was cross-clamped (18%) and on release of the side clamp (13%). The numbers of MES during the period when the aorta was cross-clamped and in association with surgical procedures were not significantly different in the two patient groups. The total number of MES was inversely correlated to nasopharyngeal temperature (
P
<.01).

Conclusions
A significantly higher number of cerebral MES were detected during VR than during CABG. The highest number occurred in VR patients when effective heart ejection was regained and in CABG patients when the aorta was cross-clamped and on release of the side clamp. The total number of MES increased at lower nasopharyngeal temperatures. Transcranial Doppler monitoring may alert the surgical team when emboli enter the cerebral circulation during CPB surgery, thus allowing preventive measures to be taken.
Cell Death Suggestive of Apoptosis After Spinal Cord Ischemia in Rabbits
Authors: Mackey Mary E. , Wu Yingji , Hu Rong , DeMaro Joseph A. , Jacquin Mark F. , Kanellopoulos Georgios K. , Hsu Chung Y. , Kouchoukos Nicholas T.
Published: June 2011

Background and Purpose
After spinal cord ischemia, some neurons remain viable after an ischemic insult but may be at risk of dying during reperfusion. We searched for morphological and biochemical features of apoptosis, which is a mechanism of delayed neuronal death, in a rabbit model of spinal cord ischemia.

Methods
The infrarenal aorta of White New Zealand rabbits (n=24) was occluded for 40 minutes using a loop tourniquet. Rabbits were killed after 12, 24, or 48 hours (n=8 per group). The loop was placed but never tightened in sham-operated rabbits (n=6). The lumbar segment of the spinal cord (L5 to L7) was used for morphological studies, including hematoxylin and eosin staining and a modified terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining method. Electron microscopy was used to examine ultrastructural morphology. In addition, lumbar tissue was used for biochemical investigation of DNA laddering by agarose gel electrophoresis.

Results
After ischemia, the affected areas contained neurons with positive TUNEL staining. Positive neurons were located in laminae III to IX, although most were concentrated in the intermediate and ventral areas. Adjacent sections stained with hematoxylin and eosin exhibited ischemic cell changes (red and ghost neurons), while apoptotic bodies were also apparent. In addition, electron microscopy of ischemic tissue samples exhibited ultrastructural characteristics of apoptosis, including nuclear condensation and relatively normal organelle morphology. Finally, isolated DNA revealed a ladder on agarose gel electrophoresis, indicating DNA fragmentation into ≈180 multiples of base pairs.

Conclusions
Spinal cord ischemia in rabbits induces morphological and biochemical changes suggestive of apoptosis. These data raise the possibility that apoptosis contributes to neuronal cell death after spinal cord ischemia.
Horseradish Peroxidase as a Histological Indicator of Mechanisms of Porcine Retinal Vascular Damage and Protection With Perfluorocarbons After Massive Air Embolism
Authors: Herren Janelle I. , Kunzelman Karyn S. , Vocelka Craig , Cochran R. P. , Spiess Bruce D.
Published: June 2011

Background and Purpose
This laboratory has previously shown that a second-generation perfluorocarbon emulsion (PFE) reduces the severity of cerebral injury induced by air embolism during cardiopulmonary bypass (CPB). Horseradish peroxidase examines vascular permeability and was used in this study of the mechanisms of cellular protection afforded by the PFE.

Methods
Twenty domestic pigs underwent CPB with a prime of standard crystalloid or PFE (5 mg/kg) and crystalloid. After 10 minutes on CPB, a 5-mL/kg bolus of room air or saline (control) was delivered via the right carotid artery. The air insult was delivered as either a single bolus or double bolus. After 1 hour of CPB and 1 hour of spontaneous reperfusion, horseradish peroxidase was injected intravenously and circulated for 15 minutes. After euthanasia, both eyes were removed, and the retinas were isolated for histological analysis.

Results
Total length of retinal vessels exhibiting horseradish peroxidase extravasation was significantly less in PFE pigs (
P
<.05). Vascular spasm and red blood cell hemorrhages were unaffected by PFE. PFE pigs exhibited mild to moderate vascular nonperfusion and red blood cell sludging; crystalloid groups demonstrated severe nonperfusion and sludging.

Conclusions
Histological staining with horseradish peroxidase indicated that mechanisms of cerebral air embolism include vascular endothelial leakage, vascular nonperfusion, and red blood cell sludging and hemorrhage. Pretreatment with PFE prevented some sequelae associated with massive air embolism and CPB.
Relation of Lesion Location to Verbal and Nonverbal Mood Measures in Stroke Patients
Authors: Gainotti Guido , Azzoni Antonella , Gasparini Francesca , Marra Camillo , Razzano Carmelina
Published: June 2011

Background and Purpose
The aim of the present study was to evaluate the relation between poststroke depression and lesion location, avoiding previous methodological shortcomings. In particular, we intended to determine whether patients with left frontal lesions showed the highest depression scores.

Methods
Patients in the study, categorized on the basis of lesion location, included 149 stroke patients with lesions located in the anterior, central, or posterior regions of the right or left hemisphere. Verbal and nonverbal mood measures as well as the Hamilton Depression Scale Overall Score were the dependent measures of our investigation. Furthermore, the number of patients who could not be assessed or could be evaluated only with the nonverbal mood measure due to the presence of severe language disorders was recorded.

Results
No significant relation was observed between depressed mood and lesion location. Approximately one quarter of the left brain–damaged patients were partially or totally excluded from the study because of severe language disorders.

Conclusions
Our data appeared to show that when methodological pitfalls and selection bias are carefully controlled, left frontal lesions are not a major determinant of poststroke depression.
Influence of Oxygen Ventilation on Doppler Microemboli Signals in Patients With Artificial Heart Valves
Authors: Georgiadis D. , Wenzel A. , Lehmann D. , Lindner A. , Zerkowski H.R. , Zierz S. , Spencer M.P.
Published: June 2011

Background and Purpose
The purpose of this study was to evaluate the influence of inhalation of 100% oxygen on microembolic signal (MES) counts in patients with artificial cardiac valves.

Methods
A total of 134 outpatients were examined. Transcranial Doppler baseline monitoring (45-minute duration) was performed in all patients under resting conditions. The first 30 patients subsequently underwent transcranial Doppler monitoring for at least 20 minutes under noninvasive positive pressure ventilation with 100% oxygen and for an additional 30 minutes under resting conditions. The same protocol was applied to all following patients with a baseline MES count ≥10, while the examination was discontinued in the remaining patients.

Results
Baseline MES counts <10, which remained unchanged during oxygen inhalation and the subsequent resting period, were observed in 26 of 30 initial patients. A total of 46 patients with MES counts ≥10 were identified. Oxygen application was feasible in 43 patients. An exponential MES decrease was noted in 42 patients during oxygen inhalation (statistically significant in 38 patients), followed by a subsequent increase in 38 of 43 patients (statistically significant in 25 patients) under resting conditions.

Conclusions
The exponential reduction of MES counts observed in this study corresponds to blood denitrogenation, thus strongly arguing for nitrogen bubbles as underlying embolic material in prosthetic valve carriers.