Effects of Surgery and Antiplatelet Therapy in Ten-Year Follow-Up from the Registry Study of Research Committee on Moyamoya Disease in Japan.

BACKGROUND: Despite the common practice of surgery and antiplatelet therapy for the prevention of recurrent stroke in patients with moyamoya disease, the benefit of these treatments is controversial. We analyzed the stroke recurrence rate in the Registry Study of Research Committee on Moyamoya Disease in Japan funded by the Health, Labor and Welfare Ministry of Japan. METHODS: An annual follow-up study of the registered cases was continued for 10 years. The rate of recurrent stroke, including cerebral infarction and hemorrhage but not transient ischemic attack and seizure, was evaluated with Kaplan-Meier analysis. RESULTS: The proportion of childhood-onset cases decreased in recently registered cases (within 10 years, n = 541) compared to remote cases (> 10 years, n = 735). Among types at disease onset in adult-onset cases, intracerebral hemorrhage decreased recently. In recent cases, the rate of subsequent cerebral hemorrhage was much higher in the hemorrhagic group (10.9 ± 3.3%/5 years) than in the ischemic group (2.0 ± .9%/5 years). The recurrence rate of cerebral infarction was lower in the surgery group (1.8 ± .9%/5 years) than in the nonsurgery group (3.8 ± 2.2%/5 years). In the adult-onset ischemic group, the proportion of surgically treated patients increased and their recurrence rate was lower than that of nonsurgery patients. In the ischemic group, the rate of cerebral infarction was not significantly different between the antiplatelet subgroup and the non-antiplatelet subgroup, whereas the rate of cerebral hemorrhage was higher in the non-antiplatelet subgroup than in the antiplatelet subgroup. CONCLUSIONS: Our results suggest revascularization surgery may suppress recurrent ischemic attacks in patients with moyamoya disease.

Discrepancy between voluntary movement and motor-evoked potentials in evaluation of motor function during clipping of anterior circulation aneurysms.

BACKGROUND: Various modalities have been used to confirm the blood flow through parent arteries or surrounding perforating arteries during surgical aneurysm clipping, including motor-evoked potentials (MEPs), Doppler ultrasound, and indocyanine green videoangiography. Nonetheless, contralateral hemiparesis due to arterial blood flow insufficiency may arise because of false-positive or false-negative errors. By performing controlled intraoperative awakening during aneurysm clipping, we compared patients' voluntary movements with simultaneous MEP. METHODS: Four patients with anterior choroidal artery aneurysms and one patient with a dorsal internal carotid artery aneurysm were included in this study. MEP and intraoperative voluntary movements under awake craniotomy were assessed simultaneously during and after the clipping procedure. RESULTS: Aneurysms were safely and successfully clipped in all patients, with no evidence of postoperative neurological deficits. Voluntary movements and MEP findings did not differ from the control state in three patients. In the other two patients, we observed a discrepancy between MEP amplitudes and voluntary movements. In one patient, deterioration and subsequent improvement in voluntary movements were preceded by MEP amplitude reduction during clipping. In the other patient, MEP amplitude did not change although voluntary movement deteriorated during temporary occlusion of the internal carotid artery. CONCLUSIONS: Intraoperative neurological assessment during aneurysmal clipping under awake craniotomy is feasible and safe, and should be valuable for the assessment of ischemia, especially in the anterior choroidal artery. From a neurophysiologic viewpoint, MEP may be insufficiently sensitive for evaluating voluntary movement under ischemia.

Hybrid operating room for the treatment of complex neurovascular and brachiocephalic lesions.

BACKGROUND: We examine the impact of the installation of integrated hybrid operating rooms (ORs) that allow both surgical and endovascular procedures and are designed for less invasive and 1-stage treatment of complex neurovascular lesions. METHODS: We retrospectively analyzed our experience in the treatment of complex neurovascular lesions in a hybrid OR. RESULTS: Three patients with distal middle cerebral artery (MCA) aneurysms underwent a proximal clip occlusion or endovascular trapping with a superficial temporal artery-MCA bypass after correct localization of the recipient branch distal to the aneurysm using superselective intra-arterial infusion of indocyanine green under an operating microscope. Two patients with innominate artery stenosis were treated with retrograde stenting from the common carotid artery (CCA) with distal protection of the internal carotid artery (ICA) alone, and with antegrade stenting with dual protection of the ipsilateral ICA and the vertebral artery. Two patients with tandem stenosis of the proximal CCA and carotid bifurcation underwent 1-stage retrograde stenting combined with a carotid endarterectomy. A patient with the innominate artery and the proximal CCA stenosis underwent staged percutaneous antegrade angioplasty of the innominate artery followed by retrograde stenting of both lesions. A patient with tandem stenosis of the subclavian and innominate arteries underwent 1-stage retrograde stenting. In 2 patients with carotid stenosis that was difficult to access via the endovascular route, carotid stenting was performed by direct puncture of the proximal CCA. No patients suffered from new postoperative neurologic deficits. CONCLUSIONS: The integration of a high-end hybrid OR enables combined endovascular and surgical procedures for complex neurovascular and brachiocephalic lesions in a 1-stage treatment.

Surgical treatment of Spetzler-Martin grade III to V cerebral arteriovenous malformations: 10 years experience in Kyoto University.

Cerebral arteriovenous malformations (AVMs) are abnormal connections between arteries and veins leading to arteriovenous shunting with nidus formation. This study reviewed the clinical outcomes of surgical treatment for AVMs of Spetzler-Martin grades III to V in our institute. In addition, we summarized the technical aspects of surgical treatment for cerebral AVMs. Our development of the surgical modality for high-grade AVMs included intraoperative digital subtraction cerebral angiography, non-stick bipolar forceps, magnetic resonance tractography, and indocyanine green videoangiography. Excellent outcomes were obtained, but about 40% of all patients with AVMs could not receive surgical treatment. Multimodality approach including Onyx embolization may extend the surgical indications.

Cerebral blood flow and metabolism of hyperperfusion after cerebral revascularization in patients with moyamoya disease.

In moyamoya disease (MMD), surgical revascularization may be complicated with postoperative hyperperfusion. We analyzed cerebral perfusion and metabolism using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) before and after bypass surgery on 42 sides of 34 adult patients with MMD. In seven cases (16.7%) with symptomatic hyperperfusion, diagnosed by qualitative (123)I-iodoamphetamine (IMP) SPECT, a subsequent PET study during postoperative subacute stages revealed significantly increased cerebral blood flow (CBF) from 34.1 ± 8.2 to 74.3 ± 12.8 mL/100 g per minute (P<0.01), a persistent increase in cerebral blood volume (CBV) from 5.77 ± 1.67 to 7.01 ± 1.44 mL/100 g and a significant decrease in oxygen extraction fraction (OEF) from 0.61 ± 0.09 to 0.40 ± 0.08 (P<0.01). Mean absolute CBF values during symptomatic hyperperfusion were more than the normal control +2 standard deviations, the predefined criteria of PET. Interestingly, two patients with markedly increased cerebral metabolic rate of oxygen (CMRO(2)) at hyperperfusion were complicated with postoperative seizure. Among preoperative PET parameters, increased OEF was the only significant risk factor for symptomatic hyperperfusion (P<0.05). This study revealed that symptomatic hyperperfusion in MMD is characterized by temporary increases in CBF >100% over preoperative values caused by prolonged recovery of increased CBV.

Transplantation of telencephalic neural progenitors induced from embryonic stem cells into subacute phase of focal cerebral ischemia.

Cerebral ischemia causes neuronal death and disruption of neural circuits in the central nervous system. Various neurological disorders caused by cerebral infarction can severely impair quality of life and are potentially fatal. Functional recovery in the chronic stage mainly depends on physical treatment and rehabilitation. We aim to establish cell therapy for cerebral ischemia using embryonic stem (ES) cells, which have self-renewing and pluripotent capacities. We previously reported that the transplanted monkey and mouse ES cell-derived neural progenitors, by stromal cell-derived inducing activity method, could survive and differentiate into various types of neurons and glial cells, and form the neuronal network in basal ganglia. In this report, we induced the differentiation of the neural progenitors from mouse ES cells using the serum-free suspension culture method and confirmed the expression of various basal ganglial neuronal markers and neurotransmitter-related markers both in vitro and in vivo, which was thought to be suitable for replacing damaged striatum after middle cerebral artery occlusion. This is the first report that used selectively induced telencephalic neural progenitors into ischemia model. Furthermore, we purified the progenitors expressing the neural progenitor marker Sox1 by fluorescence-activated cell sorting and Sox1-positive neural progenitors prevented tumor formation in ischemic brain for 2 months. We also analyzed survival and differentiation of transplanted cells and functional recovery from ischemic damage.

Potential influence of sevelamer hydrochloride on responsiveness to erythropoiesis-stimulating agents in haemodialysis patients.

AIM: Vitamin D analogues, cinacalcet, and sevelamer play pivotal roles in the management of chronic kidney disease-mineral bone disorder, and are noted to have pleiotropic effects. We examined whether these agents might be associated with the responsiveness to erythropoiesis-stimulating agents (ESA). METHODS: In this cross-sectional study including haemodialysis patients treated with ESA, we searched for clinical parameters associated with the ESA resistance index, which was calculated as the weekly ESA dose divided by the patient's haemoglobin value. RESULTS: Among 45 patients (male: female = 28 : 17, age 68 ± 10 years, haemodialysis duration 84 ± 60 months), vitamin D analogue, cinacalcet, and sevelamer were used in 95.6%, 26.7%, and 84.4% of the patients, respectively. Univariate analysis showed significant association of the ESA resistance index with transferrin saturation rate (TSAT), vitamin D analogue dose, and sevelamer dose. In multivariate analysis, the sevelamer dose and TSAT were found to be independent determinants of the ESA resistance index. CONCLUSION: Our preliminary data showed an independent association between sevelamer dose and the responsiveness to ESA in haemodialysis patients. Further studies are required to investigate the causal relationship between sevelamer and ESA responsiveness.

Asymmetric bilateral effect of the supplementary motor area proper in the human motor system.

OBJECTIVE: This study aimed to clarify the function of human supplementary motor area proper (SMA) by the single-pulse electric stimulation method and its clinical usefulness for SMA mapping. METHODS: We studied five patients with epilepsy or brain tumour who underwent invasive functional mapping with subdural electrodes. Single-pulse electric stimulation of primary motor area (MI) and SMA was carried out through pairs of subdural electrodes, and motor-evoked potentials (MEPs) were recorded from surface electromyogram on both sides and also cortico-cortical-evoked potentials (CCEPs) from electrocorticogram. RESULTS: SMA stimulation elicited: (1) MEPs and following silent periods (SPs) in the contralateral upper and lower extremities, (2) SPs with or without minimal MEPs in the ipsilateral upper extremity and (3) CCEPs in the somatotopically corresponding region of the ipsilateral MI. Compared with MI stimulation, SMA stimulation required higher stimulus intensities (mean 14.2 mA (SMA) vs. 8.5 mA (MI)) to elicit MEPs and showed significantly longer onset latencies in upper extremity (range: 4-10 ms). CONCLUSIONS: The results demonstrated an asymmetric bilateral effect of human SMA upon the corticospinal pathway. SIGNIFICANCE: Single-pulse electric cortical stimulation would be clinically useful for distinguishing SMA from MI. The asymmetric bilateral effect of SMA might be conveyed through the direct descending pathway.

Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development.

BACKGROUND: Moyamoya disease is an idiopathic vascular disorder of intracranial arteries. Its susceptibility locus has been mapped to 17q25.3 in Japanese families, but the susceptibility gene is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Genome-wide linkage analysis in eight three-generation families with moyamoya disease revealed linkage to 17q25.3 (P<10(-4)). Fine mapping demonstrated a 1.5-Mb disease locus bounded by D17S1806 and rs2280147. We conducted exome analysis of the eight index cases in these families, with results filtered through Ng criteria. There was a variant of p.N321S in PCMTD1 and p.R4810K in RNF213 in the 1.5-Mb locus of the eight index cases. The p.N321S variant in PCMTD1 could not be confirmed by the Sanger method. Sequencing RNF213 in 42 index cases confirmed p.R4810K and revealed it to be the only unregistered variant. Genotyping 39 SNPs around RNF213 revealed a founder haplotype transmitted in 42 families. Sequencing the 260-kb region covering the founder haplotype in one index case did not show any coding variants except p.R4810K. A case-control study demonstrated strong association of p.R4810K with moyamoya disease in East Asian populations (251 cases and 707 controls) with an odds ratio of 111.8 (P = 10(-119)). Sequencing of RNF213 in East Asian cases revealed additional novel variants: p.D4863N, p.E4950D, p.A5021V, p.D5160E, and p.E5176G. Among Caucasian cases, variants p.N3962D, p.D4013N, p.R4062Q and p.P4608S were identified. RNF213 encodes a 591-kDa cytosolic protein that possesses two functional domains: a Walker motif and a RING finger domain. These exhibit ATPase and ubiquitin ligase activities. Although the mutant alleles (p.R4810K or p.D4013N in the RING domain) did not affect transcription levels or ubiquitination activity, knockdown of RNF213 in zebrafish caused irregular wall formation in trunk arteries and abnormal sprouting vessels. CONCLUSIONS/SIGNIFICANCE: We provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease.

Single and local blockade of interleukin-6 signaling promotes neuronal differentiation from transplanted embryonic stem cell-derived neural precursor cells.

Safe and efficient transplantation of embryonic stem (ES) cells to the brain requires that local inflammatory and immune responses to allogeneic grafts are inhibited. To investigate cytokines that affect graft cell survival and differentiation, we used stromal cell-derived inducing activity to induce the differentiation of neural progenitor cells (NPCs) from mouse ES cells and transplanted the NPCs into mouse brain. Examination of surrounding brain tissue revealed elevated expression levels of interleukin (IL)-1ß, IL-4, and IL-6 in response to NPC transplantation. Among these, only IL-6 reduced neuronal differentiation and promoted glial differentiation in vitro. When we added anti-IL-6 receptor antibodies to NPCs during transplantation, this single and local blockade of IL-6 signaling reduced the accumulation of host-derived leukocytes, including microglia. Furthermore, it also promoted neuronal differentiation and reduced glial differentiation from the grafted NPCs to an extent similar to that with systemic and continuous administration of cyclosporine A. These results suggest that local administration of anti-IL-6 receptor antibodies with NPCs may promote neuronal differentiation during the treatment of neurological diseases with cell replacement therapy.

Hypofractionated stereotactic radiotherapy for acoustic neuromas: safety and effectiveness over 8 years of experience.

BACKGROUND: Little information is available about long-term outcomes of hypofractionated stereotactic radiotherapy (hypo-FSRT) for acoustic neuromas. In this study, the safety and effectiveness of hypo-FSRT for unilateral acoustic neuroma were reviewed over 8 years of experience at our institution. METHODS: Between May 1998 and October 2006, 27 patients were consecutively treated by linear accelerator-based hypo-FSRT. Two patients were excluded from this study because they were lost to follow-up within 12 months. The median follow-up period for the rest was 59 (range 24-133) months. Two types of treatment schedules were adopted. Thirteen patients received 30-39 Gy, given in 10-13 fractions (regimen A), whereas after July 2003, 12 patients received 20-24 Gy, given in 5-6 fractions at the tumor periphery (regimen B). These treatments were scheduled to be delivered in three fractions per week (Monday, Wednesday, Friday). The median planning target volume was 2.0, with 1.7 ml (range 0.7-10.6) in regimen A and 5.2 ml (range 0.9-9.3) in regimen B. In the pretreatment audiogram, seven patients (two in regimen A and five in regimen B) had serviceable hearing (Gardner-Robertson Class I-II). RESULTS: Local control rates were 100% with regimen A and 92% with regimen B. Serviceable hearing was preserved in four of five patients in regimen B but no patients in regimen A at the last follow-up. No permanent facial or trigeminal nerve morbidity was observed following treatment, and no salvage surgery was needed. CONCLUSIONS: Hypo-FSRT for acoustic neuromas achieved a high local control rate with minimal facial and trigeminal nerve morbidity.

Conversion of a molecular classifier obtained by gene expression profiling into a classifier based on real-time PCR: a prognosis predictor for gliomas.

BACKGROUND: The advent of gene expression profiling was expected to dramatically improve cancer diagnosis. However, despite intensive efforts and several successful examples, the development of profile-based diagnostic systems remains a difficult task. In the present work, we established a method to convert molecular classifiers based on adaptor-tagged competitive PCR (ATAC-PCR) (with a data format that is similar to that of microarrays) into classifiers based on real-time PCR. METHODS: Previously, we constructed a prognosis predictor for glioma using gene expression data obtained by ATAC-PCR, a high-throughput reverse-transcription PCR technique. The analysis of gene expression data obtained by ATAC-PCR is similar to the analysis of data from two-colour microarrays. The prognosis predictor was a linear classifier based on the first principal component (PC1) score, a weighted summation of the expression values of 58 genes. In the present study, we employed the delta-delta Ct method for measurement by real-time PCR. The predictor was converted to a Ct value-based predictor using linear regression. RESULTS: We selected UBL5 as the reference gene from the group of genes with expression patterns that were most similar to the median expression level from the previous profiling study. The number of diagnostic genes was reduced to 27 without affecting the performance of the prognosis predictor. PC1 scores calculated from the data obtained by real-time PCR showed a high linear correlation (r=0.94) with those obtained by ATAC-PCR. The correlation for individual gene expression patterns (r=0.43 to 0.91) was smaller than for PC1 scores, suggesting that errors of measurement were likely cancelled out during the weighted summation of the expression values. The classification of a test set (n=36) by the new predictor was more accurate than histopathological diagnosis (log rank p-values, 0.023 and 0.137, respectively) for predicting prognosis. CONCLUSION: We successfully converted a molecular classifier obtained by ATAC-PCR into a Ct value-based predictor. Our conversion procedure should also be applicable to linear classifiers obtained from microarray data. Because errors in measurement are likely to be cancelled out during the calculation, the conversion of individual gene expression is not an appropriate procedure. The predictor for gliomas is still in the preliminary stages of development and needs analytical clinical validation and clinical utility studies.

Activation of nuclear factor κB in cerebral arteriovenous malformations.

BACKGROUND: Cerebral arteriovenous malformations (AVMs) do not seem to be static congenital vascular malformations, but rather are dynamically changing pathologies. It is well-known from clinical situations that these AVMs can enlarge or shrink. Nuclear factor κB (NF-κB) is a nuclear transcription factor that regulates a number of physiological processes, such as inflammation, apoptosis, and cellular growth. OBJECTIVE: To analyze phosphorylation of NF-κB and related molecules in cerebral AVM specimens. METHODS: We examined 19 specimens of cerebral AVMs from 18 patients. Immunohistochemical analysis was performed using an NF-κB p65 (C22B4) rabbit monoclonal antibody, the phosphorylated form of NF-κB (PNF-κB) p65 (Ser276) rabbit antibody, and an IκBα mouse monoclonal antibody. RESULTS: Expression of NF-κB was mainly confined to the endothelial lining and the infiltrating inflammatory cells in the perivascular regions. PNF-κB showed the highest level of expression in both endothelial cells and perivascular infiltrating cells. PNF-κB was intensely expressed in the endothelium and perivascular infiltrating cells of 15 specimens (78.9%). NF-κB and IκB were also expressed in endothelial cells and perivascular infiltrating inflammatory cells, but at lower levels than PNF-κB. Immunohistochemical studies revealed that PNF-κB was mainly concentrated in the nuclei of endothelial and infiltrating inflammatory cells. On the contrary, expression of both NF-κB and IκB was mainly concentrated in the cytoplasm of endothelial and inflammatory cells. CONCLUSION: We detected activation of NF-κB in the endothelium and perivascular infiltrating inflammatory cells within the cerebral AVM nidus, suggesting a role in the pathophysiology of cerebral AVM.

Intravenous methylprednisolone reduces the risk of propofol-induced adverse effects during Wada testing.

The adverse effects and risks associated with intracarotid propofol injection during Wada testing were retrospectively compared in two groups of patients with (n = 75) and without (n = 58) intravenous methylprednisolone administered before intracarotid propofol injection. The incidences of all adverse effects were decreased in the methylprednisolone group. In particular, severe adverse effects such as increased muscle tone with twitching and rhythmic movements or tonic posture, which could adversely affect Wada test results, were seen in one patient in the methylprednisolone group and seven patients in the control group, indicating 92% risk reduction. This study suggests that Wada testing using intravenous methylprednisolone administration prior to propofol injection is a safe approach to the preoperative evaluation of brain tumors, epilepsy, and arteriovenous malformations.

Early regrowth of juvenile cerebral arteriovenous malformations: report of 3 cases and immunohistochemical analysis.

BACKGROUND: Regrowth of cerebral AVMs after angiographically documented obliteration has been observed in children. In addition, AVMs in adults are reported to be at risk of regrowth despite an angiogram confirming complete removal. However, the mechanism by which regrowth occurs has not been clarified; neither is it clear when regrowth occurs after removal. CASE DESCRIPTION: We report 3 cases showing regrowth of AVMs on postoperative angiogram performed 3 months after surgery. We also analyzed the protein levels of various factors that may influence AVM regrowth. Using immunohistochemistry, we analyzed the protein levels of the following factors: CD31 (PECAM), CD34, and CD105 (endoglin), which are endothelial or endothelial progenitor markers; VEGF, a growth factor that may influence AVM regrowth; and PCNA, a marker of proliferating cells. In addition, we analyzed the level of pERK. CONCLUSION: We report 3 cases of early regrowth of cerebral AVMs. In recurrent AVM samples obtained at second operations, increased levels of perivascular CD105 and pERK immunoreactivity were seen.

mDia1 targets v-Src to the cell periphery and facilitates cell transformation, tumorigenesis, and invasion.

The small GTPase Rho regulates cell morphogenesis through remodeling of the actin cytoskeleton. While Rho is overexpressed in many clinical cancers, the role of Rho signaling in oncogenesis remains unknown. mDia1 is a Rho effector producing straight actin filaments. Here we transduced mouse embryonic fibroblasts from mDia1-deficient mice with temperature-sensitive v-Src and examined the involvement and mechanism of the Rho-mDia1 pathway in Src-induced oncogenesis. We showed that in v-Src-transduced mDia1-deficient cells, formation of actin filaments is suppressed, and v-Src in the perinuclear region does not move to focal adhesions upon a temperature shift. Consequently, membrane translocation of v-Src, v-Src-induced morphological transformation, and podosome formation are all suppressed in mDia1-deficient cells with impaired tyrosine phosphorylation. mDia1-deficient cells show reduced transformation in vitro as examined by focus formation and colony formation in soft agar and exhibit suppressed tumorigenesis and invasion when implanted in nude mice in vivo. Given overexpression of c-Src in various cancers, these findings suggest that Rho-mDia1 signaling facilitates malignant transformation and invasion by manipulating the actin cytoskeleton and targeting Src to the cell periphery.

Confirmation of an association of single-nucleotide polymorphism rs1333040 on 9p21 with familial and sporadic intracranial aneurysms in Japanese patients.

BACKGROUND AND PURPOSE: Genetic factors are important determinants of intracranial aneurysm (IA). Recently, a multinational, genome-wide association study identified 3 loci associated with IA, located on 2q (rs700651), 8q (rs10958409), and 9p (rs1333040 and rs10757278). The aim of this study was to evaluate these associations. METHODS: Familial and sporadic cases were investigated. Familial cases, consisting of 96 subjects with IA, and 46 subjects of unknown status from 31 pedigrees were analyzed with the transmission disequilibrium test and linkage analysis. Associations of single-nucleotide polymorphisms (SNPs) with IA were tested in 419 sporadic IA cases and in 408 control subjects. Sequencing of CDKN2A, CDKN2B, and CDKN2BAS revealed additional SNPs, and their associations with IA were also tested. RESULTS: The transmission disequilibrium test revealed associations of 2 SNPs, rs700651 (P=0.036) and rs1333040 (P=0.002), with familial IA. Analysis of SNPs in sporadic cases revealed an allelic association of rs1333040 with IA (odds ratio=1.28; 95% CI, 1.04-1.57; P=0.02) but failed to show associations of rs10757278 and rs496892 with IA. We sequenced 3 candidate genes; CDKN2A, CDKN2B, and CDKN2BAS. All 6 index cases from IA families had the rs1333040-T allele and SNPs (rs10965215, rs10120688, and rs7341791) in CDKN2BAS. None of these SNPs had linkage disequilibrium with rs1333040 and was associated with IA. CONCLUSIONS: A region between introns 7 and 15 of CDKN2BAS carrying the rs1333040-T allele may confer risk for IA.

Matrigel supports survival and neuronal differentiation of grafted embryonic stem cell-derived neural precursor cells.

Cell replacement therapy holds great promise as a means of treating neurological disorders, including Parkinson's disease. However, one of the major obstacles to the success of this treatment is the low survival rate of grafted cells, which probably results from mechanical damage, acute inflammation, and immunological rejection. To overcome this problem, we investigated the effect of different types of extracellular matrix (ECM) on the survival and differentiation of embryonic stem (ES) cell-derived neural precursor cells (NPCs). We tested materials from natural sources, including collagen, ornithine/laminin, and growth factor-reduced Matrigel (gfrMG), as well as the synthetic biomaterial PuraMatrix, which consists of self-assembling polypeptides. GfrMG efficiently supported cell survival, migration, and neurite outgrowth in vitro and promoted proliferation of grafted cells in vivo, resulting in larger graft volume and an increase in the number of TH-positive dopaminergic neurons in the graft. GfrMG did not induce dopaminergic differentiation directly; rather, it reduced the invasion of pan-leukocytic CD45-positive cells into the graft. Insofar as the inflammatory or immune response in the host brain inhibits neuronal differentiation of grafted NPCs, gfrMG may increase the number of TH-positive cells by suppressing this effect. Thus, gfrMG appears to provide a suitable scaffold that supports survival and differentiation of NPCs. However, because it is derived from mouse sarcomas, a human-derived matrix or synthetic biomaterial must be developed for clinical applications.

Role of angiotensin II type 1 receptor in cerebral aneurysm formation in rats.

Cerebral aneurysm (CA) causes catastrophic subarachnoid hemorrhage which is characterized by a high mortality and morbidity rate. CA is a common disease worldwide but to date there is no medical treatment against unruptured CAs. Thus, it is important to study the mechanisms of CA formation. Our previous report demonstrated that chronic inflammatory response in cerebral arterial bifurcation by hemodynamic stress deteriorated arterial walls and formed CA. Therefore, drugs with anti-inflammatory effects might effectively treat CA formation. As renin angiotensin system (RAS) is a major inflammatory cascade and related to various vascular diseases, including aortic aneurysms, the role of angiotensin (Ang) II type 1 receptor might contribute to the progression of CAs. However, in cerebral aneurysmal walls, Ang II type 1 receptor was not up-regulated. In addition, subcutaneously administered Ang II type 1 receptor blocker did not inhibit CA formation, nor inflammation in cerebral aneurysmal walls in rat models at a sub-suppressor dose. These results indicate that RAS might play a less important role in CA formation compared to aortic anuerysms or other vascular diseases. This suggests that there are different mechanisms between the pathogenesis of cereberal and aortic aneurysms.

Postoperative quality of life outcome and employment in patients undergoing resection of epileptogenic lesions detected by magnetic resonance imaging.

The long-term postoperative improvement of quality of life (QOL) and employment were investigated in patients undergoing resection of epileptogenic lesions detected by magnetic resonance (MR) imaging to identify the associated preoperative factors. Thirty of 47 patients who underwent lesionectomy between 1987-2001 replied to questionnaires. Patients with extratemporal resection outnumbered those with temporal lobe resection. The mean follow-up period was 12.4 +/- 3.7 years. An arbitrary score for quantitatively assessing QOL was assigned. The mean increases in QOL score points were significantly higher in the late childhood onset group than those in the early childhood onset group, and were also significantly higher in the temporal resection group and extratemporal resection of non-dysplastic cortical pathology group than in the extratemporal resection of dysplastic cortical pathology group. Postoperative QOL improvement and occupational status of patients depended on the completeness of seizure control. Resection of lesions detected by MR imaging in patients with intractable epilepsy resulted in effective long-term QOL improvement and postoperative occupational status. Favorable outcome was related mainly to the pathology of the epileptogenic lesions, whether the lesion site was temporal or extratemporal, and the completeness of seizure control.