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1.  Analysis of pain level in cases treated with Invisalign aligner: comparison with fixed edgewise appliance therapy 
Progress in Orthodontics  2014;15(1):64.
The aim of this study was to evaluate and compare the difference in the level of pain using the visual analog scale (VAS) between cases treated with the edgewise appliance and Invisalign. In addition, the cause of pain and discomfort in the Invisalign cases was identified.
The sample consisted of 145 cases for the edgewise group (EG; n = 55), Invisalign group (IG; n = 38), and edgewise and Invisalign group (EIG; n = 52). VAS scores were collected during the first three stages (first stage: 0 to 7 days, second stage: 14 to 21 days, and third stage: 28 to 35 days) and at the end of the treatment (overall VAS score). Evaluation of the cause of pain was categorized into three different types of problem (category 1: non-smoothed marginal ridge or missing materials, category 2: deformation of attachments, and Category 3: deformation of the tray). Statistical comparison of VAS scores between groups was performed by two-way analysis of variance.
A significantly higher VAS score was observed at 3 and 4 days after, at 1, 2, and 3 days after, and at 2 and 3 days after in stages 1, 2, and 3, respectively, in EG compared to EIG and IG. A significant difference was observed in overall VAS scores between EG and IG in intensity of pain, number of days that pain lasted, and discomfort level. Only intensity of pain resulted in a significant difference between EG and EIG. Most of the causes of problem in the Invisalign cases were deformation of the tray.
Invisalign may offer less pain compared to the edgewise appliance during the initial stages of treatment. In the use of Invisalign, deformation of tray must be carefully checked to avoid pain and discomfort for the patients.
PMCID: PMC4240829  PMID: 25416143
Invisalign; Pain; Tooth movement; Edgewise appliance
2.  Induction of cortical plasticity for reciprocal muscles by paired associative stimulation 
Brain and Behavior  2014;4(6):822-832.
Paired associative stimulation (PAS) is widely used to induce plasticity in the human motor cortex. Although reciprocal inhibition of antagonist muscles plays a fundamental role in human movements, change in cortical circuits for reciprocal muscles by PAS is unknown.
We investigated change in cortical plasticity for reciprocal muscles during PAS. PAS consisted of 200 pairs of peripheral electric stimulation of the right median nerve at the wrist at a frequency of 0.25 Hz followed by transcranial magnetic stimulation of the left M1 at the midpoint between the center of gravities of the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles. Measures of motor cortical excitability included resting motor threshold (RMT), GABAA-mediated short-interval intracortical inhibition (SICI), and GABAB-mediated long-interval intracortical inhibition (LICI).
Motor evoked potential amplitude-conditioned LICI for the FCR muscle was significantly decreased after PAS (P = 0.020), whereas that for the ECR muscle was significantly increased (P = 0.033). Changes in RMT and SICI for the FCR and ECR muscles were not significantly different before and after PAS. Corticospinal excitability for both reciprocal muscles was increased during PAS, but GABAB-mediated cortical inhibitory functions for the agonist and antagonist muscles were reciprocally altered after PAS.
These results implied that the cortical excitability for reciprocal muscles including GABAB-ergic inhibitory systems within human M1 could be differently altered by PAS.
PMCID: PMC4212109  PMID: 25365805
Human; magnetic stimulation; motor evoked potential; paired associative stimulation; reciprocal inhibition
3.  Induction of cortical plasticity for reciprocal muscles by paired associative stimulation 
Brain and Behavior  2014;10.1002/brb3.280.
Paired associative stimulation (PAS) is widely used to induce plasticity in the human motor cortex. Although reciprocal inhibition of antagonist muscles plays a fundamental role in human movements, change in cortical circuits for reciprocal muscles by PAS is unknown.
We investigated change in cortical plasticity for reciprocal muscles during PAS. PAS consisted of 200 pairs of peripheral electric stimulation of the right median nerve at the wrist at a frequency of 0.25 Hz followed by transcranial magnetic stimulation of the left M1 at the midpoint between the center of gravities of the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles. Measures of motor cortical excitability included resting motor threshold (RMT), GABAA‐mediated short‐interval intracortical inhibition (SICI), and GABAB‐mediated long‐interval intracortical inhibition (LICI).
Motor evoked potential amplitude‐conditioned LICI for the FCR muscle was significantly decreased after PAS (P = 0.020), whereas that for the ECR muscle was significantly increased (P = 0.033). Changes in RMT and SICI for the FCR and ECR muscles were not significantly different before and after PAS. Corticospinal excitability for both reciprocal muscles was increased during PAS, but GABAB‐mediated cortical inhibitory functions for the agonist and antagonist muscles were reciprocally altered after PAS.
These results implied that the cortical excitability for reciprocal muscles including GABAB‐ergic inhibitory systems within human M1 could be differently altered by PAS.
PMCID: PMC4212109  PMID: 25365805
Human; magnetic stimulation; motor evoked potential; paired associative stimulation; reciprocal inhibition
4.  Sensorimotor Modulation Differs with Load Type during Constant Finger Force or Position 
PLoS ONE  2014;9(9):e108058.
During submaximal isometric contraction, there are two different load types: production of a constant force against a rigid restraint (force task), and maintenance of position against a constant load (position task). Previous studies reported that the time to task failure during a fatigue task was twice as long in the force task compared with the position task. Sensory feedback processing may contribute to these differences. The purpose of the current study was to determine the influence of load types during static muscle contraction tasks on the gating effect, i.e., attenuation of somatosensory-evoked potentials (SEPs) and the cortical silent period (cSP). Ten healthy subjects contracted their right first dorsal interosseus muscle by abducting their index finger for 90 s, to produce a constant force against a rigid restraint that was 20% of the maximum voluntary contraction (force task), or to maintain a constant position with 10° abduction of the metacarpophalangeal joint against the same load (position task). Somatosensory evoked potentials (SEPs) were recorded from C3′ by stimulating either the right ulnar or median nerve at the wrist while maintaining contraction. The cortical silent period (cSP) was also elicited by transcranial magnetic stimulation. Reduction of the amplitude of the P45 component of SEPs was significantly larger during the position task than during the force task and under control rest conditions when the ulnar nerve, but not the median nerve, was stimulated. The position task had a significantly shorter cSP duration than the force task. These results suggest the need for more proprioceptive information during the position task than the force task. The shorter duration of the cSP during the position task may be attributable to larger amplitude of heteronymous short latency reflexes. Sensorimotor modulations may differ with load type during constant finger force or position tasks.
PMCID: PMC4169486  PMID: 25233353
5.  Metabolomics for Biomarker Discovery in Gastroenterological Cancer 
Metabolites  2014;4(3):547-571.
The study of the omics cascade, which involves comprehensive investigations based on genomics, transcriptomics, proteomics, metabolomics, etc., has developed rapidly and now plays an important role in life science research. Among such analyses, metabolome analysis, in which the concentrations of low molecular weight metabolites are comprehensively analyzed, has rapidly developed along with improvements in analytical technology, and hence, has been applied to a variety of research fields including the clinical, cell biology, and plant/food science fields. The metabolome represents the endpoint of the omics cascade and is also the closest point in the cascade to the phenotype. Moreover, it is affected by variations in not only the expression but also the enzymatic activity of several proteins. Therefore, metabolome analysis can be a useful approach for finding effective diagnostic markers and examining unknown pathological conditions. The number of studies involving metabolome analysis has recently been increasing year-on-year. Here, we describe the findings of studies that used metabolome analysis to attempt to discover biomarker candidates for gastroenterological cancer and discuss metabolome analysis-based disease diagnosis.
PMCID: PMC4192679  PMID: 25003943
metabolomics; biomarker; serum; gastroenterological cancer; mass spectrometry
6.  Ventricular fibrillation associated with complete right bundle branch block 
A substantial number of patients with idiopathic ventricular fibrillation (IVF) present with no specific electrocardiographic (ECG) findings.
To evaluate complete right bundle branch block (RBBB) in patients with IVF.
Patients with IVF showing complete RBBB were included in the present study. Structural and primary electrical diseases were excluded, and provocation tests were performed to exclude the presence of spastic angina or Brugada syndrome (BrS). The prevalence of complete RBBB and the clinical and ECG parameters were compared either in patients with IVF who did not show RBBB or in the general population and age and sex comparable controls with RBBB.
Of 96 patients with IVF, 9 patients were excluded for the presence of BrS. Of 87 patients studied, 10 (11.5%) patients showed complete RBBB. None had structural heart diseases, BrS, or coronary spasms. The mean age was 44 ± 15 years, and 8 of 10 patients were men. Among the ECG parameters, only the QRS duration was different from that of the other patients with IVF who did not show complete RBBB. Ventricular fibrillation recurred in 3:2 in the form of storms, which were well suppressed by isoproterenol. Complete RBBB was found less often in control subjects (1.37%; P < .0001), and the QRS duration was more prolonged in patients with IVF: 139 ± 10 ms vs 150 ± 14 ms (P = .0061).
Complete RBBB exists more often in patients with IVF than in controls. A prolonged QRS complex suggests a conduction abnormality. Our findings warrant further investigation of the role of RBBB in the development of arrhythmias in patients with IVF.
PMCID: PMC3770839  PMID: 23499623
Sudden death; Idiopathic ventricular fibrillation; Right bundle branch block; Electrocardiogram; Brugada syndrome
7.  Aberrant methylation and silencing of IRF8 expression in non-small cell lung cancer 
Oncology Letters  2014;8(3):1025-1030.
The aim of the present study was to investigate the aberrant methylation and altered expression of the interferon regulatory factor 8 (IRF8) gene in non-small cell lung cancer (NSCLC). Pyrosequencing assays were performed on 191 tumor specimens from NSCLC patients. The changes in IRF8 mRNA expression, prior to and following treatment with a demethylating agent and methylation itself, were examined in 13 lung cancer cell lines by quantitative polymerase chain reaction (qPCR) and pyrosequencing. IRF8 protein expression was examined in 94 of the 191 NSCLC specimens by immunohistochemical analysis. The IRF8 methylation level was significantly higher in the tumor tissues than in matched non-malignant lung tissues (P<0.0001). IRF8 was more frequently methylated in tumor tissues compared with matched non-malignant lung tissues, as defined by a predetermined cut-off value (P<0.0001). The IRF8 methylation level was strongly correlated with the change in mRNA expression in lung cancer cell lines and with the protein expression level in primary tumors. The IRF8 gene was more frequently methylated in patients without an epidermal growth factor receptor (EGFR) mutation than in patients with an EGFR mutation (P=0.015). IRF8 methylation correlated with recurrent prognosis in adenocarcinomas (log-rank test, P=0.048). IRF8 protein expression was frequently silenced in males, smokers, patients with non-adenocarcinoma or with wild-type EGFR, or in an advanced stage. IRF8 is often silenced by its methylation, which is a frequent event in NSCLC and, therefore, methylation of IRF8 may act as a prognostic marker for recurrence. Analysis of IRF8 methylation status may provide novel opportunities for improved prognosis and therapy of resected NSCLC.
PMCID: PMC4114630  PMID: 25120651
IRF8; pyrosequencing; methylation; expression
8.  Six1 is a key regulator of the developmental and evolutionary architecture of sensory neurons in craniates 
BMC Biology  2014;12:40.
Various senses and sensory nerve architectures of animals have evolved during adaptation to exploit diverse environments. In craniates, the trunk sensory system has evolved from simple mechanosensory neurons inside the spinal cord (intramedullary), called Rohon-Beard (RB) cells, to multimodal sensory neurons of dorsal root ganglia (DRG) outside the spinal cord (extramedullary). The fish and amphibian trunk sensory systems switch from RB cells to DRG during development, while amniotes rely exclusively on the DRG system. The mechanisms underlying the ontogenic switching and its link to phylogenetic transition remain unknown.
In Xenopus, Six1 overexpression promoted precocious apoptosis of RB cells and emergence of extramedullary sensory neurons, whereas Six1 knockdown delayed the reduction in RB cell number. Genetic ablation of Six1 and Six4 in mice led to the appearance of intramedullary sensory neuron-like cells as a result of medial migration of neural crest cells into the spinal cord and production of immature DRG neurons and fused DRG. Restoration of SIX1 expression in the neural crest-linage partially rescued the phenotype, indicating the cell autonomous requirements of SIX1 for normal extramedullary sensory neurogenesis. Mouse Six1 enhancer that mediates the expression in DRG neurons activated transcription in Xenopus RB cells earlier than endogenous six1 expression, suggesting earlier onset of mouse SIX1 expression than Xenopus during sensory development.
The results indicated the critical role of Six1 in transition of RB cells to DRG neurons during Xenopus development and establishment of exclusive DRG system of mice. The study provided evidence that early appearance of SIX1 expression, which correlated with mouse Six1 enhancer, is essential for the formation of DRG-dominant system in mice, suggesting that heterochronic changes in Six1 enhancer sequence play an important role in alteration of trunk sensory architecture and contribute to the evolution of the trunk sensory system.
PMCID: PMC4084797  PMID: 24885223
Dorsal root ganglia; Enhancer; Evolution; Neural crest cell; Rohon-Beard cell; Sensory neuron; Six genes
9.  Motor Cortex-Evoked Activity in Reciprocal Muscles Is Modulated by Reward Probability 
PLoS ONE  2014;9(3):e90773.
Horizontal intracortical projections for agonist and antagonist muscles exist in the primary motor cortex (M1), and reward may induce a reinforcement of transmission efficiency of intracortical circuits. We investigated reward-induced change in M1 excitability for agonist and antagonist muscles. Participants were 8 healthy volunteers. Probabilistic reward tasks comprised 3 conditions of 30 trials each: 30 trials contained 10% reward, 30 trials contained 50% reward, and 30 trials contained 90% reward. Each trial began with a cue (red fixation cross), followed by blue circle for 1 s. The subjects were instructed to perform wrist flexion and press a button with the dorsal aspect of middle finger phalanx as quickly as possible in response to disappearance of the blue circle without looking at their hand or the button. Two seconds after the button press, reward/non-reward stimulus was randomly presented for 2-s duration. The reward stimulus was a picture of Japanese 10-yen coin, and each subject received monetary reward at the end of experiment. Subjects were not informed of the reward probabilities. We delivered transcranial magnetic stimulation of the left M1 at the midpoint between center of gravities of agonist flexor carpi radialis (FCR) and antagonist extensor carpi radialis (ECR) muscles at 2 s after the red fixation cross and 1 s after the reward/non-reward stimuli. Relative motor evoked potential (MEP) amplitudes at 2 s after the red fixation cross were significantly higher for 10% reward probability than for 90% reward probability, whereas relative MEP amplitudes at 1 s after reward/non-reward stimuli were significantly higher for 90% reward probability than for 10% and 50% reward probabilities. These results implied that reward could affect the horizontal intracortical projections in M1 for agonist and antagonist muscles, and M1 excitability including the reward-related circuit before and after reward stimulus could be differently altered by reward probability.
PMCID: PMC3948372  PMID: 24603644
10.  Pulmonary cryptococcosis presenting with a large cavity 
Respirology Case Reports  2014;2(2):61-63.
A 78-year-old woman who was receiving corticosteroids for rheumatoid arthritis was admitted to our hospital to have her fever, hemoptysis, diarrhea, and chest x-ray abnormalities, which were unresponsive to antibiotics, investigated. A chest computed tomography scan revealed infiltrative shadows and a large cavity in the right lower lobe. Laboratory tests revealed a white blood cell count of 13,100/μL, a serum C-reactive protein level of 8.75 mg/dL, a serum albumin level of 1.4 g/dL, and positivity for Cryptococcus antigen. Grocott staining of a transbronchial lung biopsy specimen detected black-brown fungi. Also, a stool sample was positive for Clostridium difficile toxin, leading to a diagnosis of pulmonary cryptococcosis and pseudomembranous colitis. The patient was given 200 mg/day intravenous fosfluconazole and 1500 mg/day oral metronidazole, and her condition improved. Immunocompromised hosts with pulmonary cryptococcosis demonstrate a wide variety of radiographic abnormalities, including nodules, cavitation, and infiltration.
PMCID: PMC4184507  PMID: 25473568
Cavitation; Cryptococcus; immunocompromised host
11.  A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury 
Neurology  2013;80(6):533-539.
To assess the efficacy and tolerability of pregabalin for the treatment of central neuropathic pain after spinal cord injury (SCI).
Patients with chronic, below-level, neuropathic pain due to SCI were randomized to receive 150 to 600 mg/d pregabalin (n = 108) or matching placebo (n = 112) for 17 weeks. Pain was classified in relation to the neurologic level of injury, defined as the most caudal spinal cord segment with normal sensory and motor function, as above, at, or below level. The primary outcome measure was duration-adjusted average change in pain. Key secondary outcome measures included the change in mean pain score from baseline to end point, the percentage of patients with ≥30% reduction in mean pain score at end point, Patient Global Impression of Change scores at end point, and the change in mean pain-related sleep interference score from baseline to end point. Additional outcome measures included the Medical Outcomes Study–Sleep Scale and the Hospital Anxiety and Depression Scale.
Pregabalin treatment resulted in statistically significant improvements over placebo for all primary and key secondary outcome measures. Significant pain improvement was evident as early as week 1 and was sustained throughout the treatment period. Adverse events were consistent with the known safety profile of pregabalin and were mostly mild to moderate in severity. Somnolence and dizziness were most frequently reported.
This study demonstrates that pregabalin is effective and well tolerated in patients with neuropathic pain due to SCI.
Classification of evidence:
This study provides Class I evidence that pregabalin, 150 to 600 mg/d, is effective in reducing duration-adjusted average change in pain compared with baseline in patients with SCI over a 16-week period (p = 0.003, 95% confidence interval = −0.98, −0.20).
PMCID: PMC3589291  PMID: 23345639
12.  Chemical Synthesis of U1 snRNA Derivatives 
Organic Letters  2013;15(17):4386-4389.
U1 snRNA is an interesting biological tool for splicing correction and regulation of gene expression. However, U1 snRNA has never been chemically synthesized. In this study, the first chemical synthesis of U1snRNA and its analogues was carried out. Moreover, it was found that the binding affinity of the modified U1 snRNA with an ethylene glycol linkage to snurportin 1 (nuclear import adaptor) was as high as that of the unmodified RNA.
PMCID: PMC3901379  PMID: 23952175
13.  Characterization of blood pressure and endothelial function in TRPV4‐deficient mice with l‐NAME‐ and angiotensin II‐induced hypertension 
Physiological Reports  2014;2(1):e00199.
Transient receptor potential vanilloid type 4 (TRPV4) is an endothelial Ca2+ entry channel contributing to endothelium‐mediated dilation in conduit and resistance arteries. We investigated the role of TRPV4 in the regulation of blood pressure and endothelial function under hypertensive conditions. TRPV4‐deficient (TRPV4−/−) and wild‐type (WT) control mice were given l‐NAME (0.5 g/L) in drinking water for 7 days or subcutaneously infused with angiotensin (Ang) II (600 ng/kg per minute) for 14 days, and blood pressure measured by radiotelemetry. TRPV4−/− mice had a lower baseline mean arterial pressure (MAP) (12‐h daytime MAP, 94 ± 2 vs. 99 ± 2 mmHg in WT controls). l‐NAME treatment induced a slightly greater increase in MAP in TRPV4−/− mice (day 7, 13 ± 4%) compared to WT controls (6 ± 2%), but Ang II‐induced increases in MAP were similar in TRPV4−/− and WT mice (day 14, 53 ± 6% and 37 ± 11%, respectively, P < 0.05). Chronic infusion of WT mice with Ang II reduced both acetylcholine (ACh)‐induced dilation (dilation to 10−5 mol/L ACh, 71 ± 5% vs. 92 ± 2% of controls) and the TRPV4 agonist GSK1016790A‐induced dilation of small mesenteric arteries (10−8 mol/L GSK1016790A, 14 ± 5% vs. 77 ± 7% of controls). However, Ang II treatment did not affect ACh dilation in TRPV4−/− mice. Mechanistically, Ang II did not significantly alter either TRPV4 total protein expression in mesenteric arteries or TRPV4 agonist‐induced Ca2+ response in mesenteric endothelial cells in situ. These results suggest that TRPV4 channels play a minor role in blood pressure regulation in l‐NAME‐ but not Ang II‐induced hypertension, but may be importantly involved in Ang II‐induced endothelial dysfunction.
We investigated the role of transient receptor potential vanilloid type 4 (TRPV4) in regulating vascular tone in vivo under normal conditions and in response to hypertensive challenges. Our results indicate that TRPV4 channels may play a complex role in the control of vascular tone and endothelial function under stress.
PMCID: PMC3967682  PMID: 24744878
Endothelium; endothelium‐derived hyperpolarizing factor; Hypertension; mesenteric arteries; nitric oxide; TRPV4
14.  Relationship between the Berg Balance Scale and Static Balance Test in Hemiplegic Patients with Stroke 
Journal of Physical Therapy Science  2013;25(8):1043-1049.
[Purpose] The purpose of this study was to analyze the relationship between results of the Berg Balance Scale (BBS) and Static Balance Test (SBT) in hemiplegic patients with stroke. [Subjects] The subjects were 39 hemiplegic patients (25 men, 14 women; mean age, 69.4 ± 11.0 years) with stroke that had occurred within the preceding 6 months and who had good understanding of verbal instructions. [Methods] The SBT consists of five posture-holding tasks (sitting, stride standing, close standing, one-foot standing on the unparalyzed leg, and one-foot standing on the paralyzed leg). Four grades, 1–4, are used to judge the ability of patients to hold these postures. The SBT and BBS were each implemented, and the relationship between test results was analyzed using correlation coefficients. [Results] The correlation coefficient for the BBS score and SBT score was 0.87. Thus, a strong correlation was seen between the BBS and SBT. [Conclusion] The SBT is thought to be an assessment index that can predict overall balance ability.
PMCID: PMC3820219  PMID: 24259912
Stroke; Balance; Assessment
15.  Modulation of the cortical silent period elicited by single- and paired-pulse transcranial magnetic stimulation 
BMC Neuroscience  2013;14:43.
The cortical silent period (CSP) elicited by transcranial magnetic stimulation (TMS) is affected by changes in TMS intensity. Some studies have shown that CSP is shortened or prolonged by short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF), Those studies, however, used different TMS intensities to adjust the amplitude of the motor evoked potential (MEP). Therefore, it is unclear whether changes in CSP duration are induced by changes in TMS intensities or by SICI and ICF. The purpose of this study was to confirm the effects of muscle contractions and stimulus intensities on MEP amplitude and the duration of CSP induced by single-pulse TMS and to clarify the effects of SICI and ICF on CSP duration.
MEP evoked by TMS was detected from the right first dorsal interosseous muscle in 15 healthy subjects. First, MEP and CSP were induced by single-pulse TMS with an intensity of 100% active motor threshold (AMT) at four muscle contraction levels [10%, 30%, 50%, and 70% electromyogram (EMG)]. Next, MEP and CSP were induced by seven TMS intensities (100%, 110%, 120%, 130%, 140%, 150%, and 160% AMT) during muscle contraction of 10% EMG. Finally, SICI and ICF were recorded at the four muscle contraction levels (0%, 10%, 30%, and 50% EMG).
MEP amplitudes increased with increases in muscle contraction and stimulus intensity. However, CSP duration did not differ at different muscle contraction levels and was prolonged with increases in stimulus intensity. CSP was shortened with SICI compared with CSP induced by single-pulse TMS and with ICF at all muscle contraction levels, whereas CSP duration was not significantly changed with ICF.
We confirmed that CSP duration is affected by TMS intensity but not by the muscle contraction level. This study demonstrated that CSP is shortened with SICI, but it is not altered with ICF. These results indicate that after SICI, CSP duration is affected by the activity of inhibitory intermediate neurons that are activated by the conditioning SICI stimulus.
PMCID: PMC3621611  PMID: 23547559
Transcranial magnetic stimulation; Motor evoked potential; Cortical silent period; Short-interval intracortical inhibition; Intracortical facilitation
16.  Neuromagnetic activation following active and passive finger movements 
Brain and Behavior  2013;3(2):178-192.
The detailed time courses of cortical activities and source localizations following passive finger movement were studied using whole-head magnetoencephalography (MEG). We recorded motor-related cortical magnetic fields following voluntary movement and somatosensory-evoked magnetic fields following passive movement (PM) in 13 volunteers. The most prominent movement-evoked magnetic field (MEF1) following active movement was obtained approximately 35.3 ± 8.4 msec after movement onset, and the equivalent current dipole (ECD) was estimated to be in the primary motor cortex (Brodmann area 4). Two peaks of MEG response associated with PM were recorded from 30 to 100 msec after movement onset. The earliest component (PM1) peaked at 36.2 ± 8.2 msec, and the second component (PM2) peaked at 86.1 ± 12.1 msec after movement onset. The peak latency and ECD localization of PM1, estimated to be in area 4, were the same as those of the most prominent MEF following active movement. ECDs of PM2 were estimated to be not only in area 4 but also in the supplementary motor area (SMA) and the posterior parietal cortex (PPC) over the hemisphere contralateral to the movement, and in the secondary somatosensory cortex (S2) of both hemispheres. The peak latency of each source activity was obtained at 54–109 msec in SMA, 64–114 msec in PPC, and 84–184 msec in the S2. Our results suggest that the magnetic waveforms at middle latency (50–100 msec) after PM are different from those after active movement and that these waveforms are generated by the activities of several cortical areas, that is, area 4 and SMA, PPC, and S2. In this study, the time courses of the activities in SMA, PPC, and S2 accompanying PM in humans were successfully recorded using MEG with a multiple dipole analysis system.
PMCID: PMC3607158  PMID: 23531918
Magnetoencephalography; MEF1; MEG; MRCF; PPC; S2; SEF; SMA
17.  A case of bicuspid aortic valve with two raphes 
Journal of Echocardiography  2013;11(2):75-76.
PMCID: PMC3671112  PMID: 23750110
18.  Aberrant methylation of LINE-1, SLIT2, MAL and IGFBP7 in non-small cell lung cancer 
Oncology Reports  2013;29(4):1308-1314.
Genome-wide DNA hypomethylation and gene hypermethylation play important roles in instability and carcinogenesis. Methylation in long interspersed nucleotide element 1 (LINE-1) is a good indicator of the global DNA methylation level within a cell. Slit homolog 2 (SLIT2), myelin and lymphocyte protein gene (MAL) and insulin-like growth factor binding protein 7 (IGFBP7) are known to be hypermethylated in various malignancies. The aim of the present study was to assess the precise methylation levels of LINE-1, SLIT2, MAL and IGFBP7 in non-small cell lung cancer (NSCLC) using a pyrosequencing assay. Methylation of all regions was examined in 56 primary NSCLCs using a pyrosequencing assay. Changes in mRNA expression levels of SLIT2, MAL and IGFBP7 were measured before and after treatment with a demethylating agent. Methylation of these genes was also examined in 9 lung cancer cell lines using RT-PCR and a pyrosequencing assay. Frequencies of hypomethylation of LINE-1 and hypermethylation of SLIT2, MAL and IGFBP7, defined by predetermined cut off values, were 55, 64, 46 and 54% in NSCLCs, respectively and exhibited tumor-specific features. The hypermethylation of all genes was well correlated with changes in expression. The methylation level and frequency of MAL were significantly higher in smokers and in patients without EGFR mutations. Through accurate measurement of methylation levels using pyrosequencing, hypomethylation of LINE-1 and hypermethylation of SLIT2, MAL and IGFBP7 were frequently detected in NSCLCs and associated with various clinical features. Analysis of the methylation profiles of these genes may, therefore, provide novel opportunities for the therapy of NSCLCs.
PMCID: PMC3621652  PMID: 23381221
LINE-1; SLIT2; MAL; IGFBP7; pyrosequencing; methylation
19.  Predicting Recovery of Cognitive Function Soon after Stroke: Differential Modeling of Logarithmic and Linear Regression 
PLoS ONE  2013;8(1):e53488.
Cognitive disorders in the acute stage of stroke are common and are important independent predictors of adverse outcome in the long term. Despite the impact of cognitive disorders on both patients and their families, it is still difficult to predict the extent or duration of cognitive impairments. The objective of the present study was, therefore, to provide data on predicting the recovery of cognitive function soon after stroke by differential modeling with logarithmic and linear regression. This study included two rounds of data collection comprising 57 stroke patients enrolled in the first round for the purpose of identifying the time course of cognitive recovery in the early-phase group data, and 43 stroke patients in the second round for the purpose of ensuring that the correlation of the early-phase group data applied to the prediction of each individual's degree of cognitive recovery. In the first round, Mini-Mental State Examination (MMSE) scores were assessed 3 times during hospitalization, and the scores were regressed on the logarithm and linear of time. In the second round, calculations of MMSE scores were made for the first two scoring times after admission to tailor the structures of logarithmic and linear regression formulae to fit an individual's degree of functional recovery. The time course of early-phase recovery for cognitive functions resembled both logarithmic and linear functions. However, MMSE scores sampled at two baseline points based on logarithmic regression modeling could estimate prediction of cognitive recovery more accurately than could linear regression modeling (logarithmic modeling, R2 = 0.676, P<0.0001; linear regression modeling, R2 = 0.598, P<0.0001). Logarithmic modeling based on MMSE scores could accurately predict the recovery of cognitive function soon after the occurrence of stroke. This logarithmic modeling with mathematical procedures is simple enough to be adopted in daily clinical practice.
PMCID: PMC3543398  PMID: 23326439
20.  Midwall ejection fraction for assessing systolic performance of the hypertrophic left ventricle 
In patients with left ventricular hypertrophy (LVH), LV midwall fractional shortening (FS) is used as a measure of LV systolic performance that is more physiologically appropriate than conventional FS. For evaluation of LV volume and ejection fraction (EF), 2-dimensional (2D) echocardiography is more accurate than M-mode echocardiography. The purpose of this study was to assess systolic performance by midwall EF using 2D speckle tracking echocardiography (STE).
Sixty patients were enrolled in the study. Patients were divided into two groups with LVH (n = 30) and without LVH (control group, n = 30). LV systolic function was compared between the two groups and the relationships of left ventricular mass index (LVMI) with LV systolic parameters, including midwall EF, were investigated.
Midwall EF in the LVH group was significantly lower than that in the control group (42.8±4.4% vs. 48.1±4.1%, p <0.0001). Midwall FS was also significantly lower in the LVH group (13.4±2.8% vs. 16.1±1.5%, p <0.0001), but EF did not differ significantly between the two groups. There were significant correlations between midwall EF and LVMI (r=0.731, p <0.0001) and between midwall FS and LVMI (r=0.693, p <0.0001), with midwall EF having the higher correlation.
These results show that midwall EF can be determined using 2D STE. Midwall EF can be used to monitor LV systolic dysfunction, which is not possible with conventional EF. Evaluation of midwall EF may allow assessment of new parameters of LV systolic function in patients with LV geometric variability.
PMCID: PMC3552820  PMID: 23167789
Midwall ejection fraction; Left ventricular systolic function; Left ventricular hypertrophy; Speckle tracking echocardiography
21.  A randomized, double-blind, multicenter, placebo-controlled phase III trial to evaluate the efficacy and safety of pregabalin in Japanese patients with fibromyalgia 
Arthritis Research & Therapy  2012;14(5):R217.
Fibromyalgia is a chronic disorder characterized by widespread pain and tenderness. Prior trials have demonstrated the efficacy of pregabalin for the relief of fibromyalgia symptoms, and it is approved for the treatment of fibromyalgia in the United States. However, prior to this study, there has not been a large-scale efficacy trial in patients with fibromyalgia in Japan.
This randomized, double-blind, multicenter, placebo-controlled trial was conducted at 44 centers in Japan to assess the efficacy and safety of pregabalin for the symptomatic relief of pain in fibromyalgia patients. Patients aged ≥18 years who had met the criteria for fibromyalgia were randomized to receive either pregabalin, starting at 150 mg/day and increasing to a maintenance dose of 300 or 450 mg/day, or placebo, for 15 weeks. The primary efficacy endpoint was mean pain score at final assessment. Secondary endpoints included Patient Global Impression of Change (PGIC) together with measures of sleep, physical functioning and quality of life.
A total of 498 patients (89% female) were randomized to receive either pregabalin (n = 250) or placebo (n = 248). Pregabalin significantly reduced mean pain score at final assessment (difference in mean change from baseline, compared with placebo -0.44; P = 0.0046) and at every week during the study (P <0.025). Key secondary endpoints were also significantly improved with pregabalin treatment compared with placebo, including PGIC (percentage reporting symptoms "very much improved" or "much improved", 38.6% vs 26.7% with placebo; P = 0.0078); pain visual analog scale (difference in mean change from baseline, compared with placebo -6.19; P = 0.0013); Fibromyalgia Impact Questionnaire total score (-3.33; P = 0.0144); and quality of sleep score (-0.73; P <0.0001). Treatment was generally well tolerated, with somnolence and dizziness the most frequently reported adverse events.
This trial demonstrated that pregabalin, at doses of up to 450 mg/day, was effective for the symptomatic relief of pain in Japanese patients with fibromyalgia. Pregabalin also improved measures of sleep and functioning and was well tolerated. These data indicate that pregabalin is an effective treatment option for the relief of pain and sleep problems in Japanese patients with fibromyalgia.
Trial Registration NCT00830167
PMCID: PMC3580529  PMID: 23062189
22.  Application of a methylation gene panel by quantitative PCR for lung cancers 
Cancer Letters  2006;247(1):56-71.
Detection of lung cancer at early stages could potentially increase survival rates. One promising approach is the application of suitable lung cancer-specific biomarkers to specimens obtained by non-invasive methods. Thus far, clinically useful biomarkers that have high sensitivity have proven elusive. Certain genes, which are involved in cellular pathways such as signal transduction, apoptosis, cell to cell communication, cell cycles and cytokine signaling are down-regulated in cancers and may be considered as potential tumor suppressor genes. Aberrant promoter hypermethylation is a major mechanism for silencing tumor suppressor genes in many kinds of human cancers. Using quantitative real time PCR, we tested 11 genes (3-OST-2, RASSF1A, DcR1, DcR2, P16, DAPK, APC, ECAD, HCAD, SOCS1, SOCS3) for levels of methylation within their promoter sequences in non-small cell lung cancers (NSCLC), adjacent non-malignant lung tissues, in peripheral blood mononuclear cells (PBMC) from cancer free patients, in sputum of cancer patients and controls. Of all the 11 genes tested 3-OST-2 showed the highest levels of promoter methylation in tumors combined with lowest levels of promoter methylation in control tissues. 3-OST-2 followed by, RASSF1A showed increased levels of methylation with advanced tumor stage (P<0.05). Thus, quantitative analysis of 3-OST-2 and RASSF1A methylation appears to be a promising biomarker assay for NSCLC and should be further explored in a clinical study. Our preliminary data on the analysis of sputum DNA specimens from cancer patients further support these observations.
PMCID: PMC3379713  PMID: 16644104
Real time PCR; Tumor suppressor gene; Non-small cell lung cancer
23.  Efficacy and safety evaluation of pregabalin treatment over 52 weeks in patients with diabetic neuropathic pain extended after a double‐blind placebo‐controlled trial 
Aims/Introduction:  Diabetic peripheral neuropathy (DPN) is often associated with pain, and thus a new treatment option is anticipated. We recently showed the efficacy of pregabalin in a randomized, double‐blind, placebo‐controlled, 14‐week trial in Japanese patients with painful DPN. In the present study, we evaluated the long‐term efficacy and safety of pregabalin for the relief of painful DPN.
Materials and Methods:  A total of 123 patients were enrolled in a 52‐week open‐label study, from among those who participated in the preceding double‐blind trial. The subjects received pregabalin 150–600 mg/day. Pain intensity was measured using the short‐form McGill pain questionnaire (SF‐MPQ: total score, visual analog scale and present pain intensity).
Results:  The efficacy parameter SF‐MPQ showed a decrease over the treatment period. The changes in visual analog scale and present pain intensity at the final evaluation were −25.4 mm and −0.7, respectively, suggesting an analgesic effect of pregabalin. Commonly reported adverse events were somnolence, weight gain, dizziness and peripheral edema, but most of them were mild to moderate in intensity. No new concerns about safety as a result of long‐term administration of pregabalin were identified.
Conclusions:  The findings from this trial suggest that long‐term treatment with pregabalin is beneficial for pain relief in patients with DPN. This trial was registered with (no. NCT00553280). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00122.x, 2011)
PMCID: PMC4014905  PMID: 24843530
Diabetic peripheral neuropathy; Neuropathic pain; Pregabalin
24.  Aberrant methylation of N-methyl-D-aspartate receptor type 2B (NMDAR2B) in non-small cell carcinoma 
BMC Cancer  2011;11:220.
N-methyl-D-aspartate receptors (NMDAR) act as tumor suppressors of digestive malignancies. The expression and genetic methylation patterns of NMDAR2B in non-small cell lung cancer (NSCLC) are unknown.
The relationship between gene methylation and expression of NMDAR2B was analyzed in NSCLC cell lines (N = 9) and clinical tissues (N = 216). The cell lines were studied using RT-PCR and 5-aza-2'-deoxycytidine treatment, while the clinical tissues were examined by methylation specific real-time quantitative PCR and immunohistochemistry. Retrospective investigation of patient records was used to determine the clinical significance of NMDAR2B methylation.
NMDAR2B was silenced in five of the nine cell lines; 5-aza-2'-deoxycytidine treatment restored expression, and was inversely correlated with methylation. Aberrant methylation of NMDAR2B, detected in 61% (131/216) of clinical NSCLC tissues, was inversely correlated with the status of protein expression in 20 randomly examined tumors. Aberrant methylation was not associated with clinical factors such as gender, age, histological type, or TNM stage. However, aberrant methylation was an independent prognostic factor in squamous cell carcinoma cases.
Aberrant methylation of the NMDAR2B gene is a common event in NSCLC. The prognosis was significantly better for cases of squamous cell carcinoma in which NMDAR2B was methylated. It may have different roles in different histological types.
PMCID: PMC3149028  PMID: 21639937
25.  Oxidative Stress and Longevity in Okinawa: An Investigation of Blood Lipid Peroxidation and Tocopherol in Okinawan Centenarians 
Background. The Free Radical Theory of Aging mechanistically links oxidative stress to aging. Okinawa has among the world's longest-lived populations but oxidative stress in this population has not been well characterized. Methods. We compared plasma lipid peroxide (LPO) and vitamin E—plasma and intracellular tocopherol levels (total α, β, and γ), in centenarians with younger controls. Results. Both LPO and vitamin E tocopherols were lower in centenarians, with the exception of intracellular β-tocopherol, which was significantly higher in centenarians versus younger controls. There were no significant differences between age groups for tocopherol: cholesterol and tocopherol: LPO ratios. Correlations were found between α-Tocopherol and LPO in septuagenarians but not in centenarians. Conclusions. The low plasma level of LPO in Okinawan centenarians, compared to younger controls, argues for protection against oxidative stress in the centenarian population and is consistent with the predictions of the Free Radical Theory of Aging. However, the present work does not strongly support a role for vitamin E in this phenomenon. The role of intracellular β-tocopherol deserves additional study. More research is needed on the contribution of oxidative stress and antioxidants to human longevity.
PMCID: PMC3068305  PMID: 21490698

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