Therapeutic Effects of Hydrogen in Animal Models of Parkinson's Disease

Since the first description of Parkinson's disease (PD) nearly two centuries ago, a number of studies have revealed the clinical symptoms, pathology, and therapeutic approaches to overcome this intractable neurodegenerative disease. 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are neurotoxins which produce Parkinsonian pathology. From the animal studies using these neurotoxins, it has become well established that oxidative stress is a primary cause of, and essential for, cellular apoptosis in dopaminergic neurons. Here, we describe the mechanism whereby oxidative stress evokes irreversible cell death, and propose a novel therapeutic strategy for PD using molecular hydrogen. Hydrogen has an ability to reduce oxidative damage and ameliorate the loss of nigrostriatal dopaminergic neuronal pathway in two experimental animal models. Thus, it is strongly suggested that hydrogen might provide a great advantage to prevent or minimize the onset and progression of PD

Role of a BRICS Bank in a multipolar world : is China establishing a new international organization to change the international order or to legitimize Chinese FDI?

published_or_final_versionInternational and Public AffairsMasterMaster of International and Public Affair

Conventional, Bayesian, and Modified Prony's methods for characterizing fast and slow waves in equine cancellous bone

Conventional, Bayesian, and the modified least-squares Prony's plus curve-fitting (MLSP + CF) methods were applied to data acquired using 1 MHz center frequency, broadband transducers on a single equine cancellous bone specimen that was systematically shortened from 11.8 mm down to 0.5 mm for a total of 24 sample thicknesses. Due to overlapping fast and slow waves, conventional analysis methods were restricted to data from sample thicknesses ranging from 11.8 mm to 6.0 mm. In contrast, Bayesian and MLSP + CF methods successfully separated fast and slow waves and provided reliable estimates of the ultrasonic properties of fast and slow waves for sample thicknesses ranging from 11.8 mm down to 3.5 mm. Comparisons of the three methods were carried out for phase velocity at the center frequency and the slope of the attenuation coefficient for the fast and slow waves. Good agreement among the three methods was also observed for average signal loss at the center frequency. The Bayesian and MLSP + CF approaches were able to separate the fast and slow waves and provide good estimates of the fast and slow wave properties even when the two wave modes overlapped in both time and frequency domains making conventional analysis methods unreliable

Role of Serine Racemase in Behavioral Sensitization in Mice after Repeated Administration of Methamphetamine

BACKGROUND: The N-methyl-D-aspartate (NMDA) receptors play a role in behavioral abnormalities observed after administration of the psychostimulant, methamphetamine (METH). Serine racemase (SRR) is an enzyme which synthesizes D-serine, an endogenous co-agonist of NMDA receptors. Using Srr knock-out (KO) mice, we investigated the role of SRR on METH-induced behavioral abnormalities in mice. METHODOLOGY/PRINCIPAL FINDINGS: Evaluations of behavior in acute hyperlocomotion, behavioral sensitization, and conditioned place preference (CPP) were performed. The role of SRR on the release of dopamine (DA) in the nucleus accumbens after administration of METH was examined using in vivo microdialysis technique. Additionally, phosphorylation levels of ERK1/2 proteins in the striatum, frontal cortex and hippocampus were examined using Western blot analysis. Acute hyperlocomotion after a single administration of METH (3 mg/kg) was comparable between wild-type (WT) and Srr-KO mice. However, repeated administration of METH (3 mg/kg/day, once daily for 5 days) resulted in behavioral sensitization in WT, but not Srr-KO mice. Pretreatment with D-serine (900 mg/kg, 30 min prior to each METH treatment) did not affect the development of behavioral sensitization after repeated METH administration. In the CPP paradigm, METH-induced rewarding effects were demonstrable in both WT and Srr-KO mice. In vivo microdialysis study showed that METH (1 mg/kg)-induced DA release in the nucleus accumbens of Srr-KO mice previously treated with METH was significantly lower than that of the WT mice previously treated with METH. Interestingly, a single administration of METH (3 mg/kg) significantly increased the phosphorylation status of ERK1/2 in the striatum of WT, but not Srr-KO mice. CONCLUSIONS/SIGNIFICANCE: These findings suggest first, that SRR plays a role in the development of behavioral sensitization in mice after repeated administration of METH, and second that phosphorylation of ERK1/2 by METH may contribute to the development of this sensitization as seen in WT but not Srr-KO mice

Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis

The incidence of brain metastasis is increasing, however, little is known about molecular mechanism responsible for lung cancer-derived brain metastasis and their development in the brain. In the present study, brain pathology was examined in an experimental model system of brain metastasis as well as in human brain with lung cancer metastasis. In an experimental model, after 3–6 weeks of intracardiac inoculation of human lung cancer-derived (HARA-B) cells in nude mice, wide range of brain metastases were observed. The brain sections showed significant increase in glial fibrillary acidic protein (GFAP)-positive astrocytes around metastatic lesions. To elucidate the role of astrocytes in lung cancer proliferation, the interaction between primary cultured mouse astrocytes and HARA-B cells was analyzed in vitro. Co-cultures and insert-cultures demonstrated that astrocytes were activated by tumor cell-oriented factors; macrophage migration inhibitory factor (MIF), interleukin-8 (IL-8) and plasminogen activator inhibitor-1 (PAI-1). Activated astrocytes produced interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β), which in turn promoted tumor cell proliferation. Semi-quantitative immunocytochemistry showed that increased expression of receptors for IL-6 and its subunits gp130 on HARA-B cells. Receptors for TNF-α and IL-1β were also detected on HARA-B cells but down-regulated after co-culture with astrocytes. Insert-culture with astrocytes also stimulated the proliferation of other lung cancer-derived cell lines (PC-9, QG56, and EBC-1). These results suggest that tumor cells and astrocytes stimulate each other and these mutual relationships may be important to understand how lung cancer cells metastasize and develop in the brain

Convergent evolution of SARS-CoV-2 Omicron subvariants leading to the emergence of BQ.1.1 variant

In late 2022, various Omicron subvariants emerged and cocirculated worldwide. These variants convergently acquired amino acid substitutions at critical residues in the spike protein, including residues R346, K444, L452, N460, and F486. Here, we characterize the convergent evolution of Omicron subvariants and the properties of one recent lineage of concern, BQ.1.1. Our phylogenetic analysis suggests that these five substitutions are recurrently acquired, particularly in younger Omicron lineages. Epidemic dynamics modelling suggests that the five substitutions increase viral fitness, and a large proportion of the fitness variation within Omicron lineages can be explained by these substitutions. Compared to BA.5, BQ.1.1 evades breakthrough BA.2 and BA.5 infection sera more efficiently, as demonstrated by neutralization assays. The pathogenicity of BQ.1.1 in hamsters is lower than that of BA.5. Our multiscale investigations illuminate the evolutionary rules governing the convergent evolution for known Omicron lineages as of 2022

Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two Omicron subvariants

In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions

当院における便潜血陽性者に対する大腸CT(CTコロノグラフィー)検査の有用性:大腸がん検診への導入と課題

大腸がん検診におけるスクリーニング検査としての大腸CT(CT colonography: CTC)検査の有用性を検討するために,当院における便潜血陽性者に対するCTCと大腸内視鏡検査の精度比較を行った.2009年7月から2014年1月までに川崎医科大学附属病院で施行されたCTC検査673件中,スクリーニング目的で行われた411件の中で便潜血陽性者に対して行われた183名を対象とした.全例CTC検査と同日に全大腸内視鏡検査も行った.対象とする病変は内視鏡観察あるいは病理組織学的に腺腫,がんと診断されたものとした.CTCの前処置は,経口腸管洗浄剤に水溶性造影剤による標識(タギング)を付けて行った.CT装置は16列Multi-slice CT(MSCT),腸管拡張は自動炭酸ガス注入器を使用した.CTC読影は,まず仮想内視鏡(3D)で行い,後に多断面再構成像(Multi-planar reconstruction: MPR 像(2D))を行う3D primary 法で行った.183名(男性98名,女性85名,年齢40～86歳,平均年齢62.1歳±0.8歳)のうち,病変を認めなかったのは87名(47.5%)であり,病変を認めたのは96名(53%)であった.総病変数は191個であり,うち6mm以上の病変は77個(40%)で,そのうち10mm以上のものは46個(24%)であった.大腸癌は25例(全病変中13%)で,うち腺腫内癌16例(全病変中8%)であった.側方発育型腫瘍は8例(4%)(大きさ平均17mm)であった.病変のうち,内視鏡的切除が行われたものは34病変であり,手術が行われたものは22病変であった.病変形態別による描出率は隆起型病変80%で,平坦型病変65%であった.病変サイズ別の精度は10mm以上の病変(n=46)で感度96%,陽性適中率98%であり,6mm以上の病変(n=77)で感度83%,陽性適中率79%であった.CTCは便潜血陽性者において良好な精度を示し,大腸がんスクリーニング法としての可能性がある.The purpose of this study was to estimate the sensitivity and specificity of CT colonography (CTC) for colorectal cancer screeing following positive fecal occult blood test (FOBT) in Japan. To compare detection rates of colorectal cancer and adenoma between CTC and optical total colonoscopy (TCS). This study included 183 patients with positive result of FOBT in Japanese colorectal cancer screening program. The patients had both CTC and TCS on the same day. 96 patients (53%) had colorectal lesions, on the other hand 87 patients had no lesions. The total number of lesions was 191, including 77 lesions 6 mm in maximum diameter and larger, including 46 lesions 10 mm and larger