The effect of intraventricular () infusion of a subpressor dose (6.25 or 12.5ng/kg/min) of angiotensin II (AII) on the pressor responses to intravenous (IV) infusion of All were studied in pentobarbital anesthetized rats. This study was undertaken to determine whether the central iso-renin angiotensin system alters pressor responsiveness to IV infused AII. Pressor responses to IV infusion of AII were potentiated by concurrent infusion of a subpressor dose of AII. pressor doses of AII decreased plasma renin activity, however, subpressor doses of AII did not.
These results suggest that the central iso-renin angiotensin system plays an important role in pressor responsiveness to IV AII and that the potentiation of IV AII is not related to decreases in endogenous AII as a result of administered AII.

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Intravitreal (

) injections are the current method for retinal drug delivery and have been widely used in humans, although it is well known that injections often cause an increase in intraocular pressure (IOP) that closely relates to the injection volume. Because of the anatomical and physiological similarities of the monkey and human eye, cynomolgus monkeys are often used for preclinical studies on new treatments using large molecules or gene therapy requiring application. However, there is only limited information on the maximal dosing volume for injections in cynomolgus monkeys. To determine an appropriate maximal dosing volume for injections, comprehensive ocular examinations were conducted in -injected eyes of cynomolgus monkeys. Up to a dosing volume of 150 µL/eye by injection, there were no injection-related ocular findings in pupillary light reflex gross observations, slit lamp biomicroscopic and indirect ophthalmoscopic and fundus autofluorescent examinations, intraocular pressure, optical coherence tomography of the anterior and posterior segments of the eye, axial length measurement, electroretinogram waveforms, or histopathological examinations of treated eyes. However, leakage of the dosing solution from an eye was observed at 150 µL/eye, indicating a technical limitation for the maximal applicable volume. In addition, recovery from IOP elevation immediately after injection of 150 µL/eye was slower than after injections of 50 or 100 µL/eye. Therefore, we recommend a maximal volume of 100 µL/eye for injections in cynomolgus monkeys.

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Aim: The nationwide verification of intravenous thrombolysis (

) was rarely performed after the extension of the therapeutic time window of alteplase or after the expansion of mechanical thrombectomy (MT). We aimed to examine the long-term change in accurate real-world outcomes of in patients with acute ischemic stroke (AIS) using the Japan Stroke Databank, a representative Japan-wide stroke database.

Methods: We extracted all patients with AIS who received

with alteplase between October 11, 2005, the approval date for alteplase use for AIS in Japan, and December 31, 2020. Patients were categorized into three groups using two critical dates in Japan as cutoffs: the official extension date of the therapeutic time window for to within 4.5 h of symptom onset and the publication date of the revised guideline, where the evidence level of MT was heightened. We assessed the yearly trend of implementation rates and the secular changes and three-group changes in clinical outcomes at discharge.

Results: Of 124,382 patients with AIS, 9,569 (7.7%) received

(females, 41%; median age, 75 years). The implementation rate has generally increased over time and plateaued in recent years. The proportion of favorable outcomes (modified Rankin Scale score of 0–2) increased yearly over 15 years. The results of the changes in the outcomes of the three groups were similar to those of the annual changes.

Conclusions: We revealed that

implementation rates in patients with AIS increased, and the functional outcome in these patients improved over 15 years. Therefore, the Japanese dissemination strategy is considered appropriate and effective.

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The incidence and the direct cause of syncope in ventricular tachycardia (VT) among patients with old myocardial infarction (OMI, n = 48), dilated cardiomyopathy (DCM, n = 18) and no evidence of heart disease (, n=43) were compared. The presence or absence of syncope in each patient was surveyed by a standardized questionaire and a variety of electrocardiographic parameters for aggravating arrhythmias were measured. Syncope occurred in 19 of 43 OMI patients (40%). in 5 of 18 DCM patients (28%) and 6 of 43 patients (14%) and significantly more often in OMI than (p<0.01). Ventricular fibrillation (VF) was confirmed in 14 of the 19 OMI patients with syncope, in 3 of the 5 DCM patients with syncope and 1 of 6 patients with syncope. The incidence of VF was significantly higher in OMI than in (p<0.01). Mean VT cycle lengths (VTRR'm) in OMI patients with and without syncope were 0.35±0.07 sec and 0.42±0.10 sec. respectively (p<0.05). VTRR'ms in DCM patients with and without syncope were 0.₃±0.10 sec and 0.42±0.10 sec, respectivrly (NS). VTRR'ms in patients with and without syncope were 0.27±0.04 sec and 0.41±0.10 sec, respectively (p<0.01). The results show that the high frequency of VT rate was the main cause of syncope in . while VF was the main cause of syncope in OMI. There were no significant differences in the coupling interval, prematurity index, vulnerability index and QTc between groups with and without syncope in any of the underlying diseases. There were also no significant differences in the ejection fraction between the 2 groups. Therefore, it is considered that there is a diffrence in the direct cause of syncope between VT patients with OMI and . Impaired ventricular function was not an important factor of syncope. Both VF and rapid VT are the main causes of syncope in OMI, while rapid VT is the main cause of syncope in . This may be one of the reasons why patients generally do not experience sudden cardiac death.

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The effects of the prostaglandin F_2α (PGF_2α) given into the third cerebral ventricle on the unit activity of neurosecretory neurones in the paraventricular nucleus (PVN) were studied in urethane-anesthetized rats. The firing activity of PVN neurones was recorded extracellularly and 50 neurones were antidromically identified as neurosecretory neurones. Thirty of them were classified oxytocinergic neurones because they gave a burst of action potential 12-15 sec before reflex milkejection and the remaining twenty PVN neurones which showed no response prior toreflex milk ejections were regarded as non-oxytocinergic ones.
Twenty-five (83%) of the 30 oxytocinergic neurones increased in the firing rate following the intraventricular () injection of PGF_2α (500ng in 1μl of isotonic saline) and the responses lasted for about 20-30min. The remaining 5 (17%) oxytocinergic neurones showed no response in the firing rate to PGF_2α. Fifteen (75%) of the20nonoxytocinergic neurones decreased in the firing activity in response to PGF_2α, and the remaining 5 (25%) of them showed no response. injection of isotonic saline (1μEl) did not affect the firing activityof both the oxytocinergic and nonoxytocinergic cells. The intramammary pressure was slightly increased by the administration of PGF_2α.
These findings indicate that PGF_2α has a differential action on oxytocinergic and non-oxytocinergic neurones in rats.

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While the use of in vitro-transcribed mRNA (

-mRNA) in therapeutics is a rapidly expanding area, the transfection of the exogenous -mRNA is accompanied by a risk of immune activation. This immunological defense mechanism suppresses cellular translation process and can reduce transfection efficiency to a considerable extent. In the present study, we investigated the in vitro effects of Integrated Stress Response Inhibitor (ISRIB), and dexamethasone, a steroidal anti-inflammatory drug, on the transfection activity of a lipid nanoparticle (LNP) that was composed of ionizable lipids and -mRNA. In the case of transfection to mouse embryonic fibroblast (MEF) cells, ISRIB mainly enhanced the transfection activity at an early stage of transfection (0–6 h). In contrast, dexamethasone caused an increase in transfection activity at intermediate-late stages of transfection (4–48 h). We also investigated the in vivo effects of dexamethasone using an LNP on that the -mRNA and lipid-conjugated dexamethasone (Dex-Pal) were co-loaded. The intravenous administration of the LNP successfully enhanced the protein expression in a mouse liver by up to 6.6-fold. Collectively, the co-delivery of an anti-inflammatory drug is a promising approach for enhancing transfection efficiency of -mRNA.

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A 68-year-old man who had undergone a prior radiofrequency catheter ablation (RFCA) of idiopathic ventricular tachycardia () originating from the right ventricle near the His bundle was referred for a RFCA of another . A 12-lead electrocardiogram exhibited a right bundle branch block and inferior axis QRS morphology with a tachycardia cycle length of 354 ms which suggested that the originated from the left ventricular outflow tract (LVOT). The RFCA at LVOT just below the aortic valve, left coronary cusp, and right coronary cusp (RCC) failed to eliminate the . However, this session was taken over to the 2nd session, because left bundle branch block had occurred during the RFCA at RCC. After the was successfully eliminated by the RFCA at LVOT just below the aortic valve, a sporadic premature ventricular complex (PVC) originating from the right ventricular outflow tract (RVOT) appeared. An elimination of the PVC, however, was abandoned, because the RFCA transiently caused advanced atrioventricular block. This case suggests that a proximal part of the His-Purkinje system might locate at the upper portion than usual in some case.

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The purpose of this study is to investigate the long-term prognosis of ventricular tachycardia (VT) mainly with respect to sudden death (SCD) in patients with ischemic heart disease (IHD), idiopathic cardiomyopathy (ICM), miscellaneous heart disease (MHD) and idiopathic ventricular tachycardia (). The study included 117 patients with VT (80 male, 37 female). The number of patients with IHD, ICM, MHD and was 14/40 (35%), 4/17 (24%), 6/25 (24%) and zero (0%), respectively. The other having had syncope in IHD, ICM, MHD and was 19/40 (48%), 7/18 (39%), 6/26% (23%) and 6/33 (18%), respectively. Out of the 19 IHD patients with syncope, 15 had had ventricular fibrillation (VF), which was induced by a disopyramide injection. In , the patients with syncope had a significantly higher VT rate than those without syncope (p < 0.01). There were no significantly differences in the electrocardiographical high risk parameters for SCD, the age, follow-up periods, the presence or absence of VF and ejection fraction between the SCD and the surviving groups. Consequently, it is suggested that is not related to SCD but careful attention should be paid to syncope when the rapid VT rate is observed although VT with organic heart disease is closely related both to SCD and syncope. In addition, it is considered that the above electrocardiographical parameters and so on were not always independent predictors of SCD among the patients having VT.

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In contrast with standard systemic drugs, the toxicity study of ophthalmic drug has unique design and packaging characteristics. The present survey aimed to characterize the nonclinical toxicological strategy of intravitreal administration (

) drugs by summarizing the toxicity study packages and comparing toxicity findings with clinical side effects. Safety pharmacology studies, toxicity studies, and clinical adverse reactions of the following seven drugs were surveyed: pegaptanib sodium, ranibizumab, aflibercept, brolucizumab, faricimab, triamcinolone acetonide, and ranibizumab biosimilar. The toxicity study packages for drugs were constructed according to ICH guidelines, although there were several differences between the modalities, application categories, and drugs. The characteristics of toxicity study packages include the fact that many safety pharmacology and acute toxicity endpoints need not be conducted as separate studies owing to the low systemic exposure. In addition, local toxicity findings (especially intraocular inflammation) require caution due to the relatively invasive administration method necessitates, and monkeys were mainly used as animal species in the studies. Notably, certain drugs were found to have the severe adverse reactions of retinal vascular lesions, probably owing to immunoreaction. Importantly, these immunoreaction-related adverse reactions were not detected in these nonclinical toxicity studies. Therefore, risk assessments using toxicity studies, immunogenicity, and host impurities are important for the prediction and control of adverse reactions. This survey provides valuable information for the construction of a toxicity study design for drug development.

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2018年に出版された慢性疼痛治療ガイドラインでは，薬物，インターベンショナル治療（

），心理社会的アプローチ，リハビリテーションについて記載され，それぞれを組み合わせながら集学的に治療していくことを推奨している．神経ブロックを含めた種々のを施行する場合，痛みの原因を診断して，適応を考慮しながら治療することが重要である．効果的な神経ブロックとは，痛み治療に有用である．神経ブロックを含めたを加えることは，早期に慢性疼痛を改善させる手段となり，ペインクリニック的な集学的治療を構築していく契機となると考えている．

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Effects of the intracerebroventricular () infusion of a subpressor dose (3 ng/kg/min) of angiotensin II (ang II) on the pressor responses to intravenous (IV) infusions of ang II and to IV bolus injections of norepinephrine (NE) were studied in conscious rats. This study was undertaken to determine whether activations of the brain renin-angiotensin system alter pressor responsiveness to IV infusions of ang II and IV injections of NE in the conscious state. Pressor responses to IV infusions of ang II and IV injections of NE were potentiated by the concurrent infusion of the subpressor dose of ang II. Plasma renin activity (PRA), plasma corticosterone (B), and plasma prolactin concentration (PRL) were also measured before and during the infusion of the subpressor (3 ng/kg/min) or the pressor (50 ng/kg/min) dose of ang II in order to determine the mechanisms for this pressor hyperresponsiveness to vasoconstrictor substances. The subpressor dose of ang II increased PRA, but did not significantly change B and PRL. The pressor dose of ang II decreased PRA and increased B, but did not significantly change PRL. These results suggest that the brain renin-angiotensin system plays an important role in pressor responsiveness to IV ang II and NE. Although the mechanisms are not fully understood, pressor hyperresponsiveness to IV ang II and NE by an intracerebroventricularly administered subpressor dose of ang II may be related to increased sympathetic outflow, because of the increment in PRA.

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DNA-content of nuclei from pollen was determined using flow cytometry. The pollen from diploid genotypes gave rise to a 1C- and a 2C-peak of identical size, representing the vegetative and the generative nuclei. Pollen of the interspecific hybrid (L. auratum×L. henryi) presented only 2C- and 4C-peaks, while in the interspecific hybrids (L.בEnchantment’×L.pumilum) 1C-, 2C- and 4C-peaks were distinguished. The different C-levels, representing the DNA-contents of the generative and vegetative nuclei in G1 and G2 phase respectively, can be related to haploid and diploid pollen. Results of a meiotic analysis, a number of crossing experiments and pollen measurements agreed with the outcome of the flow cytometric determinations. The flow cytometry method enables the large scale screening of collections of genotypes for their potential of 2n-pollen production.

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The torque controlled full toroidal (Infinitely Variable Transmission) provides significant fuel economy benefit over conventional stepped ratio transmissions. This is achieved, in part, by using high overdrive ratios. This benefit must be provided alongside good driveability, which requires the system to have a fast response while being well damped. This paper gives a theoretical overview of the dynamic response of the focusing on different interactions between the full toroidal variator and hydraulic control circuits. The concept of system stability is applied to sub-systems and their interactions to indicate design requirements of this torque controlled transmission.

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  術前の補水療法は，点滴による輸液（）が行われてきたが，経口補水療法（ORT）に変えるとに伴うリスクは消失する．術前ORTの導入により神奈川県立がんセンターにおける輸液関連のインシデントは減少した（ vs. ORT：27 vs. 15件/月，P=0.0003）．術前ORT導入により医療業務が簡素化され，医師，薬剤師，看護師など多職種の業務負担の軽減となった．術前ORTを導入すると，医療収益（食事療養費）が発生する．術前ORTの導入により医療安全・医療の質が向上し，さらに医療業務の最適化により効率性と経済性が高まった．

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 急性期脳梗塞に対する再開通療法として, 静注血栓溶解療法 (intravenous thrombolysis :

) と機械的血栓回収療法 (mechanical thrombectomy : MT) は標準的治療となったが, さらなる転帰改善を目指し, さまざまな取り組みが進んでいる. ではテネクテプラーゼの導入が進み, MTでは広範囲虚血領域を有する例や遠位中血管閉塞例を対象とした試験が進行中である. また, とMTの併用療法, MTと神経保護薬の併用療法, MTを迅速に行うための診療体制についてもエビデンスが蓄積されている. これらの結果により, 再開通療法のさらなる進歩が期待される.

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It has passed 16 years since intravenous thrombolysis (

) was approved for acute ischemic stroke in Japan. It is crucial not to delay with the minimum required examination and imaging. According to the Japan Stroke Data Bank, the recent administration rate of in ischemic stroke was 10.8%, and the mean door to needle time (DNT) was 62.7 minutes in 2018, but further improvement is expected. In the recent report from the Czech Republic, the administration rate of was 23.5%, and the median DNT was 25 minutes in 2018 by the national stroke registry and feedback system. In Japan, the Stroke and Cardiovascular Disease Control Act was enacted in 2018, and each prefecture will start the promotion plan in 2022. Recent trials using patients' selection with DWI–FLAIR mismatch or perfusion lesion–ischemic core mismatch revealed the efficacy of in ischemic stroke with unclear onset time, including wake–up stroke. A meta–analysis of individual patient data also showed the efficacy. It is important to adequately add imaging evaluation to detect DWI–FLAIR mismatch or perfusion lesion–ischemic core mismatch in ischemic stroke with unclear onset time.

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The efficient energetics of human walking could possibly be used to fulfill the total power requirement of human knee, without requiring any additional sources of energy. This study intends to addresses this issue by examining the idea of a novel self-powered actuator for artificial knee joints of wearable robots. The self-powered Flywheel-Infinitely Variable Transmission (F-

) is an actuator whose only source of power is a flywheel that stores and delivers energy from and to the knee joint by changing the speed ratio of the according to the phase of the gait cycle. This study evaluates the efficacy of this novel actuator by estimating the amount of energy it can deliver to the knee joint while the subject walks on level ground at varied speeds.

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Background:The composition of intra-arterial clots might influence the efficacy of mechanical thrombectomy (MT) in ischemic stroke (IS) due to the acute occlusions within large cerebral arteries. The aims were to assess the factors associated with blood clot structure and the impact of thromboembolus structure on MT using stent-retrievers in patients with acute large artery IS in the anterior circulation.

Methods and Results:In an observational cohort study, we studied the components of intra-arterial clots retrieved from large cerebral arteries in 80 patients with acute IS treated with MT with or without i.v. thrombolysis (

). Histology of the clots was carried out without knowledge of the clinical findings, including the treatment methods. The components of the clots, their age, origin and semi-quantitative graded changes in the architecture of the fibrin components (e.g., “thinning”) were compared via neuro-interventional, clinical and laboratory data. The most prominent changes in the architecture of the fibrin components in the thromboemboli were associated with (applied in 44 patients; OR, 3.50; 95% CI: 1.21–10.10, P=0.02) and platelet count (OR, 2.94; 95% CI: 1.06–8.12, P=0.04).

Conclusions:In patients with large artery IS treated with the MT using stent-retrievers, bridging therapy with

preceding MT and higher platelet count were associated with significant changes of the histological structure of blood clots.

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【背景および目的】血栓回収療法（MT）において，静注rt-PA併用の安全性への影響は必ずしも明確ではない．静注血栓溶解療法適正治療指針の適応外や慎重投与に相当し，MT単独で治療した症例の成績を明らかにする．【方法】2018，2019年に単施設で実施した前方循環主幹動脈閉塞に対する MT 102例について後ろ向きに検討した．rt-PA静注併用群と非併用群の2群に分け比較した．【結果】患者背景に2群間で有意差を認めなかった．有効再開通，出血性合併症に2群間で有意差を認めなかった．転帰良好（90日後 mRS 0–2）は併用群 64％，非併用群 51％で有意差は認めなかった．【結論】出血性合併症が懸念され，MT単独で治療した成績は，併用群と比較し有意に劣る結果ではなかった．併用が懸念される症例においても，MTによる有効再開通が転帰良好につながり得ると考えられた．

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