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京都府立医科大学附属北部医療センター 神経内科, Department of Neurology, North Medical Center, Kyoto Prefectural University of Medicine, 症例は63歳女性。3日前からの異常言動を主訴に救急受診した。血液検査と髄液検査に異常はなく、頭部MRI拡散強調画像(DWI)で両側前頭葉のU-fiber領域に高信号をみとめた。画像所見から神経核内封入体病(NIID)を疑った。皮膚生検でp62抗体陽性の核内封入体をみとめ、NIIDと診断した。慢性進行性であることが多いが、DWIにてU-fiber領域に高信号をみとめる症例では、急性発症の症状であっても積極的に皮膚生検を考慮すべきである。(著者抄録)

A 63-year-old woman with no medical history of note developed acute-onset abnormal behavior persisting for one week. Mild disturbance of consciousness was noted on physical examination. Her blood and spinal fluid test results were normal. On brain MRI, diffusion-weighted image showed a high-intensity signal in U-fiber areas of the bilateral frontal lobes, and fluid-attenuated inversion recovery showed white matter lesions. We suspected neuronal intranuclear inclusion disease (NIID) based on brain MRI findings; therefore, we performed a skin biopsy and genetic test. Pathological findings of the skin biopsy revealed the presence of anti-p62-positive intranuclear inclusion bodies in fibroblasts and adipocytes. The genetic test showed GGC repeat expansion of NOTCH2NLC, but no mutation of FMR1. Thus, we diagnosed her with NIID. The acute-onset abnormal behavior was improved by levetiracetam. The present case indicates that patients with a high-intensity area in the corticomedullary junction should undergo a skin biopsy, even though they may present with non-specific symptoms such as acute-onset abnormal behavior.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is definitely diagnosed by genetic testing. Such testing involves the analysis of exons 2-24 of NOTCH3, which encode the epidermal growth factor-like repeat domain, where CADASIL mutations are localized. We previously reported clinical diagnostic criteria for screening CADASIL-suspected Japanese patients prior to genetic testing. Because of its high sensitivity but low specificity, most patients need to undergo genetic testing. In this study, we aimed to develop the CADASIL scale-J, a modified scale to prioritize access to genetic testing for CADASIL-suspected Japanese patients. Methods: We modified the CADASIL scale reported by Pescini et al based on clinical features of 126 CADASIL patients and 53 NOTCH3-negative CADASIL-like patients diagnosed up until March 2016 (Phase 1). For validation, we recruited 69 consecutive patients for genetic testing of NOTCH3 from April 2016 to March 2017 (Phase 2). Results: We developed the CADASIL scale-J with a score ranging from 0 to 25 and the cut-off value of 16, using 8 items: hypertension, diabetes, young onset (≤50 years old), pseudobulbar palsy, stroke/TIA, family history, subcortical infarction, and temporal pole lesion. The sensitivity and specificity of the CADASIL scale-J were 78.9% and 85.7%, respectively. In Phase 2, we obtained a positive predictive value of 70.0% and a negative predictive value of 89.2%. In this study, we identified 54 mutations, 7 of which were novel. Conclusions: The CADASIL scale-J is helpful to prioritize access to genetic testing for CADASIL-suspected Japanese patients.

Caffeine is considered to be a neuroprotective agent against Parkinson's disease (PD) and is expected to offer a blood-based biomarker for the disease. We herein investigated the ability of this biomarker to discriminate between PD and neurodegenerative diseases. To quantify caffeine concentrations in serum and plasma, we developed a specific competitive enzyme-linked immunosorbent assay (ELISA). To validate the diagnostic performance of the assay, we conducted a case control-study of two independent cohorts among controls and patients with PD and multiple system atrophy (MSA). Parallelism, recovery rate, and intra- and inter-assay precision of our assay were within the standard of acceptance. In the first cohort of 31 PD patients, 18 MSA patients and 33 age-matched controls, serum caffeine levels were significantly lower in PD patients than in Controls (p = 0.018). A similar trend was also observed in the MSA group, but did not reach the level of significance. In the second cohort of 50 PD patients, 50 MSA patients and 45 age-matched controls, plasma caffeine levels were significantly decreased in both PD and MSA groups compared to Controls (p < 0.001). This originally developed ELISA offered sufficient sensitivity to detect caffeine in human serum and plasma. We reproducibly confirmed decreased blood concentrations of caffeine in PD compared to controls using this ELISA. A similar trend was observed in the MSA group, despite a lack of consistent significant differences across cohorts.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an orphan disease clinically characterized by migraine, recurrent strokes, and dementia. Currently, there are no disease-modifying therapies, and it is difficult to prevent cerebral ischemic events in CADASIL patients by conventional antithrombotic medication. We hypothesized that an antimigraine agent, lomerizine hydrochloride, may prevent strokes in CADASIL patients, based on its effect on increasing cerebral blood flow.This was an open-labeled clinical trial in which 30 adult CADASIL patients received lomerizine at 10 mg/d. Numbers of symptomatic strokes during the 2 years after the start of lomerizine administration were compared with those in the 2 years before its initiation. The effect of lomerizine on preventing strokes was evaluated based on the incidence rate ratio (IR) calculated with the Mantel-Haenszel method.When including all 30 patients (analysis 1), the IR was less than 1 (0.46; 95% confidence interval [CI], 0.19-1.12) but did not reach significance. To evaluate the effect of lomerizine on secondary prevention, subgroups of 15 patients with stroke episodes occurring any time before lomerizine administration (analysis 2) and 10 patients with stroke episodes during the 2 years before lomerizine administration (analysis 3) were analyzed. The IR values were 0.33 (95% CI, 0.12-0.94) in analysis 2 and 0.17 (95% CI, 0.04-0.67) in analysis 3.Our results suggest the effect of lomerizine on preventing secondary stroke in CADASIL patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by NOTCH3, primarily affects small cerebral arteries; however, stenosis of major intracranial arteries has occasionally been reported. Recent studies identified a close association between the c.14576GA (p.R4859K, rs112735431) variant of the ring finger protein 213 (RNF213) gene and sporadic intracranial arterial stenosis (ICAS). To determine whether RNF213 is associated with ICAS in CADASIL, we genotyped rs112735431 for 124 patients with CADASIL. The c.14576GA carrier rate in CADASIL patients with ICAS (4/17; 23.5%) was significantly higher compared with those without ICAS (2/107; 1.9%) (P = 0.0032). Among patients with ICAS, frequency of territorial infarction was significantly higher in c.14576GA carriers (75.0%) than in non-carriers (20.0%) (P = 0.0410). In addition, rate of ≥50% stenosis or occlusion tended to be higher in c.14576GA carriers (4/4; 100%) than in non-carriers (6/13; 46.2%) (P = 0.1029). We conclude that RNF213 is a gene associated with susceptibility to ICAS in CADASIL patients. MRA follow-up and close observation are necessary for CADASIL patients with the RNF213 variant, as they may be predisposed to ICAS.

Purpose Definite diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy (CADASIL) is mostly done by identification of NOTCH3 mutations. We aimed to develop criteria for selecting patients suspected for CADASIL to undergo genetic testing. Subjects and methods All subjects were Japanese. We recruited CADASIL patients genetically diagnosed up until 2011 (n = 37, Group 1) or after 2011 (n = 65, Group 2), 67 young stroke patients (≤ 55 years old), and 53 NOTCH3-negative CADASIL-like patients. The members of Japanese research committee for hereditary cerebral small vessel disease discussed and generated the new criteria to maximize positive rate in Group 1 CADASIL patients, followed by validation of sensitivity and specificity. Results In Group 1 CADASIL patients, the ages at onset excluding migraine were distributed widely (37–74 years old) and bimodal ( 55 years old). Frequencies of an autosomal dominant family history and vascular risk factor(s) were 73 and 65%, respectively. From these findings, the panel considered appropriate cut-off values and weighting for each item. In CADASIL Group 1 versus young stroke controls, the sensitivity and specificity of the new criteria were 97.3% and 80.6%, respectively. However, in CADASIL Group 2 versus NOTCH3-negative controls, the sensitivity and specificity were 96.9% and 7.5%, respectively. Forty mutations of NOTCH3 distributed in exons 2–8, 11, 14, 18, 19, and 21 were identified in this study. Ten mutations were unreported ones. Conclusion We propose the new criteria of high sensitivity, which will help physicians to assess the need for genetic testing.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3, and characterized by recurrent cerebral ischemic events without vascular risk factors, mood disturbance, and dementia. MRI testing shows cerebral white matter hyperintensities, especially in the external capsule and temporal pole. Typical mutations are cysteine-related missense ones located in one of 34 EGF-like repeats (EGFr) in the NOTCH3 receptor. To identify genotype-phenotype correlations, 179 Japanese CADASIL probands were recruited. Of the 68 mutations identified, p.Cys388Arg, p.Cys435Phe, p.Gly481Cys, p.Cys743Tyr, and p.Cys1009Phe were novel ones. The genotype-phenotype correlation was analyzed based on the three most common mutations: p.Arg75Pro, p.Arg141Cys, and p.Arg182Cys. p.Arg141Cys showed typical CADASIL phenotypes, whereas p.Arg75Pro showed mild and atypical phenotypes, a low frequency of stroke/TIA, high frequency of hypertension, and low frequency of temporal pole lesions. p.Arg182Cys showed various initial symptoms other than stroke/TIA. Subsequently, we analyzed the effect of the mutation location on the age at onset of stroke/TIA. We found that mutations in EGFr 1-6 excluding the cysteine-sparing mutation p.Arg75Pro were significantly correlated with a younger age at onset of stroke/TIA compared with those in EGFr 7-34. This was in agreement with a recent European report, suggesting that the effect of the mutation location is a consensus finding in CADASIL worldwide.

Purpose It is universally recognized that the anterior choroidal artery (AChA) supplies the posterior two-third of the posterior limb of internal capsule (PLIC). On the other hand, the blood supply to the anterior one third of the PLIC has remained undetermined. We posit the anterior one third of the PLIC is also supplied by the AChA referring the previous microsurgical descriptions. Methods Ninety consecutive patients with isolated acute infarction in the PLIC were studied. We classified patients into 4 groups. 1. The anterior type that involved the anterior one-third part of the PLIC. 2. The posterior type that involved the caudal two-third part of the PLIC, 3. The combined type that located in the full length of the PLIC, 4. The dot type that restricted within PLIC up to10mm in diameter. Results Patient numbers in groups 1 through 4 were 7 (7.7%), 46 (51.1%), 9 (10.6%) and 28 (31.1%). The anterior type involved the medial part of pallidum (MPP) in 5 patients (71.4%) and none in the lateral thalamus (LT), while the posterior type involved MPP only in 6 patients (13.0%) and LT in 33 patients (71.7%). Conclusion Corresponding to previous microsurgical descriptions, an occlusion of the proximal branches may cause anterior type infarct and that of the distal branches may cause posterior type infarcts. The anterior one third of the PLIC is also supplied by the branches of the AChA, albeit the low prevalence.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a major hereditary small vessel disease caused by mutations in NOTCH3. The variations in progression and severity among patients suggest that the CADASIL phenotype is modified by some genetic and environmental factors. Recent studies have shown the potential roles of gut microbiota in human diseases. We hypothesized that gut microbiota modifies the disease phenotype. We performed gut microbial meta 16S rRNA analysis of fecal samples from 15 CADASIL patients and 16 controls. The microbial α- and β-diversities and taxonomy were compared between CADASIL patients and controls and between CADASIL patients with and without an ischemic stroke history. No significant difference in α- or β-diversity was observed in either case-control or subgroup comparisons. In the taxonomic microbial analysis, there was a significant increase in abundance of 6 genera and significant decrease in 2 genera in CADASIL patients compared with controls. There was a significant decrease in abundance of 2 genera in CADASIL patients with compared with those without stroke. This is the first study on CADASIL focusing on gut microbiota. Our findings suggest that gut microbiota modifies the onset and progression of CADASIL.

A 74-year-old man gradually developed muscular weakness in the upper extremities, followed by dyspnea and dysarthria over a 6-month period. He was admitted to our facility and diagnosed as having amyotrophic lateral sclerosis (ALS) based on clinical and neurophysiological findings. Two months later, transtracheal positive pressure ventilation (TPPV) was started. During his clinical course, orthostatic hypotension occurred a few times. He also had two episodes of transient cardiac arrest, and he died 15 months after disease onset. At autopsy, the brain, weighing 850 g, showed diffuse cortical atrophy, preferentially involving the frontal lobes. Microscopic findings included severe loss of neurons in the motor cortex, the motor nuclei of the brainstem and the anterior horns of the spinal cord, and mild loss of axons and myelin in the corticospinal tract. Trans-activation response DNA protein 43 (TDP-43) immunoreactive cytoplasmic inclusions, the pathognomonic findings for ALS, were noted in the nucleus facialis, nucleus ambiguus, and in the anterior horn of the spinal cord. In addition, Lewy bodies and Lewy neurites were found in the brainstem and in the nucleus intermediolateralis of the thoracic cord. The concomitant alpha-synuclein pathology may have been partly related to possible autonomic dysfunction underlying the two episodes of cardiac arrest.

Background: Intracranial atherosclerotic disease is one of the most common causes of ischemic stroke especially in Asians, Hispanics and blacks. Although middle cerebral artery (MCA) stenosis is increasingly being recognized with the advent of magnetic resonance angiography (MRA) or transcranial Doppler ultrasonography, few studies have focused on acute neurological worsening (NW) in patients with MCA stenosis. We investigated the relationship between NW and lesion patterns detected by diffusion-weighted imaging (DWI). Methods: We studied 44 consecutive patients out of a total of 2,863 consecutive patients who had symptomatic lesions in the territory of the MCA and in whom MRA and/or conventional angiography showed isolated MCA stenosis ≥50% in the MCA trunk. Acute DWI lesion patterns were classified as follows: (1) pial artery territory infarcts (PAI); (2) small cortical and/or subcortical infarcts (SCS); (3) deep penetrating artery territory infarcts (DPI); (4) cortical border zone infarcts (CBZ), and (5) internal border zone infarcts (IBZ). NW was defined as worsening by ≥2 points on the National Institutes of Health Stroke Scale (NIHSS) during the first 7 days. Functional outcome was assessed by the modified Rankin Scale (mRS) at 3 months after stroke onset. Poor outcome was defined as ≥3 on the mRS. The severity of MCA stenosis on MRA was further categorized as 50-75% (moderate) and >75% or focal signal loss with the presence of distal MCA signal (severe). Results: There were 14 patients (31.8%) who showed NW and 16 patients (36.3%) who showed poor outcomes. Nine of the 14 patients with NW showed poor outcomes (64.2%). The most frequent lesions in the present study were SCS (n = 16, 36.3%), followed by IBZ (n = 12, 27.2%) and DPI (n = 11, 25.0%). Prevalence of IBZ was significantly higher in the group with NW compared to that without NW (p = 0.0081), while the prevalence of SCS, DPI, PAI and CBZ did not differ between the two groups. Logistic regression analysis showed significantly high age- and sex-adjusted odds ratios (ORs) for NW only for IBZ (OR 10.9, p = 0.0051). The degree of stenosis did not correlate with NW and lesion patterns. Conclusions: Only IBZ among various lesion patterns correlated strongly with NW. IBZ are considered to be more associated with hemodynamic compromise, while embolic pathogeneses contribute more to CBZ or SCS. Early interventional medical treatments such as thrombolytic or anti-platelet therapy or stenting should be considered in cases of IBZ in MCA stenosis.

Although the relationships between chronic kidney disease (CKD) and cognitive impairment (CI) have been highlighted, the etiology of CI in CKD remains uncertain. Subjects comprised 224 consecutive patients with symptomatic lacunar infarction who underwent magnetic resonance imaging and ambulatory blood pressure monitoring (ABPM). Diurnal blood pressure (BP) patterns were categorized into three groups: dippers, non-dippers and risers. Lacunar infarcts (LIs), including both symptomatic and silent and diffuse white matter lesions (WMLs), were graded into three grades according to their degree. The results of kidney function were evaluated using estimated glomerular filtration rate (eGFR), categorized into three groups: stage 1,60; stage 2, 30-60; and stage 3,30 ml min(-1) per 1.73 m(2). There were 44 patients with CI. Confluent WMLs, including WML 2 and WML 3, were found in 36 patients (81.8%), and multiple lacunae including LI 2 and LI 3 were found in 30 patients (68.1%) with CI. Age75 years (odds ratio (OR), 5.5; P0.05), male sex (OR, 2.8; P0.05), non-dippers (OR, 6.3; P0.05) and risers (OR, 5.6; P0.05), eGFR 30-60 ml min(-1) per 1.73 m(2) (OR, 2.9; P0.05) and eGFR30 ml min(-1) per 1.73 m(2) (OR, 23.8; P0.01), WML grade 2 (OR, 5.1; P0.01) and WML grade 3 (OR, 45.2; P0.001) and LI grade 2 (OR, 3.2; P0.05) and LI grade 3 (OR, 6.4; P0.05) were independently associated with CI. Age75 years (OR, 4.1; P0.05), eGFR 30-60 ml min(-1) per 1.73 m(2) (OR, 3.7; P0.05) and eGFR30 ml min(-1) per 1.73 m(2) (OR, 8.7; P0.05) were independently associated with WML grade 3. Extensive small vessel diseases, CKD and non-dipping status were independently associated with CI. CKD appears to mainly contribute to vascular CI, whereas possibilities of overlapping with other mechanisms such as degenerative CI cannot be excluded. Strict night time BP control and renoprotective treatment may be warranted to prevent CI.

元金沢大学大学院自然科学研究科生命科学専攻 / キッセイ薬品工業株式会社 開発研究部 薬理研究所, 金沢大学環日本海域環境研究センター生物多様性研究部門, Siboglinid worms live on carbohydrates produced by symbiotic bacteria. In this study, α-glucosidase-like activity was detected in the surface of the body and in the trophosome of Oligobrachia mashikoi. The enzyme exhibiting this activity was partially purified by consecutively applying the crude enzyme extract to Con-A-Sepharose and Sephadex-200 HR columns. The enzyme sample thus obtained gave a single activity peak at a position corresponding to 550 kDa in the Sephadex-200 HR gel filtration column. The enzyme was active in the range of pH 6.0-8.0, with a maximum activity at around pH 6.5. It specifically hydrolyzed maltose, and was inhibited by voglibose and miglitol. Moreover, a glucose transporter 2-like protein was detected by immunohistochemical and Western-blotting analyses using anti-rat GLUT2 polyclonal antibody. These results raise the question how this unique species lives. © 2008 Zoological Society of Japan.

The Jodo Hall of the Buddhist temple Jodo-Ji (1197, designated national treasure) was originally built by a priest Chogen on a low hill with a broad westward view in the Obe-no-sho manor area, and its frontal axis leans at an angle of approximately nine degrees from due west toward the north. Focusing on this deviation of the frontal axis, this research studies the characteristics of the frontal axis of the Jodo Hall and the features of scenery open out on this frontal axis.

本研究は，17色のカラーカードと建築物を対象とし，自然光の下で行う体系的な測色により，見かけの色と視距離との関係に関する基礎的知見を得ることを目的とする． 太陽光の変化·照度の影響を考慮した測色の結果，視距離の増加にともない，高明度域·高彩度域の色ほど大きく変化することがわかった．また，2器の測色計を用いて，照度の影響を取り除いた測色を行った．その結果，視点と視対象の間の大気·空間が，見かけの明度と見かけの彩度に与える効果が明らかになった．さらに，視距離と見かけの色との関係をあらわす推定式を求め，任意の視距離における構造物の見かけの色を推定する方法を示した．

In the present study, we demonstrate how to perform, using quantum annealing, the singular value decomposition and the principal component analysis. Quantum annealing gives a way to find a ground state of a system, while the singular value decomposition requires the maximum eigenstate. The key idea is to transform the sign of the final Hamiltonian, and the maximum eigenstate is obtained by quantum annealing. Furthermore, the adiabatic time scale is obtained by the approximation focusing on the maximum eigenvalue., Comment: 6 pages, 4 figures

A series of hexafluoroisopropylidene group-containing aromatic polyether and copolyethers with a wide range of unit ratios were synthesized by high-temperature solution polycondensation of 2,2-bis(4-hydroxyphenyl)-1,1,1,3,3,3-hexafluoropropane (1a), 2,2-bis(4-hydroxyphenyl)propane (1b), or both with bis(4-fluorophenyl)phenylphosphine oxide, and the effect of fluorine substitution on the properties of these polymers is discussed in relation to the fluorine contents. High- to moderate-molecular-weight polyethers with reduced viscosities of 0.39–0.55 dL g−1 were obtained in high yields by using anhydrous potassium carbonate as a base and N,N-dimethylacetamide as a medium at 160 °C for 48 h. Regardless of the fluorine contents, these polymers all were soluble in various organic solvents, including benzene, chloroform, and tetrahydrofuran, and afforded colorless, transparent, and tough films by solution casting. The contact angles of the films to water increased significantly with increasing fluorine content. The glass transition temperatures also increased monotonously with the increase of fluorine content, whereas the temperatures of 5% weight loss and 10% weight loss under nitrogen were scarcely affected by fluorine substitution. These films with and without fluorine exhibited a very sharp cutoff at a wavelength shorter than 290 nm and are colorless. Optically estimated dielectric constant of 1a-based homopolyether was 2.79, which was remarkably lower than the value of 1b-based homopolyether, 2.97.

Tensile strength and creep behavior of a two-dimensional (2D) laminate carbon–carbon composite (C/C) were examined from room temperature to 2773 K in an inert atmosphere. The tensile strength of the C/C was monotonically enhanced with increasing test temperatures. In particular, significant improvement was observed at temperatures higher than 1773 K. In this temperature range, nonlinear stress–strain curves were observed at low deformation rates, but with increasing test speed, the stress–strain curves became linear until total fracture. The source of the apparent nonlinearity was thus concluded to be creep deformation, which appeared from 1773 K. Two ruling mechanisms for the strength enhancement of the C/C at elevated temperatures were identified. The first source was degassing of absorbed water, which had a dominant influence on the strength enhancement up to 1773 K. The second was creep deformation. This phenomenon was notable at temperatures higher than 1773 K, and produced much larger enhancement than the degassing.

A Cynomolgus monkey hemodialysis model was used to evaluate the efficacy of a new factor Xa (FXa) inhibitor as an anticoagulant for hemodialysis. We tested the selective FXa inhibitor KFA-1411, using doses of 0.15 mg/ kg/hr, 0.3 mg/kg/hr, and 0.6 mg/kg/hr by continuous infusion in combination with a single loading-dose at the start. As a reference control, dalteparin, which is a low-molecular-weight heparin, was used at a dose of 20 IU/kg/hr plus 30 IU/kg single loading. As a monitoring method for KFA-1411, clotting time was measured in blood samples obtained from the body (systemic) and from the extracorporeal circulation (in-circuit). At KFA-1411 doses of 0.3 mg/ kg/hr and 0.6 mg/kg/hr hemodialysis was maintained with essentially no change in the intra-bloodline pressure in the extracorporeal circulation. With dalteparin, the pressure increased almost to the upper limit (set at 250 mmHg). The clot-deposition score measured, after testoration of normal circulation, in the dialyzer and air-trap chamber in the extracorporeal circulation was improved in a dose‐dependent manner in the KFA-1411 groups. There were no large differences between humans and Cynomolgus monkeys in the in vitro plasma anticoagulant activities of KFA1411 and dalteparin. These results indicate that this selective FXa inhibitor could be used as an anticoagulant for hemodialysis. Both activated partial thromboplastin time (APTT) and prothrombin time (PT) can be used to monitor the anticoagulant activity in the extracorporeal circulation, and a drug dose that has sufficient anticoagulant efficacy for hemodialysis will prolong in-circuit-APTT about 2 times and in-circuit-PT about 3 times compared to normal.

This study examined a low-molecular-weight factor-Xa inhibitor, KFA-1411 (3-[N-(3-amidinophenyl)-N-[N-[4-[1-(1-iminoethyl)piperidin-4- yl]phenyl]carbamoylmethyl]aminomethyl]phenoxyacetic acid monosulfonate-dihydrate). KFA-1411 selectively inhibited FXa among the serine proteases in the human blood-coagulation cascade with a Ki value of 1.73 nM, (selectivity ratio, 15000 versus its action on thrombin). The anticoagulant action of KFA-1411 in human plasma almost equaled that of the selective thrombin inhibitor, argatroban. KFA-1411 did not inhibit platelet aggregation at the concentration at which it showed an anticoagulant action. In contrast, argatroban, heparin, and low-molecular-weight heparin (LMWH; dalteparin) inhibited thrombin-induced platelet aggregation at concentrations lower than those needed for their anticoagulant actions. The FXa-inhibiting action of KFA-1411 differed among animal species, the maximum effect being seen in humans, followed by monkeys and rabbits, with rats and mice showing about one-tenth the potency seen in humans. A species variation was also observed among the values obtained for KFA-1411 in respect of anticoagulant activity in plasma (monkeys again being closest to humans). These results indicate that KFA-1411 may exhibit antithrombotic efficacy without an unwanted platelet-related action in the future treatment of various thrombotic diseases. The experimental model of monkeys is recommended for estimation of the clinical effects and safety of KFA-1411 in humans.

KDR-5169, 4-amino-5-chloro- N -[1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl]-2-(2-hydroxyethoxy)benzamide hydrochloride dihydrate, is a new prokinetic with a dual action, i.e., stimulation of the 5-HT 4 receptor and antagonism of the dopamine D2 receptor. In this study, we determined in vitro activities of KDR-5169 towards both receptors and demonstrated the effect of the compound on gastrointestinal motor activity in conscious dogs and rats. In dogs, intravenous KDR-5169 stimulated upper gastrointestinal motility in the fasting state and also eliminated the depressive effect of 3,4-dihydroxyphenylalanine ( l -DOPA) on this motility in the postprandial state. The effect of KDR-5169 on gastric emptying was further characterized by the use of three rat gastroparesis models (dopamine D2 receptor agonist (quinpirol)-, abdominal surgery-, or combined-situation-induced). Domperidone (a dopamine D2 receptor antagonist) was effective in the quinpirol-delay and combination-delay models, and cisapride and mosapride (5-HT 4 receptor agonists) were effective in the surgery-delay model. Only KDR-5169 eliminated the delay of gastric emptying in all three models. In addition, KDR-5169 accelerated emptying to above the normal level in the combination-delay model. These results suggest that KDR-5169 would be effective in various types of gastric ileus caused by different mechanisms.

Penetrating artery infarcts that are predominantly caused by occlusion at the vessel orifices of larger caliber penetrating arteries by atheromatous plaque can represent a distinctive stroke entity as intracranial branch atheromatous disease (BAD) 1. BAD often shows progressive motor deficits leading to severe disability 2. Thrombolytic therapy by tissue plasminogen activator has not been demonstrated to be effective for BAD 3. We designed a combined use of antiplatelet agents for BAD. During 12 years, 313 consecutive patients with BAD located within the territories of lenticulostriate arteries (LSAs) and anterior pontine arteries (APAs) were prospectively collected. Treatment protocols are as follows: phase 1 (2001–2005, n = 105), the medical treatment that was considered best; phase 2 (2005–2009, n = 104), a combined treatment of argatroban, cilostazol, and edaravone; and phase 3 (2009–20012, n = 104), additional clopidogrel on top of the phase 2 protocol. Functional outcome was assessed by the modified Rankin scale (mRS) at one-month after stroke onset. As a result, in the total population, the phase 2 and the phase 3 showed better outcome than the phase 1 (P = 0·0004 and P

The effect of moisture absorption on fracture behaviors of acrylonitrile-butadiene-styrene (ABS) resin has been studied. For comparison, polystyrene (PS) and styrene-acrylonitrile (SAN) resin have been tested. The fracture toughness of PS and SAN resins is determined by the ASTM standard test method for brittle polymers. The fracture toughness of ABS resin is obtained on the basis of the multiple specimens method. The fracture toughness of PS and SAN resin decreases with the increase in moisture absorption. On the other hand, the fracture toughness of ABS resin slightly decreases despite enormous moisture absorption. On the specimens absorbing moisture, a bright whitening region and a milky coloring region are distinguished in the stress-whitening region, and the milky coloring region expands around the bright whitening region at the crack tip. From the transmission electron microscopic observation, the precraze formation can be recognized in this region. The crack-tip shielding effect induced by this formation compensates the fracture toughness decrease due to moisture absorption. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 72: 435–442, 1999

This paper deals with the mutual interference of multiple two-dimensional interface cracks in a surface coating layered material under thermal stresses due to rolling/sliding contact with heat input. Contact loading is simulated as a contact pressure load with both the normal and shear components having parabolic distribution. Attention here is focused on the energy release rate at the crack tips which provide a measure for quantifying the magnitude of interface crack growth. In the present crack analysis, the interface cracks are replaced by the distributed edge dislocations, and the crack face friction is negrected. The problem is reduced to simultaneous singular integral equations for dislocation densities. The integral equations can be solved numerically by considering the nature of the singularities at the crack tips. The numerical results of the energy release rate showing the effects of the mutual interference of a pair of interface cracks are given for some tribological material coatings on a steel substrate. The effects of the frictional coefficient, the heat input strength and the coating thickness upon the magnitude of the energy release rate and it's mutual interference are considered numerically.

We analyze the stress intensity factors for multiple-edge cracks emanating from a circular hole in an infinite plate with a moving heat source rotating around the circular hole. Numerical calculations for the stress intensity factors are carried out for the case of two radial edge cracks. The interference effects on the stress intensity factors with the included angle between two radial cracks are investigated, and the effects of the angular velocity on the results are also considered In addition, for the case of standing heat source, we attempt to measure the thermal stress intensity factors using the strain gage We compare the experimental results with the current numerical results.