Ca2+-dependent inositol 1,4,5-trisphosphate and nitric oxide signaling in cerebellar neurons

Intracellular Ca(2+) signals are important for the regulation of synaptic functions in the central nervous system. In this review, I summarize findings of our recent studies on upstream and downstream Ca(2+) signaling mechanisms in cerebellar synapses using novel molecular imaging methods. Inositol 1,4,5-trisphosphate (IP(3))-induced Ca(2+) release plays a pivotal role in central synapses. The visualization of IP(3) at fine dendrites of Purkinje cells (PCs) using a fluorescent IP(3) indicator showed that intracellular Ca(2+) concentration has a stimulatory effect on phospholipase C activity, which catalyzes IP(3) production. This indicates that metabotropic and ionotropic glutamate receptors collaborate to generate IP(3) signals. Using a novel nitric oxide (NO) indicator, the spatial distribution of NO signals originating from parallel fiber (PF) terminals was visualized. Our results show that the NO signal decays steeply with distance from the site of production in the cerebellum and is dependent on PF stimulation frequency in a biphasic manner. NO released from PF terminals generated a synapse-specific long-term potentiation of PF-PC synapse when PF was stimulated at certain frequencies. These imaging studies clarified new aspects of the regulatory mechanisms of synaptic functions.     

Allogeneic hematopoietic stem cell transplantation as part of postremission therapy improves survival for adult patients with high-risk acute lymphoblastic leukemia: a metaanalysis

BACKGROUND: The prognosis for adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory primarily because of the high incidence of recurrence. Therefore, optimal postremission therapy is a matter of vital concern. In particular, the clinical efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) should be clarified. METHODS: Rigorous criteria were used to select 7 studies of adult ALL that prospectively assessed overall survival (OS) using natural randomization based on donor availability combined with intention-to-treat analyses. The authors then performed a metaanalysis to evaluate the role of allogeneic HSCT. RESULTS: Seven studies that included 1274 patients were selected. A metaanalysis demonstrated that patients in the donor groups had significantly better survival than patients in the no-donor groups (hazard ratio [HR], 1.29; 95% confidence interval [95% CI], 1.02-1.63 [P = .037]). When only high-risk patients were included in the analysis, the superiority of the survival advantage was even greater (HR, 1.42; 95% CI, 1.06-1.90 [P = .019]). A meta-regression analysis revealed that compliance with allogeneic HSCT showed a significant and positive correlation with survival (coefficient, 0.022; P < .01), suggesting that the greater the proportion of patients who actually received allogeneic HSCT, the better the survival of the donor group. No beneficial effects of autologous HSCT were observed. CONCLUSIONS: The current findings demonstrated that allogeneic HSCT improves the outcome of adult patients with high-risk ALL. Although these analyses were based on abstracted data, the results indicated that allogeneic HSCT should be considered for such patients if a suitable donor is available.     

Green tea component, catechin, induces apoptosis of human malignant B cells via production of reactive oxygen species.

PURPOSE: Green tea polyphenol, (-)-epigallocatechin-3-gallate, has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. The aim of this study was to investigate the possibility of (-)-epigallocatechin-3-gallate as a novel therapeutic agent for the patients with B-cell malignancies including multiple myeloma. EXPERIMENTAL DESIGN: We investigated the effects of (-)-epigallocatechin-3-gallate on the induction of apoptosis in HS-sultan as well as myeloma cells in vitro and further examined the molecular mechanisms of (-)-epigallocatechin-3-gallate-induced apoptosis. RESULTS: (-)-Epigallocatechin-3-gallate rapidly induced apoptotic cell death in various malignant B-cell lines in a dose- and time-dependent manner. (-)-Epigallocatechin-3-gallate-induced apoptosis was in association with the loss of mitochondrial transmembrane potentials (Deltapsim); the release of cytochrome c, Smac/DIABLO, and AIF from mitochondria into the cytosol; and the activation of caspase-3 and caspase-9. Elevation of intracellular reactive oxygen species (ROS) production was also shown during (-)-epigallocatechin-3-gallate-induced apoptosis of HS-sultan and RPMI8226 cells as well as fresh myeloma cells. Antioxidant, catalase, and Mn superoxide dismutase significantly reduced ROS production and (-)-epigallocatechin-3-gallate-induced apoptosis, suggesting that ROS plays a key role in (-)-epigallocatechin-3-gallate-induced apoptosis in B cells. Furthermore, a combination with arsenic trioxide (As2O3) and (-)-epigallocatechin-3-gallate significantly enhanced induction of apoptosis compared with As2O3 alone via decreased intracellular reduced glutathione levels and increased production of ROS. CONCLUSIONS: (-)-Epigallocatechin-3-gallate has potential as a novel therapeutic agent for patients with B-cell malignancies including multiple myeloma via induction of apoptosis mediated by modification of the redox system. In addition, (-)-epigallocatechin-3-gallate enhanced As2O3-induced apoptosis in human multiple myeloma cells.     

Two autopsy cases with Pelizaeus-Merzbacher disease phenotype of adult onset, without mutation of proteolipid protein gene

We report the autopsy cases of two brothers which are pathologically compatible with Pelizaeus-Merzbacher disease (PMD). Both patients had a late onset (at the ages of 29 and 42 years) and chronic neurological symptoms including tremor, ataxia and dementia. The T2-weighted magnetic resonance imaging of the younger brother demonstrated increased signal areas with sparing of small areas in the cerebral white matter. The postmortem examinations, obtained at the ages of 45 and 61 years, showed similar neuropathological findings. Histologically, a cardinal finding was a lack of myelin in large parts of white matter with the preservation of islands of intact myelin, resulting in a “tigroid” appearance. Only small amounts of sudanophilic material were present. The axons were relatively well preserved, but oligodendrocytes were numerically reduced. Ultrastructurally, myelin sheaths in the white matter were markedly thin. Immunohistochemistry showed that proteolipid protein (PLP) was reduced in the affected white matter. However, genetic studies did not reveal exonic mutations or duplications of the PLP gene. We conclude that the two cases are a rare type of dysmyelinating disorder with PMD phenotype of adult onset and could be caused by previously unrecognized abnormalities of the PLP gene or other genes. Received: 28 September 1998 / Revised: 25 January 1999, 12 April 1999 / Accepted: 12 April 1999     

Centrally administered orexin/hypocretin activates HPA axis in rats

The effects of i.c.v. administration of orexin/hypocretin on plasma ACTH, corticosterone and c-fos mRNA in the paraventricular nucleus (PVN) of the rat were examined. Plasma ACTH levels were markedly increased at 30 min after i.c.v. administration of orexin-A. Plasma corticosterone levels were significantly increased in a dose-related manner 30 min after i.c.v. administration of orexin-A and orexin-B. In situ hybridization histochemistry revealed that the induction of the c-fos mRNA in the parvocellular division of the PVN was increased in a dose-related manner 30 min after i.c.v. administration of orexin-A and orexin-B. These results suggest that central orexin/hypocretin activates hypothalamo-pituitary-adrenal (HPA) axis and may be involved in stress-induced activation of the HPA axis.     

Role of SCOX in determination of Drosophila melanogaster lifespan

In man, COX (cytochrome c oxidase) deficiency is reported to be related to mutation of the SCO2 (synthesis of cytochrome c oxidase 2) gene, which encodes one of the copper-donor chaperones involved in the assembly of mitochondrial cytochrome c oxidase. Such COX deficiency due to the genetic condition leads to heart disease and the Leigh syndrome and is frequently fatal in childhood. Synthesis of cytochrome c oxidase X (SCOX) is a Drosophila orthologue of human SCO2. Here, we generated SCOX-knockdown flies and the full length SCOX transgenic flies to investigate the in vivo roles of SCOX. Our results demonstrated knockdown of SCOX gene in all cells and tissues to be associated with lethality at larval or pupal stages and this correlated with a decrease in ATP level. In contrast, the full length SCOX transgenic flies showed a longer lifespan than wild type flies and control flies carrying Act5C-GAL4 alone and this correlated with an increase in ATP level. Finally, when cultured on paraquat-added medium, full length SCOX transgenic flies also exhibited an elongated lifespan. Therefore, we hypothesized that SCOX plays an important role in ATP production and consumption, which helps to prevent production of mitochondrial reactive oxygen species and/or impairment of mitochondrial activity under oxidative stress.     

Coexpression of glial and neuronal markers in the neurocytic rosettes of rosette-forming glioneuronal tumors

Rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) is a new entity in the WHO 2007 Classification of Tumors of the Central Nervous System. RGNT has two components: neurocytic rosettes and low-grade gliomas. Neurocytic rosettes are conventionally described as consisting of uniform neurocytes. However, some studies have reported rosette-forming tumor cells that expressed glial markers such as Olig2. We indicated the expression of glial markers including Olig2, cyclinD1, glial fibrillary acidic protein (GFAP), and platelet-derived growth factor receptor alpha (PDGFRα) in the neurocytic rosettes in our previous study, and we suggested that these tumor cells had a heterogeneous nature. In this study, we used double and triple immunostaining to demonstrate that these tumor cells have both glial and neuronal characteristics. We found that rosette-forming tumor cells coexpressed Olig2/cyclinD1 and synaptophysin. Furthermore, the cores of the rosettes coexpressed GFAP/PDGFRα in the peripheral zone and synaptophysin in the central zone. These findings imply that rosette-forming tumor cells have a similar nature to neuronal-glial progenitor cells, and we believe that the nomination “neurocytic rosette” may be unsuitable given their heterogeneous nature. Our study appears to clarify some of the properties of RGNT tumor cells and may help elucidate the histogenesis of RGNT.     

An Alternative Approach to Atopic Dermatitis: Part I-Case-Series Presentation

Atopic dermatitis (AD) is a complex disease of obscure pathogenesis.A substantial portion of AD patients treated with conventionaltherapy become intractable after several cycles of recurrence.Over the last 20 years we have developed an alternative approachto treat many of these patients by diet and Kampo herbal medicine.However, as our approach is highly individualized and the Kampoformulae sometimes complicated, it is not easy to provide evidenceto establish usefulness of this approach. In this Review, todemonstrate the effectiveness of the method of individualizedKampo therapy, results are presented for a series of patientswho had failed with conventional therapy but were treated afterwardsin our institution. Based on these data, we contend that thereexist a definite subgroup of AD patients in whom conventionaltherapy fails, but the ‘Diet and Kampo’ approachsucceeds, to heal. Therefore, this approach should be consideredseriously as a second-line treatment for AD patients. In theDiscussion, we review the evidential status of the current conventionalstrategies for AD treatment in general, and then specificallydiscuss the possibility of integrating Kampo regimens into it,taking our case-series presented here as evidential basis. Weemphasize that Kampo therapy for AD is more ‘art’than technology, for which expertise is an essential pre-requisite.