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COVID-19 is pandemic since 2020 and further information is necessary on the risk factors associated with the infection of SARS-CoV-2. As an entry mechanism, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as receptor and transmembrane serine protease 2 (TMPRSS2) to activate fusion with host plasma membrane. Because dysgeusia is an early symptom of COVID-19, we here studied the expression of ACE2 and TMPRSS2 in the tongue and the associated tissues of mice and humans with immunohistochemistry and immunoblot analysis. ACE2 expression was low in the human tongue but was observed in the squamous epithelium, perineurium, arterial wall, salivary glands as well as taste buds. In contrast, mice showed high expression. In sharp contrast, TMPRSS2 expression was high in all the cells mentioned above in humans but relatively low in mice except for salivary glands. We then performed semi-quantitation of immunohistochemistry data of human ACE2 and TMPRSS2 and analyzed for age, sex, alcohol intake, and smoking habit with logistic regression analysis. We found that alcohol intake and female gender were the significant risk factors for increasing TMPRSS2 expression. In conclusion, TMPRSS2 is an important factor to be considered regarding SARS-CoV-2 entry and amplification in the oral cavity, which is promoted through drinking habit.

Lingual artery (LA) aneurysms are particularly rare, and pseudoaneurysms are associated with trauma, infection, and surgical intervention. LA aneurysms can be fatal if not recognised or treated; however, only a few cases of idiopathic LA aneurysms have been reported in the literature, all of which have been described as pseudoaneurysms. To address this knowledge gap in reporting a true LA aneurysm, here, we describe a 55-year-old woman with an idiopathic aneurysm of the lingual artery. The lesion was detected by another department on a computed tomographic angiography of the neck, which was performed as a post-aneurysmectomy evaluation of the right internal carotid artery. The embolisation failed twice, after which we performed an aneurysmectomy of the left atrium. A histopathological examination of the excised aneurysms revealed fibromuscular dysplasia (FMD). Thus, we believe that FMD may be a cause of external LA aneurysms. Our findings will be relevant for oral surgeons and physicians who may consider FMD as a differential diagnosis when treating multiple LA aneurysms.

Previous studies have shown that dissolved substances in some natural hot springs have analgesic/anti-nociceptive and anti-inflammatory actions. However, the mechanisms underlying how such dissolved substances exert these actions are not fully understood. In the present study on mice, we examined the analgesic/anti-nociceptive and anti-inflammatory properties of a mineral cream containing natural hot spring ingredients. The anti-nociceptive effects of the mineral cream were assessed by using the von Frey test. Application of the mineral cream to the hind paw of mice produced a significant anti-nociceptive effect compared to control. The anti-nociceptive effects of the mineral cream were also assessed following the injection of complete Freund's adjuvant (CFA) into the hind paws of mice after pre-treatment for one or four weeks with the mineral cream. Histological experiments with light microscopy showed that the mineral cream did not reduce inflammation caused by the CFA treatment. In addition, the mineral cream did not inhibit oxidative stress as evidenced by increased levels of oxidative metabolites (d-ROMs) and biological anti-oxidant potential (BAP). These results suggest that the mineral cream does not exert a protective effect against inflammation, and that the constituents of the mineral cream may produce their anti-nociceptive effects transdermally via different mechanisms including the nervous system.

The 5-HT5A receptor is arguably the least understood 5-HT receptor. Despite widespread expression in human and rodent brains it lacks specific ligands. Our previous results suggest that 5-HT5A receptor antagonists may be effective against cognitive impairment in schizophrenia. In this study, using behavioral, immunohistochemical, electrophysiological and microdialysis techniques, we examined the mechanism by which ASP5736, a novel and selective 5-HT5A receptor antagonist, exerts a positive effect in animal models of cognitive impairment. We first confirmed the effect of ASP5736 on cognitive deficits in rats treated subchronically with phencyclidine hydrochloride (PCP) using an attentional set shifting task. Subsequently, we identified 5-HT5A receptors in dopaminergic (DAergic) neurons and parvalbumin (PV)-positive interneurons in the ventral tegmental area (VTA) and in PV-positive interneurons in the medial prefrontal cortex (mPFC). Burst firing of the DAergic cells in the parabrachial pigmental nucleus (PBP) in the VTA, which predominantly project to the mPFC, was significantly enhanced by treatment with ASP5736. In contrast, ASP5736 exerted no significant effect on either the firing rate or burst firing in the DA cells in the paranigral nucleus (PN), that project to the nucleus accumbens (N. Acc.). ASP5736 increased the release of DA and gamma-aminobutyric acid (GABA) in the mPFC of subchronically PCP-treated rats. These results support our hypothesis that ASP5736 might block the inhibitory 5-HT5A receptors on DAergic neurons in the VTA that project to the mPFC, and interneurons in the mPFC, and thereby improve cognitive impairment by preferentially enhancing DAergic and GABAergic neurons in the mPFC.

Introduction: Direct oral anticoagulants are widely used in patients with nonvalvular atrial fibrillation (AF) to reduce the risk of stroke and systemic embolism, however, there is not enough real-world data of their effectiveness and safety in patients with worsening renal function (WRF). Xarelto post-authorization safety and effectiveness study in Japanese patients with atrial fibrillation (XAPASS) is a prospective observational post-marketing surveillance study mandated by the Japanese authority. It aims to examine safety and effectiveness of rivaroxaban in everyday clinical practice. This analysis investigated one year outcomes among patients with WRF and stable renal function (SRF) in XAPASS. Methods: One year follow-up data of 9578 patients enrolled in XAPASS were analyzed to evaluate baseline characteristics and safety/effectiveness profile among patients with WRF and SRF. WRF was defined as a decrease of more than 20% from enrollment creatinine clearance measurement at any time point during the study. SRF was defined as the absence of WRF at any time. Results: We identified 1229 patients (12.8%) with WRF and 6280 patients (65.6%) with SRF among 9578 patients. WRF patients were significantly older, and had significantly higher mean CHA 2 DS 2 -VASc score and modified HAS-BLED score compared to SRF patients. Prevalence of hypertension, congestive heart failure, ischemic stroke/transient ischemic attack, and myocardial infarction was higher in WRF patients. There was no difference in rates of major bleeding (hazard ratio (HR) 1.20; 95% confidence interval (CI) 0.75-1.90; p=0.45) or the composite endpoint of stroke, systemic embolism or myocardial infarction (HR 1.06; 95% CI 0.65-1.71; p=0.82) between patients with WRF and SRF. WRF patients experienced a higher incidence of transfusion of 2 units or more (0.46 versus 0.14 events per 100 patient-years; HR 3.19; 95% CI 1.04-9.74; p=0.03) versus SRF patients. Rates of other major bleeding subgroups defined according to ISTH criteria were similar between patients with WRF and SRF. Conclusions: WRF during rivaroxaban treatment did not significantly increase the rates of major bleeding or thromboembolic events, although it was associated with a higher incidence of transfusion of 2 units or more.

Metal dental restoration materials cause dose enhancement upstream and dose disturbance downstream of the high‐density inhomogeneous regions in which these materials are used. In this study, we evaluated the impact of a dental metallic crown (DMC) on intensity‐modulated radiotherapy (IMRT) and volumetric‐modulated arc therapy (VMAT) for head and neck cancer. Additionally, the possibility of sparing the oral mucosa from dose enhancement using an individual intraoral mouthpiece was evaluated. An experimental oral phantom was designed to verify the dosimetric impact of a DMC. We evaluated the effect on single beam, parallel opposing beam, arc beam, IMRT, and VMAT treatment plans. To evaluate the utility of a 3‐mm‐thick intraoral mouthpiece, the doses across the mouthpiece were measured. For single beam irradiation, the measured doses at the entrance and exit planes of the DMC were 51% higher and 21% lower than the calculated dose by the treatment planning system, respectively. The maximum dose enhancements were 22% and 46% for parallel opposing beams and the 90° arc rotation beam, respectively. For IMRT and VMAT, the measured doses adjacent to the DMC were 12.2%±6.3% (mean±1.96 SD) and 12.7%±2.5% higher than the calculated doses, respectively. With regard to the performance of the intraoral mouthpiece for the IMRT and VMAT cases, the disagreement between measured and calculated doses at the outermost surface of the mouthpieces were −2.0%, and 2.0%, respectively. Dose enhancements caused by DMC‐mediated radiation scattering occurred during IMRT and VMAT. Because it is difficult to accurately estimate the dose perturbations, careful consideration is necessary when planning head and neck cancer treatments in patients with DMCs. To spare the oral mucosa from dose enhancement, the use of an individual intraoral mouthpiece should be considered. PACS numbers: 87.55.km, 87.55.N‐, 87.55.Qr

Previous studies have shown that dissolved substances in some natural hot springs have analgesic/anti-nociceptive and anti-inflammatory actions. However, the mechanisms underlying how such dissolved substances exert these actions are not fully understood. In the present study on mice, we examined the analgesic/anti-nociceptive and anti-inflammatory properties of a mineral cream containing natural hot spring ingredients. The anti-nociceptive effects of the mineral cream were assessed by using the von Frey test. Application of the mineral cream to the hind paw of mice produced a significant anti-nociceptive effect compared to control. The anti-nociceptive effects of the mineral cream were also assessed following the injection of complete Freund's adjuvant (CFA) into the hind paws of mice after pre-treatment for one or four weeks with the mineral cream. Histological experiments with light microscopy showed that the mineral cream did not reduce inflammation caused by the CFA treatment. In addition, the mineral cream did not inhibit oxidative stress as evidenced by increased levels of oxidative metabolites (d-ROMs) and biological anti-oxidant potential (BAP). These results suggest that the mineral cream does not exert a protective effect against inflammation, and that the constituents of the mineral cream may produce their anti-nociceptive effects transdermally via different mechanisms including the nervous system.

Background Alpha-glucosidase inhibitors are recommended in some international guidelines as first-line, second-line and third-line treatment options but are not used worldwide due to perceived greater effectiveness in Asians than Caucasians. Methods Data from ten post-marketing non-interventional studies using acarbose, the most widely used alpha-glucosidase inhibitor, from 21 countries, provinces and country groups were pooled. Effects on glycated hemoglobin (HbA1c) were analysed for four major ethnicity/region groups (European Caucasians and Asians from East, Southeast and South Asia) to identify differences in the response to acarbose. Results The safety and efficacy populations included 67 682 and 62 905 patients, respectively. Mean HbA1c in the total population decreased by 1.12 ± 1.31% at the 3-month visit from 8.4% at baseline (p

CD109 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, whose expression is upregulated in squamous cell carcinomas of the lung, esophagus, uterus and oral cavity. CD109 negatively regulates transforming growth factor (TGF)-beta signaling in keratinocytes by directly modulating receptor activity. In this study, we further characterized CD109 regulation of TGF-beta signaling and cell proliferation. We found that CD109 is produced as a 205 kDa glycoprotein, which is then processed in the Golgi apparatus into 180 kDa and 25 kDa proteins by furin (furinase). 180 kDa CD109 associated with GPI-anchored 25 kDa CD109 on the cell surface and was also secreted into the culture medium. To investigate whether furinase cleavage of CD109 is necessary for its biological activity, we mutated arginine 1273 in the CD109 furinase cleavage motif (amino acid 1270-RRRR-1273) to serine (R1273S). Interestingly, CD109 R1273S neither significantly impaired TGF-beta signaling nor affected TGF-beta-mediated suppression of cell growth, although it was expressed on the cell surface as a 205 kDa protein. Consistent with this finding, the 180 kDa and 25 kDa CD109 complex, but not CD109 R1273S, associated with the type I TGF-beta receptor. These findings indicate that processing of CD109 into 180 kDa and 25 kDa proteins by furin, followed by complex formation with the type I TGF-beta receptor is required for the regulation of TGF-beta signaling in cancer cells and keratinocytes.

Dopaminergic neurons are more vulnerable than other types of neurons in cases of Parkinson disease and ischemic brain disease. An increasing amount of evidence suggests that endogenous dopamine plays a role in the vulnerability of dopaminergic neurons. Although glutamate toxicity contributes to the pathogenesis of these disorders, the sensitivity of dopaminergic neurons to glutamate toxicity has not been clarified. In this study, we demonstrated that dopaminergic neurons were preferentially affected by glutamate toxicity in rat mesencephalic cultures. Glutamate toxicity in dopaminergic neurons was blocked by inhibiting extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase, and p38 MAPK. Furthermore, depletion of dopamine by alpha-methyl-dl-p-tyrosine methyl ester (alpha-MT), an inhibitor of tyrosine hydroxylase (TH), protected dopaminergic neurons from the neurotoxicity. Exposure to glutamate facilitated phosphoryration of TH at Ser31 by ERK, which contributes to the increased TH activity. Inhibition of ERK had no additive effect on the protection offered by alpha-MT, whereas alpha-MT and c-jun N-terminal kinase or p38 MAPK inhibitors had additive effects and yielded full protection. These data suggest that endogenous dopamine is responsible for the vulnerability to glutamate toxicity of dopaminergic neurons and one of the mechanisms may be an enhancement of dopamine synthesis mediated by ERK.

Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic (DA) neuronal cell loss in the substantia nigra. Although the entire pathogenesis of PD is still unclear, both environmental and genetic factors contribute to neurodegeneration. Epidemiologic studies show that prevalence of PD is lower in smokers than in nonsmokers. Nicotine, a releaser of dopamine from DA neurons, is one of the candidates of antiparkinson agents in tobacco. To assess the protective effect of nicotine against rotenone-induced DA neuronal cell toxicity, we examined the neuroprotective effects of nicotine in rotenone-induced PD models in vivo and in vitro. We observed that simultaneous subcutaneous administration of nicotine inhibited both motor deficits and DA neuronal cell loss in the substantia nigra of rotenone-treated mice. Next, we analyzed the molecular mechanisms of DA neuroprotective effect of nicotine against rotenone-induced toxicity with primary DA neuronal culture. We found that DA neuroprotective effects of nicotine were inhibited by dihydro-beta-erythroidine (DHbetaE), alpha-bungarotoxin (alphaBuTx), and/or PI3K-Akt/PKB (protein serine/threonine kinase B) inhibitors, demonstrating that rotenone-toxicity on DA neurons are inhibited via activation of alpha4beta2 or alpha7 nAChRs-PI3K-Akt/PKB pathway or pathways. These results suggest that the rotenone mouse model may be useful for assessing candidate antiparkinson agents, and that nAChR (nicotinic acetylcholine receptor) stimulation can protect DA neurons against degeneration.

Background: We recently began using preoperative chemotherapy delivered by superselective intraarterialinfusion via the superficial temporal artery as a treatment for oral cancer. However, catheterization is difficultin some patients because of the presence of a common trunk and angiectopia and hemadostenosis of theexternal carotid artery and tumor nutrient arteries. The purpose of this study was to conduct a clinicoanatomicalinvestigation of the external carotid artery and tumor nutrient arteries by digital subtraction angiography.Method: We conducted an anatomical investigation of the external carotid artery and its branches in 58 patients (69 sites) by digital subtraction angiography.Results: There were many variations in the branch patterns of the external carotid artery. In 53.6% of thepatients, branches arose in the order of the superior thyroid, lingual, facial, occipital, and maxillary arteries fromthe proximal side. In 24.6 % of the patients, the lingual artery formed a common trunk with the facial artery. In1.4%, the lingual artery formed a common trunk with the superior thyroid artery. The length of the faciolingualtrunk in 76.5% of the patients was long and anticancer agents flowed into both the lingual and the facial arteries.Severe hemadostenosis of the main trunk of the external carotid artery was observed in 7.2% of the patients.Severe angiectopia of the main trunk of the external carotid artery interferred with catheterization in 5.8 % of thepatients.Conclusion: These results provide a clinicoanatomical basis for intraarterial infusion via the superficial temporalartery. The noteworthy points for catheterization were the presence and length of the common trunk of the tumornutrient arteries and the existence of angiectopia or hemadostenosis of the external carotid artery.

Caveolin-1 is a component of lipid rafts, and is considered to be a tumor suppressor molecule. However, the mechanisms by which caveolin-1 functions in cancer cells are not well understood. We generated caveolin-1 transfectant cells (Cav-1(+) cells) using a human melanoma cell line (SK-MEL-28) and investigated the effects of caveolin-1 overexpression on the GD3-mediated malignant properties of melanomas. Cav-1(+) cells had decreased cell growth and motility, and reduced phosphorylation levels of p130Cas and paxillin relative to controls. In floatation analysis, although GD3 was mainly localized in glycolipid-enriched microdomain (GEM)/rafts in control cells, it was dispersed from GEM/rafts in Cav-1(+) cells. Correspondingly, GD3 in Cav-1(+) cells stained uniformly throughout the membrane, whereas control cells showed partial staining of the membrane, probably at the leading edge. p130Cas and paxillin were stained in the leading edges and colocalized with GD3 in the control cells. In contrast, these molecules were diffusely stained and no definite leading edges were detected in Cav-1(+) cells. These results suggest that caveolin-1 regulates GD3-mediated malignant signals by altering GD3 distribution and leading edge formation. These results reveal one of the mechanisms by which caveolin-1 curtails the malignant properties of tumor cells.

The cause of selective dopaminergic neuronal degeneration in Parkinson disease has still not been resolved, but it has been hypothesized that oxidative stress and the ubiquitin-proteasome system are important in the pathogenesis. In this report, we investigated the effect of proteasome inhibition on oxidative stress-induced cytotoxicity in PC12 cells, an in vitro model of Parkinson disease. Treatment with proteasome inhibitors provided significant protection against toxicity by 6-hydroxydopamine and H(2)O(2) in a concentration-dependent manner. The measurement of intracellular reactive oxygen species using 2',7'-dichlorofluorescein diacetate demonstrated that lactacystin, a proteasome inhibitor, significantly reduced 6-hydroxydopamineand H(2)O(2)-induced reactive oxygen species production. Proteasome inhibitors elevated the amount of glutathione and phosphorylated p38 mitogen-activated protein kinase (MAPK) prior to glutathione elevation. The treatment with lactacystin induced the nuclear translocation of NF-E2-related factor 2 (Nrf2) and increased the level of mRNA for gamma-glutamylcysteine synthetase, a rate-limiting enzyme in glutathione synthesis. Furthermore, SB203580, an inhibitor of p38 MAPK, abolished glutathione elevation and cytoprotection by lactacystin. These data suggest that proteasome inhibition afforded cytoprotection against oxidative stress by the elevation of glutathione content, and its elevation was mediated by p38 MAPK phosphorylation.

頭頸部癌に対する超選択的動注化学療法は，Seldinger法を用いた大腿動脈からの方法と浅側頭動脈よりの逆行性にカテーテルを挿入する方法（HFT法）とに大きくわけられる。HFT法はカテーテルの長期留置ができることから放射線との連日同時併用が可能であり，比較的安全性の高い治療方法である。今回われわれは進行口腔癌に対してdocetaxelとcisplatinを用い，超選択的動注化学療法と放射線療法との連日同時併用療法を行い，原発温存症例につき検討した。口腔癌T3，4の23例について検討した結果，19例（83%）については原発がコントロールされ，4例（17%）が再発した。4例中3例は手術を施行し，局所制御されている。23例中21例（87%）が生存し2例が死亡した。2例の内訳は1例が原発の再発で局所のコントロールができず，あとの1例は遠隔転移によるものであった。生存率は，1年生存率95.5%，3年生存率79.5%，5年生存率79.5%であった。超選択的動注化学療法では治療前に腫瘍の栄養動脈を同定し，確実に抗癌剤を投与することが重要である。HFT法を用いた連日同時放射線化学療法は生存率の向上，原発温存，さらには頸部郭清術の回避などの多くの利点を期待できる治療法である。

This is the author-created version of Springer, Yamamoto, Noriyuki ; Hashimoto, Masaaki, International Journal of Biometeorology, 51(3), 2007, 201-208. The original publication is available at www.springerlink.com. author, Like humans, the heart rate (HR) of anesthetized rats immersed in CO2-water is lower than that when immersed in tap water at the same temperature. To investigate the afferent signal pathway in the mechanism of HR reduction, Wistar rats were anesthetized with urethane and then the spinal cord was transected between T4 and T5. The animals were immersed up to the axilla in a bathtub of tap-water (CO2 contents: 10–20 mg·l−1) or of CO2-water (965–1,400 mg·l−1) at 35°C while recording HR, arterial blood pressure, and arterial blood gas parameters (PaCO2, PaO2, pH). Arterial blood gas parameters did not change during immersion, irrespective of CO2 concentration of the bath water, whereas the HR was reduced in the CO2-water bath. The inhalation of CO2-mixed gas (5 % CO2, 20 % O2, 75 % N2) resulted in increased levels of blood gases and an increased HR during immersion in all types of water tested. The HR reduction observed in sham transected control animals immersed in CO2-water disappeared after subsequent spinal cord transection. These results show that the dominant afferent signal pathway to the brain, which is involved in inducing the reduced HR during immersion in CO2-water, is located in the neuronal route and not in the bloodstream.

Stem cells from human exfoliated deciduous teeth (SHEDs) can regenerate various tissues. We investigated the impact of SHED-conditioned medium (SHED-CM) on myocardial injury in a mouse model of ischemia-reperfusion (I/R). Wild-type (WT) mice were subjected to myocardial ischemia followed by reperfusion. SHED-CM was intravenously injected at 5 min after reperfusion. Administration of SHED-CM reduced myocardial infarct size as well as decreased apoptosis and inflammatory cytokine levels, such as TNF-α, IL-6 and IL-β, in the myocardium following I/R. In cultured cardiac myocytes, SHED-CM significantly suppressed apoptosis under hypoxia/serum-deprivation and reduced LPS-induced expression of pro-inflammatory genes. Furthermore, anti-apoptotic action of SHED-CM was stronger than bone marrow-derived stem cell (BMSC)-CM or adipose-derived stem cell (ADSC)-CM in cardiac myocytes. SHED-CM contains a higher concentration of hepatocyte growth factor (HGF) than BMSC-CM and ADSC-CM and neutralization of HGF attenuated the inhibitory actions of SHED-CM on apoptosis in cardiac myocytes. Finally, WT mice were intravenously treated with an HGF-depleted SHED-CM, followed by myocardial I/R. HGF depletion significantly attenuated the inhibitory actions of SHED-CM on myocardial infarct size and apoptosis after I/R. SHED-CM protects the heart from acute ischemic injury because it suppresses inflammation and apoptosis. SHED-CM could be a useful treatment option for acute myocardial infarction.

Oxidative stress and the ubiquitin-proteasome system play a key role in the pathogenesis of Parkinson disease. Although the herbicide paraquat is an environmental factor that is involved in the etiology of Parkinson disease, the role of 26S proteasome in paraquat toxicity remains to be determined. Using PC12 cells overexpressing a fluorescent protein fused to the proteasome degradation signal, we report here that paraquat yielded an inhibitory effect on 26S proteasome activity without an obvious decline in 20S proteasome activity. Relative low concentrations of proteasome inhibitors caused the accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is targeted to the ubiquitin-proteasome system, and activated the antioxidant response element (ARE)-dependent transcription. Paraquat also upregulated the protein level of Nrf2 without increased expression of Nrf2 mRNA, and activated the Nrf2-ARE pathway. Consequently, paraquat induced expression of Nrf2-dependent ARE-driven genes, such as γ-glutamylcysteine synthetase, catalase, and hemeoxygenase-1. Knockdown of Nrf2 or inhibition of γ-glutamylcysteine synthetase and catalase exacerbated paraquat-induced toxicity, whereas suppression of hemeoxygenase-1 did not. These data indicate that the compensatory activation of the Nrf2-ARE pathway via inhibition of 26S proteasome serves as part of a cellular defense mechanism to protect against paraquat toxicity.

Background aims Acute respiratory distress syndrome (ARDS) is a severe inflammatory disorder characterized by acute respiratory failure, resulting from severe, destructive lung inflammation and irreversible lung fibrosis. We evaluated the use of stem cells derived from human exfoliated deciduous teeth (SHEDs) or SHED-derived serum-free conditioned medium (SHED-CM) as treatments for bleomycin (BLM)-induced mice acute lung injury (ALI), exhibiting several pathogenic features associated with the human disease ARDS. Methods Mice with BLM-induced ALI with or without SHED or SHED-CM treatment were examined for weight loss and survival. The lung tissue was characterized by histological and real-time quantitative polymerase chain reaction analysis. The effects of SHED-CM on macrophage differentiation in vitro were also assessed. Results A single intravenous administration of either SHEDs or SHED-CM attenuated the lung injury and weight loss in BLM-treated mice and improved their survival rate. Similar recovery levels were seen in the SHEDs and SHED-CM treatment groups, suggesting that SHED improves ALI by paracrine mechanisms. SHED-CM contained multiple therapeutic factors involved in lung-regenerative mechanisms. Importantly, SHED-CM attenuated the BLM-induced pro-inflammatory response and generated an anti-inflammatory/tissue-regenerating environment, accompanied by the induction of anti-inflammatory M2-like lung macrophages. Furthermore, SHED-CM promoted the in vitro differentiation of bone marrow–derived macrophages into M2-like cells, which expressed high levels of Arginase1 , CD206 and Ym-1 . Discussion Our results suggest that SHED-secreted factors provide multifaceted therapeutic effects, including a strong M2-inducing activity, for treating BLM-induced ALI. This work may open new avenues for research on stem cell–based ARDS therapies.

BACKGROUND Traditional risk factors of cardiovascular disease do not fully explain the accelerated atherosclerosis present in patients with end-stage renal disease (ESRD). The goal of this study was to identify the association of clinical and laboratory factors including seropositivity for Chlamydia pneumoniae determined by a specific enzyme-linked immunosorbent assay (ELISA) with the presence of coronary artery disease identified by coronary angiography in ESRD patients. METHODS We prospectively enrolled 161 consecutive ESRD patients undergoing haemodialysis for >6 months (106 men, 55 women; mean age 63.1+/-10.2 years; mean dialysis duration 91.3+/-90.1 months). All patients underwent coronary angiography within 1 week after blood sampling. The associations of coronary artery disease with clinical parameters including C. pneumoniae IgA and IgG seropositivity were analysed using multiple logistic regression models. RESULTS Coronary stenosis >50% was found in 102 of 161 haemodialysis patients (63.4%). Of the 102 patients, 75.5% were asymptomatic. Seropositivity for C. pneumoniae IgA was found in patients with coronary stenosis (77 out of 102, 75.5%) more frequently (P

水処理装置 (以下RO装置) から個人用透析装置 (以下透析装置) までのRO水供給ライン (以下RO水ライン) は通常洗浄消毒されず, 一度汚染されると細菌繁殖が起こる可能性がある. われわれは, RO水ラインの洗浄消毒に適当と思われる残留性が低く強い酸化力のあるオゾン水に着目した. 今回, 新しく開発された高濃度オゾン水生成装置OZROCK-2 (ワールドメディカル社製) をRO装置後のRO水ライン上に設置し, オゾン水単独によるRO水ライン清浄化の保持と透析装置および周辺機器の洗浄消毒を行った. OZROCK-2は大気から分離した酸素ガスを用い電気分解にてオゾンガスを発生させ, RO水と混合することでオゾン水を生成する. OZROCK-2をRO装置直後のRO水ラインに設置し, オゾン水を流すことにより全てのRO水ラインおよび関連装置をオゾン水単独での洗浄・消毒が可能であった. 清浄化の指標であるET活性値は, 末端個人用透析装置入口において, オゾン水導入前後における15か月平均で, それぞれ導入前77.03±71.2EU/L, 後で3.83±7.2EU/Lと有意に低下した.オゾン水による透析装置への影響については, 使用6か月目に一部の透析装置にタンパク様物質の付着がみられたため, 塩素系薬剤との併用で解消した. また, 使用12か月目で一部メーカーの電磁弁弁シートに脱色が確認されたが, 部品の性能に問題はなかった.オゾン水によるRO水ラインおよび透析周辺機器の洗浄消毒は有効であり, 透析液の清浄化保持に有用と思われた.

Alpha-glucosidase inhibitors are widely used especially in Asian countries as a treatment option for type 2 diabetes patients with high postprandial glycemia (PPG). The higher carbohydrate in the Indian diets lead to greater prandial glycemic excursion, increased glucosidase, and incretin activity in the gut and may need special therapeutic strategies to tackle these glucose peaks. This is the subgroup analysis of Indian subjects who participated in the GlucoVIP study that investigated the effectiveness and tolerability of acarbose as add-on or monotherapy in a range of patients with type 2 diabetes mellitus. A total of 1996 Indian patients were included in the effectiveness analysis. After 12.5 weeks (mean), the mean change in 2-hour PPG from baseline was −74.4 mg/dl, mean HbA1c decreased by -1.0%, and mean fasting blood glucose decreased by -37.9 mg/dl. The efficacy of acarbose was rated "very good" or "good" in 91.1% of patients, and tolerability as "very good" or "good" in 88.0% of patients. The results of this observational study suggest that acarbose was effective and well tolerated in the Indian patients with T2DM.

Parkinson's disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies. alpha-Synuclein is a major component of Lewy bodies, but the process of its accumulation and its relationship to dopaminergic neuronal death has not been resolved. Although the pathogenesis has not been clarified, mitochondrial complex I is suppressed, and caspase-3 is activated in the affected midbrain. Here we report that a combination of 1-methyl-4-phenylpyridinium ion (MPP(+)) or rotenone and proteasome inhibition causes the appearance of alpha-synuclein-positive inclusion bodies. Unexpectedly, however, proteasome inhibition blocked MPP(+)- or rotenone-induced dopaminergic neuronal death. MPP(+) elevated proteasome activity, dephosphorylated mitogen-activating protein kinase (MAPK), and activated caspase-3. Proteasome inhibition reversed the MAPK dephosphorylation and blocked caspase-3 activation; the neuroprotection was blocked by a p42 and p44 MAPK kinase inhibitor. Thus, the proteasome plays an important role in both inclusion body formation and dopaminergic neuronal death but these processes form opposite sides on the proteasome regulation in this model.

虚血性心疾患は血液透析患者の主要な死因の一つである. 冠動脈疾患の検出に心臓核医学検査は有用であるが運動・薬剤負荷を必要とし, 透析患者では, その実施・判定に困難を伴うことが多い. 正常心筋はエネルギー源の70%以上を効率のよい脂肪酸β酸化に依存しているが, 心筋虚血時には脂肪酸のβ酸化が抑制され, 代わってグルコースを利用した解糖系へ移行する. 透析患者の冠動脈病変検出における心筋脂肪酸代謝イメージング製剤である123I-BMIPPの安静時検査の有用性を検討した.慢性腎不全による維持血液透析患者130例 (平均透析期間88.5か月, 男性77例, 女性53例, 平均年齢63.8歳) に対し心筋血流製剤である塩化タリウム (201TI) ならびに123I-BMIPPのSPECT (single photon emission computed tomography) を施行し, その後60日以内に施行された冠動脈造影検査所見と対比した. 左室心筋を17分画し, TIおよびBMIPP SPECT所見を視覚的に判定, スコア化し (0: 正常-4: 欠損), その総計をTIならびにBMIPP summed scoreとした.冠動脈造影の結果, 対象患者の71.5%に75%以上の有意狭窄を認めた. BMIPP summed score 6以上を陽性とした場合, BMIPP-SPECTの冠動脈病変の総合正診率は90.0% (感度: 98.0%, 特異度: 65.6%) であった. 一方, TI-SPECTでは, TI summed score 1以上を陽性とした場合, 感度84.7%, 特異度46.9%, 総合正診率75.0%であった. ROC解析の結果, 冠動脈病変診断能を示すAUC (area under the curve) は, BMIPP SPECT 0.895, TI SPECT 0.727であった.BMIPP-SPECTはTI-SPECTに比して高い精度で冠動脈病変を検出できる. 慢性血液透析患者の冠動脈造影検査の適応判定ならびに冠動脈疾患合併の安全なスクリーニング検査として臨床的に有用である.

Background. The incidence of intracardiac thrombosis in haemodialysis patients has not been studied. Here we determined the incidence in end-stage renal disease patients on maintenance haemodialysis. Methods. Transoesophageal echocardiography was performed in 215 patients (125 males, 90 females; mean age 60 ± 9 years). Any potential candidate with current or past chronic or intermittent atrial fibrillation or with cardiovascular diseases was excluded from the study. Results. Thrombi were found in the left atrial appendages in 71 out of 215 subjects (33%). Based on multiple logistic regression analyses, the probability of finding a thrombus was found to be increased in patients on chronic antiplatelet therapy (odds ratio 4.268) and in those with diabetes mellitus and a low haematocrit (� 0.3; odds ratio 7.173). Other clinical parameters, including gender, age, duration of haemodialysis, blood pressure, left ventricular dimension, smoking habit or type of anticoagulation during dialysis, were not associated with the incidence of left atrial appendage thrombosis. Conclusions. Maintenance haemodialysis patients have a high incidence of left atrial appendage thrombosis. Either chronic use of antiplatelet drugs or the background conditions requiring antiplatelet therapy, and the concomitant presence of diabetes mellitus and a low haematocrit may be involved in left atrial appendage thrombosis.

目的: 慢性腎不全による維持血液透析例の左室肥大の成因について, 糖尿病 (DM) 罹患の有無の観点から臨床的に検討した. 対象と方法: 維持血液透析患者486例 (DM145例, 非DM341例) を対象に, 透析前に心臓超音波検査を施行し, 心機能とともに心室中隔径 (IVST), 相対的左室壁厚 (rLVWT), 左室重量係数 (LVMI) を計測した. 透析施行直前のヘマトクリット値, 血漿BNP濃度, 血漿アルドステロン濃度を測定し, 左室肥大との関係を検討した. 結果: 非DM例では, 左室壁ストレスの指標である血漿BNP濃度は, LVMI (r=0.245, p=0.0001), IVST (r=0.250, p=0.0001), rLVWT (r=0.149, p=0.006) と正相関を示した. LVWIは, 透析前後の平均血圧および脈圧, IVSTならびにrLVWTは, 透析前後の脈圧と正相関を示した. DM例では, LVMI, IVST, rLVWTのいずれも血漿BNP濃度, 透析前後の血圧・脈圧値との関連はなかった. 非DM・DM例ともに, ヘマトクリット値, 血漿アルドステロン濃度は左室肥大の指標との関連を認めなかった. 結論: 非DM性透析患者では持続的な容量・圧負荷による左室壁ストレス増加に対して左室心筋リモデリングによる代償性の左室肥大を生じる. DM性透析患者では, 左室肥大は圧・容量負荷とは関係なく生じ, 左室壁ストレスに対する心筋リモデリング・代償性左室肥大の機構に障害がある可能性がある.

Stage III, IVの38例の口腔癌患者に対して浅側頭動脈よりの超選択的動注法を用いた術前放射線化学療法を施行した。化学療法はCBDCA: 460mg/m2, 放射線治療は40Gyを連日併用で4週間行い, 後に根治手術を施行した。カテーテル挿入率は89.4%であり, 挿入が不可能であった症例は舌動脈と顔面動脈との長い共同幹などが原因であった。重篤な合併症はみられなかった。臨床効果はCRが9例 (26.5%), PRが25例 (73.5%) であった。原発巣の摘出物の病理効果は grade III, IVが10例 (29.4%), grade IIbが23例 (67.6%), grade IIaが2例 (5.8%) であった。経過観察期間は8ケ月から最高63ケ月であり, 平均35ケ月であった。予後は5年累積生存率は67.8%と高い値であった。浅側頭動脈からの超選択的動注療法は連日の放射線との併用療法が可能であり, また合併症も少なく, 有用性が期待できた。