Sumio Ishiai

Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke

Transplantation of human mesenchymal stem cells has been shown to reduce infarct size and improve functional outcome in animal models of stroke. Here, we report a study designed to assess feasibility and safety of transplantation of autologous human mesenchymal stem cells expanded in autologous human serum in stroke patients. We report an unblinded study on 12 patients with ischaemic grey matter, white matter and mixed lesions, in contrast to a prior study on autologous mesenchymal stem cells expanded in foetal calf serum that focused on grey matter lesions. Cells cultured in human serum expanded more rapidly than in foetal calf serum, reducing cell preparation time and risk of transmissible disorders such as bovine spongiform encephalomyelitis. Autologous mesenchymal stem cells were delivered intravenously 36-133 days post-stroke. All patients had magnetic resonance angiography to identify vascular lesions, and magnetic resonance imaging prior to cell infusion and at intervals up to 1 year after. Magnetic resonance perfusion-imaging and 3D-tractography were carried out in some patients. Neurological status was scored using the National Institutes of Health Stroke Scale and modified Rankin scores. We did not observe any central nervous system tumours, abnormal cell growths or neurological deterioration, and there was no evidence for venous thromboembolism, systemic malignancy or systemic infection in any of the patients following stem cell infusion. The median daily rate of National Institutes of Health Stroke Scale change was 0.36 during the first week post-infusion, compared with a median daily rate of change of 0.04 from the first day of testing to immediately before infusion. Daily rates of change in National Institutes of Health Stroke Scale scores during longer post-infusion intervals that more closely matched the interval between initial scoring and cell infusion also showed an increase following cell infusion. Mean lesion volume as assessed by magnetic resonance imaging was reduced by >20% at 1 week post-cell infusion. While we would emphasize that the current study was unblinded, did not assess overall function or relative functional importance of different types of deficits, and does not exclude placebo effects or a contribution of recovery as a result of the natural history of stroke, our observations provide evidence supporting the feasibility and safety of delivery of a relatively large dose of autologous mesenchymal human stem cells, cultured in autologous human serum, into human subjects with stroke and support the need for additional blinded, placebo-controlled studies on autologous mesenchymal human stem cell infusion in stroke.

IGF-I regulates tight-junction protein claudin-1 during differentiation of osteoblast-like MC3T3-E1 cells via a MAP-kinase pathway.

Insulin-like growth factor I (IGF-I) is expressed in many tissues, including bone, and acts on the proliferation and differentiation of osteoblasts as an autocrine/paracrine regulator. Tight-junction proteins have been detected in osteoblasts, and direct cell-to-cell interactions may modulate osteoblast function with respect, for example, to gap junctions. In order to investigate the regulation of expression of tight-junction molecules and of function during bone differentiation, osteoblast-like MC3T3-E1 cells and osteocyte-like MLO-Y4 cells were treated with IGF-I. In both MC3T3-E1 cells and MLO-Y4 cells, the tight-junction molecules occludin, claudin-1, -2, and -6, and the gap-junction molecule connexin 43 (Cx43) were detected by reverse transcription with polymerase chain reaction. In MC3T3-E1 cells but not MLO-Y4 cells, mRNAs of claudin-1, -2, and -6, Cx43, and type I collagen, and proteins of claudin-1 and Cx43 were increased after treatment with IGF-I. Such treatment significantly decreased paracellular permeability in MC3T3-E1 cells. The expression of claudin-1 in MC3T3-E1 cells after IGF-I treatment was mainly upregulated via a mitogen-activated protein (MAP)-kinase pathway and, in part, modulated by a PI3-kinase pathway, whereas Cx43 expression and the mediated gap-junctional intercellular communication protein did not contribute to the upregulation. Furthermore, in MC3T3-E1 cells during wound healing, upregulation of claudin-1 was observed together with an increase of IGF-I and type I collagen. These findings suggest that the induction of tight-junction protein claudin-1 and paracellular permeability during the differentiation of osteoblast-like MC3T3-E1 cells after treatment with IGF-I is regulated via a MAP-kinase pathway, but not with respect to gap junctions.

The Excursion of the Median Nerve during Nerve Gliding Exercise: An Observation with High-resolution Ultrasonography

The purpose of this study was to assess the relationship between the positioning of upper extremity and gliding distance of the median nerve during passive and active motion of the wrist and fingers. The longitudinal gliding of the medial nerve in the forearm was measured in 34 healthy subjects by ultrasonographic dynamic images. Those images were analyzed in a cross-correlation algorithm advocated by Dilley et al. (2001). In this experiment, passive extension of the wrist and fingers was applied manually by an examiner in four positions (elbow flexion and extension with forearm pronation, and elbow flexion and extension with forearm supination), two types of active finger motions (Hook and Grasp) were performed by the subjects. The distally oriented median nerve gliding ranged from 1.9 (in elbow extension with forearm pronation) to 3.0mm (in elbow flexion with forearm supination) during passive extension of the wrist and fingers. There was a statistically significant difference in nerve gliding between the positions (p=0.001). During active digital movement, the proximally oriented nerve gliding was observed from 0.8 (in the hook) to 1.3mm (in the grasp). There was a significant difference in nerve gliding between the two ways of active finger motions (p=0.001). On the basis of the data obtained from this study, it is concluded that forearm supination is the preferred position for the passive median nerve gliding exercise because of large distally oriented nerve gliding. The active digital motion with full finger grip may be an effective procedure to produce proximally oriented median nerve gliding.

Neural Basis of Language: An Overview of An Evolving Model

The neural basis of language had been considered as a simple model consisting of the Broca’s area, the Wernicke’s area, and the arcuate fasciculus (AF) connecting the above two cortical areas. However, it has grown to a larger and more complex model based upon recent advancements in neuroscience such as precise imaging studies of aphasic patients, diffusion tensor imaging studies, functional magnetic resonance imaging studies, and electrophysiological studies with cortical and subcortical stimulation during awake surgery. In the present model, language is considered to be processed through two distinct pathways, the dorsal stream and the ventral stream. The core of the dorsal stream is the superior longitudinal fasciculus/AF, which is mainly associated with phonological processing. On the other hand, semantic processing is done mainly with the ventral stream consisting of the inferior fronto-occipital fasciculus and the intratemporal networks. The frontal aslant tract has recently been named the deep frontal tract connecting the supplementary motor area and the Broca’s area and it plays an important role in driving and initiating speech. It is necessary for every neurosurgeon to have basic knowledge of the neural basis of language. This knowledge is essential to plan safer surgery and preserve the above neural structures during surgery.

Synergic Effects of Rehabilitation and Intravenous Infusion of Mesenchymal Stem Cells After Stroke in Rats

Background Intravenous infusion of mesenchymal stem cells (MSCs) derived from adult bone marrow improves behavioral function in rat stroke models. Rehabilitation therapy through physical exercise also provides therapeutic efficacy for cerebral ischemia. Objective The purpose of this study was to investigate whether synergic effects of daily rehabilitation and intravenous infusion of MSCs has therapeutic effects after stroke in rats. Design This was an experimental study. Methods A permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal vascular occlusion with a microfilament. Four experimental groups were studied: group 1 (vehicle only, n=10), group 2 (vehicle + exercise, n=10), group 3 (MSCs only, n=10), and group 4 (MSCs + exercise, n=10). Rat MSCs were intravenously infused at 6 hours after MCAO, and the rats received daily rehabilitation with treadmill running exercise for 20 minutes. Lesion size was assessed at 1, 14, and 35 days using magnetic resonance imaging. Functional outcome was assessed using the Limb Placement Test. Results Both combined therapy and MSC infusion reduced lesion volume, induced synaptogenesis, and elicited functional improvement compared with the groups without MSC infusion, but the effect was greater in the combined therapy group. Limitations A limitation of this study is that the results were limited to an animal model and cannot be generalized to humans. Conclusions The data indicate that the combined therapy of daily rehabilitation and intravenous infusion of MSCs improved functional outcome in a rat MCAO model.

Rehabilitation and long-term course of nontraumatic myelopathy associated with surfing.

A nontraumatic spinal cord injury related to surfing is called surfers myelopathy. The case of a 26-yr-old man who became paraplegic after surfing without apparent traumatic events is described. Physical examination revealed a spinal cord injury at T12 according to the American Spinal Injury Association Impairment Scale A. The initial magnetic resonance image revealed a fusiform swelling of the spinal cord from T7-8 to the conus, which was hyperintense on T2-weighted images. After 6 mos of rehabilitation, the patient was followed for more than 1 yr after onset. He became able to walk with knee-ankle-foot-orthoses without assistance. A magnetic resonance image obtained 1 yr after the onset of paraplegia showed an atrophic spinal cord from T7-8 to the conus. The course of the neurologic findings and the imaging studies suggest that the pathogenesis of surfers myelopathy may be ischemia of the anterior spinal artery territory induced by the abnormal trunk posture while surfing.

Investigating Parental Caregiver Burden for Children with Disabilities using a Japanese version of the Zarit Caregiver Burden Interview (J-ZBI)

障害児の介護負担は高齢者とは違う特徴があると予想される．障害児を介護する保護者の負担を調査するために，肢体不自由養護学校就学児の保護者135 人を対象として，日本語版Zarit介護負担尺度（J-ZBI）などを用いて，アンケート調査を行った．有効回答が得られた69 人の回答結果から，全体のJ-ZBIの平均点は，25.6 点（SD 13.0）で，CES-Dの平均得点は10.8 点（SD 7.1）であった．保護者のSF-36の得点は，同年代の国民平均よりも低く，QOLが低下していた．保護者にとって障害児の介護負担は，精神的負担よりも身体的負担が強く感じられていた．J-ZBIで保護者を2 群に分けると，点数が高く，より介護負担が重いと考えられた保護者群は，CES-Dでうつ状態と判定される人数の割合が多く，同群の障害児のADL自立程度が低かった．保護者の身体的負担を軽減するサービスの利用で，介護負担は軽減される可能性がある．

Structural connectivity in spatial attention network: reconstruction from left hemispatial neglect

Left hemispatial neglect (neglect) is an impaired state of spatial attention. We aimed to reconstruct structural connectivity in the spatial attention network and to identify disconnection patterns underlying neglect. We enrolled 59 right-handed patients who had their first-ever infarction in the right hemisphere and classified them into neglect group (34 patients with neglect) and control group (25 patients without neglect). The neglect group was further subcategorized into 6 subgroups based on infarcted vascular territories. Diffusion tensor imaging data were obtained from all patients. Fractional anisotropy maps were compared between neglect group/subgroups and the control group by using non-parametric voxel-based analysis, generating a lesion path mask. Probabilistic tractography analysis using the lesion path mask reconstructed the following structural connectivity in the spatial attention network, which is specifically damaged in neglect patients: (1) superior longitudinal fasciculus (SLF) I connecting the superior parietal lobule/intraparietal sulcus with the superior frontal gyrus/frontal eye field (SFG/FEF) (dorsal attention network); (2) SLF III/the arcuate fasciculus (AF) and the extreme capsule/inferior fronto-occipital fasciculus (IFOF) connecting the right inferior parietal lobule/temporoparietal junction/superior temporal gyrus (IPL/TPJ/STG) with the middle frontal gyrus/inferior frontal gyrus (ventral attention network); (3) the thalamic radiations to the spatial attention-related cortices; and (4) SLF II and IFOF interconnecting dorsal and ventral attention networks. Individual analysis indicated that isolated damage in SLF I, SLF II, SLF III/AF or the thalamic radiations to IPL/TPJ/STG due to posterior cerebral artery infarction, or simultaneous damage in four thalamic radiations due to anterior choroidal artery infarction, underlies different phenotypes of neglect.

Depressive disorder may be associated with raphe nuclei lesions in patients with brainstem infarction

BACKGROUND Depression is a common symptom after stroke, but its neural substrates remain unclear. The ascending serotonergic system originates from the raphe nuclei in the brainstem. We hypothesized that depressive disorder due to brainstem infarction is associated with damage to the raphe nuclei. METHODS We prospectively enrolled 19 patients who had the first-ever acute isolated brainstem infarction in an observational cross-sectional study. All patients were evaluated by using the Montgomery Åsberg Depression Rating Scale (MADRS), the clinician-rated version of Apathy Evaluation Scale (AES-C) and Mini-Mental State Examination (MMSE). Depressive disorder was diagnosed according to DSM-5 and MADRS score of 12 or greater. Diffusion tensor imaging and proton density-weighted images were used to identify damage in the raphe nuclei. Accordingly, patients were classified into either the raphe-nuclei-damaged or intact group. Prevalence of depressive disorder and the MADRS, AES-C, and MMSE scores were compared between the two groups. RESULTS Depressive disorder was more frequent in the damaged group (n=6) than in the intact group (n=13) (83% vs. 15%; P=0.01). MADRS scores were higher in the damaged group than in the intact group (mean±1 SD, 17.5±7.9 vs. 7.0±4.4; P=0.002), whereas the AES-C and MMSE scores did not differ between groups. LIMITATIONS We did not assess the damage to the ascending projection fibers from the raphe nuclei. CONCLUSIONS Our results suggest that damage to the raphe nuclei underlies depressive disorder due to brainstem infarction, possibly via serotonergic denervation.

Nutritional Status and Energy Intake as Predictors of Functional Status After Cardiac Rehabilitation in Elderly Inpatients With Heart Failure ― A Retrospective Cohort Study ―

BACKGROUND Whether the short-term effect of cardiac rehabilitation (CR) in elderly patients with heart failure (HF) is influenced by nutritional status is uncertain, so the present study investigated the effect of nutritional status on functional recovery after CR in elderly HF inpatients.Methods and Results:We enrolled 145 patients admitted for treatment of HF who were aged ≥65 years and had a low functional status defined as a Barthel index (BI) score ≤85 points at the commencement of CR. Nutritional status was assessed by the Mini Nutritional Assessment Short Form (MNA-SF) and total energy intake per day. The primary endpoint was functional status determined by the BI score at discharge. The median CR period was 20 days (interquartile range: 14-34 days), and 87 patients (60%) were functionally dependent (BI score ≤85) at discharge. Multivariate logistic regression analysis showed that MNA-SF score (odds ratio [OR]: 0.76, P=0.02) and total energy intake at the commencement of CR (OR: 0.91, P=0.02) were independent predictors of functional dependence after CR. MNA-SF score ≤7 and total energy intake ≤24.5 kcal/kg/day predicted functional dependence at discharge with moderate sensitivity and specificity. CONCLUSIONS MNA-SF score and total energy intake at the commencement of CR are novel predictors of the extent of functional recovery of elderly HF inpatients after in-hospital CR.