Kazuhito Matsuzaki

Bilateral deep brain stimulation of the globus pallidus internus in tardive dystonia

Tardive dystonia is a disabling movement disorder as a consequence of exposure to neuroleptic drugs. We followed 6 patients with medically refractory tardive dystonia treated by bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) for 21 ± 18 months. At last follow‐up, the Burke‐Fahn‐Marsden Dystonia Rating Scale (BFMDRS) motor score improved by 86% ± 14%, and the BFMDRS disability score improved by 80% ± 12%. Bilateral GPi‐DBS is a beneficial therapeutic option for the long‐term relief of tardive dystonia.

Akt2 and Akt3 play a pivotal role in malignant gliomas

Akt, one of the major downstream effectors of phosphatidylinositol 3-kinase, is hyper-expressed and activated in a variety of cancers including glioblastoma. However, the expression profiles of the Akt isoforms Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma and their functional roles in malignant glioma are not well understood. Therefore, we examined the protein and mRNA expression patterns of Akt isoforms in tissues from human astrocytomas, glioblastomas, and non-neoplastic regions. We also explored the biological role of each Akt isoform in malignant glioma cells using RNA interference-mediated knock-down and the over-expression of plasmid DNA of each isoform. The expression of Akt1 protein and mRNA was similar in glioma and normal control tissues. Although the protein and mRNA level of Akt2 increased with the pathological grade of malignancy, the expression of Akt3 mRNA and protein decreased as the malignancy grade increased. In U87MG, T98G, and TGB cells, the down-regulation of Akt2 or Akt3 by RNA interference reduced the expression of the phosphorylated form of Bad, resulting in the induction of caspase-dependent apoptosis. Akt1 knock-down did not affect cell growth or survival. We first demonstrate that the over-expression of Akt2 or Akt3 down-regulated the expression of the other protein and that endogenous Akt3 protein showed high kinase activity in U87MG cells. Our data suggest that Akt2 and Akt3 play an important role in the viability of human malignant glioma cells. Targeting Akt2 and Akt3 may hold promise for the treatment of patients with gliomas.

Subthalamic nucleus deep brain stimulation for camptocormia associated with Parkinson's disease

Camptocormia becomes increasingly recognized as a disabling symptom associated with Parkinsons disease (PD). We here report six patients with advanced PD in whom continuous bilateral stimulation of the subthalamic nucleus produced substantial (mean 78% ± 9.1% of the thoracolumbar angle) improvement of camptocormia along with other motor symptoms.

REIC/Dkk-3 induces cell death in human malignant glioma

The progression of glioma to more malignant phenotypes results from the stepwise accumulation of genetic alterations and the consequent disruption of the apoptotic pathway and augmentation of survival signaling. REIC/Dkk-3, a member of the human Dickkopf (Dkk) family, plays a role as a suppressor of the growth of several human cancers; however, to date it has not been identified in brain tumors. We compared the gene and protein expression of REIC/Dkk-3 in human malignant glioma and normal brain tissues using quantitative real-time PCR, Western blotting, and immunohistochemistry. We also performed small interfering REIC/Dkk-3 (siREIC/Dkk-3) knockdown and REIC/Dkk-3 overexpression experiments to examine the role of REIC/Dkk-3 in human malignant glioma cells in vitro. In brain tissue from patients with malignant glioma, the gene and protein expression of REIC/Dkk-3 was lower than in normal brain tissue and was related to the malignancy grade. In the primary glioblastoma cell line, REIC/Dkk-3 transfection led to apoptosis owing to the activation of phosphorylated JUN, caspase-9, and caspase-3 and the reduction of beta-catenin; in REIC/Dkk-3 knockdown experiments, cell growth was augmented. Our results suggest that REIC/Dkk-3 regulates the growth and survival of these cells in a caspase-dependent and -independent way via modification of the Wnt signaling pathway. Our work is the first documentation that the gene and protein expression of REIC/Dkk-3 is down-regulated in human malignant glioma. Our demonstration of the mechanisms underlying REIC/Dkk-3-induced cell death indicates that REIC/Dkk-3 plays a pivotal role in the biology of human malignant glioma and suggests that REIC/Dkk-3 is a promising candidate for molecular target therapy.

Serum response factor is modulated by the SUMO-1 conjugation system

Serum stimulation leads to activation of the serum response factor (SRF)-mediated transcription of immediate-early genes such as c-fos via various signal transduction pathways. We have previously reported that promyelocytic leukemia protein (PML) is involved in the transcriptional regulation by SRF. PML is one of the well-known substrates for modification by small ubiquitin-related modifier-1 (SUMO-1) and several SUMO-1-modified proteins associate with PML. Here, we report that SRF is modified by SUMO-1 chiefly at lysine(147) within the DNA-binding domain. Substitution of this target lysine for alanine did not affect the translocation of SRF to PML-nuclear bodies. The SRF mutant augmented the transcriptional activity under Rho A-stimulated condition but not under serum-starved condition, suggesting that activated SRF is suppressed by its sumoylation. These data support the transcriptional role of SUMO-1 conjugating system in cellular serum response.

THALAMIC VO-COMPLEX VS PALLIDAL DEEP BRAIN STIMULATION FOR FOCAL HAND DYSTONIA

Focal hand dystonia (FHD) is a primary dystonia produced by the excessive co-contraction of antagonistic muscles of the hand and forearm.1,2 Although deep brain stimulation (DBS) is now recognized as a beneficial option to treat a wide spectrum of dystonias,3 little is known regarding its effects on FHD. This is a report of DBS of the thalamic Vo-complex nucleus or the globus pallidus internus (GPi) effecting the complete, sustained relief of medically intractable FHD. The term Vo-complex refers to the combination of the ventralis oralis anterior nucleus (Voa) and ventralis oralis posterior nucleus (Vop) of the thalamus. ### Case report. A 34-year-old right-handed man without a notable medical history experienced gradual onset of writers cramp of the right hand beginning at age 31. At age 32 he also noted progressively worsening stiffness of the fingers and wrist of his left hand. As the focal injection of botulinum toxin and sequential pharmacologic trials that included clonazepam, baclofen, and etizolam produced unsatisfactory results, they were discontinued. On admission, his physical and mental condition was normal. Brain MRI and laboratory studies revealed no abnormal findings. The causes of secondary dystonia were excluded as far as possible. There were no neurologic abnormalities except for …

Impact of bilateral pallidal stimulation on DYT1-generalized dystonia in Japanese patients

Early‐onset generalized dystonia attributable to a DYT1 gene mutation is a hyperkinetic movement disorder that responds poorly to pharmacotherapy. In this video brief, we show that continuous bilateral stimulation of the globus pallidus internus produced sustained and marked improvements in the motor symptoms and functional disabilities of Japanese patients with DYT1‐generalized dystonia.

Up-regulation of endogenous PML induced by a combination of interferon-beta and temozolomide enhances p73/YAP-mediated apoptosis in glioblastoma

Interferon-beta (IFN-β) is reported to augment anti-tumor effects by temozolomide in glioblastoma via down-regulation of MGMT. Promyelocytic leukemia (PML), a gene induced by IFN-β, is a tumor suppressor. Here, we report for the first time that in combination therapy, an IFN-β-induced increase in endogenous PML contributes to anti-tumor effects in p53 wild- and mutant glioma cells in a xenograft mice model. The increased PML promoted the accumulation of p73, a structural and functional homolog of p53, to fuse the coactivator Yes-associated-protein in the PML nuclear bodies. The adjuvant therapy targeted at PML may be a promising therapeutic strategy for glioblastoma.

PML-nuclear bodies are involved in cellular serum response

Background: Serum stimulation leads to the activation of various signal transduction pathways in cells, and the resultant signals are integrated into the serum response factor (SRF)‐dependent transcription of immediate‐early genes such as c‐fos.

Promyelocytic leukemia protein induces apoptosis due to caspase-8 activation via the repression of NFκB activation in glioblastoma

Promyelocytic leukemia (PML) protein plays an essential role in the induction of apoptosis; its expression is reduced in various cancers. As the functional roles of PML in glioblastoma multiforme (GBM) have not been clarified, we assessed the expression of PML protein in GBM tissues and explored the mechanisms of PML-regulated cell death in GBM cells. We examined the PML mRNA level and the expression of PML protein in surgical GBM specimens. PML-regulated apoptotic mechanisms in GBM cells transfected with plasmids expressing the PML gene were examined. The protein expression of PML was significantly lower in GBM than in non-neoplastic tissues; approximately 10% of GBM tissues were PML-null. The PML mRNA levels were similar in both tissue types. The overexpression of PML activated caspase-8 and induced apoptosis in GBM cells. In these cells, PML decreased the expression of transactivated forms of NFkappaB/p65, and c-FLIP gene expression was suppressed. Therefore, PML-induced apoptosis resulted from the suppression of the transcriptional activity of NFkappaB/p65. PML overexpression decreased phosphorylated IkappaBalpha and nuclear NFkappaB/p65 and increased the expression of the suppressor of cytokine signaling (SOCS-1). A proteasome inhibitor blocked the reduction of activated p65 by PML. The reduction of PML is associated with the pathogenesis of GBM. PML induces caspase-8-dependent apoptosis via the repression of NFkappaB activation by which PML facilitates the proteasomal degradation of activated p65 and the sequestration of p65 with IkappaBalpha in the cytoplasm. This novel mechanism of PML-regulated apoptosis may represent a therapeutic target for GBM.