Intrastriatal Memantine Infusion

Although the administration of dopamine precursor levodopa remains as the mainstay for the treatment of Parkinson’s disease, long-term exposure to levodopa often causes a disabling complication, referred to as levodopa-induced dyskinesias. Therefore, the development of new therapeutic interventions to dampen levodopa-induced dyskinesias and parkinsonian motor deficits is needed in the treatment of Parkinson’s disease. Intracerebral brain infusion has the merit of being able to specifically deliver any drug into any brain part. By using an intracerebral infusion system equipped with implantable, programmable, and refillable pumps, we show herein that continuous intrastriatal administration of memantine (MMT), which is a non-competitive N-methyl-D-aspartate receptor antagonist, attenuates levodopa-induced dyskinesias and parkinsonian signs in 6-hydroxydopamine-lesioned hemiparkinsonian mice that received daily levodopa treatment. Corroborating the general thought that overactivation of the striatal N-methyl-D-aspartate receptor function might generate levodopa-induced dyskinesias and parkinsonism, our results suggest that a continuous intrastriatal MMT infusion can be beneficial for the management of Parkinson’s disease with levodopa-induced dyskinesias. Our study also provides indications for the prototypic use of pharmacological deep-brain modulation through intracerebral infusion systems for treating medically intractable movement disorders

Video-based assessments of the hind limb stepping in a mouse model of hemi-parkinsonism

Unilateral injection of 6-hydroxydopamine (6-OHDA) is commonly used to generate a rodent model of Parkinson’s disease (PD). Although motor deficits of the lower extremities represent one of the major clinical symptoms in PD patients, validated tests for assessing motor impairments of the hind limb in 6-OHDA mice are currently unavailable. We here report the video-based assessments of the asymmetric use of hind limbs in 6-OHDA mice. A significantly decreased number of spontaneous hind limb stepping was observed in the contralateral-to-lesioned side, and was dose dependently reversed by levodopa, suggesting that it could be utilized for screening PD therapeutics

Hepatitis C Treatment in Elderly Patients

The patients with chronic hepatitis C (CHC) are getting older and the demands for treatment to those patients are increasing due to the high risk of development of hepatocellular carcinoma. Elderly patients were previously defined as 60 years and over, however definition of the elderly patients shifted to be older year to year. Interferon (IFN) and ribavirin combination therapy was significantly improved efficacy of treatment, however ribavirin induces anemia, resulted in lower efficacy due to reduction of ribavirin for the elderly patients. And efficacy of over 60 years old was comparable to the patients under 60 years. In the CHC patients with genotype 1, the efficacy of elderly patient was significantly lower than that of younger patients, especially in female. Direct-acting antivirals (DAAs) therapy makes treatment efficacy improved to over 90% and side effect of treatment was dramatically reduced compared to IFN-based therapy. The efficacy of dual oral therapy by using asunaprevir (ASV) and daclatasvir (DCA) for elderly patients with hepatitis C virus (HCV) genotype 1b has not been fully clarified. In this article we would like to show the efficacy of elderly patients with CHC, especially patients infected with genotype 1b, from the era of IFN monotherapy to the era of new DAAs

c-Abl Inhibition Exerts Antiparkinsonian Effects

Parkinson’s disease (PD) is caused by a progressive degeneration of nigral dopaminergic cells leading to striatal dopamine deficiency. From the perspective of antiparkinsonian drug mechanisms, pharmacologic treatment of PD can be divided into symptomatic and disease-modifying (neuroprotective) therapies. An increase in the level and activity of the Abelson non-receptor tyrosine kinase (c-Abl) has been identified in both human and mouse brains under PD conditions. In the last decade, it has been observed that the inhibition of c-Abl activity holds promise for protection against the degeneration of nigral dopaminergic cells in PD and thereby exerts antiparkinsonian effects. Accordingly, c-Abl inhibitors have been applied clinically as a disease-modifying therapeutic strategy for PD treatment. Moreover, in a series of studies, including that presented here, experimental evidence suggests that in a mouse model of parkinsonism induced by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, c-Abl inhibition exerts an immediate effect improving motor impairments by normalizing altered activity in striatal postsynaptic signaling pathways mediated by Cdk5 (cyclin-dependent kinase 5) and DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein 32 kDa). Based on this, we suggest that c-Abl inhibitors represent an ideal antiparkinsonian agent that has both disease-modifying and symptomatic effects. Future research is required to carefully evaluate the therapeutic efficacy and clinical challenges associated with applying c-Abl inhibitors to the treatment of PD

Distribution of Camphor Monooxygenase Genes in Soil Bacteria

In microbial degradation of camphor, the first step is oxidation by multiunit enzyme, camphor monooxygenase, encoded by cam genes (camA,B,C). Seven camphor-utilizing bacterial strains have been isolated from soil at various locations. CamA,B,C genes of Pseudomonas putida strain PpG1 and strain GF2001 were used as probes to explore their abundance in the camphor-utilizing bacteria. Southern analysis revealed that all of the cam genes of GF2001 could hybridize well to the SpeI-digested genomic DNA of strains tested, whereas PpG1 cam genes were not. This result suggested that the GF2001 type cam genes are widely distributed among the camphorutilizing strains in the environment. Thus strain GF2001 and seven newly isolated strains share a common evolutionary origin. Key words: Camphor monooxygenase genes, gene distribution, sail bacteria

The Subaru FMOS Galaxy Redshift Survey (FastSound). III. The mass-metallicity relation and the fundamental metallicity relation at z∼1.4z\sim1.4

We present the results from a large near-infrared spectroscopic survey with Subaru/FMOS (\textit{FastSound}) consisting of $\sim$ 4,000 galaxies at $z\sim1.4$ with significant H$\alpha$ detection. We measure the gas-phase metallicity from the [N~{\sc ii}]$\lambda$6583/H$\alpha$ emission line ratio of the composite spectra in various stellar mass and star-formation rate bins. The resulting mass-metallicity relation generally agrees with previous studies obtained in a similar redshift range to that of our sample. No clear dependence of the mass-metallicity relation with star-formation rate is found. Our result at $z\sim1.4$ is roughly in agreement with the fundamental metallicity relation at $z\sim0.1$ with fiber aperture corrected star-formation rate. We detect significant [S~{\sc ii}]$\lambda\lambda$6716,6731 emission lines from the composite spectra. The electron density estimated from the [S~{\sc ii}]$\lambda\lambda$6716,6731 line ratio ranges from 10 -- 500 cm$^{-3}$, which generally agrees with that of local galaxies. On the other hand, the distribution of our sample on [N~{\sc ii}]$\lambda$6583/H$\alpha$ vs. [S~{\sc ii}]$\lambda\lambda$6716,6731/H$\alpha$ is different from that found locally. We estimate the nitrogen-to-oxygen abundance ratio (N/O) from the N2S2 index, and find that the N/O in galaxies at $z\sim1.4$ is significantly higher than the local values at a fixed metallicity and stellar mass. The metallicity at $z\sim1.4$ recalculated with this N/O enhancement taken into account decreases by 0.1 -- 0.2 dex. The resulting metallicity is lower than the local fundamental metallicity relation.Comment: 14 pages, 10 figures, 2 tables, accepted for publication in PAS