Although mononuclear cells (MNCs) from bone marrow are being investigated in phase I clinical trials in stroke patients, dose response, therapeutic time window and biodistribiton have not been well-characterized in animal stroke models. Long Evans rats underwent common carotid artery/middle cerebral artery occlusion (CCA/MCAo) and 24 hrs later were randomized to receive saline IV or a bone marrow aspiration followed by an IV infusion of autologous separated MNCs (1 million, 10 million or 30 million cells/kg). In another experiment, rats underwent CCAo/MCAo and were randomized at 24 hrs, 72 hrs or 7 days after stroke to receive a saline injection or 10 million/kg MNCs. All animals were evaluated on the cylinder and corner tests up to 28 days. MNCs were tracked using Q-dot nanocrystals to monitor biodistribution. Animals treated with MNCs at 10 million and 30 million cells/kg at 24 hrs after stroke had significant reductions in neurological deficits and lesion size compared to saline controls or animals treated with 1 million cells/kg. There was no difference in neurological deficits in the 10 and 30 million cell/kg groups at 28 days. Animals treated with MNCs at 72 hrs but not at 7 days showed a significant reduction in neurological deficits by 28 days. Labeled MNCs were found in the brain, spleen, lung, liver, and kidney at 1 hr and exponentially decreased over the ensuing week. In conclusion, we found a maximum reduction in neurological deficits at 10 and 30 million cells/kg and a therapeutic time window up to 72 hrs after stroke.
RATIONALE : Preclinical work demonstrates that the transcription factor peroxisome proliferator-activated receptor gamma plays an important role in augmenting phagocytosis while modulating oxidative stress and inflammation. We propose that targeted stimulation of phagocytosis to promote efficient removal of the hematoma without harming surrounding brain cells may be a therapeutic option for intracerebral hemorrhage. AIMS : The primary objective is to assess the safety of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in increasing doses for three-days followed by a maintenance dose, when administered to patients with spontaneous intracerebral hemorrhage within 24 h of symptom onset compared with standard care. We will determine the maximum tolerated dose of pioglitazone. STUDY DESIGN : This is a prospective, randomized, blinded, placebo-controlled, dose-escalation safety trial in which patients with spontaneous intracerebral hemorrhage are randomly allocated to placebo or treatment. The Continual Reassessment Method for dose finding is used to determine the maximum tolerated dose of pioglitazone. Hematoma and edema resolution is evaluated with serial magnetic resonance imaging (MRI) at specified time points. Functional outcome will be evaluated at three- and six-months. OUTCOMES : The primary safety outcome is mortality at discharge. Secondary safety outcomes include mortality at three-months and six-months, symptomatic cerebral edema, clinically significant congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Radiographic outcomes will explore the time frame for resolution of 25%, 50%, and 75% of the hematoma. Clinical outcomes are measured by the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, modified Rankin Scale, Stroke Impact Scale-16, and EuroQol at three- and six-months.
Background and Purpose
Perfusion computerized tomography (PCT) has been used to assess the extent of blood brain barrier (BBB) breakdown. The purpose of this study was to determine the predictive value of (BBB) permeability (BBBP) measured using PCT for development of malignant middle cerebral artery infarction (MMCA) requiring hemicraniectomy (HC).
Methods
We retrospectively identified patients from our stroke registry that had MCA infarction and were evaluated with admission PCT. BBBP and cerebral blood volume (CBV) maps were generated and infarct volumes calculated. Clinical and radiographic characteristics were compared between those who underwent HC versus those who did not undergo hemicraniectomy (NHC).
Results
122 patients (12 (HC), 110 (NHC)) were identified. 12 patients who underwent HC had developed edema, midline shift or infarct expansion. Infarct permeability area (IParea), infarct CBV area (ICBVarea), and infarct volumes were significantly different (p<0.018, p<0.0211, p<0.0001, p<0.0014) between HC and NHC groups. Age (p=0.03) and admission National Institutes of Health Stroke Scale (NIHSS) (p=0.0029) were found to be independent predictors for HC. Using logistic regression modeling, there was an association between increased IParea and HC. The odds ratio for HC based on a 5, 10, 15 or 20 cm2 increase in IParea were 1.179, 1.390, 1.638 or 1.932, respectively (95% CI 1.035-1.343, 1.071-1.804, 1.108-2.423, 1.146-3.255).
Conclusion
Increased IParea is associated with an increased likelihood for undergoing HC. Since early HC for MMCA has been associated with better outcomes, the IParea on admission PCT might be a useful tool to predict MMCA and need for HC.
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