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1.  Effects of Alda-1, an Aldehyde Dehydrogenase-2 Agonist, on Hypoglycemic Neuronal Death 
PLoS ONE  2015;10(6):e0128844.
Hypoglycemic encephalopathy (HE) is caused by a lack of glucose availability to neuronal cells, and no neuroprotective drugs have been developed as yet. Studies on the pathogenesis of HE and the development of new neuroprotective drugs have been conducted using animal models such as the hypoglycemic coma model and non-coma hypoglycemia model. However, both models have inherent problems, and establishment of animal models that mimic clinical situations is desirable. In this study, we first developed a short-term hypoglycemic coma model in which rats could be maintained in an isoelectric electroencephalogram (EEG) state for 2 min and subsequent hyperglycemia without requiring anti-seizure drugs and an artificial ventilation. This condition caused the production of 4-hydroxy-2-nonenal (4-HNE), a cytotoxic aldehyde, in neurons of the hippocampus and cerebral cortex, and a marked increase in neuronal death as evaluated by Fluoro-Jade B (FJB) staining. We also investigated whether N-(1,3-benzodioxole-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1), a small-molecule agonist of aldehyde dehydrogenase-2, could attenuate 4-HNE levels and reduce hypoglycemic neuronal death. After confirming that EEG recordings remained isoelectric for 2 min, Alda-1 (8.5 mg/kg) or vehicle (dimethyl sulfoxide; DMSO) was administered intravenously with glucose to maintain a blood glucose level of 250 to 270 mg/dL. Fewer 4-HNE and FJB-positive cells were observed in the cerebral cortex of Alda-1-treated rats than in DMSO-treated rats 24 h after glucose administration (P = 0.002 and P = 0.020). Thus, activation of the ALDH2 pathway could be a molecular target for HE treatment, and Alda-1 is a potentially neuroprotective agent that exerts a beneficial effect on neurons when intravenously administered simultaneously with glucose.
PMCID: PMC4471358  PMID: 26083658
2.  Effect of in-hospital physical activity on cardiovascular prognosis in lower extremity bypass for claudication 
Journal of Physical Therapy Science  2015;27(6):1855-1859.
[Purpose] This study aimed to evaluate the effect of in-hospital physical activity on patient prognosis after lower extremity bypass surgery for peripheral arterial disease. [Subjects and Methods] A total of 13 patients (16 limbs; 11 males and 2 females; mean age [standard deviation], 72.8 [5.9] years) who underwent lower extremity bypass surgery for Fontaine stage 2 peripheral arterial disease were included in this study and assigned to either an active group (n = 6) to perform increased physical activity after surgery or an inactive group (n = 7) to perform decreased physical activity after surgery. Daily in-hospital physical activity levels were measured continuously with a triaxial accelerometer. The occurrence of adverse cardiovascular events within a 2 year follow-up period was compared between groups. [Results] At discharge, the patients in the active group were able to walk more steps daily than those in the inactive group. The incidence of adverse events was 16.7% in the active group and 71.4% in the inactive group. [Conclusion] A higher in-hospital physical activity level was associated with a better long-term prognosis after lower extremity bypass surgery in patients with peripheral arterial disease.
PMCID: PMC4499998  PMID: 26180335
Peripheral arterial disease; Lower extremity bypass surgery; Physical activity
3.  The effect of a physiotherapy intervention on intestinal motility 
[Purpose] It is important to facilitate intestinal motility in patients with reduced bowel movement through physiotherapy. The purpose of the present study was to compare the effects of passive exercise of the lower limbs and trunk (PELT) and combination therapies (COM) with those of conventional thermotherapy (TT) on bowel sounds (BSs) in healthy adult subjects. Since autonomic activity (AA) significantly influences intestinal motility, we also investigated the relation between intestinal motility and AA by measurement of BSs. [Subjects] The subjects were 16 healthy adult males. [Methods] The subjects were randomly assigned to 3 different physiotherapies, and BSs and sympathetic nerve activity were measured before and after the physiotherapies. [Results] While BSs significantly increased following all physiotherapies, the temporal changes in BSs were different among the physiotherapies. AA measurement showed that PELT and TT significantly decreased the heart rate. While the high-frequency (HF) component was increased in all physiotherapy groups, the increases in HF did not reach statistical significance. There were no significant correlations between BSs and AA. [Conclusion] We found that all of the tested physiotherapies increased BSs, suggesting that they are clinically useful for treatment of patients with reduced intestinal motility due to limited spontaneous movement or inability to rise up from bed.
PMCID: PMC4305552  PMID: 25642064
Intestinal motility; Passive exercise; Thermotherapy
4.  Changes in EEG Complexity with Electroconvulsive Therapy in a Patient with Autism Spectrum Disorders: A Multiscale Entropy Approach 
Autism spectrum disorders (ASD) are heterogeneous neurodevelopmental disorders that are reportedly characterized by aberrant neural networks. Recently developed multiscale entropy analysis (MSE) can characterize the complexity inherent in electroencephalography (EEG) dynamics over multiple temporal scales in the dynamics of neural networks. We encountered an 18-year-old man with ASD whose refractory catatonic obsessive–compulsive symptoms were improved dramatically after electroconvulsive therapy (ECT). In this clinical case study, we strove to clarify the neurophysiological mechanism of ECT in ASD by assessing EEG complexity using MSE. Along with ECT, the frontocentral region showed decreased EEG complexity at higher temporal scales, whereas the occipital region expressed an increase at lower temporal scales. Furthermore, these changes were associated with clinical improvement associated with the elevation of brain-derived neurotrophic factor, which is a molecular hypothesis of ECT, playing key roles in ASD pathogenesis. Changes in EEG complexity in a region-specific and temporal scale-specific manner that we found might reflect atypical EEG dynamics in ASD. Although MSE is not a direct approach to measuring neural connectivity and the results are from only a single case, they might reflect specific aberrant neural network activity and the therapeutic neurophysiological mechanism of ECT in ASD.
PMCID: PMC4341548  PMID: 25767444
autism spectrum disorders; brain-derived neurotrophic factor; EEG complexity; electroconvulsive therapy; multiscale entropy; obsessive–compulsive disorder
5.  Effects of Angiopoietin-1 on Hemorrhagic Transformation and Cerebral Edema after Tissue Plasminogen Activator Treatment for Ischemic Stroke in Rats 
PLoS ONE  2014;9(6):e98639.
An angiogenesis factor, angiopoietin-1 (Ang1), is associated with the blood-brain barrier (BBB) disruption after focal cerebral ischemia. However, whether hemorrhagic transformation and cerebral edema after tissue plasminogen activator (tPA) treatment are related to the decrease in Ang1 expression in the BBB remains unknown. We hypothesized that administering Ang1 might attenuate hemorrhagic transformation and cerebral edema after tPA treatment by stabilizing blood vessels and inhibiting hyperpermeability. Sprague-Dawley rats subjected to thromboembolic focal cerebral ischemia were assigned to a permanent ischemia group (permanent middle cerebral artery occlusion; PMCAO) and groups treated with tPA at 1 h or 4 h after ischemia. Endogenous Ang1 expression was observed in pericytes, astrocytes, and neuronal cells. Western blot analyses revealed that Ang1 expression levels on the ischemic side of the cerebral cortex were decreased in the tPA-1h, tPA-4h, and PMCAO groups as compared to those in the control group (P = 0.014, 0.003, and 0.014, respectively). Ang1-positive vessel densities in the tPA-4h and PMCAO groups were less than that in the control group (p = 0.002 and <0.001, respectively) as well as that in the tPA-1h group (p = 0.047 and 0.005, respectively). These results suggest that Ang1-positive vessel density was maintained when tPA was administered within the therapeutic time window (1 h), while it was decreased when tPA treatment was given after the therapeutic time window (4 h). Administering Ang1 fused with cartilage oligomeric protein (COMP) to supplement this decrease has the potential to suppress hemorrhagic transformation as measured by hemoglobin content in a whole cerebral homogenate (p = 0.007) and cerebral edema due to BBB damage (p = 0.038), as compared to administering COMP protein alone. In conclusion, Ang1 might be a promising target molecule for developing vasoprotective therapies for controlling hemorrhagic transformation and cerebral edema after tPA treatment.
PMCID: PMC4045756  PMID: 24896569
6.  Isolated Unilateral Absence of the Left Pulmonary Artery: A Case Report 
Annals of Vascular Diseases  2014;7(2):178-182.
We report the case of a 37-year-old man with isolated unilateral absence of the pulmonary artery (UAPA), which was diagnosed upon the occurrence of hemoptysis. Plain chest radiography demonstrated decreased left pulmonary volume. Computed tomography of the chest revealed the complete absence of the left pulmonary artery. Angiography revealed marked dilation of the left bronchial artery, inferior phrenic artery, internal thoracic artery, and the arterial branches of the thyrocervical trunk. These arteries were considered as collateral circulation to the left lung. In cases with UAPA, collateral circulation should be evaluated by angiography to obtain useful information for treatment.
PMCID: PMC4072871  PMID: 24995067
pulmonary artery; hemoptysis; angiography
7.  Molecular Markers for Granulovacuolar Degeneration Are Present in Rimmed Vacuoles 
PLoS ONE  2013;8(11):e80995.
Rimmed vacuoles (RVs) are round-oval cytoplasmic inclusions, detected in muscle cells of patients with myopathies, such as inclusion body myositis (IBM) and distal myopathy with RVs (DMRV). Granulovacuolar degeneration (GVD) bodies are spherical vacuoles containing argentophilic and hematoxyphilic granules, and are one of the pathological hallmarks commonly found in hippocampal pyramidal neurons of patients with aging-related neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. These diseases are common in the elderly and share some pathological features. Therefore, we hypothesized that mechanisms of vacuolar formation in RVs and GVD bodies are common despite their role in two differing pathologies. We explored the components of RVs by immunohistochemistry, using antibodies for GVD markers.
Subjects included one AD case, eight cases of sporadic IBM, and three cases of DMRV. We compared immunoreactivity and staining patterns for GVD markers. These markers included: (1) tau-modifying proteins (caspase 3, cyclin-dependent kinase 5 [CDK5], casein kinase 1δ [CK1δ], and c-jun N-terminal kinase [JNK]), (2) lipid raft-associated materials (annexin 2, leucine-rich repeat kinase 2 [LRRK2], and flotillin-1), and (3) other markers (charged multi-vesicular body protein 2B [CHMP2B] and phosphorylated transactive response DNA binding protein-43 [pTDP43]) in both GVD bodies and RVs. Furthermore, we performed double staining of each GVD marker with pTDP43 to verify the co-localization.
GVD markers, including lipid raft-associated proteins and tau kinases, were detected in RVs. CHMP2B, pTDP43, caspase 3, LRRK2, annexin 2 and flotillin-1 were detected on the rim and were diffusely distributed in the cytoplasm of RV-positive fibers. CDK5, CK1δ and JNK were detected only on the rim. In double staining experiments, all GVD markers colocalized with pTDP43 in RVs.
These results suggest that RVs of muscle cells and GVD bodies of neurons share a number of molecules, such as raft-related proteins and tau-modifying proteins.
PMCID: PMC3842945  PMID: 24312256
8.  Phosphorylated MAPK/ERK1/2 may not always represent its kinase activity in a rat model of focal cerebral ischemia with or without ischemic preconditioning 
Neuroscience  2012;209:155-160.
The ERK 1/2 protein require a dual phosphorylation at conserved threonine and tyrosine residues to be fully activated under normal physiological conditions. Thus, ERK1/2 kinase activity is often defined by the quantity of phosphorylated kinase. However, this may not accurately represent its true activity under certain pathological conditions. We investigated whether ERK1/2 kinase activity is proportional to its phosphorylation state in a rat focal ischemia model with and without rapid ischemic preconditioning. We showed that phosphorylated-ERK1/2 protein levels were increased 2.6±0.07 fold, and ERK1/2 kinase activity was increased 10.6±1.9 fold in animals receiving ischemic preconditioning alone without test ischemia compared with sham group (P<0.05, n=6/group), suggesting that phosphorylated-ERK1/2 protein levels represent its kinase activity under these conditions. However, preconditioning plus test ischemia robustly blocked ERK1/2 kinase activity, while it increased phosphorylated-ERK1/2 protein levels beyond those receiving test ischemia alone, suggesting that phosphorylated-ERK1/2 protein levels were not representative of actual kinase activity in this pathological condition. In conclusion, protein phosphorylation levels of ERK1/2 do not always correspond to kinase activity, thus, measuring the true kinase activity is essential.
PMCID: PMC3322316  PMID: 22366512
ischemic preconditioning; kinase activity; MAPK; ERK1/2; focal ischemia; stroke
9.  Comparison between oscillometric- and Doppler-ABI in elderly individuals 
Peripheral arterial disease (PAD) generally remains under-recognized, mainly due to the specialized technical skills required to detect the low values of the ankle-brachial index (ABI). As a simpler and faster alternative to the standard method using continuous-wave Doppler ultrasound, we evaluated automated oscillometric ABI measurement by VP-2000 with an elderly cohort of 113 subjects (age range, 61 to 88 years). The standard deviation in ABIs measured by the Doppler method was statistically greater than that measured by the oscillometric method for each of the two legs (P < 0.001). Correlations in ABIs between the two methods were 0.46 for the left leg and 0.61 for the right leg; this result appears to have been caused by interobserver variation in the Doppler ABI measurements. While the trend showing greater differences between average oscillometric- and Doppler-ABIs was significant at the lower ABI ranges, there was little indication of differences in measurements having an average ABI > 1.1. The difference between the methods was suggestively larger in subjects who were smokers than in non-smokers (P = 0.09), but the difference was not affected by other potential atherosclerotic risk factors, including age at examination (P > 0.50). A larger difference at lower ABIs led to better PAD detection by the Doppler method compared to the oscillometric method (sensitivity = 50%, specificity = 100%), although the overall agreement was not small (Cohen’s Kappa = 0.65). Our findings indicate that oscillometric devices can provide more accurate estimation of the prevalence of PAD in elderly individuals than the conventional Doppler method.
PMCID: PMC3593766  PMID: 23493262
ankle-brachial index; oscillometry; Doppler; peripheral arterial disease
10.  Inhibition of VEGF signaling pathway attenuates hemorrhage after tPA treatment 
An angiogenic factor, vascular endothelial growth factor (VEGF), might be associated with the blood–brain barrier (BBB) disruption after focal cerebral ischemia; however, it remains unknown whether hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment is related to the activation of VEGF signaling pathway in BBB. Here, we hypothesized that inhibition of VEGF signaling pathway can attenuate HT after tPA treatment. Rats subjected to thromboembolic focal cerebral ischemia were assigned to a permanent ischemia group and groups treated with tPA at 1 or 4 hours after ischemia. Anti-VEGF neutralizing antibody or control antibody was administered simultaneously with tPA. At 24 hours after ischemia, we evaluated the effects of the antibody on the VEGF expression, matrix metalloproteinase-9 (MMP-9) activation, degradation of BBB components, and HT. Delayed tPA treatment at 4 hours after ischemia promoted expression of VEGF in BBB, MMP-9 activation, degradation of BBB components, and HT. Compared with tPA and control antibody, combination treatment with tPA and the anti-VEGF neutralizing antibody significantly attenuated VEGF expression in BBB, MMP-9 activation, degradation of BBB components, and HT. It also improved motor outcome and mortality. Inhibition of VEGF signaling pathway may be a promising therapeutic strategy for attenuating HT after tPA treatment.
PMCID: PMC3130331  PMID: 21304556
hemorrhagic transformation; ischemia; rat; tPA; VEGF
11.  Lithium Treatment Reduces Brain Injury Induced by Focal Ischemia with Partial Reperfusion and the Protective Mechanisms Dispute the Importance of Akt Activity 
Aging and Disease  2012;3(3):226-233.
Lithium is a mood stabilizer shown to have neuroprotective effects against several chronic and acute neuronal injuries, including stroke. However, it is unknown whether lithium treatment protects against brain injury post-stroke in a rat model of permanent distal middle cerebral artery occlusion (MCAo) combined with transient bilateral common carotid artery occlusion (CCAo), a model that mimics human stroke with partial reperfusion. In addition, whether lithium treatment alters Akt activity as measured by the kinase activity assay has not been reported, although it is known to inhibit GSK3β activity. After stroke, Akt activity contributes to neuronal survival while GSK3β activity causes neuronal death. We report that a bolus of lithium injection at stroke onset robustly reduced infarct size measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining at 48 h post-stroke and inhibited cell death in the ischemic penumbra, but not in the ischemic core, as shown by TUNEL staining performed 24 h post-stroke. However, lithium treatment did not alter the reduction in Akt activity as measured by Akt kinase assay. We further showed that lithium did not alter phosphorylated GSK3β protein levels, or the degradation of β-catenin, a substrate of GSK3β, which is consistent with previous findings that long-term treatment is required for lithium to alter GSK3β phosphorylation. In summary, we show innovative data that lithium protects against stroke in a focal ischemia model with partial reperfusion, however, our results dispute the importance of Akt activity in the protective effects of lithium.
PMCID: PMC3375079  PMID: 22724081
Lithium; Akt; Cerebral focal ischemia; GSK3β; β-catenin
12.  A prospective follow-up study of the association of radiation exposure with fatal and non-fatal stroke among atomic bomb survivors in Hiroshima and Nagasaki (1980–2003) 
BMJ Open  2012;2(1):e000654.
Use of medical radiotherapy has increased markedly in recent decades. Whether the consequence includes an increased risk of cardiovascular disease remains to be determined. The purpose of this study was to examine the association between radiation exposure and the incidence of stroke among Japanese atomic bomb survivors.
A prospective follow-up study.
Setting and participants
Radiation exposure from the atomic bombing was assessed in 9515 subjects (34.8% men) with 24-year follow-up from 1980. Subjects were free of prevalent stroke when follow-up began.
Outcome measures
Stroke events and the underlying cause of death were reviewed to confirm the first-ever stroke. Subtypes (ischaemic and haemorrhagic events) were categorised based on established criteria according to the definitions of typical/atypical stroke symptoms.
Overall mean radiation dose (±SD) in units of gray (Gy) was 0.38±0.58 (range: 0–3.5). During the study period, 235 haemorrhagic and 607 ischaemic events were identified. For men, after adjusting for age and concomitant risk factors, the risk of haemorrhagic stroke rose consistently from 11.6 to 29.1 per 10 000 person-years as doses increased from <0.05 to ≥2 Gy (p=0.009). Incidence also rose within the dose range <1 Gy (p=0.004) with no dose threshold. In women, the risk of haemorrhagic stroke rose with increasing radiation exposure but not until doses reached a threshold of 1.3 Gy (95% CI 0.5 to 2.3). Among women, for doses <1.3 Gy, differences in stroke risk were modest (13.5 per 10 000 person-years), while it increased to 20.3 per 10 000 person-years for doses that ranged from 1.3 to <2.2 Gy and to 48.6 per 10 000 person-years for doses that were higher (p=0.002). In both sexes, dose was unrelated to ischaemic stroke.
While the risk of haemorrhagic stroke increases with rising radiation exposure for both sexes, effects in women are less apparent until doses exceed a threshold at 1.3 Gy.
Article summary
Article focus
Use of medical radiotherapy has increased in recent decades.
Whether the consequence includes an increased risk of cardiovascular disease is unknown.
Our purpose was to examine the association between radiation exposure and the incidence of stroke among atomic bomb survivors in Japan.
Key messages
Risk of haemorrhagic stroke increased with rising radiation exposure for both sexes, although effects in women were less apparent until doses exceeded a threshold at 1.3 Gy.
Radiation exposure was unrelated to ischaemic stroke.
Strengths and limitations of this study
This report provides information on the incidence of stroke using data from clinical examinations and mortality records following a structured research protocol.
Measurement of radiation exposure adheres to a precise system of quantification.
While best attempts were made to properly classify strokes outcomes, diagnostic uncertainties persist.
PMCID: PMC3274709  PMID: 22307102
13.  Granulovacuolar Degenerations Appear in Relation to Hippocampal Phosphorylated Tau Accumulation in Various Neurodegenerative Disorders 
PLoS ONE  2011;6(11):e26996.
Granulovacuolar degeneration (GVD) is one of the pathological hallmarks of Alzheimer's disease (AD), and it is defined as electron-dense granules within double membrane-bound cytoplasmic vacuoles. Several lines of evidence have suggested that GVDs appear within hippocampal pyramidal neurons in AD when phosphorylated tau begins to aggregate into early-stage neurofibrillary tangles. The aim of this study is to investigate the association of GVDs with phosphorylated tau pathology to determine whether GVDs and phosphorylated tau coexist among different non-AD neurodegenerative disorders.
An autopsied series of 28 patients with a variety of neurodegenerative disorders and 9 control patients were evaluated. Standard histological stains along with immunohistochemistry using protein markers for GVD and confocal microscopy were utilized.
The number of neurons with GVDs significantly increased with the level of phosphorylated tau accumulation in the hippocampal regions in non-AD neurodegenerative disorders. At the cellular level, diffuse staining for phosphorylated tau was detected in neurons with GVDs.
Our data suggest that GVDs appear in relation to hippocampal phosphorylated tau accumulation in various neurodegenerative disorders, while the presence of phosphorylated tau in GVD-harbouring neurons in non-AD neurodegenerative disorders was indistinguishable from age-related accumulation of phosphorylated tau. Although GVDs in non-AD neurodegenerative disorders have not been studied thoroughly, our results suggest that they are not incidental findings, but rather they appear in relation to phosphorylated tau accumulation, further highlighting the role of GVD in the process of phosphorylated tau accumulation.
PMCID: PMC3207829  PMID: 22073234
14.  Assessment of EEG dynamical complexity in Alzheimer’s disease using multiscale entropy 
Multiscale entropy (MSE) is a recently proposed entropy-based index of physiological complexity, evaluating signals at multiple temporal scales. To test this method as an aid to elucidating the pathophysiology of Alzheimer’s disease (AD), we examined MSE in resting state EEG activity in comparison with traditional EEG analysis.
We recorded EEG in medication-free 15 presenile AD patients and 18 age- and sex-matched healthy control (HC) subjects. MSE was calculated for continuous 60-second epochs for each group, concurrently with power analysis.
The MSE results from smaller and larger scales were associated with higher and lower frequencies of relative power, respectively. Group analysis demonstrated that the AD group had less complexity at smaller scales in more frontal areas, consistent with previous findings. In contrast, higher complexity at larger scales was observed across brain areas in AD group and this higher complexity was significantly correlated with cognitive decline.
MSE measures identified an abnormal complexity profile across different temporal scales and their relation to the severity of AD.
These findings indicate that entropy-based analytic methods with applied at temporal scales may serve as a complementary approach for characterizing and understanding abnormal cortical dynamics in AD.
PMCID: PMC2914820  PMID: 20400371
Alzheimer’s disease (AD); Electroencephalogram (EEG); Complexity; Multiscale entropy (MSE); Mini-Mental State Examination (MMSE); Power analysis
15.  Antipsychotics reverse abnormal EEG complexity in drug-naïve schizophrenia: A multiscale entropy analysis 
NeuroImage  2010;51(1):173-182.
Multiscale entropy (MSE) analysis is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. To evaluate this analytic approach as an aid to elucidating the pathophysiologic mechanisms in schizophrenia, we examined MSE in EEG activity in drug-naïve schizophrenia subjects pre- and post-treatment with antipsychotics in comparison with traditional EEG analysis. We recorded eyes-closed resting state EEG from frontal, temporal, parietal and occipital regions in drug-naïve 22 schizophrenia and 24 age-matched healthy control subjects. Fifteen patients were re-evaluated within 2–8 weeks after the initiation of antipsychotic treatment. For each participant, MSE was calculated on one continuous 60 second epoch for each experimental session. Schizophrenia subjects showed significantly higher complexity at higher time scales (lower frequencies), than that of healthy controls in fronto-centro-temporal, but not in parieto-occipital regions. Post-treatment, this higher complexity decreased to healthy control subject levels selectively in fronto-central regions, while the increased complexity in temporal sites remained higher. Comparative power analysis identified spectral slowing in frontal regions in pre-treatment schizophrenia subjects, consistent with previous findings, whereas no antipsychotic treatment effect was observed. In summary, multiscale entropy measures identified abnormal dynamical EEG signal complexity in anterior brain areas in schizophrenia that normalized selectively in fronto-central areas with antipsychotic treatment. These findings show that entropy-based analytic methods may serve as a novel approach for characterizing and understanding abnormal cortical dynamics in schizophrenia, and elucidating the therapeutic mechanisms of antipsychotics.
PMCID: PMC2849166  PMID: 20149880
Drug-naïve schizophrenia; Electroencephalography (EEG); Complexity; Multiscale entropy (MSE); Antipsychotics
16.  The pathophysiology of prospective memory failure after diffuse axonal injury - Lesion-symptom analysis using diffusion tensor imaging 
BMC Neuroscience  2010;11:147.
Prospective memory (PM) is one of the most important cognitive domains in everyday life. The neuronal basis of PM has been examined by a large number of neuroimaging and neuropsychological studies, and it has been suggested that several cerebral domains contribute to PM. For these activation studies, a constellation of experimental PM trials was developed and adopted to healthy subjects. In the present study, we used a widely used clinical PM assessment battery to determine the lesions attributable to PM failure, with the hypothesis that lesion-symptom analysis using diffusion tensor imaging (DTI) in subjects with diffuse axonal injury (DAI) can reveal the neuronal basis of PM in everyday life.
Fourteen DAI patients (age: range of 18-36, median 24) participated in this study. PM failure was scored in the range of 0-6 using three sub-tests of the Rivermead Behavioural Memory Test. The PM scores of DAI patients were in the range of 2-6 (median 4.5, inter-quartile range 2.25). The severity of axonal injury following DAI was examined using fractional anisotropy (FA), one of the DTI parameters, at voxel level in each subject. We then obtained clusters correlated with PM failure by conducting voxel-based regression analysis between FA values and PM scores. Three clusters exhibited significant positive correlation with PM score, the left parahippocampal gyrus, left inferior parietal lobe, and left anterior cingulate.
This is the first lesion-symptom study to reveal the neuronal basis of PM using DTI on subjects with DAI. Our findings suggest that the neuronal basis of PM is in the left parahippocampal gyrus, left inferior parietal lobe, and/or left anterior cingulate. These findings are similar to those of previous activation studies with loading experimental PM tasks.
PMCID: PMC2998523  PMID: 21092119
17.  Age-related variation in EEG complexity to photic stimulation: A multiscale entropy analysis 
This study was intended to examine variations in electroencephalographic (EEG) complexity in response to photic stimulation (PS) during aging to test the hypothesis that the aging process reduces physiologic complexity and functional responsiveness.
Multiscale entropy (MSE), an estimate of time-series signal complexity associated with long-range temporal correlation, is used as a recently proposed method for quantifying EEG complexity with multiple coarse-grained sequences. We recorded EEG in 13 healthy elderly subjects and 12 healthy young subjects during pre-PS and post-PS conditions and estimated their respective MSE values.
For the pre-PS condition, no significant complexity difference was found between the groups. However, a significant MSE change (complexity increase) was found post-PS only in young subjects, thereby revealing a power-law scaling property, which means long-range temporal correlation.
Enhancement of long-range temporal correlation in young subjects after PS might reflect a cortical response to stimuli, which was absent in elderly subjects. These results are consistent with the general “loss of complexity/diminished functional response to stimuli” theory of aging.
Our findings demonstrate that application of MSE analysis to EEG is a powerful approach for studying age-related changes in brain function.
PMCID: PMC2880484  PMID: 19231279
Multiscale entropy; Aging; Electroencephalography; Complexity; Long-range temporal correlation; Photic stimulation
18.  The Akt signaling pathway contributes to postconditioning’s protection against stroke; the protection is associated with the MAPK and PKC pathways 
Journal of neurochemistry  2008;105(3):943-955.
We previously reported that ischemic postconditioning with a series of mechanical interruptions of reperfusion reduced infarct volume 2 days after focal ischemia in rats. Here, we extend this data by examining long-term protection and exploring underlying mechanisms involving the Akt, mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways. Post-conditioning reduced infarct and improved behavioral function assessed 30 days after stroke. Additionally, postconditioning increased levels of phosphorylated Akt (Ser473) as measured by western blot and Akt activity as measured by an in vitro kinase assay. Inhibiting Akt activity by a phosphoinositide 3-kinase inhibitor, LY294002, enlarged infarct in postconditioned rats. Postconditioning did not affect protein levels of phosphorylated-phosphatase and tensin homologue deleted on chromosome 10 or -phosphoinositide-dependent protein kinase-1 (molecules upstream of Akt) but did inhibit an increase in phosphorylated-glycogen synthase kinase 3β, an Akt effector. In addition, postconditioning blocked β-catenin phosphorylation subsequent to glycogen synthase kinase, but had no effect on total or non-phosphorylated active β-catenin protein levels. Furthermore, postconditioning inhibited increases in the amount of phosphorylated-c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in the MAPK pathway. Finally, postconditioning blocked death-promoting δPKC cleavage and attenuated reduction in phosphorylation of survival-promoting εPKC. In conclusion, our data suggest that postconditioning provides long-term protection against stroke in rats. Additionally, we found that Akt activity contributes to postconditioning’s protection; furthermore, increases in εPKC activity, a survival-promoting pathway, and reductions in MAPK and δPKC activity; two putative death-promoting pathways correlate with postconditioning’s protection.
PMCID: PMC2746404  PMID: 18182053
Akt; cerebral ischemia; mitogen-activated protein kinase; postconditioning; protein kinase C; β-catenin
19.  Hypothermia Blocks β-catenin Degradation after Focal Ischemia in Rats 
Brain research  2008;1198:182-187.
Dephosphorylated and activated glycogen synthase kinase (GSK) 3β hyperphophorylates β-catenin, leading to its ubiquitin-proteosome-mediated degradation. β-catenin-knockdown increases while β-catenin overexpression prevents neuronal death in vitro; in addition, protein levels of β-catenin are reduced in the brain of Alzheimer’s patients. However, whether β-catenin degradation is involved in stroke-induced brain injury is unknown. Here we studied activities of GSK3 β and β-catenin, and the protective effect of moderate hypothermia (30 °C) on these activities after focal ischemia in rats. The results of Western blot showed that GSK3 β was dephosphorylated at 5 and 24 hours after stroke in the normothermic (37 °C) brain; hypothermia augmented GSK3β dephosphorylation. Because hypothermia reduces infarction, these results contradict with previous studies showing that GSK3β dephosphorylation worsens neuronal death. Nevertheless, hypothermia blocked degradation of total GSK3β protein. Corresponding to GSK3β activity in normothermic rats, β-catenin phosphorylation transiently increased at 5 hours in both the ischemic penumbra and core, and the total protein level of β-catenin degraded after normothermic stroke. Hypothermia did not inhibit β-catenin phosphorylation, but it blocked β-catenin degradation in the ischemic penumbra. In conclusion, moderate hypothermia can stabilize β-catenin, which may contribute to the protective effect of moderate hypothermia.
PMCID: PMC2350209  PMID: 18241848
Focal ischemia; hypothermia; GSK-3β; β-catenin
20.  Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3′-phosphate and 3′-phosphoglycolate ends 
Nucleic Acids Research  2007;35(11):3797-3809.
Aprataxin is the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ataxia with oculomotor apraxia type 1 (EAOH/AOA1), the clinical symptoms of which are predominantly neurological. Although aprataxin has been suggested to be related to DNA single-strand break repair (SSBR), the physiological function of aprataxin remains to be elucidated. DNA single-strand breaks (SSBs) continually produced by endogenous reactive oxygen species or exogenous genotoxic agents, typically possess damaged 3′-ends including 3′-phosphate, 3′-phosphoglycolate, or 3′-α, β-unsaturated aldehyde ends. These damaged 3′-ends should be restored to 3′-hydroxyl ends for subsequent repair processes. Here we demonstrate by in vitro assay that recombinant human aprataxin specifically removes 3′-phosphoglycolate and 3′-phosphate ends at DNA 3′-ends, but not 3′-α, β-unsaturated aldehyde ends, and can act with DNA polymerase β and DNA ligase III to repair SSBs with these damaged 3′-ends. Furthermore, disease-associated mutant forms of aprataxin lack this removal activity. The findings indicate that aprataxin has an important role in SSBR, that is, it removes blocking molecules from 3′-ends, and that the accumulation of unrepaired SSBs with damaged 3′-ends underlies the pathogenesis of EAOH/AOA1. The findings will provide new insight into the mechanism underlying degeneration and DNA repair in neurons.
PMCID: PMC1920238  PMID: 17519253
21.  Cardiopulmonary Responses at Various Angles of Cycle Backrest Inclination 
The purpose of this study was to evaluate cardiopulmonary responses during submaximal cycle exercise at various angles of backrest inclination. Ten healthy Japanese men of mean age 25.9 yrs, height 170.6 cm, and body mass 66.1 kg, performed cycle exercises at a constant workload which reached the anaerobic threshold, at 20 degrees, 40 degrees, and 60 degrees of backrest inclination from the vertical plane, but the angle between the seat and back rest was kept at 110 degrees. The results were as follows: 1) Both cardiac output and stroke volume showed a higher value at the resting control state and during exercise as the backrest angle increased. 2) Oxygen consumption, carbon dioxide output, heart rate, gas exchange ratio, and oxygen pulse were not affected by the angle of backrest inclination. 3) Tidal volume at 20 degrees of backrest inclination was higher than at 60 degrees. 4) No significant differences were found in minute ventilation between each backrest angle. These findings suggest that changes in the backrest angle significantly alter cardiopulmonary parameters at rest and during exercise; in particular, an angle difference of 40 degrees may be enough to alter tidal volume, cardiac output and stroke volume, but not the minute ventilation.
PMCID: PMC4316490  PMID: 25792911
cardiopulmonary response; body angle; exercise test
22.  The Effects of Posture on the Ventilatory Responses During Exercise 
This study was undertaken to evaluate the postural effect on ventilatory responses during both supine and sitting exercise. Seven healthy men performed two exercise tests utilizing the ramp protocol (20 watts/min) with a cycle ergometer in each position. The results were as follows: The oxygen uptake and the oxygen pulse measured at 180 watts and at anaerobic threshold in the sitting were significantly higher compared with those in the supine position. The average of carbon-dioxide output, minute ventilation and tidal volume at lower exercise intensities showed higher values in the sitting compared with those in the supine position, whereas there were no significant differences for respiratory rate. There was significant difference in the slope of the minute ventilation to carbon-dioxide output plot between sitting and supine position. In conclusion, the higher minute ventilation in the sitting position was mainly performed by higher tidal volume which may counteract the effects of an increase in physiological dead space. The lower slope of the minute ventilation to carbon-dioxide output plot which shows more effective ventilation in the supine position may be due to decreased physiological dead space and higher diffusion capacity.
PMCID: PMC4316495  PMID: 25792876
posture; ventilatory response; exercise
23.  Phosphatidylinositol-4,5-bisphosphate is enriched in granulovacuolar degeneration bodies and neurofibrillary tangles 
Among the pathological findings in Alzheimer’s disease (AD), the temporal and spatial profiles of granulovacuolar degeneration (GVD) bodies are characteristic in that they seem to be related to those of neurofibrillary tangles (NFTs), suggesting a common mechanism underlying the pathogenesis of these structures. Flotillin-1, a marker of lipid rafts, accumulates in lysosomes of tangle-bearing neurones in AD patients. In addition, recent reports have shown that GVD bodies accumulate at the nexus of the autophagic and endocytic pathways. The aim of this study was to elucidate the distribution of the lipid component of lipid rafts, phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2], in AD and other neurodegenerative disorders.
We compared PtdIns(4,5)P2 immunoreactivity in the hippocampus, entorhinal cortex and neocortex of five AD cases, 17 cases of other neurodegenerative disorders and four controls. In addition, we performed double staining using markers of GVD, NFTs and lipid rafts for further characterization.
Immunohistochemical analysis revealed that PtdIns(4,5)P2 was selectively enriched in GVD bodies and NFTs. Although immunoreactivity for PtdIns(4,5)P2 was also evident in NFTs composed of hyperphosphorylated tau, PtdIns(4,5)P2 was segregated from phosphorylated tau within NFTs by double immunofluorescence staining. In contrast, PtdIns(4,5)P2 colocalized with the lipid raft markers flotillin-1 and annexin 2, within GVD bodies and NFTs.
These results suggest that lipid raft components including PtdIns(4,5)P2 play a role in the formation of both GVD bodies and NFTs.
PMCID: PMC4298759  PMID: 23631697
Alzheimer’s disease; granulovacuolar degeneration; lipid raft; neurofibrillary tangle; phosphatidylinositol-4; 5-bisphosphate

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