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Zonisamide (ZNS) is an effective drug for not only motor symptoms but also non-motor symptoms in Parkinson's disease. However, the actions of ZNS as an anti-Parkinsonian drug are not well understood. To clarify the actions of ZNS in vivo , we administered ZNS to mice and examined the effects on neurotransmitter metabolism and behaviors, focusing on motor and non-motor symptoms. Administration of ZNS decreased dopamine (DA) turnover in various brain regions, including the striatum. In behavioral tests, ZNS enhanced locomotor activity and novelty seeking in the open field test, light-dark transition test, and the social interaction test. Consistent with these results of DA metabolism in ZNS-treated mice, monoamine oxidase activity was significantly inhibited by ZNS in primary neurons and astrocytes. Collectively, these data suggest that ZNS inhibits monoamine oxidase activity and decreases DA turnover, which increases locomotor activity and novelty seeking in mice. ZNS is potentially useful to improve not only motor symptoms but also neuropsychiatric non-motor symptoms such as apathy in PD. [ABSTRACT FROM AUTHOR]

Involvement of iron in the development of neurodegenerative disorders has long been suggested, and iron that cannot be stored properly is suggested to induce iron toxicity. To enhance iron uptake and suppress iron storage in neurons, we generated transgenic (Tg) mice expressing iron regulatory protein 2 (IRP2), a major regulator of iron metabolism, in a neuron-specific manner. Although very subtle, IRP2 was expressed in all regions of brain examined. In the Tg mice, mitochondrial oxidative insults were observed including generation of 4-hydroxynonenal modified proteins, which appeared to be removed by a mitochondrial quality control protein Parkin. Inter-crossing of the Tg mice to Parkin knockout mice perturbed the integrity of neurons in the substantia nigra and provoked motor symptoms. These results suggest that a subtle, but chronic increase in IRP2 induces mitochondrial oxidative insults and accelerates neurodegeneration in a mouse model of Parkinson's disease. Thus, the IRP2 Tg may be a useful tool to probe the roles of iron-induced mitochondrial damages in neurodegeraration research. [ABSTRACT FROM AUTHOR]

Since the introduction of carotid stenting (CAS), a combined treatment for bilateral lesions using carotid endarterectomy (CEA) and CAS has been developed. However, there has been only 1 report about CEA then CAS. Herein we describe 2 patients with bilateral severe carotid stenosis who were treated by CEA for the symptomatic side and CAS for the contralateral asymptomatic side. A 71-year-old man underwent CEA for the symptomatic side. Although the patient suffered hyperperfusion syndrome after CEA, he recovered fully after 3 weeks of rehabilitation. Two months later, CAS was performed for the asymptomatic side, and he was discharged with no deficit. A 67-year-old man underwent CEA for the symptomatic side. The patient developed no postoperative neurologic deficits except for hoarseness. Four weeks later, CAS was performed for the contralateral asymptomatic side. After the procedure, however, severe hypotension occurred, and treatment by continuous injection of catecholamine was necessary to maintain systematic blood pressure. The patient was ultimately discharged with no deficit. The combined therapy of CAS for the asymptomatic side and then CEA for the symptomatic side has been recommended by several authors. However, one of the problems of this strategy is the higher incidence of postprocedural hemodynamic complications, and hypotension after CAS may be dangerous for the symptomatic hemisphere. We suggest a combined therapy using CEA for the symptomatic side and then CAS for the asymptomatic side can be 1 beneficial treatment option for patients with bilateral carotid stenosis without coronary artery disease. [ABSTRACT FROM AUTHOR]

Abstract: This communication reports on O2 reduction with a biocathode composed of poly(3-methylthiophene) (P3MT) and laccase based on direct electron transfer (DET). The biocathode was fabricated simply by adsorption of laccase on a P3MT film which was formed on a gold electrode by electrochemical polymerization. Properties of the biocathode were examined by measuring steady-state currents at an arbitrary potential in buffer solutions saturated with O2 or N2 at room temperature. Efficient O2 reduction was achieved with the biocathode, which was attributed to DET from the P3MT film to laccase. The biocathode gave the O2 reduction current density of −150μA/cm2 at +0.40V (vs. Ag/AgCl). The onset potential of O2 reduction was +0.64±0.01V (vs. Ag/AgCl) at pH4.5. The O2 reduction current became maximum in the pH range 4.0–5.0. This pH dependency of the O2 reduction current is corresponding to that of the activity of native laccase. In addition, the O2 reduction current increased markedly with increasing amount of the charge passed through in the formation of the P3MT film. [Copyright &y& Elsevier]

An observational excavation control method for a mountain tunnel excavated adjacent to an existing tunnel in active service is presented. The new and existing tunnels both having a width of 11.7 m was separated from each other by a distance of 20 m. Besides the small pillar width, a fracture zone with clayey material due to hydrothermal alteration, which would appear in the middle of the new tunnel alignment, had to be taken into account. Under such circumstances, the excavation control of the new tunnel was required to minimize the adverse effect on the existing tunnel. Prior to the excavation, detailed geological surveys on the fracture zone and FEM analyses incorporating the survey results have been carried out. The relationship between the incremental stresses occurring in the concrete lining of the existing tunnel and the expected wall displacement of the new tunnel is established. It has therefore become possible to control the excavation based on the wall displacement of the new tunnel and to select the necessary reinforcement and support method. With this control method the new tunneling construction has been performed without any adverse effect on the existing tunnel. [Copyright &y& Elsevier]

A new series of thienopyrimidinones is synthesized and evaluated as selective phosphodiesterase 7 (PDE7) inhibitors for the treatment of inflammatory diseases. The modification of the substituents on thienopyrimidinone revealed that an isopropylamino group at the 2-position was favorable for aqueous solubility. The introduction of 3-pyrrolidines at the 7-position resulted in good solubility, highly potent activity, and good PDE7 selectivity. Among the synthesized compounds, compound 46 exhibited the greatest inhibition of ear edema in a phorbol ester-induced mouse model. [ABSTRACT FROM AUTHOR]

Drug resistance remains a serious problem in leukemia therapy. Among newly developed nucleoside antimetabolites, clofarabine has broad cytotoxic activity showing therapeutic promise and is currently approved for relapsed acute lymphoblastic leukemia. To investigate the mechanisms responsible for clofarabine resistance, we established two clofarabine-resistant lymphoblastic leukemia cell lines from parental lines. To elucidate the mechanisms against clofarabine resistance in two newly established clofarabine-resistant cell lines, we measured the expression of export pumps multidrug resistance protein 1, multidrug resistance–associated protein 1, and ATP-binding cassette subfamily G member 2. There were no differences in the expression between clofarabine-sensitive and -resistant cell lines. Next, we determined expression of deoxycytidine kinase (dCK) , which phosphorylates clofarabine to exert cytotoxicity, in clofarabine-sensitive and -resistant cells. Clofarabine-resistant cells showed significantly decreased expression of dCK RNA when compared with sensitive cells. To elucidate the mechanisms of decreased dCK expression in clofarabine-resistant cells, we analyzed the methylation status of CpG islands of the dCK promoter and found no differences in methylation status between clofarabine-sensitive and -resistant cells. Next, we measured the acetylation status of histone and found that total histone acetylation, and histone H3 and H4 acetylation on chromatin immunoprecipitation assay were significantly decreased in resistant cells. Melatonin is an indolamine that functions in the regulation of chronobiological rhythms to exert cytotoxic effects. We examined the effects of melatonin in clofarabine-resistant cells and found that melatonin treatment led to significantly increased cytotoxicity with clofarabine in resistant cells via increased acetylation. Melatonin may be a useful candidate for overcoming clofarabine resistance in two newly established clofarabine resistant leukemia cell lines. [ABSTRACT FROM AUTHOR]

The discovery and SAR study of a new series of soluble and highly potent phosphodiesterase (PDE) 7 inhibitors are described herein. We explored a new lead compound with improved solubility, which led to the discovery of a 2-(4-pyridylamino)thieno[3,2- d ]pyrimidin-4(3 H )-one series. The introduction of 3-piperidines at the 7-position resulted in the significant enhancement of PDE7 activity. In particular, compound 32 also showed strong PDE7 inhibitory activity; good selectivity against PDE3, 4, and 5; and good aqueous solubility. [ABSTRACT FROM AUTHOR]

We performed intravenous CT angiography using multidetector-row helical computed tomography (MDCT) in a 63-year-old man with spinal arteriovenous malformation (AVM). The CT angiography demonstrated feeding arteries, varix-like structure, draining veins and their relationship to the spinal cord. Although selective angiography is essential in planning treatment for spinal AVMs as well as in establishing the diagnosis of the disease, CT angiography can be a good supplementary technique for visualizing precise location of abnormal vessels in a certain case of spinal AVM. [Copyright &y& Elsevier]

Abstract: Objective: The aim of this study was to investigate the relationship between abnormal acetabular labrum depicted by radial magnetic resonance and progressive joint space narrowing (JSN) of hip dysplasia. Methods: Subjects were 23 joints [21 patients; mean age: 35.1 years (16–53 years)] that had acetabular dysplasia with lateral center-edge angle of Wiberg (CE angle) greater than 5° and smaller than 25° (mean, 16.4°), which did not show any arthrotic changes on plain radiograms and were followed up for 3 years or longer. Radial images of acetabular labrum were classified into three stages. Results: Progression of JSN was not significantly related to CE angle but to progression of MRI stage (P=.006). In multivariate analysis, one rank progression of MRI stage was significantly associated with progression of JSN (adjusted OR=11.41, 95% CI: 1.51–86.24, P=.018). Conclusion: Our findings showed that in patients whose acetabular dysplasia has 5–25° CE angle, MRI staging based on radial MRI is a better factor for prediction of progression of JSN than CE angle. [Copyright &y& Elsevier]

Purpose: To investigate the discrepancy between the arteriovenous malformations seen on magnetic resonance angiography (MRA) and on stereotactic digital subtracted angiography (DSA). Methods and Materials: The target volume on stereotactic DSA (VDSA ) and the target volume on MRA (VMRA ) were separately delineated in 28 intracranial arteriovenous malformations. The coordinates of the center and the outer edges of VDSA and VMRA were calculated and used for the analyses. Results: The standard deviations (mean value) of the displacement of centers of VMRA from VDSA were 2.67 mm (−1.82 mm) in the left-right direction, 3.23 mm (−0.08 mm) in the anterior-posterior direction, and 2.16 mm (0.91 mm) in the craniocaudal direction. VMRA covered less than 80% of VDSA in any dimensions in 9 cases (32%), although no significant difference was seen in the target volume between each method, with a mean value of 11.9 cc for VDSA and 12.3 cc for VMRA (p = 0.948). Conclusion: The shift of centers between each modality is not negligible. Considering no significant difference between VDSA and VMRA , but inadequate coverage of the VDSA by VMRA , it is reasonable to consider that the target on MRA might include the feeding artery and draining vein and possibly miss a portion of the nidus. [Copyright &y& Elsevier]

BACKGROUNDWhen considering the treatment strategies for dural arteriovenous fistulas (DAVFs), it is important to clarify the exact location of the fistula and venous drainage route from both DAVFs and normal brain tissue. DAVFs with leptomeningeal retrograde venous drainage carry a high risk of neurological deficits and require aggressive treatment. When AVFs involve the dural sinus, transvenous embolization via the transfemoral approach is usually the first choice of treatment. For DAVFs draining directly into the cortical veins without dural sinus involvement, transarterial embolization may be a curative treatment. However, when embolization is technically difficult or results in incomplete occlusion, surgical treatment is required. The purpose of the present study was to review our experience with surgical treatment of DAVFs.METHODSThe present series included 17 patients; 9 had DAVFs involving the dural sinus with leptomeningeal retrograde venous drainage and 8 had DAVFs draining directly into the cortical veins. For DAVFs involving the sinus, embolization of the diseased sinus by direct surgical exposure was performed in 8 patients, and surgical excision in one. For DAVFs draining directly into the cortical veins, interruption of the draining veins close to DAVFs was undertaken in 7 and surgical excision in 1.RESULTSComplete obliteration of DAVFs was demonstrated in 16 patients. At final follow-up, 15 patients were asymptomatic and the other 2 showed clinical improvement.CONCLUSIONSFor DAVFs involving the dural sinus, direct operative sinus packing is indicated. For DAVFs directly draining into the cortical veins, surgical interruption of the draining veins is indicated. [Copyright &y& Elsevier]