We previously evaluated the short-term follow-up preliminary data of mesenchymal stem cells (MSCs) transplantation in patients with ischemic stroke. The present study was conducted to evaluate the long-term safety and efficacy of i.v. MSCs transplantation in a larger population. To accomplish this, we performed an open-label, observerblinded clinical trial of 85 patients with severe middle cerebral artery territory infarct. Patients were randomly allocated to one of two groups, those who received i.v. autologous ex vivo cultured MSCs (MSC group) or those who did not (control group), and followed for up to 5 years. Mortality of any cause, long-term side effects, and new-onset comorbidities were monitored. Of the 52 patients who were finally included in this study, 16 were the MSC group and 36 were the control group. Four (25%) patients in the MSC group and 21 (58.3%) in the control group died during the follow-up period, and the cumulative surviving portion at 260 weeks was 0.72 in the MSC group and 0.34 in the control group (log-rank; p 5 .058). Significant side effects were not observed following MSC treatment. The occurrence of comorbidities including seizures and recurrent vascular episodes did not differ between groups. When compared with the control group, the follow-up modified Rankin Scale (mRS) score was decreased, whereas the number of patients with a mRS of 0-3 increased in the MSC group (p 5 .046). Clinical improvement in the MSC group was associated with serum levels of stromal cell-derived factor-1 and the degree of involvement of the subventricular region of the lateral ventricle. Intravenous autologous MSCs transplantation was safe for stroke patients during long-term follow-up. This therapy may improve recovery after stroke depending on the specific characteristics of the patients. STEM

Parkinson's disease (PD) is a common, progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra (SN). Numerous studies have provided evidence suggesting that neuroinflammation plays an important role in the pathogenesis of PD. In this study, we used lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models to investigate whether human mesenchymal stem cells (hMSCs) have a protective effect on the dopaminergic system through anti-inflammatory mechanisms. The hMSC treatment significantly decreased LPS-induced microglial activation, tumor necrosis factor (TNF)-a, inducible nitric oxide synthase (iNOS) mRNA expression, and production of NO and TNF-a compared with the LPS-only treatment group. In co-cultures of microglia and mesencephalic dopaminergic neurons, hMSC treatment significantly decreased the loss of tyrosine hydroxylase-immunopositive (TH-ip) cells. The hMSC treatment in rats showed that TH-ip neuronal loss induced by LPS stimulation in the SN was considerably decreased and was clearly accompanied by a decrease in activation of microglia, as well as TNF-a and iNOS mRNA expression and production of TNF-a. These data suggest that hMSCs have a neuroprotective effect on dopaminergic neurons through anti-inflammatory actions mediated by the modulation of microglial activation. Along with various trophic effects and trans-differentiational potency, the anti-inflammatory properties of MSCs could have major therapeutic implications in the treatment of PD. V V C

Object The clinical features of blood blister–like aneurysms (BBAs) that arise at nonbranching sites of the internal carotid artery (ICA) differ from those of saccular aneurysms. In this study, the authors attempt to describe optimal treatments for BBAs, which have yet to be clearly established. Methods Ten of 483 patients with aneurysmal subarachnoid hemorrhage who had been seen at the authors’ institution between March 2001 and June 2005 had intraoperatively confirmed BBAs at nonbranching sites of the ICA. All ten patients were women between the ages of 37 and 64 years (mean age 49.3 years); five had a history of hypertension. The BBAs were localized to the right side of the ICA in seven cases. All patients were successfully treated; clipping was undertaken in six, clipping combined with wrapping in three, and trapping in one. These methods were used in conjunction with various other surgical techniques such as brain relaxation by draining cerebrospinal fluid, anterior clinoidectomy, exposing the cervical ICA, gentle subpial dissection (for aneurysms that adhered to the frontal lobe), complete trapping of the ICA before clipping, and protecting the brain. Clip slippage occurred at the end of dural closing in two cases; the aneurysm was completely obliterated using multiple clips combined with ICA stenosis in one of these cases and ICA trapping with good collateral flow in the other. An excellent clinical outcome was achieved in eight patients, whereas two patients were disabled from massive vasospasm. The authors retrospectively reviewed radiological and surgical data in all cases to determine which treatment methods produced a favorable outcome. Conclusions Blood blister–like aneurysms located at nonbranching sites of the ICA are difficult to treat. Preoperative awareness and careful consideration of these lesions during surgery can prevent poor clinical outcomes.

Parkinson’s disease is a common progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra. We investigated whether cell therapy with human mesenchymal stem cells (hMSCs) had a protective effect on progressive dopaminergic neuronal loss in vitro and in vivo. In primary mesencephalic cultures, hMSCs treatment significantly decreased MG‐132‐induced dopaminergic neuronal loss with a significant reduction of caspase‐3 activity. In rats received systemic injection of MG‐132, hMSCs treatment in MG‐132‐treated rats dramatically reduced the decline in the number of tyrosine hydroxylase (TH)‐immunoreactive cells, showing an approximately 50% increase in the survival of TH‐immunoreactive cells in the substantia nigra compared with the MG‐132‐treated group. Additionally, hMSC treatment significantly decreased OX‐6 immunoreactivity and caspase‐3 activity. Histological analysis showed that the number of NuMA‐positive cells was 1.7% of total injected hMSCs and 35.7% of these cells were double‐stained with NuMA and TH. Adhesive‐removal test showed that hMSCs administration in MG‐132‐treated rats had a tendency to decrease in the mean removal time. This study demonstrates that hMSCs treatment had a protective effect on progressive loss of dopaminergic neurons induced by MG‐132 in vitro and in vivo. Complex mechanisms mediated by trophic effects of hMSCs and differentiation of hMSCs into functional TH‐immunoreactive neurons may work in the neuroprotective process.

Although ex vivo culture expansion is necessary to use autologous mesenchymal stem cells (MSCs) in treating stroke patients, and several researchers have utilized culture-expanded cells in their studies, the effects of culture expansion on neurogenesis and trophic support are unknown. Thus, we evaluated the impact of the passage of MSCs on their effects in a rat stroke model. The IV application of ex vivo-cultured human MSCs, earlier (passage 2) or later passage (passage 6), was performed in a rat stroke model. Behavioral tests, immunohistochemical studies, and quantitative analysis using the CAST-grid system were performed to evaluate the degree of neurogenesis. We also evaluated the levels of trophic factors in both control and MSC-treated rat brain extract. Compared to rats that received later-passage human MSCs, behavioral recovery and neurogenesis as revealed by bromodeoxyuridine staining were more pronounced in rats that received earlier-passage human MSCs (p < 0.01 in both cases). Double staining showed that most of the endogenous neuronal progenitor cells, but few human MSCs, expressed neuronal and glial phenotypes. Tissue levels of trophic factors, including glial cell line-derived neurotrophic factor, nerve growth factor, vascular endothelial growth factor, and hepatocyte growth factor, were higher in earlier-passage MSC-treated brains than in control or later-passage MSC-treated brains (p < 0.01 in all cases). Our results indicate that ischemia-induced neurogenesis was enhanced by the IV administration of human MSCs. The effects were more pronounced with earlier-passage than with later-passage human MSCs, which may be related to the differential capacity in trophic support, depending on their passage.