Attenuated Mycobacterium lepraemurium Vaccine Non-Protective against Mycobacterium intracellulare Infection in Mice

Since Mycobacterium lepraemurium (Mlm) is closely related to Mycobacterium intracellulare, with respect to its antigenicity, attenuated Mlm obtained by passages on 1% Ogawa egg medium was examined for possible effects as a vaccine against M. intracelJulare infection. Four weeks after subcutaneous injection of Mlm (1.4 x 107 bacilli), mice were infected intravenously with 2.4 x 107 organisms per mouse of M. intracellulare. During the first 12 weeks, no difference was noted in the rate of progression of M. intracellulare infection between mice given or not given Mlm-vaccine, when severity of the infection was measured on the basis of the number of viable M. intracellulare in the lungs and spleen. Therefore, Mlm-vaccine is probably not efficacious in protecting mice against M. intracellulare infection

A novel anti-TNF-α drug ozoralizumab rapidly distributes to inflamed joint tissues in a mouse model of collagen induced arthritis

In clinical studies, the next-generation anti-tumor necrosis factor-alpha (TNF-α) single domain antibody ozoralizumab showed high clinical efficacy shortly after the subcutaneous injection. To elucidate the mechanism underlying the rapid onset of the effects of ozoralizumab, we compared the biodistribution kinetics of ozoralizumab and adalimumab after subcutaneous injection in an animal model of arthritis. Alexa Fluor 680-labeled ozoralizumab and adalimumab were administered by subcutaneous injection once (2 mg/kg) at five weeks after induction of collagen-induced arthritis (CIA) in an animal arthritis model. The time-course of changes in the fluorescence intensities of the two compounds in the paws and serum were evaluated. The paws of the CIA mice were harvested at four and eight hours after the injection for fluorescence microscopy. Biofluorescence imaging revealed better distribution of ozoralizumab to the joint tissues than of adalimumab, as early as at four hours after the injection. Fluorescence microscopy revealed a greater fluorescence intensity of ozoralizumab in the joint tissues than that of adalimumab at eight hours after the injection. Ozoralizumab showed a significantly higher absorption rate constant as compared with adalimumab. These results indicate that ozoralizumab enters the systemic circulation more rapidly and is distributed to the target tissues earlier and at higher levels than conventional IgG antibodies. Our investigation provides new insight into the mechanism underlying the rapid onset of the effects of ozoralizumab in clinical practice.Oyama S., Ebina K., Etani Y., et al. A novel anti-TNF-α drug ozoralizumab rapidly distributes to inflamed joint tissues in a mouse model of collagen induced arthritis. Scientific Reports 12, 18102 (2022); https://doi.org/10.1038/s41598-022-23152-6

Unique structure of ozoralizumab, a trivalent anti-TNFα NANOBODY® compound, offers the potential advantage of mitigating the risk of immune complex-induced inflammation

Biologics have become an important component of treatment strategies for a variety of diseases, but the immunogenicity of large immune complexes (ICs) and aggregates of biologics may increase risk of adverse events is a concern for biologics and it remains unclear whether large ICs consisting of intrinsic antigen and therapeutic antibodies are actually involved in acute local inflammation such as injection site reaction (ISR). Ozoralizumab is a trivalent, bispecific NANOBODY® compound that differs structurally from IgGs. Treatment with ozoralizumab has been shown to provide beneficial effects in the treatment of rheumatoid arthritis (RA) comparable to those obtained with other TNFα inhibitors. Very few ISRs (2%) have been reported after ozoralizumab administration, and the drug has been shown to have acceptable safety and tolerability. In this study, in order to elucidate the mechanism underlying the reduced incidence of ISRs associated with ozoralizumab administration, we investigated the stoichiometry of two TNFα inhibitors (ozoralizumab and adalimumab, an anti-TNFα IgG) ICs and the induction by these drugs of Fcγ receptor (FcγR)-mediated immune responses on neutrophils. Ozoralizumab-TNFα ICs are smaller than adalimumab-TNFα ICs and lack an Fc portion, thus mitigating FcγR-mediated immune responses on neutrophils. We also developed a model of anti-TNFα antibody-TNFα IC-induced subcutaneous inflammation and found that ozoralizumab-TNFα ICs do not induce any significant inflammation at injection sites. The results of our studies suggest that ozoralizumab is a promising candidate for the treatment of RA that entails a lower risk of the IC-mediated immune cell activation that leads to unwanted immune responses

昭和南海地震震源域-四国沖～紀伊半島沖-の構造変化

BE12-54講演要旨 / ブルーアース2012（2012年3月22日～23日, 東京海洋大学品川キャンパス

Structural variation from off Shikoku to the Kii Peninsula related to various earhthquake phenomena

南海トラフで繰り返し発生する巨大地震の中には、東海・東南海・南海地震が連動して発生する超巨大地震のケースがあることが指摘されている。このような超巨大地震について、どのような場合に連動し、あるいは非連動性巨大地震となるのかを明らかにすることが必要である。連動型地震の滑り域の範囲がどこまで広がるかを見積もることが重要な課題であり、そのためには南海トラフから沈み込むフィリピン海プレートの形状およびプレート境界周辺の構造、地震活動に関する詳細かつ高精度な情報が必要である。また、南海地震単独で発生した場合についても、深部および浅部低周波地震発生域まで含めた正確な破壊の広がりの把握、複雑な破壊分布の原因を明らかにするために南海地震破壊域とその縁辺での地殻構造や地震活動は重要な情報となる。平成20年度は日向灘、平成21年度は四国沖で調査を実施し、平成22年度は調査海域を東方の紀伊半島沖まで拡大し、沈み込み帯の地殻構造、巨大地震の発生、地震活動の相互関係の解明を目的として、南海・地震破壊域における沈み込みに関する詳細な構造のイメージングおよび地震のアスペリティに関する構造を明らかにするためのデータの取得、および西南日本の付加体先端部付近で発生している低周波地震や微動を含む自然地震観測を実施した。 　本講演では、四国沖?紀伊半島沖の平成21~22年度の調査結果について述べる。平成21年10月、および平成22年10~11月、（独）海洋研究開発機構の海洋調査船「かいれい」によって短周期海底地震計各々180台と大容量チューンドエアガン（7800cu. in.)を用いた屈折法・広角反射法探査を実施した（図１）。海底地震計設置期間中に自然地震観測も実施した。四国沖では21観測点、紀伊半島沖では20観測点による約9ヶ月間の長期地震観測も実施した（一部実施中）。なお、本調査は文部科学省からの受託研究「東海・東南海・南海地震の連動性評価のための 調査観測・研究」の個別研究テーマ「南海トラフ域海域地震探査・地震観測」（平成20年度から受託）の一環として実施した。 　一部の調査測線の解析の結果、足摺岬沖から日向灘に向かって約6km/sの古い付加体を示す岩体の分布が海側に張り出していること、また、SK05の構造モデルによると、SK03とSK02の中間付近からSK01付近までの付加堆積物が極端に薄いことなど、トラフ平行方向に構造変化があることがわかり、破壊様式の違いに関係する構造ではないかと考えられる。また、測線延長上のHi-net陸上観測点のデータを加えた海陸統合解析を実施しており、これにより深部低周波地震現象と構造との関連性が明らかになると期待されるC11-10発表要旨, 日本地震学会2011年度秋季大会（2011年10月12日～15日, 静岡県静岡市

Prominent reflector beneath around the segmentation boundary between Tonankai-Nankai earthquake area

In the Nankai Trough subduction seismogenic zone, the Nankai and Tonankai earthquakes had often occurred simultaneously, and caused a great event. In most cases, first break of such large events of Nankai Trough usually begins from southwest off the Kii Peninsula so far. The idea of split Philippine Sea plate between the Kii Peninsula and the Shikoku Island, which explains seismicity, tectonic background, receiver function image and historical plate motion, was previously suggested. Moreover, between the Kii Peninsula and the Shikoku Island, there is a gap of deep low-frequency events observed in the belt-like zone along the strike of the subducting Philippine Sea plate. In 2010 and 2011, we conducted the large-scale high-resolution wide-angle and reflection (MCS) seismic study, and long-term observation from off Shikoku and Kii Peninsula. Marine active source seismic data have been acquired along grid two-dimensional profiles having the total length of ~800km/year. A three-dimensional seismic tomography using active and passive seismic data observed both land and ocean bottom stations have been also performed. From those data, we found a possible prominent reflector imaged in the offshore side in the Kii channel at the depth of ~18km. The velocity just beneath the reflector cannot be determined due to the lack of ray paths. Based of the amplitude information, we interpret the reflector as the forearc Moho based on the velocity gap (from ~6.4km/s to ~7.4km/s). However, the reflector is shallower than the forearc Moho of other area along the Nankai Trough. Similar reflectors are recognized along other seismic profiles around the Kii channel. In this presentation, we will show the result of structure analysis to understand the peculiar structure including the prominent reflector around the Kii channel. Relation between the structure and the existence of the segmentation of the Nankai megathrust earthquake or seismic gap of the deep low-frequency events will be also discussed. This study is part of 'Research concerning Interaction Between the Tokai, Tonankai and Nankai Earthquakes' funded by Ministry of Education, Culture, Sports, Science and Technology, Japan.Poster abstract T43C-2670 presented at 2013 Fall Meeting, AGU, San Francisco, Calif., 9-13 Dec

Gaps between Activities of Daily Living Performance and Capacity in People with Mild Dementia

Persons with mild dementia can effectively maintain and improve their quality of life (QOL) by regularly performing their daily activities. However, research on activities of daily living (ADL) in this population often fails to distinguish between ADL performance and ADL capability, that is, actual independence in daily lives and potential independence in an ideal setting. This study aimed to identify the potential gaps between ADL performance and capability in individuals with mild dementia. A total of 137 community-dwelling older adults (aged ≥ 65 years) who had been diagnosed with dementia and assessed as 0.5 and 1 on a global clinical dementia rating (CDR). Participants were evaluated for basic ADL (BADL) and instrumental ADL (IADL) using the Hyogo Activities of Daily Living Scale (HADLS). Around 35 individuals who met the inclusion criteria were enrolled in the study. BADL performance and BADL capacity were not significantly different (p = 0.128); however, participants rated IADL capacity significantly higher than IADL performance (p < 0.01). Gaps between performance and capability were observed for IADL but not for BADL. This study distinguishes between ADL performance and capability in individuals with mild dementia and is the first to identify the IADL-specific gap between these two components; pertinent targeted interventions are vital in closing this gap. Environmental adjustments are important to improve QOL of persons with mild dementia

Dining from the coast to the summit : Salmon and pine nuts determine the summer body condition of female brown bears on the Shiretoko Peninsula

Body condition in mammals fluctuates depending on energy intake and expenditure. For brown bears (Ursus arctos), high-protein foods facilitate efficient mass gain, while lipids and carbohydrates play important roles in adjusting dietary protein content to optimal levels to maximize energy intake. On the Shiretoko Peninsula, Hokkaido, Japan, brown bears have seasonal access to high-lipid pine nuts and high-protein salmon. To assess seasonal and annual fluctuation in the body condition of adult female brown bears in relation to diet and reproductive status, we conducted a longitudinal study in a special wildlife protection area on the Shiretoko Peninsula during 2012-2018. First, analyses of 2,079 bear scats revealed that pine nuts accounted for 39.8% of energy intake in August and salmon accounted for 46.1% in September and that their consumption by bears varied annually. Second, we calculated the ratio of torso height to torso length as an index of body condition from 1,226 photographs of 12 adult females. Results indicated that body condition continued to decline until late August and started to increase in September when salmon consumption increased. In addition, body condition began to recover earlier in years when consumption of both pine nuts and salmon was high. Furthermore, females with offspring had poorer body condition than solitary females, in particular in late August in years with low salmon consumption. Our findings suggest that coastal and subalpine foods, which are unique to the Shiretoko Peninsula, determine the summer body condition of female brown bears, as well as their survival and reproductive success