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In this research, we aimed to predict the relative risk of the recent new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the basis of our previous research. We first performed molecular docking simulation analyses of the spike proteins with human angiotensin-converting enzyme 2 (ACE2) to determine the binding affinities to human cells of three new variants of SARS-CoV-2: Omicron BQ.1, XBB, and XBB.1.5 We then investigated the three variants to discover the evolutionary distance of the spike protein gene (S gene) from the Wuhan, Omicron BA.1, and Omicron BA.4/5 variants, to understand the changes in the S gene.The results indicated that the XBB.1.5 variant had the highest binding affinity of the spike protein with ACE2 and the longest evolutionary distance of the S gene. Thisin silicoevidence suggested that the XBB.1.5 variant may produce infections that spread more widely and faster than can infections of preexisting variants.

Core body temperature (CBT) is considered a valuable marker for circadian rhythm. This study aimed to investigate the changes in CBT that are associated with the symptoms of circadian rhythm sleep-wake disorder (CRSWD) post-treatment in children.Twenty-eight school-age children [10 boys and 18 girls; mean age (±standard deviation), 13.68 ± 0.93 years] who were admitted to our hospital with CRSWD underwent treatment for 6-8 weeks according to the following protocol: lights-out for sleep at 21:00; phototherapy for waking at 6:00 or 7:00; light exercise everyday (eg, a 20- to 30-min walk). CBT was continuously measured for 24 h on the first day of admission and on the first day after treatment.The mean time of sleep onset/offset (±standard deviation; in hours:minutes) 1 week before admission and 1 week after treatment were 23:53 ± 2:26/9:58 ± 2:15 and 21:17 ± 0:19/6:46 ± 0:32, respectively. The mean times of sleep onset and offset measured post-treatment were significantly earlier than those measured pre-treatment (p 0.001). The mean CBT and mean minimum CBT during sleep were significantly lower on the first day post-treatment than on the first day of admission (p = 0.011 and p 0.001, respectively).Symptom improvements in patients with CRSWD were associated with a decrease in CBT during sleep, suggesting that CBT may be a biomarker for improvements in CRSWD. These results help elucidate the cause of this sleep disorder.

ObjectivesIn our previous research, we developed a mathematical model via molecular simulation analysis to predict the infectivity of seven SARS-CoV-2 variants. In this report, we aimed to predict the relative risk of the recent new variants of SARS-CoV-2 as based on our previous research.MethodsWe subjected Omicron BA.4/5 and BA.2.75 variants of SARS-CoV-2 to the analysis to determine the absolute evolutionary distance of the spike protein gene (S gene) of the variants from the Wuhan variant so as to appreciate the changes in the spike protein. We performed the molecular docking simulation analyses of the spike proteins with human angiotensin-converting enzyme 2 (ACE2) to understand the docking affinities of these variants. We then compared the evolutionary distances and the docking affinities of these variants with those of the seven variants that we had analyzed in our previous research.ResultsThe evolutionary distances of the S gene in BA.4/5 and BA.2.75 from the Wuhan variant were longer than those of the other variants. BA.2.75 had the highest docking affinity of the spike protein with ACE2 (ratio per Wuhan variant).ConclusionThe important results from this analysis are the following: BA.2.75 has both the highest docking affinity and the longest evolutionary distance of the S gene. These results suggest that BA.2.75 infection can spread farther than can infections of preexisting variants.

Variants of a coronavirus (SARS-CoV-2) have been spreading in a global pandemic. Improved understanding of the infectivity of future new variants is important so that effective countermeasures against them can be quickly undertaken. In our research reported here, we aimed to predict the infectivity of SARS-CoV-2 by using a mathematical model with molecular simulation analysis, and we used phylogenetic analysis to determine the evolutionary distance of the spike protein gene (S gene) of SARS-CoV-2. We subjected the six variants and the wild type of spike protein and human angiotensin-converting enzyme 2 (ACE2) to molecular docking simulation analyses to understand the binding affinity of spike protein and ACE2. We then utilized regression analysis of the correlation coefficient of the mathematical model and the infectivity of SARS-CoV-2 to predict infectivity. The evolutionary distance of the S gene correlated with the infectivity of SARS-CoV-2 variants. The coefficient of the mathematical model obtained with results of molecular docking simulation also correlated with the infectivity of SARS-CoV-2 variants. These results suggest that the data from the docking simulation for the receptor binding domain of variant spike proteins and human ACE2 were valuable for prediction of SARS-CoV-2 infectivity. In addition, we developed a mathematical model for prediction of SARS-CoV-2 variant infectivity by using binding affinity obtained via molecular docking and the evolutionary distance of the S gene.

The disease model of familial amyloidotic polyneuropathy-7.2-hMet30 mice-manifests amyloid deposition that consists of a human amyloidogenic mutant transthyretin (TTR) (TTR V30M). Our previous study found amyloid deposits in 14 of 27 7.2-hMet30 mice at 21-24 months of age. In addition, non-fibrillar TTR deposits were found in amyloid-negative 7.2hMet30 mice. These results suggested that TTR amyloidogenesis required not only mutant TTR but also an additional factor (or factors) as an etiologic molecule. To determine the differences in serum proteome in amyloid-positive and amyloid-negative mice in the 7.2-hMet30 model, we used proteomic analyses and studied serum samples obtained from these mice. Hemopexin (HPX) and transferrin (Tf) were detected in the serum samples from amyloid-positive mice and were also found in amyloid deposits via immunohistochemistry, but serum samples from amyloid-negative mice did not contain HPX and Tf. These two proteins were also not detected in non-fibrillar TTR deposits. In addition, in silico analyses suggested that HPX and Tf facilitate destabilization of TTR secondary structures and misfolding of TTR. These results suggest that HPX and Tf may be associated with TTR amyloidogenesis after fibrillogenesis in vivo.

Acupuncture treatment utilizes the stimulation of metal acupuncture needles that are manually inserted into a living body. In the last decades, laser light has been used as an alternative to needles to stimulate acupuncture points. We previously reported suppression of myostatin (Mstn) gene expression in skeletal muscle by means of femtosecond laser (FL) irradiation, after electroacupuncture, in which acupuncture needles are stimulated with a low-frequency microcurrent. The purpose of the study here was to investigate the efficacy of FL irradiation in mouse skeletal muscle with regard to protein synthesis. After irradiation of the hindlimbs, we first analyzed Mstn gene expression and Mstn protein level in the skeletal muscle. We then evaluated phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream target 70-kDa ribosomal protein S6 kinase (p70S6K). The results showed that FL irradiation significantly reduced the amount of Mstn protein and enhanced the phosphorylation of p70S6K in of the mTOR/S6K signaling pathway. We suggest that FL irradiation activated the protein synthetic pathway in the skeletal muscle. In conclusion, we determined that FL irradiation can serve as an alternative for acupuncture needles and has the potential of being a new non-invasive acupuncture treatment of skeletal muscle.

Epidermal growth factor receptor (EGFR) gene mutations are the most established genomic biomarkers for the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). The most frequent deletion in exon 19 is delE746_750, followed by del747_753insS and del747_750insP. Since investigations of delE746 have not been reported previously, it is unclear if delE746 conveys sensitivity to TKI effect of TKI on EGFR delE746. The objective was to characterize delE746 of the EGFR gene and to explore the effects of TKIs on the delE746. We assessed the ability of gefitinib to inhibit phosphorylation of clonal L929 cell lines expressing EGFR with delE746. 3-D structures of the EGFR proteins were also used to investigate the interaction with gefitinib. The delE746 mutant EGFR-expressing cells exhibited gefitinib-sensitive autophosphorylation, which altered the structure of the EGFR and increased the instances of docking during docking simulations of gefitinib with the EGFR-TK. This mutant revealed that it exhibited molecular conformation alterations, and more frequent binding with gefitinib compared to wild-type EGFR. We administered EGFR-TKI, gefitinib to a Japanese woman with lung cancer that contained delE746. The patient achieved partial response after a 5 month of treatment with gefitinib. Our study revealed biological, structural, and probably clinical features of the delE746 form of EGFR.

我々は視覚障害者向けの鍼灸、特に経絡と経穴に関する教育材料の研究に取り組んだ。この教材では、鍼灸分野における概念間の関係の体系的な理解を可能にすべく、オントロジーを用いた。オントロジーの概念図によりオントロジー教材を作成し、これを鍼灸の講義で使用した群とオントロジー教材未使用群とで経絡・経穴の試験の結果を比較し、その有効性を解析した。その結果、オントロジー教材を使用した学生の経絡・経穴の試験の得点は、オントロジー教材未使用群の学生の得点よりも有意(P < 0.001)に高く、経絡と経穴の学習にオントロジー教材有効である事が明らかになった。この結果は、オントロジーの視覚障害者教育への利用が視覚障害者の鍼灸理論の学習へも有効であることを示唆している。, In this study we developed learning material of acupuncture - acupoints and meridians - for visually impaired people. For this learning material, we used ontology to construct the relations between the concepts in the acupuncture and moxibustion field which also enables tactical understanding similarly as visual understanding. We then used our learning material in the acupuncture lecture for the visually impaired students, and quantitatively analysed its efficacy to compare the results with the group which did not use the learning material. As a result, the students, who used our learning material, scored significantly higher in the examination than the students of non-use group (P < 0.001), suggesting that our learning material was effective for learning of acupuncture theory.

我が国では、緑内障や糖尿病性網膜色素変性症の罹病率の増大に伴い、弱視者の数が増加している。これらの中途視覚障害者の多くは中高年で残存視覚への依存が大きく、点字の習得が困難である。加えて、点字教育を担当する教師も減っており、これら中途視覚障害者の点字学習をより困難にしている。そこで我々は、残存視覚 (RV)のみを使用する画面によるプログラム、画面と点字ディスプレイ(BD)が協働するプログラム、画面と音声アシスト(BDV) が点字ディスプレイと協働するプログラム、の3種類のWebベースのe-ラーニングプログラムと基本API (Application Programming Interface) を研究開発した。, In Japan, number of people with low vision is increasing along with the increased morbidity of glaucoma or diabetic retinitis pigmentosa, etc. It is difficult for the acquired visually impaired to learn and acquire Braille because most of them are middle-aged and so they usually rely on their residual vision. In addition, the number of Braille teachers are not sufficient and rather reducing in Japan, and this situation makes more difficult for the visually impaired to learn Braille. Therefore, we research and develop three styles of Web-based e-learning programs for Japanese Braille and the Application Programming Interface (API) for displaying Braille characters: one for only computer screen that utilize residual vision (RV), another one which cooperates with Braille display (BD), and the other for tactile Braille that cooperates with Braille display and voice assistance (BDV).

Shakuyaku-kanzo-to (Shao-Yao-Gan-Cao-Tang) is a Kampo medicine, which is known to be effective against muscle cramps as well as crampy pain in the gastrointestinal smooth muscle and skeletal muscle. However, glycyrrhizin in this medicine also causes adverse drug reactions such as hypokalemia, hypertension, and edema. We analyzed the therapeutic efficacy of Shakuyaku-kanzo-to for painful muscle cramps associated with lumbar spinal stenosis and clarified its minimum effective dose. 58 patients with lumbar spinal stenosis and painful muscle cramps were included. We evaluated the therapeutic efficacy of Shakuyaku-kanzo-to (n=16) comparing with eperisone hydrochloride (n=14). We then examined the minimum effective dose of Shakuyaku-kanzo-to in the remaining 28 patients. Shakuyaku-kanzo-to reduced the frequency of painful muscle cramps to less than 50% in 13 of 16 patients. However, eperisone hydrochloride reduced it to the same level in 4 of 14 patients. The onset of the maximum therapeutic effect of Shakuyaku-kanzo-to was less than 3 days from the start of treatment in 11 of 15 patients. Regarding the minimum effective dose for painful muscle cramps, 2.5 g of Shakuyaku-kanzo-to used as needed had a therapeutic effect that was equivalent to the regular use of 7.5 g/day (given in divided doses three times daily). Our data show that Shakuyaku-kanzo-to is effective for painful muscle cramps associated with lumbar spinal stenosis. The dosage of 2.5 g of Shakuyaku-kanzo-to as needed had a therapeutic effect that was equal to the regular use of 7.5 g/day.

Photomechanical laser ablation due to focused femtosecond laser irradiation was induced on the hind legs of living mice, and its clinical influence on muscle cell proliferation was investigated via histological examination and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis to examine the expression of the gene encoding myostatin, which is a growth repressor in muscle satellite cells. The histological examination suggested that damage of the tissue due to the femtosecond laser irradiation was localized on epidermis and dermis and hardly induced in the muscle tissue below. On the other hand, gene expression of the myostatin of muscle tissue after laser irradiation was suppressed. The suppression of myostatin expression facilitates the proliferation of muscle cells, because myostatin is a growth repressor in muscle satellite cells. On the basis of these results, we recognize the potential of the femtosecond laser as a tool for noncontact, high-throughput acupuncture in the treatment of muscle disease.

BACKGROUND AND PURPOSE Catechins, biologically active polyphenols in green tea, are known to have a protective effect against cardiovascular diseases. In this study, we investigated direct actions of green tea catechins on cardiac muscle function to explore their uses as potential drugs for cardiac muscle disease. EXPERIMENTAL APPROACH The effects of catechins were systematically investigated on the force-pCa relationship in skinned cardiac muscle fibres to determine their direct effects on cardiac myofilament contractility. The mechanisms of action of effective catechins were investigated using troponin exchange techniques, quartz crystal microbalance, nuclear magnetic resonance and a transgenic mouse model. KEY RESULTS (-)-Epicatechin-3-gallate (ECg) and (-)-epigallocatechin-3-gallate (EGCg), but not their stereoismers (-)-catechin-3-gallate and (-)-gallocatechin-3-gallate, decreased cardiac myofilament Ca2+ sensitivity probably through its interaction with cardiac troponin C. EGCg restored cardiac output in isolated working hearts by improving diastolic dysfunction caused by increased myofilament Ca2+ sensitivity in a mouse model of hypertrophic cardiomyopathy. CONCLUSIONS AND IMPLICATIONS The green tea catechins, ECg and EGCg, are Ca2+ desensitizers acting through binding to cardiac troponin C. These compounds might be useful compounds for the development of therapeutic agents to treat the hypertrophic cardiomyopathy caused by increased Ca2+ sensitivity of cardiac myofilaments.

UDP-glucuronosyltransferase 1A1 (UGT1A1) is an endoplasmic reticulum membrane protein that catalyses glucuronidation. Mutant UGT1A1 possesses a different conjugation capacity, and the molecular mechanisms regulating these conjugation reactions are as yet unclear. To elucidate these molecular mechanisms, we simulated and analysed the glucuronidation of wild-type UGT1A1 and six UGT1A1 mutants, with bilirubin as the substrate. We found that only the orientation of the substrates correlated with the conjugation capacity in in vitro experiments. Inasmuch as glucuronidation is an intermolecular rearrangement reaction, we find that the conjugation reaction proceeds only when the hydroxyl group of the substrate is oriented towards the coenzyme, which allows the proton transfer to occur.

【目的】鍼通電刺激が、 身体の不活動にどのような影響を及ぼすかは不明である。 本研究の目的は、 骨格筋の不活動モデルである後肢懸垂後からの再接地による筋萎縮の回復過程において、 鍼通電刺激が筋量や筋線維横断面積の回復に及ぼす効果の解明である。 さらに、 マクロファージ による筋衛星細胞の活性化の可能性も検討する。 【方法】ICR雄性マウス(8週齢)を非処置群(NT群; n=5)、 後肢懸垂群(HS群; n=5)、 コントロール群(CT群; n=5)および鍼通電刺激群(EA群; n=5)の４群に分けた。 HS群、 CT群、 EA群は14日間の後肢懸垂を行った。 さらに、 CT群とEA群は再接地後14日間飼育した。 後肢懸垂は、 マウスの尾部を固定し、 飼育ケージから吊す方法を用いた。 EA群は、 再接地直後から2日に1度、 下腿三頭筋へ2本の鍼を刺入し、 10Hz、 5-7Vで30分間の鍼通電刺激を行った。 そして、 ヒラメ筋の筋量、 筋線維横断面積およびマクロファージ浸潤数を解析した。 【結果】筋量及び筋線維横断面積は、 NT群と比較してHS群で低下した (P

X-linked hypohidrotic ectodermal dysplasia (XLHED), which is characterized by hypodontia, hypotrichosis, and hypohidrosis, is caused by mutations in ED1, the gene encoding ectodysplasin-A (EDA). This protein belongs to the tumor necrosis factor ligand superfamily. We analyzed ED1 in two Japanese patients with XLHED. In patient 1, we identified a 4-nucleotide insertion, c.119-120insTGTG, in exon 1, which led to a frameshift mutation starting from that point (p.L40fsX100). The patient's mother was heterozygous for this mutation. In patient 2, we identified a novel missense mutation, c.1141G>C, in exon 9, which led to a substitution of glycine with arginine in the TNFL domain of EDA (p.G381R). This patient's mother and siblings showed neither symptoms nor ED1 mutations, so this mutation was believed to be a de novo mutation in maternal germline cells. According to molecular simulation analysis of protein structure and electrostatic surface, p.G381R increases the distance between K375 in monomer A and K327 in monomer B, which suggests an alteration of overall structure of EDA. Thus, we identified two novel mutations, p.L40fsX100 and p.G381R, in ED1 of two XLHED patients. Simulation analysis suggested that the p.G381R mutation hampers binding of EDA to its receptor via alteration of overall EDA structure.

We created knock-in mice in which a deletion of 3 base pairs coding for K210 in cardiac troponin (cTn)T found in familial dilated cardiomyopathy patients was introduced into endogenous genes. Membrane-permeabilized cardiac muscle fibers from mutant mice showed significantly lower Ca 2+ sensitivity in force generation than those from wild-type mice. Peak amplitude of Ca 2+ transient in cardiomyocytes was increased in mutant mice, and maximum isometric force produced by intact cardiac muscle fibers of mutant mice was not significantly different from that of wild-type mice, suggesting that Ca 2+ transient was augmented to compensate for decreased myofilament Ca 2+ sensitivity. Nevertheless, mutant mice developed marked cardiac enlargement, heart failure, and frequent sudden death recapitulating the phenotypes of dilated cardiomyopathy patients, indicating that global functional defect of the heart attributable to decreased myofilament Ca 2+ sensitivity could not be fully compensated by only increasing the intracellular Ca 2+ transient. We found that a positive inotropic agent, pimobendan, which directly increases myofilament Ca 2+ sensitivity, had profound effects of preventing cardiac enlargement, heart failure, and sudden death. These results verify the hypothesis that Ca 2+ desensitization of cardiac myofilament is the absolute cause of the pathogenesis of dilated cardiomyopathy associated with this mutation and strongly suggest that Ca 2+ sensitizers are beneficial for the treatment of dilated cardiomyopathy patients affected by sarcomeric regulatory protein mutations.

A 71-year-old male presented with left hemiparesis and confused conversation. Computed tomography showed a mass lesion with rim enhancement in the right parietal lobe. He developed meningeal irritation the day after admission. Emergent fluid-attenuated inversion recovery (FLAIR) magnetic resonance (MR) imaging revealed a clear hyperintense component in the right lateral ventricle and niveau formation inside the intracerebral lesion, indicating intraventricular rupture of the brain abscess. The patient underwent aspiration of the abscess and ventricular drainage with antibiotic administration. Nocardia asteroides was isolated from the aspirated pus, so systemic and direct administration of effective antibiotics was subsequently commenced. These procedures resulted in gradual improvement of his clinical course, and he left our hospital. Several days after discharge, he developed acute pan-peritonitis due to malignant lymphoma. He appeared to be progressively deteriorating after an exploratory laparotomy, and died on the 17th day after the laparotomy. Intraventricular rupture of nocardia brain abscess can be successfully treated after early definitive diagnosis with FLAIR MR imaging.

A 5-year-old boy was struck by a pickup truck, and admitted with Glasgow Coma Scale score of 14. Initial computed tomography (CT) showed no evidence of intracerebral lesions except for a skull fracture. Repeat CT 5 hours later showed hyperdense middle cerebral artery (MCA) sign, but he did not show any focal signs. Eighteen hours after the accident, he developed left hemiparesis. CT revealed a fresh infarction in the right MCA territory, associated with definite hyperdense MCA sign. He was immediately transferred to our hospital for further evaluation. Emergent angiography revealed a rat tail-shaped occlusion of the right internal carotid artery at the C-3 level. Cross-filling of the right MCA territory was insufficient for collateral circulation. He was treated conservatively because of the significant risk of hemorrhagic change from the established infarction. His hemiparesis improved gradually, and he was discharged on foot. Hyperdense MCA sign in a child is an important clinical sign for the early detection of cerebral ischemia after blunt carotid injury, before any focal signs appear.

Functional consequences of the six mutations (R145G, R145Q, R162W, DeltaK183, G203S, K206Q) in cardiac troponin I (cTnI) that cause familial hypertrophic cardiomyopathy (HCM) were studied using purified recombinant human cTnI. The missense mutations R145G and R145Q in the inhibitory region of cTnI reduced the intrinsic inhibitory activity of cTnI without changing the apparent affinity for actin. On the other hand, the missense mutation R162W in the second troponin C binding region and the deletion mutation DeltaK183 near the second actin-tropomyosin region reduced the apparent affinity of cTnI for actin without changing the intrinsic inhibitory activity. Ca(2+) titration of a fluorescent probe-labeled human cardiac troponin C (cTnC) showed that only R162W mutation impaired the cTnC-cTnI interaction determining the Ca(2+) affinity of the N-terminal regulatory domain of cTnC. Exchanging the human cardiac troponin into isolated cardiac myofibrils or skinned cardiac muscle fibers showed that the mutations R145G, R145Q, R162W, DeltaK183 and K206Q induced a definite increase in the Ca(2+)-sensitivity of myofibrillar ATPase activity and force generation in skinned muscle fibers. Although the mutation G203S also showed a tendency to increase the Ca(2+) sensitivity in both myofibrils and skinned muscle fibers, no statistically significant difference compared with wild-type cTnI could be detected. These results demonstrated that most of the HCM-linked cTnI mutations did affect the regulatory processes involving the cTnI molecule, and that at least five mutations (R145G, R145Q, R162W, DeltaK183, K206Q) increased the Ca(2+) sensitivity of cardiac muscle contraction.

Slow skeletal muscle troponin I (ssTnI) expressed predominantly in perinatal heart confers a marked resistance to acidic pH on Ca 2+ regulation of cardiac muscle contraction. To explore the molecular mechanism underlying this phenomenon, we investigated the roles of TnI isoforms (ssTnI and cardiac TnI (cTnI)) in the thin filament activation by strongly binding cross-bridges, by exchanging troponin subunits in cardiac permeabilized muscle fibers. Fetal cardiac muscle showed a marked resistance to acidic pH in activation of the thin filament by strongly binding cross-bridges compared to adult muscle. Exchanging ssTnI into adult fibers altered the pH sensitivity from adult to fetal type, indicating that ssTnI also confers a marked resistance to acidic pH on the cross-bridge-induced thin filament activation. However, the adult fibers containing ssTnI or cTnI but lacking TnC showed no pH sensitivity. These findings provide the first evidence for the coupling between strongly binding cross-bridges and a pH-sensitive interaction of TnI with TnC in cardiac muscle contraction, as a molecular basis of the mechanism conferring the differential pH sensitivity on Ca 2+ regulation.

We report a case of ruptured tectal arteriovenous malformation (AVM) that was demonstrated angiographically only after removal of an unruptured occipital AVM. A 57-year-old man presented with sudden onset of diplopia and tinnitus. Computed tomography revealed a small hemorrhage in the right tectum mesencephali with intraventricular hemorrhage. Magnetic resonance imaging and angiography disclosed AVM in the right occipital lobe which was separate from the hemorrhagic lesion. Angiography demonstrated that the right occipital AVM was fed by the parieto-occipital artery and drained into the superior sagittal sinus and vein of Galen. However, no abnormal vascular lesion was detected near the tectum mesencephali. As venous hypertension was considered the reason for hemorrhage, the occipital AVM was completely resected. Postoperative angiography demonstrated disappearance of the occipital AVM, but it also disclosed a small tectal AVM fed by branches from the superior cerebellar artery, which had not been detected on preoperative angiography. This was considered the true cause of hemorrhage, and gamma knife surgery was accordingly performed. Even if an AVM is demonstrated, if the lesion does not correspond to the hemorrhage we recommend serial angiographical evaluation so that a small AVM is not missed.

A 64-year-old man underwent microvascular decompression of the left superior cerebellar artery (SCA) for left trigeminal neuralgia (TN) using a sling of Teflon tape fixed to the tentorium with fibrin glue. The TN disappeared immediately after surgery, but recurred unusually rapidly at 2 weeks later at the same intensity as before. Second surgery revealed the SCA was suspended from the tentorium, but the trigeminal nerve was stretched and displaced superolaterally because of adhesion to the superior petrosal vein. The adhesion was thought to involve the fibrin glue used during the sling retraction procedure. The nerve was meticulously dissected from the adhesion, and the trigeminal nerve was placed in the correct position. The postoperative course was uneventful, and the TN disappeared completely. We recommend that the smallest amount of the fibrin glue possible be used to avoid adhesion to the surrounding neurovascular elements.

Acupuncture therapy is utilized to cure many diseases and to maintain health. We have been studying the molecular mechanism of acupuncture and obtained its molecular evi‐ dence [1-4]. The World Health Organization has listed more than 40 indications for acu‐ puncture [5], and the National Institutes of Health (NIH) has accepted the validity of acupuncture treatment [6,7]. One of the popular uses of acupuncture treatment is to treat muscle exhaustion, including stiff shoulders. Major acupuncture techniques involve pene‐ tration of the skin by thin, solid metallic needles, which are manipulated manually or are stimulated electrically. The efficacy of such muscle therapy is attributed to the over‐ proliferation of muscle cells induced by the damage of muscle in response to the needle penetration. We recently reported that myostatin gene expression is suppressed by elec‐ troacupuncture (EA) [1].

The effects of 30% galactose (Gal)-feeding on Gal-induced albuminuria were examined in transgenic mice (Tg), in which human aldose reductase (hAR) was expressed by an MHC class I promoter (hAR-Tg). Both in hAR-Tg and the littermates, urinary albumin excretion (UAE) increased and reached its peak at 2 to 4 wks after the start of Gal-feeding, and decreased thereafter in spite of the steady increase of renal galactitol. On the other hand, the increased urine volume (UV) in Gal-fed mice, the suppression of UV and UAE in Gal-fed hAR-Tg with aldose reductase inhibitor (ARI) were observed. The similar time course between the changes of UV and UAE, and the positive correlation between UV and UAE suggest that galactitol accumulation via the polyol pathway is partially responsible for the increased UV and increased UAE in Galfed mice.

The ultrastructure of the central terminals of nociceptive primary afferent (Cl terminals) neurons in the mouse substantia gelatinosa was studied by the cytochemical method using fluoride-resistant acid phosphatase (FRAP). Small roundish, slender, sinuous and large scalloped terminals showed FRAP reactivity. The FRAP reaction was seen as electron dense granular deposits between spherical synaptic vesicles and around the membrane of the synaptic vesicles. Especially, dark, small sinuous and large scalloped terminals showed intense FRAP reactivity. From the previous studies, these terminals were in accord with the capsaicin-sensitive Cl terminals. Furthermore, larger, roundish terminals with less packed spherical synaptic vesicles, many mitochondria and a few dense cored synaptic vesicles showed FRAP reactivity. Our recent results that Cll terminals are also sensitive to capsaicin support the FRAP activity of the Cll terminals in the present study. Thus, various types of FRAP-positive Cl terminals and some Cll terminals are considered to be central endings of the capsaicin-sensitive nociceptive primary afferents.

Along with the increased morbidity of glaucoma or diabetic retinitis pigmentosa, etc., number of people with vision loss is also increasing in Japan. It is difficult for the visually impaired to learn and acquire braille because most of them are middle-aged. In addition, number of braille teachers are not sufficient and reducing in Japan, and this situation makes more difficult for the visually impaired. Therefore, we research and develop a Web-based e-learning program for tactile braille, that cooperate with braille display and voice assistance., {"references":["J. Jiménez, J. Olea, Torres J, I. Alonso, D. Harder, K. Fischer. Biography\nof louis braille and invention of the braille alphabet. Surv Ophthalmol\n2009; 54(1): 142-9","Japanese Braille Committee. Japanese Braille Transcription Rules, 2001.\nTokyo: Daikatsuji Co. Ltd.; 2001 (in Japanese).","Ministry of Education, Science and Culture in Japan. Guidance for\nteaching Japanese braille learning 2003.","Sugano A, Hanaoka S, Sagara K, Asahara M, Miura K, Ohta M,\nMatsumoto Y, Ohsima T, Takaoka Y. An approach toward a barrier-free\nhospital using a Japanese-into-Braille translating server \"eBraille.\" IEICE\nTechnical Report 108(488), 19-24, 2009","Aki Sugano, Mika Ohta, Tsuyoshi Oda, Kenji Miura, Shuji Goto, Masako\nMatsuura, Eiichi Maeda, Toshiko Ohshima, Yuji Matsumoto, Yutaka\nTakaoka: eBraille: A web based translation program for Japanese text to\nBraille. Internet Research 20(5), 582-592, 2010","Takahasi S, Sakai J, Tokizawa K, Hanyuda H, Maekawa Y and Iyoda M.\nSupport System for Japanese Braille Learner Using WWW. IEICE\nTechnical Report 98(563), 97-104, 1999."]}

Along with the advances in medicine, providing medical information to individual patient is becoming more important. In Japan such information via Braille is hardly provided to blind and partially sighted people. Thus we are researching and developing a Web-based automatic translation program “eBraille" to translate Japanese text into Japanese Braille. First we analyzed the Japanese transcription rules to implement them on our program. We then added medical words to the dictionary of the program to improve its translation accuracy for medical text. Finally we examined the efficacy of statistical learning models (SLMs) for further increase of word segmentation accuracy in braille translation. As a result, eBraille had the highest translation accuracy in the comparison with other translation programs, improved the accuracy for medical text and is utilized to make hospital brochures in braille for outpatients and inpatients., {"references":["Act on the Protection of Personal Information (Japan Law No.57, 2003).\n(in Japanese) URL:\nhttp://law.e-gov.go.jp/ htmldata/H15/H15HO057.html (accessed 2011May 9)","J. Jiménez, J. Olea, Torres J, I. Alonso, D. Harder, K. Fischer. Biography\nof louis braille and invention of the braille alphabet. Surv Ophthalmol 2009; 54(1): 142-9","Japanese Braille Committee. Japanese Braille Description Rules, 2001.\nTokyo: Daikatsuji Co. Ltd.; 2001 (in Japanese). ISBN:978-4860550004","Kadota M. Japanese Braille Tutorial. 1997; URL:\nhttp://www.duxburysystems.com/Japanese_Braille_Tutorial.pdf\n(accessed 2011 March 18)","Unger JM. Japanese Braille. Visible Language 1984; 18(3):254-266.","Kudo T. YamCha: Yet Another Multipurpose CHunk Annotator. URL:\nhttp://chasen.org/~taku/software/YamCha/ (accessed 2011 May 9)","Japan Intractable Diseases Information Center. URL:\nhttp://www.nanbyou.or.jp/english/ (accessed 2011 June 9)","Trubetzkoy NS. Grundzüge der Phonologie (Principles of Phonology).\nBerkeley, CA: University California Press; 1958/1969.","Matsumoto Y, Kitauchi A, Yamashita T, Hirano Y. Japanese\nMorphological Analysis System ChaSen Version 2.0 Manual.\nInformation Science Technical Report TR99009, Nara Institute of\nScience and Technology. URL:\nhttp://library.naist.jp/mylimedio/dllimedio/show.cgi?bookid=23003(acc\nessed 2011 May 25)"]}

Aging is of critical interest in the medical, health, and social domains, especially in developed countries and newly industrializing countries. Because muscle atrophy in elderly individuals can cause falls, its prevention is important. Moreover, prevention of agingrelated reduced skeletal muscle mass may allow a higher quality of life in the elderly, because reduced muscle function is linked to the occurrence of several chronic diseases (Handschin & Spiegelman, 2008). High-intensity resistance training effectively maintains muscle mass and strength, but rigorous training is difficult for elderly people (Seynnes et al., 2007). Acupuncture is a well-known traditional technique in eastern Asia that is used to maintain health and cure many diseases. Major acupuncture techniques utilize penetration of the skin by thin, solid metallic needles, which are manipulated manually or are stimulated electrically. This electrical needle stimulation is called electroacupuncture (EA) (Klein & Trachtenberg, 1997). EA is effective not only for pain but also for muscle problems, such as stiffness, exhaustion, and atrophy, in many patients including elderly people (Zhang, 2003). Acupuncture studies have reported the nerve routes of acupuncture signal transmission, effects via the spinal reflex, and reactions in the brain (Cho et al., 1998; Murase & Kawakita, 2000; Uchida et al., 2000). Figure 1 is a schematic diagram showing the routes of EA stimuli between treated points and organs. In a previous investigation on acupuncture, only a neural mechanism of pain reduction was clear; endogenous opioid (beta endorphin and enkephalin) is induced under the acupuncture anesthesia (Chung & Dickenson, 1980). However, the molecular mechanisms of other effects of acupuncture were as yet not defined (Acupuncture, 1997). Scientific evidence of efficacy is an important as for the CAM research, as for research in Western medicine. The enhancement of blood flow in target organs of acupuncture treatment, which is a major reason for the effectiveness of acupuncture (Niimi & Yuwono, 2000), cannot sufficiently explain the recovery of muscle from exhaustion because it is not clear how the supplied oxygen and nutrients would be used during the cellular recovery process. Many cellular and physiological processes are regulated at the transcription level of gene expression. The identification of genes specifically modulated during the process of acupuncture would provide an initial step toward elucidation of the underlying mechanisms of this technique.

Heat shock proteins (Hsp) are a family of stress-inducible molecular chaperones that play multiple roles in a wide variety of animals. However, the roles of Hsps in parasitic nematodes remain largely unknown. To elucidate the roles of Hsps in the survival and longevity of nematodes, particularly at the 2 most critical stages in their lifecycle, the infective-L3 stage and adult stage, which is subjected to host-derived immunological pressure, we examined the temporal gene transcription patterns of Hsp12.6, Hsp20, Hsp70, and Hsp90 throughout the developmental course of the nematode Nippostrongylus brasiliensis by reverse transcriptase real-time PCR. Nb-Hsp70 and Nb-Hsp90 expression were observed throughout the nematode's lifecycle, while the expression of Nb-Hsp20 was restricted to adults. Interestingly, Nb-Hsp12.6 showed a biphasic temporal expression pattern; i.e., it was expressed in infective-L3 larvae and in adults during worm expulsion from immunocompetent rats. However, the activation of Nb-Hsp12.6 in adult worms was aborted when they infected permissive athymic-rnu/rnu rats and was only marginal when they infected mast-cell-deficient Ws/Ws rats, which exhibited a low response of rat mast cell protease (RMCP) II and resistin-like molecule (Relm)- β expression compared to those observed in immunocompetent rats. Moreover, the activation of Nb-Hsp12.6 was reversed when adult worms were transplanted into the naive rat intestine. These features of Nb-Hsp12.6, the expression of which is not only stage-specific in infective-L3, but is also inducible by mucosal immunity in adults, have implications for the survival strategies of parasitic nematodes in deleterious environmental conditions both outside and inside the host.

Licorice ingestion, as well as mutations in theHSD11B2gene, inhibits 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) enzyme activity, causing the syndrome of apparent mineral corticoid excess (AME). However, the combined effect of licorice ingestion and anHSD11B2mutation has never been reported, until now. In this study, we demonstrated that licorice ingestion can produce overt hypertension in an individual without medical history of hypertension who is heterozygous for wild-type and mutantHSD11B2genes. Our patient was a 51-year-old female with serious hypertension who had been taking herbal medicine containing licorice for more than one year. She was clinically diagnosed as having licorice intoxication, because she did not present with hypertension after ceasing the herbal medicine.Molecular analysis showed that she carried a missense mutation, c.40C>T, inHSD11B2. In conclusion, licorice ingestion is an environmental risk factor for hypertension or AME state in patients with a mutation inHSD11B2.Carrying a mutation inHSD11B2is, conversely, a genetic risk factor for licorice-induced hypertension or AME state. Herbal medicine containing licorice may, therefore, be contraindicated in patients with anHSD11B2mutation.

We have been investigating the molecular efficacy of electroacupuncture (EA), which is one type of acupuncture therapy. In our previous molecular biological study of acupuncture, we found an EA-induced gene, named acupuncture-induced 1-L (Aig1l), in mouse skeletal muscle. The aims of this study consisted of identification of the full-length cDNA sequence ofAig1lincluding the transcriptional start site, determination of the tissue distribution ofAig1land analysis of the effect of EA onAig1lgene expression. We determined the complete cDNA sequence including the transcriptional start site via cDNA cloning with the cap site hunting method. We then analyzed the tissue distribution ofAig1lby means of northern blot analysis and real-time quantitative polymerase chain reaction. We used the semiquantitative reverse transcriptase-polymerase chain reaction to examine the effect of EA onAig1lgene expression. Our results showed that the complete cDNA sequence ofAig1lwas 6073 bp long, and the putative protein consisted of 962 amino acids. All seven tissues that we analyzed expressed theAig1lgene. In skeletal muscle, EA induced expression of theAig1lgene, with high expression observed after 3 hours of EA. Our findings thus suggest that theAig1lgene may play a key role in the molecular mechanisms of EA efficacy.

Numerous studies have reported the clinical efficacy of temozolomide (TMZ) treatment for high-grade glioma, but information on Japanese populations has been limited. This study assessed the safety and early outcomes of TMZ treatment, with or without combination therapy.The subjects comprised ten patients with high-grade glioma [glioblastoma multiforme (GBM), n=3, gliosarcoma (GS), n=1, anaplastic oligodendroglioma (AO), n=3, anaplastic mixed oligoastrocytoma (AOA), n=1, and anaplastic ependymoma (AE), n=2]. All the patients were initially treated with conventional radiotherapy following surgical resection with or without adjuvant chemotherapy. As second- or third-line chemotherapy, patients received TMZ for recurrence or tumor progression. As combination therapy, the local administration of tumor necrosis factor-alpha and the addition of carboplatin and etoposide were included for three patients during the course of oral TMZ treatment.Partial response (PR) to TMZ therapy was achieved by four out of the ten patients (objective response rate, 40%), while three patients displayed stable disease (SD) and three showed disease progression (PD). One of the patients receiving combination therapy has continued to show shrinkage of the relapsed tumor. Despite prior radio- and chemotherapy, most patients experienced only grade 1-2 hematotoxicity that was well-controlled by conservative therapy.TMZ chemotherapy is effective for the treatment of high-grade glioma in some patients without serious toxicity. Assessing the true efficacy of TMZ will require a larger study with comparison of long-term outcomes between other agents or combined therapeutic modalities.

We report a case of ruptured tectal arteriovenous malformation (AVM) that was demonstrated angiographically only after removal of an unruptured occipital AVM. A 57-year-old man presented with sudden onset of diplopia and tinnitus. Computed tomography revealed a small hemorrhage in the right tectum mesencephali with intraventricular hemorrhage. Magnetic resonance imaging and angiography disclosed AVM in the right occipital lobe which was separate from the hemorrhagic lesion. Angiography demonstrated that the right occipital AVM was fed by the parieto-occipital artery and drained into the superior sagittal sinus and vein of Galen. However, no abnormal vascular lesion was detected near the tectum mesencephali. As venous hypertension was considered the reason for hemorrhage, the occipital AVM was completely resected. Postoperative angiography demonstrated disappearance of the occipital AVM, but it also disclosed a small tectal AVM fed by branches from the superior cerebellar artery, which had not been detected on preoperative angiography. This was considered the true cause of hemorrhage, and gamma knife surgery was accordingly performed. Even if an AVM is demonstrated, if the lesion does not correspond to the hemorrhage we recommend serial angiographical evaluation so that a small AVM is not missed.

A 37-year-old woman presented with a rare cavernous malformation of the ventral midbrain with brainstem hemorrhage manifesting as sudden onset of headache and vomiting. The lesion was removed successfully through a transsylvian approach and a medial peduncular route. Postoperatively, her oculomotor nerve paresis worsened temporarily, but diplopia disappeared 2 months after surgery. We recommend the transsylvian-transpeduncular approach if the lesion is located in the ventral midbrain and faces the ventral surface of the brainstem, because of the effective access with minimal neurological deficits.

Transthyretin (TTR) associated amyloidosis is an autosomal dominant disorder characterized by peripheral and autonomic neuropathy. Both genetic and environmental factors are thought to be involved in development of TTR associated amyloidosis. Previously, we demonstrated that amyloid deposition was observed in various tissues of transgenic mouse lines carrying a human mutant TTR (Met30) gene. To analyze the influence of environmental factors on TTR amyloidosis, these amyloidogenic transgenic mouse models were kept under conventional (CV) or specific pathogen free (SPF) conditions. Although the serum levels of Met30 for mice housed in the CV and SPF conditions were similar, amyloid deposition was observed in CV conditions, but not in SPF conditions. In addition, the extent of amyloid deposition in transgenic mice was dependent on duration kept under CV conditions. There were significant differences in proportion of amyloid deposition in several tissues between CV and SPF conditions. Maintenance of these mice at 30 degrees C did not induce amyloid deposition in SPF conditions. These results suggest that the SPF conditions can completely prevent amyloid deposition, and that environmental factors can affect the onset and progression even in a single gene disorder.

A 64-year-old man underwent microvascular decompression of the left superior cerebellar artery (SCA) for left trigeminal neuralgia (TN) using a sling of Teflon tape fixed to the tentorium with fibrin glue. The TN disappeared immediately after surgery, but recurred unusually rapidly at 2 weeks later at the same intensity as before. Second surgery revealed the SCA was suspended from the tentorium, but the trigeminal nerve was stretched and displaced superolaterally because of adhesion to the superior petrosal vein. The adhesion was thought to involve the fibrin glue used during the sling retraction procedure. The nerve was meticulously dissected from the adhesion, and the trigeminal nerve was placed in the correct position. The postoperative course was uneventful, and the TN disappeared completely. We recommend that the smallest amount of the fibrin glue possible be used to avoid adhesion to the surrounding neurovascular elements.

Complementary and alternative medicine (CAM) may provide patients with an alternative to traditional medicine, but an assessment of its efficacy is required. One CAM method, electroacupuncture (EA) treatment, is a maneuver that utilizes stimulation of acupuncture needles with a low-frequency microcurrent. To study the effect of short-term EA, we evaluated the differential expression of genes induced by EA in mouse skeletal muscle for up to 24 h. We then used RT-PCR to confirm the expression patterns of six differentially expressed genes. Bioinformatics analysis of their transcription control regions showed that EA-inducible genes have numerous common binding motifs that are related to cell differentiation, cell proliferation, muscle repair, and hyperplasia. These results suggested that EA treatment may induce cell proliferation in skeletal muscle. To verify this possibility, we used EA to stimulate mouse skeletal muscle daily for up to 1 mo and examined the long-term effects. Immunohistochemical analysis showed that nuclei of muscle cells treated with EA for 1 mo, especially nuclei of satellite cells, reacted with anti-human PCNA. Also, expression of the gene encoding myostatin, which is a growth repressor in muscle satellite cells, was suppressed by daily EA treatment for 1 wk; EA treatment for 1 mo resulted in more marked suppression of the gene. These molecular findings constitute strong evidence that EA treatment suppresses myostatin expression, which leads to a satellite cell-related proliferative reaction and repair in skeletal muscle.

Type I familial amyloidotic polyneuropathy (FAP), a systemic amyloidosis, is characterized by aggregation of variant transthyretin (TTR Val30Met) into stable, insoluble fibrils. This aggregation is caused by genetic and environmental factors. Genetic factors have been studied extensively. However, little is known about environmental or physiological factors involved in the disease process, and their identification may be important for development of effective treatment. X-ray crystallography of normal and amyloidogenic human TTR Val30Met in type I FAP showed that the −SH side chain of cysteine at position 10 (Cys10) forms a hydrogen bond with Gly57 in normal TTR but not in TTR Val30Met. This result suggests a crucial role for the free Cys10 residue and possible involvement of physiological factors affecting Cys residue reactivity in TTR amyloidogenesis. To analyze amyloidogenesis in vivo, our group generated murine FAP models by transgenic technology, with human TTR Val30Met. The three lines of transgenic mice expressed amyloidogenic mutant TTR (Cys10/Met30), wild-type TTR (Cys10/Val30), and artificial Cys-free mutant TTR (Ser10/Met30). Histochemical investigation showed deposition of amyloid derived from human TTR only in amyloidogenic mutant TTR (Cys10/Met30) mice. Thus, the −SH residue in Cys10 plays a crucial role in TTR Val30Met amyloidogenesis in vivo. These data suggest the possibility of innovative treatment via physiological factors modulating Cys10 residue reactivity.