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Background: Oculomotor nerve palsy is often associated with diabetes mellitus or caused by compression by a cerebral aneurysm. Here, we report a rare case of oculomotor nerve palsy caused by compression by the posterior cerebral artery (PCA)., Case Description: A 66-year-old woman suddenly developed diplopia and right blepharoptosis. Her symptoms suggested incomplete right oculomotor nerve palsy. Magnetic resonance imaging showed that a sharp curve in the right PCA had compressed the right oculomotor nerve. Microvascular decompression surgery was performed. Intraoperative findings showed that the P2 portion of the PCA had caused an indentation in the oculomotor nerve in the prepontine cistern. The transposition of the PCA with a prosthesis released the pressure. After the operation, her right blepharoptosis gradually improved. She had fully recovered by 48 days after the operation., Conclusion: Neurovascular compression (NVC) is recognized as the cause of hemifacial spasms, trigeminal neuralgia, and glossopharyngeal neuralgia. This case report demonstrated that NVC can also cause oculomotor nerve palsy. A high index of clinical suspicion can detect vascular compression of the oculomotor nerve. Prompt diagnosis and appropriate surgical management can achieve clinical improvement., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Surgical Neurology International.)

During rubber hand illusion (RHI), participants feel that a rubber (fake) hand is their own (i.e., embodiment of the rubber hand) if the unseen real hand and seen rubber hand are stroked synchronously (i.e., visuo-tactile stimuli). The RHI is also evoked if the real and rubber hands are placed in the same position (i.e., visual-proprioceptive congruency), which can be performed using a mirror setting. Using electroencephalography (EEG) and mirror settings, we compared μ rhythm (8-13 Hz) event-related desynchronization (ERD; an index of sensorimotor activation) while watching the movements of embodied or non-embodied rubber hands, which was preceded by an observation of the rubber hand with or without synchronous visuo-tactile stimuli. The illusory ownership of the fake hand was manipulated using visual continuity with (RHI) and without (non-RHI) a fake forearm. Resultantly, an ownership-dependent μ rhythm ERD was found when delivering visuo-tactile stimuli; a greater and more persistent μ rhythm ERD during the rubber hand movement was identified in the RHI in comparison to the non-RHI condition. However, no difference was observed between the two when observing the fake hand alone. These findings suggest the possibility that a self-related multisensory interaction between body representation (top-down processing) and visuo-tactile inputs (bottom-up processing) before a fake hand movement produces ownership-dependent sensorimotor activations during subsequent movement observations.

During the rubber hand illusion (RHI), individuals feel a fake hand as their own (ownership) and a perceived position of their real hand shifts toward the fake hand (proprioceptive drift; PD), which represents updating of multisensory hand representations. Bimanual tactile temporal order judgment (TOJ) includes processes of localizing tactile stimuli in space, for which multisensory hand representations are essential. According to the common processes, we examined tactile TOJ performance during the RHI and non-RHI. Temporal resolution (TR) as TOJ accuracy worsened during the non-RHI compared to the RHI. Additionally, a significant correlation between TR and PD was observed only in the non-RHI condition. However, the point of subjective simultaneity (PSS), which offers relative weighting of tactile inputs from the right and left hands, was correlated with illusory hand ownership. These results suggest that PSS and TR from tactile TOJ during RHI relate to self-attribution and localization of the hand, respectively., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The rubber hand illusion (RHI) is a perceptual illusion, whereby a fake hand is recognized as one's own hand when a fake hand and felt real hand are stroked synchronously. RHI strength is mainly assessed using a questionnaire rating and proprioceptive drift (PD). PD is characterized by the proprioceptively sensed location of the participant's own hand shifting toward the location of the fake hand after RHI. However, the relationship between the two measures of hand ownership and location remains controversial due to mixed findings: some studies report correlations between them, while others show that they are independent. Here, we demonstrated significant PD without RHI using delayed visual feedback. In this RHI study, video images of the fake hand were delivered to the subjects, and four delay intervals of visual feedback (80, 280, 480, and 680ms) were introduced. In four of six conditions, the delay interval was fixed throughout the condition. In the other two conditions, four delays were delivered in a predetermined order (i.e., serial condition; higher predictability) or in a pseudo-random order (i.e., random condition; low predictability). For the four conditions with a fixed delay, the questionnaire ratings and PD declined significantly when the delay interval exceeded circa 300ms. In both the serial and random conditions, no illusory ownership of the fake hand was reported in the questionnaire. In contrast, greater PD was found in the random condition but not in the serial condition. Our findings suggest that hand ownership and localization are caused by distinct multisensory integration processes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shibuya, Unenaka and Ohki.)

Background: The aim of this study was to investigate whether default mode network (DMN) connectivity and brain white matter integrity at baseline were associated with severe cognitive impairments at baseline and poor cognitive outcomes after shunt placement in patients with idiopathic normal pressure hydrocephalus (iNPH)., Methods: Twenty consecutive patients with iNPH whose symptoms were followed for 6 months after shunt placement and 10 healthy controls (HCs) were enrolled. DMN connectivity and brain white matter integrity at baseline in the patients with iNPH and HCs were detected by using resting-state functional magnetic resonance imaging (MRI) with independent component analysis and diffusion tensor imaging, respectively, and these MRI indexes were compared between the patients with iNPH and HCs. Performance on neuropsychological tests for memory and executive function and on the gait test was assessed in the patients with iNPH at baseline and 6 months after shunt placement. We divided the patients with iNPH into the relatively preserved and reduced DMN connectivity groups using the MRI indexes for DMN connectivity and brain white matter integrity, and the clinical measures were compared between the relatively preserved and reduced DMN connectivity groups., Results: Mean DMN connectivity in the iNPH group was significantly lower than that in the HC group and was significantly positively correlated with Rey auditory verbal learning test (RAVLT) immediate recall scores and frontal assessment battery (FAB) scores. Mean fractional anisotropy of the whole-brain white matter skeleton in the iNPH group was significantly lower than that in the HC group. The reduced DMN connectivity group showed significantly worse performance on the RAVLT at baseline and significantly worse improvement in the RAVLT immediate recall and recognition scores and the FAB scores than the preserved DMN connectivity group. Moreover, the RAVLT recognition score highly discriminated patients with relatively preserved DMN connectivity from those with relatively reduced DMN connectivity., Conclusions: Our findings indicated that iNPH patients with reduced DMN connectivity relative to the severity of brain white matter disruption have severe memory deficits at baseline and poorer cognitive outcomes after shunt placement. However, further larger-scale studies are needed to confirm these findings., (© 2021. The Author(s).)

The rubber hand illusion (RHI) is a phenomenon whereby participants recognize a fake hand as their own. Studies have examined the effects of observing fake hand movements after the RHI on brain sensorimotor activity, although results remain controversial. To address these discrepancies, we investigated the effects of observation of fake hand rotation after the RHI on sensorimotor mu (μ: 8-13 Hz) and beta (β: 15-25 Hz) rhythm event-related desynchronization (ERD) using electroencephalography (EEG). Questionnaire results and proprioceptive drift revealed that the RHI occurred in participants when their invisible hand and fake visible hand were stroked synchronously but not during asynchronous stroking. Independent component (IC) clustering from EEG data during movement observation identified three IC clusters, including the right sensorimotor, left sensorimotor, and left occipital cluster. In the right sensorimotor cluster, we observed distinct modulation of μ and β ERD during fake hand rotation. Illusory ownership over the fake hand enhanced μ ERD but inversely attenuated β ERD. Further, the extent of μ ERD correlated with proprioceptive drift, but not with questionnaire ratings, whereas the converse results were obtained for β ERD. No ownership-dependent ERD modulation was detected in the left sensorimotor cluster. Alpha (α: 8-13 Hz) rhythm ERD of the left occipital cluster was smaller in the synchronous condition than in the asynchronous condition, but α ERD was not correlated with questionnaire rating or drift. These findings suggest that observing embodied fake hand rotation induces distinct cortical processing in sensorimotor brain areas., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The discovery of a novel class of state-dependent voltage-gated sodium channel (Na V )1.7 inhibitors is described. By the modification of amide or urethane bond in Na V 1.7 blocker III, structure-activity relationship studies that led to the identification of novel Na V 1.7 inhibitor 2i (DS01171986) were performed. Compound 2i exhibited state-dependent inhibition of Na V 1.7 without Na V 1.1, Na V 1.5 or human ether-a-go-go related gene (hERG) liabilities at concentrations up to 100 μM. Further biological profiling successfully revealed that 2i possessed potent analgesic properties in a murine model of neuropathic pain (ED 50 : 3.4 mg/kg) with an excellent central nervous system (CNS) safety margin (> 600 fold).

Background: The present study aimed to clarify the association between left atrial (LA) size and ischemic events after ischemic stroke or transient ischemic attack (TIA) in patients with nonvalvular atrial fibrillation (NVAF)., Methods: Acute ischemic stroke or TIA patients with NVAF were enrolled. LA size was classified into normal LA size, mild LA enlargement (LAE), moderate LAE, and severe LAE. The ischemic event was defined as ischemic stroke, TIA, carotid endarterectomy, carotid artery stenting, acute coronary syndrome or percutaneous coronary intervention, systemic embolism, aortic aneurysm rupture or dissection, peripheral artery disease requiring hospitalization, or venous thromboembolism., Results: A total of 1,043 patients (mean age, 78 years; 450 women) including 1,002 ischemic stroke and 41 TIA were analyzed. Of these, 351 patients (34%) had normal LA size, 298 (29%) had mild LAE, 198 (19%) had moderate LAE, and the remaining 196 (19%) had severe LAE. The median follow-up duration was 2.0 years (interquartile range, 0.9-2.1). During follow-up, 117 patients (11%) developed at least one ischemic event. The incidence rate of total ischemic events increased with increasing LA size. Severe LAE was independently associated with increased risk of ischemic events compared with normal LA size (multivariable-adjusted hazard ratio, 1.75; 95% confidence interval, 1.02-3.00)., Conclusion: Severe LAE was associated with increased risk of ischemic events after ischemic stroke or TIA in patients with NVAF., (© 2020 S. Karger AG, Basel.)

In the rubber hand illusion (RHI), the subject recognizes a fake hand as his or her own. We recently found that the observation of embodied fake hand movement elicited mu-rhythm (8-13 Hz) desynchronization on electroencephalography (EEG), suggesting brain activation in the sensorimotor regions. However, it is known that mu-rhythm desynchronization during action observation is confounded with occipital alpha-rhythm desynchronization, which is modulated by attention. This study examined the independence of brain activities in the sensorimotor and occipital regions relating to the movement observation under the RHI. The invisible participant's left and fake right hands were stroked simultaneously, which was interrupted by unexpected fake hand movements. A mirror-reversed image of the fake hand was shown on a monitor in front of the participant with a delay of 80, 280, or 480 ms. Illusion strength decreased as a function of the delay. EEG independent component analysis (ICA) and ICA clustering revealed six clusters with observation-induced desynchronization of 8-13 Hz frequency band. In the right sensorimotor cluster, mu-rhythm desynchronization was the greatest under the 80-ms delay, while alpha-rhythm desynchronization of the occipital clusters did not show delay-dependence. These results suggest that brain activation in the sensorimotor areas (i.e., mu-rhythm desynchronization) induced by embodied fake hand movement is independent of that in the occipital areas (alpha-rhythm desynchronization)., (Copyright © 2019 Shibuya, Unenaka, Zama, Shimada and Ohki.)

Background We aimed to clarify associations between prior anticoagulation and short- or long-term clinical outcomes in ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation. Methods and Results A total of 1189 ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation who were hospitalized within 7 days after onset were analyzed. Of these, 813 patients (68.4%) received no prior anticoagulation, 310 (26.1%) received prior warfarin treatment with an international normalized ratio ( INR ) <2 on admission, 28 (2.4%) received prior warfarin treatment with an INR ≥2 on admission, and the remaining 38 (3.2%) received prior direct oral anticoagulant treatment. Prior warfarin treatment was associated with a lower risk of death or disability at 3 months compared with no prior anticoagulation ( INR <2: adjusted odds ratio: 0.58; 95% CI, 0.42-0.81; P=0.001; INR ≥2: adjusted odds ratio: 0.40; 95% CI, 0.16-0.97; P=0.043) but was not associated with a lower risk of death or disability at 2 years. Prior warfarin treatment with an INR ≥2 on admission was associated with a higher risk of ischemic events within 2 years compared with no prior anticoagulation (adjusted hazard ratio: 2.94; 95% CI, 1.20-6.15; P=0.021). Conclusions Prior warfarin treatment was associated with a lower risk of death or disability at 3 months but was not associated with a lower risk of death or disability at 2 years in ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation. Prior warfarin treatment with an INR ≥2 on admission was associated with a higher risk of ischemic events within 2 years. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01581502.

Bodily self-consciousness consists of agency (i.e., the feeling of controlling one's actions and causing external events) and body ownership (i.e., the feeling that one's body belongs to one's self). If a visual presentation of a virtual (fake) hand matches the active movement of a real hand, both the agency and body ownership of the virtual hand are induced [i.e., the active virtual hand illusion (VHI)]. However, previous active VHI studies have rarely considered the effects of goal-related movement errors (i.e., motor performance) on the senses of agency and ownership. Hence, the current study aimed to clarify the relationship between the active VHI and motor performance. To induce the VHI, 18 healthy subjects (three men and 15 women; 20.7 ± 7.3 years) were required to continuously move a virtual hand around a circle at a predetermined speed (i.e., spatial and temporal goals) using their active hand movements. While moving the virtual hand actively, five visual feedback delays were introduced: 90, 210, 330, 450, and 570 ms. It was found that the subjective ratings of both the agency and body ownership of the virtual hand decreased as a function of the delay intervals, whereas most of the spatial and temporal movement errors linearly increased. Using multiple regression analyses, we examined whether the agency and ownership ratings could be explained effectively by both the delay and movement errors. The results demonstrated that the agency was determined not only by the delay but also by the movement variability, whereas the body ownership was mostly determined by the delay. These findings suggest a possibility that the goal-related motor performance of the active VHI influences the agency judgment more strongly, while its effect on the ownership judgment is weaker.

Cervical myelopathy (CM) caused by spinal cord compression can lead to reduced hand dexterity. However, except for the 10 sec grip-and-release test, there is no objective assessment system for hand dexterity in patients with CM. Therefore, we evaluated the hand dexterity impairment of patients with CM objectively by asking them to perform a natural prehension movement. Twenty-three patients with CM and 30 age-matched controls were asked to reach for and grasp a small object with their right thumb and index finger and to subsequently lift and hold it. To examine the effects of tactile afferents from the fingers, objects with surface materials of differing textures (silk, suede, and sandpaper) were used. All patients also underwent the Japanese Orthopedic Association (JOA) test. Preoperative patients showed significantly greater grip aperture during reach-to-grasp movements and weaker grip force than controls only while attempting to lift the most slippery object (silk). Patients, immediately after surgery, ( n = 15) tended to show improvements in the JOA score and in reaction time and movement time with respect to reaching movements. Multiple regression analysis demonstrated that some parameters of the prehension task could successfully predict subjective evaluations of dexterous hand movements based on JOA scores. These results suggest that quantitative assessments using prehension movements could be useful to objectively evaluate hand dexterity impairment in patients with CM.

Background: We determined the 2-year long-term risk-benefit profile in patients with stroke or transient ischemic attack (TIA) receiving warfarin or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry in Japan.Methods and Results:NVAF patients within 7 days after onset of ischemic stroke/TIA were enrolled in 18 stroke centers. Outcome measures included ischemic and bleeding events and death in the 2-year follow-up period. We enrolled 1,116 patients taking either warfarin (650 patients) or DOACs (466 patients) at acute hospital discharge. DOAC users were younger and had lower National Institutes of Health Stroke Scale, CHADS 2 and discharge modified Rankin Scale scores than warfarin users (P<0.0001 each). Incidences of stroke/systemic embolism (adjusted hazard ratio, 1.07; 95% CI, 0.66-1.72), all ischemic events (1.13; 0.72-1.75), and ischemic stroke/TIA (1.58; 0.95-2.62) were similar between groups. Risks of intracranial hemorrhage (0.32; 0.09-0.97) and death (0.41; 0.26-0.63) were significantly lower for DOAC users. Infection was the leading cause of death, accounting for 40% of deaths among warfarin users., Conclusions: Stroke/TIA patients receiving DOACs for secondary prevention were younger and had lower stroke severity and risk indices than those receiving warfarin. Estimated cumulative incidences of stroke and systemic embolism within 2 years were similar between warfarin and DOACs users, but those of death and intracranial hemorrhage were significantly lower among DOAC users.

In the rubber hand illusion (RHI), individuals perceive a fake hand as their own when the hidden real hand and visible fake hand are synchronously stroked. Several RHI studies have reported that visual manipulation of the embodied fake hand inversely affects the perceptual processing of the observer's own hand (e.g., thermal or pain sensitivity). In this study, we examined whether motor manipulation of the fake hand similarly affects the observer's motor system. Our study employed a novel RHI paradigm wherein stroking was interrupted by unexpected movement of the fake hand (i.e., finger spreading) while measuring electroencephalography (EEG). We found that participants often spontaneously moved their hands in accordance with the movement of the fake hand only in the RHI (synchronous) sessions. EEG analyses revealed enhanced neural activation (mu-rhythm desynchronization) of the motor system during observation of the fake hand movement. Moreover, motor activation was greater in the synchronous than in the asynchronous condition and significantly correlated with the feeling of body ownership over the fake hand. These findings provide strong behavioral and neurophysiological evidence of 'motor back projection', in which the movement of an illusory embodied body part is inversely transferred to the sensorimotor system of the observer., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: We aimed to clarify associations between pre-admission risk scores (CHADS2, CHA2DS2-VASc, and HAS-BLED) and 2-year clinical outcomes in ischemic stroke or transient ischemic attack (TIA) patients with non-valvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry., Methods: From 18 Japanese stroke centers, ischemic stroke or TIA patients with NVAF hospitalized within 7 days after onset were enrolled. Outcome measures were defined as death/disability (modified Rankin Scale score ≥3) at 2 years, 2-year mortality, and ischemic or hemorrhagic events within 2 years., Results: A total of 1,192 patients with NVAF (527 women; mean age, 78 ± 10 years), including 1,141 ischemic stroke and 51 TIA, were analyzed. Rates of death/disability, mortality, and ischemic or hemorrhagic events increased significantly with increasing pre-admission CHADS2 (p for trend <0.001 for death/disability and mortality, p for trend = 0.024 for events), CHA2DS2-VASc (p for trend <0.001 for all), and HAS-BLED (p for trend = 0.004 for death/disability, p for trend <0.001 for mortality, p for trend = 0.024 for events) scores. Pre-admission CHADS2 (OR per 1 point, 1.52; 95% CI 1.35-1.71; p <0.001 for death/disability; hazard ratio (HR) per 1 point, 1.23; 95% CI 1.12-1.35; p <0.001 for mortality; HR per 1 point, 1.14; 95% CI 1.02-1.26; p = 0.016 for events), CHA2DS2-VASc (1.55, 1.41-1.72, p < 0.001; 1.21, 1.12-1.30, p < 0.001; 1.17, 1.07-1.27, p < 0.001; respectively), and HAS-BLED (1.33, 1.17-1.52, p < 0.001; 1.23, 1.10-1.38, p < 0.001; 1.18, 1.05-1.34, p = 0.008; respectively) scores were independently associated with all outcome measures., Conclusions: In ischemic stroke or TIA patients with NVAF, all pre-admission risk scores were independently associated with death/disability at 2 years and 2-year mortality, as well as ischemic or hemorrhagic events within 2 years., (© 2018 S. Karger AG, Basel.)

Corticospinal excitation is mediated by polysynaptic pathways in several vertebrates, including dexterous monkeys. However, indirect non-monosynaptic excitation has not been clearly observed following transcranial electrical stimulation (TES) or cervicomedullary stimulation (CMS) in humans. The present study evaluated indirect motor pathways in normal human subjects by recording the activities of single motor units (MUs) in the biceps brachii (BB) muscle. The pyramidal tract was stimulated with weak TES, CMS, and transcranial magnetic stimulation (TMS) contralateral to the recording side. During tasks involving weak co-contraction of the BB and hand muscles, all stimulation methods activated MUs with short latencies. Peristimulus time histograms (PSTHs) showed that responses with similar durations were induced by TES (1.9 ± 1.4 ms) and CMS (2.0 ± 1.4 ms), and these responses often showed multiple peaks with the PSTH peak having a long duration (65.3% and 44.9%, respectively). Such long-duration excitatory responses with multiple peaks were rarely observed in the finger muscles following TES or in the BB following stimulation of the Ia fibers. The responses obtained with TES were compared in the same 14 BB MUs during the co-contraction and isolated BB contraction tasks. Eleven and three units, respectively, exhibited activation with multiple peaks during the two tasks. In order to determine the dispersion effects on the axon conduction velocities (CVs) and synaptic noise, a simulation study that was comparable to the TES experiments was performed with a biologically plausible neuromuscular model. When the model included the monosynaptic-pyramidal tract, multiple peaks were obtained in about 34.5% of the motoneurons (MNs). The experimental and simulation results indicated the existence of task-dependent disparate inputs from the pyramidal tract to the MNs of the upper limb. These results suggested that intercalated interneurons are present in the spinal cord and that these interneurons might be equivalent to those identified in animal experiments.

Body ownership and agency are fundamental to self-consciousness. These bodily experiences have been intensively investigated using the rubber hand illusion, wherein participants perceive a fake hand as their own. After presentation of the illusion, the position of the participant's hand then shifts toward the location of the fake hand (proprioceptive drift). However, it remains controversial whether proprioceptive drift is able to provide an objective measurement of body ownership, and whether agency also affects drift. Using the virtual hand illusion (VHI), the current study examined the effects of body ownership and agency on proprioceptive drift, with three different visuo-motor tasks. Twenty healthy adults (29.6 ± 9.2 years old) completed VH manipulations using their right hand under a 2 × 2 factorial design (active vs. passive manipulation, and congruent vs. incongruent virtual hand). Prior to and after VH manipulation, three different tasks were performed to assess proprioceptive drift, in which participants were unable to see their real hands. The effects of the VHI on proprioceptive drift were task-dependent. When participants were required to judge the position of their right hand using a ruler, or by reaching toward a visual target, both body ownership and agency modulated proprioceptive drift. Comparatively, when participants aligned both hands, drift was influenced by ownership but not agency. These results suggest that body ownership and agency might differentially modulate various body representations in the brain.

Background and Purpose: The discrimination between paroxysmal and sustained (persistent or permanent) atrial fibrillation (AF) has not been considered in the approach to secondary stroke prevention. We aimed to assess the differences in clinical outcomes between mostly anticoagulated patients with sustained and paroxysmal AF who had previous ischemic stroke or transient ischemic attack., Methods: Using data from 1192 nonvalvular AF patients with acute ischemic stroke or transient ischemic attack who were registered in the SAMURAI-NVAF study (Stroke Management With Urgent Risk-Factor Assessment and Improvement-Nonvalvular AF; a prospective, multicenter, observational study), we divided patients into those with paroxysmal AF and those with sustained AF. We compared clinical outcomes between the 2 groups., Results: The median follow-up period was 1.8 (interquartile range, 0.93-2.0) years. Of the 1192 patients, 758 (336 women; 77.9±9.9 years old) and 434 (191 women; 77.3±10.0 years old) were assigned to the sustained AF group and paroxysmal AF groups, respectively. After adjusting for sex, age, previous anticoagulation, and initial National Institutes of Health Stroke Scale score, sustained AF was negatively associated with 3-month independence (multivariable-adjusted odds ratio, 0.61; 95% confidence interval, 0.43-0.87; P=0.006). The annual rate of stroke or systemic embolism was 8.3 and 4.6 per 100 person-years, respectively (multivariable-adjusted hazard ratio, 1.95; 95% confidence interval, 1.26-3.14) and that of major bleeding events was 3.4 and 3.1, respectively (hazard ratio, 1.13; 95% confidence interval, 0.63-2.08)., Conclusions: Among patients with previous ischemic stroke or transient ischemic attack, those with sustained AF had a higher risk of stroke or systemic embolism compared with those with paroxysmal AF., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01581502., (© 2016 American Heart Association, Inc.)

Aims: This study was performed to determine the short-term risk-benefit profiles of patients treated with oral anticoagulation for acute ischemic stroke or transient ischemic attack using a multicenter, prospective registry., Methods: A total of 1137 patients (645 men, 77 ± 10 years old) with acute ischemic stroke/transient ischemic attack taking warfarin (662 patients) or non-vitamin K antagonist oral anticoagulants (dabigatran in 205, rivaroxaban in 245, apixaban in 25 patients) for nonvalvular atrial fibrillation who completed a three-month follow-up survey were studied. Choice of anticoagulants was not randomized. Primary outcome measures were stroke/systemic embolism and major bleeding., Results: Both warfarin and non-vitamin K antagonist oral anticoagulants were initiated within four days after stroke/transient ischemic attack onset in the majority of cases. Non-vitamin K antagonist oral anticoagulant users had lower ischemia- and bleeding-risk indices (CHADS2, CHA2DS2-VASc, HAS-BLED) and milder strokes than warfarin users. The three-month cumulative rate of stroke/systemic embolism was 3.06% (95% CI 1.96%-4.74%) in warfarin users and 2.84% (1.65%-4.83%) in non-vitamin K antagonist oral anticoagulant users (adjusted HR 0.96, 95% CI 0.44-2.04). The rate of major bleeding was 2.61% (1.60%-4.22%) and 1.11% (0.14%-1.08%), respectively (HR 0.63, 0.19-1.78); that for intracranial hemorrhage was marginally significantly lower in non-vitamin K antagonist oral anticoagulant users (HR 0.17, 0.01-1.15). Major bleeding did not occur in non-vitamin K antagonist oral anticoagulant users with a CHADS2 score <4 or those with a discharge modified Rankin Scale score ≤2., Conclusions: Stroke or systemic embolism during the initial three-month anticoagulation period after stroke/transient ischemic attack was not frequent as compared to previous findings regardless of warfarin or non-vitamin K antagonist oral anticoagulants were used. Intracranial hemorrhage was relatively uncommon in non-vitamin K antagonist oral anticoagulant users, although treatment assignment was not randomized. Early initiation of non-vitamin K antagonist oral anticoagulants during the acute stage of stroke/transient ischemic attack in real-world clinical settings seems safe in bleeding-susceptible Japanese population., (© 2016 World Stroke Organization.)

This report describes a 15-year-old woman presenting posterior reversible encephalopathy syndrome (PRES) due to azathioprine. She was under treatment for ulcerative colitis. She was prescribed azathioprine seven days before admission. Four days after, she complained of headache. Then, she disturbed consciousness and showed generalized convulsive seizure on the day of admission. Magnetic resonance imaging (MRI) revealed vasogenic edema in both hemispheres. She was discontinued azathioprine and treated by anticonvulsant. Her symptoms were recovered and the MRI findings were disappeared. We diagnosed as PRES due to azathioprine because of clinical course and MRI findings. Only one case of PRES due to azathioprine is reported previously. Our case is the first report that showed the changes and improvement of MRI findings along the clinical course.

Information regarding squalene synthases (SQSs) from prokaryotes is scarce. We aimed to characterize the SQS from Methylococcus capsulatus. We studied its reaction mechanism by kinetic analysis and evaluated the structure of the substrate/inhibitor-binding sites via homology modeling. The cloned M. capsulatus SQS was expressed in Escherichia coli and purified by nickel-nitrilotriacetic acid column chromatography. Interestingly, M. capsulatus SQS was water-soluble and did not require any detergent for its higher activity, unlike other SQSs studied previously; supplementation of any type of detergent inhibited enzyme activity. The specific activity and the kinetic values (Km and kcat ) for the substrate farnesyl diphosphate and NADPH are reported. The substrate analog farnesyl methylenediphosphonate showed potent inhibition toward the enzyme. We prepared the site-specific mutants directed at potential active-site residues (58) DXX(61) E(62) D (S1 site) and (213) DXX(216) D(217) D (S2 site), which were assumed to be involved in the binding of the substrate farnesyl diphosphate through the Mg(2+) ion. We first demonstrated that the S1 site and the two basic residues (R55 and K212) were responsible for the binding of farnesyl diphosphate. Furthermore, we examined the catalytic roles of the highly conserved aromatic residues and demonstrated that the Y164 residue abstracts the proton of cation 5, which is produced during the first half-reaction (Scheme 1), to afford presqualene diphosphate, and that the W224 residue stabilizes the intermediary cation 5 via the cation-π interaction. Furthermore, we confirm for the first time that the F32 and the Y51 residues also stabilize the carbocation intermediate(s) generated during the second half-reaction., (© 2014 FEBS.)

We describe a 31-year-old, right-handed man who exhibited pure word deafness (PWD) due to a localization-related seizure. The patient was suddenly unable to comprehend spoken words, whereas he had no difficulty in speaking, comprehending written language, or discriminating non-verbal sounds. Diffusion-weighted imaging and fluid-attenuated inversion recovery on brain magnetic resonance imaging revealed hyperintense lesions in the left superior temporal gyrus (STG) and left superior marginal gyrus (SMG). Furthermore, brain single-photon emission computed tomography showed that these lesions were hyperperfused. An electroencephalogram (EEG) showed multiple spike-and-slow-wave complexes spreading to the left temporal regions. Immediately after administering midazolam intravenously, the patient was able to comprehend spoken words, and the epileptiform discharges in the left temporal regions disappeared. These findings indicate that he suffered from PWD resulting from a dysfunction of the left hemisphere alone. Furthermore, they suggest that the left STG and left SMG play an important role in the recognition of spoken words.

Little is known about the neuronal mechanisms underlying the temporal ordering of tactile signals. We examined the brain regions involved in judgments of the temporal order of successive taps delivered to both hands. Participants received identical stimuli while engaging in 2 different tasks: Judging the temporal order and judging the numerosity of points of tactile stimulation. Comparisons of the functional magnetic resonance imaging data obtained during the 2 tasks revealed regions that were more strongly activated with the judgments of the temporal order than with the judgments of numerosity under both arms-uncrossed and -crossed conditions: The bilateral premotor cortices, the bilateral middle frontal gyri, the bilateral inferior parietal cortices and supramarginal gyri, and the bilateral posterior part of the superior and middle temporal gyri. Stronger activation was found in some of these areas that implicated for remapping tactile stimuli to spatial coordinates after the participants crossed their arms. The activation in the perisylvian areas overlapped with the human visual-motion-sensitive areas in the posterior part. Based on these results, we propose that the temporal order of tactile signals is determined by combining spatial representations of stimuli in the parietal and prefrontal cortices with representations of "motion" or "changes" in the multisensory perisylvian cortex.

GPR142 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR142 agonists stimulate insulin secretion in the presence of high glucose concentration, so that they could be novel insulin secretagogues with reduced or no risk of hypoglycemia. We report here the optimization of HTS hit compound 1 toward a proof of concept compound 33, which showed potent glucose lowering effects during an oral glucose tolerance test in mice and monkeys.

A 57 year-old man developed broad-based unsteady gait and memory loss over a period of one year. On admission, bradykinesia and impairment of postural reflex were evident. Mini-mental state examination scored 27/ 30. Urinary control was normal. MRI revealed symmetric dilatation of lateral and 3rd ventricles, but the 4th ventricle appeared normal. Partial obstruction of the aqueduct with a membranous structure was disclosed by fast imaging employing steady state acquisition (FIESTA), and the diagnosis of late-onset aqueductal membranous occlusion (LAMO) was made. The symptoms were ameliorated shortly after endoscopic aqueductoplasty (EAP) and endoscopic third ventriculostomy (ETV). Membranous occlusion of the aqueduct can be detected by FIESTA and it can be cured by neuro-endoscopic measures.

Brain activity during a verbal fluency task (VFT) has been the target of many functional imaging studies. Most studies using near-infrared spectroscopy (NIRS) have reported major activation in the frontal pole, but those using PET or fMRI have not. This led us to hypothesize that changes in the NIRS signals measured in the forehead during VFT were due to changes in skin blood flow. To test this hypothesis, we measured NIRS signals and the Doppler tissue blood flow signals in the foreheads of 50 participants. The measurements were performed while each participant produced words during two 60-s periods with an interval of 100 s. In addition to a conventional optode separation distance of 30 mm (FAR channels), we used a short distance--5mm (NEAR channels)--to measure NIRS signals that originated exclusively from surface tissues. The oxygenated hemoglobin (oxyHb) concentration in the FAR and NEAR channels, as well as the Doppler blood flow signal, increased in a similar manner during the two periods of word production; the signal increase in the first period was twice as high as that in the second period. Accordingly, the mean changes in oxyHb concentration in the FAR channels were correlated closely with the changes in the NEAR channels (R(2) = 0.91) and with the integrated Doppler skin blood flow signal (R(2) = 0.94). Furthermore, task-related NIRS responses disappeared when we blocked skin blood flows by pressing a small area that covered a pair of optodes. Additionally, changes in the FAR channel signals were correlated closely with the magnitude of pulsatile waves in the Doppler signal (R(2) = 0.92), but these signals were not highly correlated with the pulse rate (R(2) = 0.43). These results suggest that a major part of the task-related changes in the oxyHb concentration in the forehead is due to task-related changes in the skin blood flow, which is under different autonomic control than heart rate., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background Context: In animal studies, distal and proximal arm movements are differently affected by spinal pyramidotomy because of the contributions of spinal interneuronal systems. In animals, interneuronal systems are also suggested to contribute to the recovery of dexterous hand movements. However, no clinical tests to evaluate proximal arm movements and functions of interneuronal systems have been described., Purpose: To compare parameters from proximal arm movements between patients and controls and in patients before and after decompression surgery., Study Design: A cross-sectional and longitudinal study performed at Kyorin University School of Medicine, Japan., Patient Sample: Patients with clinical features of cervical spondylotic myelopathy, without coexisting neurological abnormality., Methods: Twenty-eight patients and 15 age-matched controls performed reach-to-touch movements. Analysis of these movements identified several parameters, including time for online correction (correction time) induced by sudden target jump. Parameters were compared with scores from conventional tests, such as Japanese Orthopedic Association (JOA) score, 10-second grip-and-release test, manual muscle testing, and motor-evoked potential., Results: Preoperatively, patients showed long correction time and variable touch position, neither of which correlated with any scores from conventional tests. Reaching parameters recovered markedly immediately after decompression surgery, whereas conventional scores, which mainly assess hand functions, recovered much more slowly. Correction time and JOA score showed correlations when postoperative data were included, and long-term recovery of JOA score was more predictable with the inclusion of data for correction times from before and immediately after surgery., Conclusion: Analysis of arm movements is useful to evaluate symptoms and predict recovery of hand functions after surgery in patients with cervical myelopathy. These results suggest the importance of interneuronal systems, in addition to the pyramidal tract, for motor control even in humans., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Successive tactile stimuli, delivered one to each hand, are referred to spatial representation before they are ordered in time (Yamamoto and Kitazawa in Nat Neurosci 4:759-765 2001a). In the present study, we examined if this applies even when they are delivered unilaterally to fingers of a single hand. Tactile stimuli were delivered left-to-rightward relative to the body (2nd-3rd-4th) or in reverse with stimulus onset asynchrony of 100 ms. Simultaneously with the delivery of tactile stimuli, three of nine small squares arranged in a matrix of 3 x 3 were turned on as if they appeared near the tips of the fingers. Although subjects were instructed to ignore the visual stimuli and make a forced choice between the two orders of tactile stimuli, the correct-judgment probability depended on the direction of visual stimuli. It was greater than 95% when the direction of visual stimuli matched that of the tactile stimuli, but less than 50% when they were opposite to each other. When the right hand was rotated counterclockwise on the horizontal plane (90 degrees ) so that the fingers were pointing to the left, the preferred direction of visual stimuli that yielded the peak correct judgment was also rotated, although not to the full extent. These results show that subjects cannot be basing their tactile temporal order judgment solely on a somatotopic map, but rather on a spatial map on which both visual and tactile signals converge.

Object: The "wearing-off" phenomenon often hampers the treatment of Parkinson disease (PD). Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) is known to ameliorate the wearing-off phenomenon, the mechanism by which it does this remains unclear. As part of an inquiry into the mechanism of STN DBS, the authors measured synaptic dopamine levels in the striatum by performing positron emission tomography (PET) with [11C]raclopride., Methods: Three patients with PD who were experiencing the wearing-off phenomenon underwent PET scanning before and after DBS of the STN. The clinical features in these patients were evaluated by applying the Hoehn and Yahr, United Parkinson's Disease Rating, and Schwab and England Activities of Daily Living Scales. Before and after surgery, PET scans were obtained using [11C]raclopride prior to and 1 hour following an oral administration of levodopa. Regions of interest for the [11C]raclopride binding potential (RacloBP) were set in the bilateral putamen and the caudate nucleus. All clinical scores were dramatically improved postoperatively. Deep brain stimulation of the STN reduced the baseline RacloBP in both the putamen and caudate nucleus, but the differences between the pre- and postoperative levels were insignificant. Before DBS of the STN, the levodopa administration significantly reduced RacloBP in the putamen (p < 0.0001). Postoperatively the drug-induced reduction in RacloBP became statistically insignificant. The drug-induced increase in synaptic dopamine concentrations in the putamen preoperatively was estimated to be approximately four times higher than that after surgery (p < 0.01). The drug-induced RacloBP change in the caudate nucleus was similar to that in the putamen, although the magnitude of the change was lower (p < 0.005). The drug-induced increase in the caudate nucleus was also reduced postoperatively (p < 0.05)., Conclusions: Deep brain stimulation of the STN induces the stabilization of synaptic dopamine concentrations in the striatum and may attribute to the alleviation of levodopa-related motor fluctuations.

Using transcranial magnetic stimulation (TMS), we examined whether sensory input from a finger affects activity of the ipsilateral primary motor cortex (M1) when human subjects hold a virtual object bimanually and whether this ipsilateral activation varies under different contexts. Subjects used both index fingers to hold two plates, which were subjected to unpredictable pulling loads from torque motors. Loads were delivered in a random sequence to either plate or concurrently to both, although the latter occurred most frequently. Finger forces vertical to the plates and surface electromyographs from the first dorsal interosseous muscles were recorded bilaterally during the task. TMS was sometimes applied over the finger area of the left M1 at variable times relative to load onset to examine cortical excitability. Strength of TMS was set around the active motor threshold of the right finger muscle while subjects waited for loading to the handheld plates. When one plate was singly loaded, the M1 contralateral to the loaded finger was activated, causing automatic force increases in the finger. In addition, the ipsilateral M1 was activated during such loading, associated with transient force increases in the contralateral nonloaded finger. Activations in the ipsilateral M1 were also observed during concurrent loading, when activations were stronger than those following single loading of the contralateral plate. Ipsilateral activations weakened when concurrent loading was less frequent. These results suggest interactions between bilateral sensorimotor cortices during bimanual coordinated movements, with strength varying by context.

We report two patients of status epilepticus, in which detailed brain magnetic resonance image (MRI) studies were performed. In one patient apparent diffusion coefficient (ADC) increased in the right temporopareital regions in the acute phase. This patient finally has good clinical course without neurological deficits, and abnormal findings on MRI also disappeared. In another patient ADC increased in the similar regions in the acute phase, and an MRI demonstrated cortical laminar necrosis on T1-weighted scans in the same regions in the posticteric phase about 3 months later. The patient had a poorer prognosis with moderate dementia. It has been demonstrated that increased ADC reflects extracellular edema, while decreased ADC indicates cytotoxic edema. ADC mapping appears to be useful for predicting the reversibility of brain damages due to status epilepticus.

We synthesized bicyclic ether sialidase inhibitors such as tetrahydro-furan-2-yl, tetrahydro-pyran-2-yl, and oxepan-2-yl derivatives related to zanamivir. These compounds substituted by diol at the C-3' and C-4' positions resulted in the retention of low nanomolar inhibitory activities against not only influenza A virus sialidase but also influenza A virus in cell culture. Compound 11a in particular showed comparable efficacy in vivo relative to that of oseltamivir phosphate.

Sordaricin derivatives possessing a cyclohexane ring appendage attached via an ether, thioether, amine, oxime, ester or amide linkage were synthesized and their antifungal activity was evaluated in vitro. Compounds containing a thioether bond or an oxime bond as a linkage exhibited potent MICs (< or = 0.125 microg/mL) against four Candida albicans strains including azole-low-susceptible strains. They were also active (MIC < or = 0.125 microg/mL) against Candida glabrata. Their in vivo efficacy was confirmed in a murine intravenous infection model with Candida albicans.