Safety of tapering tacrolimus dose in patients with well-controlled anti-acetylcholine receptor antibody-positive myasthenia gravis.

BACKGROUND AND PURPOSE: Tapering immunosuppressants is desirable in patients with well-controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction-associated exacerbation is not known. The aim of this study was to clarify the frequency of reduction-associated exacerbation when tacrolimus is tapered in stable patients with anti-acetylcholine receptor antibody-positive MG, and to determine the factors that predict exacerbations. METHODS: We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction-associated exacerbation was defined as the appearance or worsening of one or more MG symptoms <3 months after the reduction. RESULTS: Tacrolimus dosage was successfully tapered in 110 patients (96%) without any exacerbation. Five patients (4%) experienced an exacerbation, but symptoms were reversed in all patients when the tacrolimus dose was increased to the previous maintenance level. No patient developed an MG crisis. The age at onset was significantly earlier (30 vs. 56 years, P = 0.025) and the reduction in dosage was significantly larger (2.0 vs. 1.0 mg/day, P = 0.002) in patients with reduction-associated exacerbation than in those without exacerbation. The cut-off values determined in a receiver-operating characteristic curve analysis were 52 years (sensitivity, 57%; specificity, 100%) for the age at onset and 1.5 mg (sensitivity, 80%; specificity, 100%) for the dose reduction. CONCLUSION: Tapering of tacrolimus was possible in most patients with well-controlled anti-acetylcholine receptor antibody-positive MG. Early age at onset and a large reduction from maintenance dosage were associated with exacerbation. Reductions ≤1.5 mg/day from the maintenance dosage should be considered for patients with late-onset disease.

Prospective predictors of exacerbation status in severe asthma over a 3-year follow-up.

BACKGROUND: A predisposition to exacerbations is being recognized as a distinct phenotype with "previous exacerbations" representing the strongest clinical factor associated with future exacerbation. Thus, to identify additional novel biomarkers associated with asthma exacerbations, "past exacerbation status" must be included as a confounding factor. OBJECTIVE: This study aimed to characterize the clinical and biomarker features associated with asthma exacerbations in severe asthma. METHODS: We evaluated clinical parameters from 105 severe asthmatics yearly for 3 years, as well as their exacerbation status. We classified the subjects into 3 groups: (i) consistent non-exacerbators (CNE, subjects who did not experience any exacerbation over the 3-year period); (ii) consistent frequent exacerbators (CFE, subjects with frequent exacerbation, defined as those who had 2 or more exacerbations within 1 year, throughout the 3-year period); and (iii) intermittent exacerbators (IE). We conducted multivariate analysis for comparisons among the groups for multiple factors, including several Th2-related biomarkers, in addition to the "past exacerbation status." RESULTS: Thirty-nine subjects were classified as CNE, 15 as CFE, and 51 as IE. Frequent exacerbations in the previous year predicted exacerbations for the following year (P < .001). Among the several Th2-related biomarkers, only FeNO was associated with exacerbation status. When we analysed the data after the second visit, the impact of FeNO on predicting future exacerbation remained significant, even after considering the exacerbation status during the first year (P < .05). CONCLUSIONS AND CLINICAL RELEVANCE: Measurement of FeNO has a significant potential to predict future asthma exacerbation, which is independent of the "past exacerbation history."

Genomewide association study identifies HAS2 as a novel susceptibility gene for adult asthma in a Japanese population.

BACKGROUND: It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments in risk and explain only a small proportion of familial clustering. OBJECTIVE: To identify additional genetic determinants of susceptibility to asthma using a selected Japanese population with reduced tobacco smoking exposure. METHODS: We performed a GWAS by genotyping a total of 480 098 single-nucleotide polymorphisms (SNPs) for a Japanese cohort consisting of 734 healthy controls and 240 patients with asthma who had smoked for no more than 10 pack-years. The SNP with the strongest association was genotyped in two other independent Japanese cohorts consisting of a total of 531 healthy controls and 418 patients with asthma who had smoked for no more than 10 pack-years. For the hyaluronan synthase 2 (HAS2) gene, we investigated SNP-gene associations using an expression quantitative trait loci (eQTL) database and also analysed its gene expression profiles in 13 different normal tissues. RESULTS: In the discovery GWAS, a SNP located upstream of HAS2, rs7846389, showed the strongest statistical significance (P = 1.43 × 10(-7) ). In the two independent replication cohorts, rs7846389 was consistently associated with asthma (nominal P = 0.0152 and 0.0478 in the first and second replication cohorts, respectively). In the meta-analysis, association of rs7846389 with susceptibility to asthma reached the level of genomewide significance (P = 7.92 × 10(-9) ). This variant was strongly correlated with HAS2 mRNA expression. The strongest expression of the gene was detected in the lung. CONCLUSIONS: Our study identified HAS2 as a novel candidate gene for susceptibility to adult asthma.

Epigallocatechin 3-gallate suppresses interleukin-1ß-induced inflammatory responses in intervertebral disc cells in vitro and reduces radiculopathic pain in rats.

Intervertebral disc (IVD) disease, which is characterised by age-related changes in the adult disc, is the most common cause of disc failure and low back pain. The purpose of this study was to analyse the potential of the biologically active polyphenol epigallocatechin 3-gallate (EGCG) for the treatment of painful IVD disease by identifying and explaining its anti-inflammatory and anti-catabolic activity. Human IVD cells were isolated from patients undergoing surgery due to degenerative disc disease (n = 34) and cultured in 2D or 3D. An inflammatory response was activated by IL-1ß, EGCG was added, and the expression/activity of inflammatory mediators and pathways was measured by qRT-PCR, western blotting, ELISA, immunofluorescence and transcription factor assay. The small molecule inhibitor SB203580 was used to investigate the involvement of the p38 pathway in the observed effects. The analgesic properties of EGCG were analysed by the von Frey filament test in Sprague-Dawley rats (n = 60). EGCG significantly inhibited the expression of pro-inflammatory mediators and matrix metalloproteinases in vitro, as well as radiculopathic pain in vivo, most probably by modulation of the activity of IRAK-1 and its downstream effectors p38, JNK and NF-κB.

Dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF-kappaB inhibitor, inhibits allergic inflammation and airway remodelling in murine models of asthma.

BACKGROUND: Dehydroxymethylepoxyquinomicin (DHMEQ) is a newly developed compound that inhibits nuclear factor κB activation and is reported to ameliorate animal models of various inflammatory diseases without significant adverse effects. Because nuclear factor κB is a transcription factor that plays a critical role in the pathophysiology of asthma, DHMEQ may be of therapeutic benefit in asthma. OBJECTIVE: The purpose of this study was to evaluate the effects of DHMEQ on airway inflammation and remodelling in murine models of asthma. METHODS: The BALB/c mice were sensitized and then challenged acutely or chronically with ovalbumin and administered DHMEQ intraperitoneally before each challenge. Inflammation of airways, lung histopathology and airway hyper responsiveness to methacholine challenge were evaluated. In addition, the effect of DHMEQ on production of cytokines and eotaxin-1 by murine splenocytes, human peripheral blood mononuclear cells and bronchial epithelial cells was investigated. RESULTS: Airway hyper responsiveness was ameliorated in both acutely and chronically challenged models by treatment with DHMEQ. DHMEQ significantly reduced eosinophilic airway inflammation and levels of Th2 cytokines in bronchoalveolar lavage fluid in the acute model. It also inhibited parameters of airway remodelling including mucus production, peribronchial fibrosis and the expression of α-smooth muscle actin. Moreover, the production of Th2 cytokines from murine splenocytes and human peripheral blood mononuclear cells and the production of eotaxin-1 by bronchial epithelial cells were inhibited by DHMEQ. CONCLUSIONS AND CLINICAL RELEVANCE: These results indicate that DHMEQ inhibits allergic airway inflammation and airway remodelling in murine models of asthma. DHMEQ may have therapeutic potential in the treatment of asthma.

The prevalence of rhinitis and its association with smoking and obesity in a nationwide survey of Japanese adults.

BACKGROUND: Rhinitis is a common disease, and its prevalence is increasing worldwide. Several studies have provided evidence of a strong association between asthma and rhinitis. Although smoking and obesity have been extensively analyzed as risk factors of asthma, associations with rhinitis are less clear. OBJECTIVE: The aims of our study were (i) to evaluate the prevalence of rhinitis using the European Community Respiratory Health Survey (ECRHS) questionnaire in Japanese adults and (ii) to evaluate the associations of smoking and body mass index (BMI) with rhinitis. METHODS: Following our study conducted in 2006-2007 to determine the prevalence of asthma using the ECRHS questionnaire, our present analysis evaluates the prevalence of rhinitis and its association with smoking and BMI in Japanese adults 20-79 years of age (N = 22819). We classified the subjects (20-44 or 45-79 years) into four groups as having (i) neither rhinitis nor asthma; (ii) rhinitis without asthma; (iii) asthma without rhinitis; or (iv) rhinitis with asthma. We then evaluated associations with smoking and BMI in each group. RESULTS: The overall age-adjusted prevalence of rhinitis was 35.1% in men and 39.3% in women. A higher prevalence was observed in the younger population than in the older population. Active smoking and obesity were positively associated with asthma without rhinitis. In contrast, particularly in the 20- to 44-year age-group, active smoking and obesity were negatively associated with rhinitis without asthma. CONCLUSION: The results of the present study suggest that smoking and obesity may have different effects on the development of rhinitis and asthma.

Headache prevalence and long working hours: the role of physical inactivity.

OBJECTIVES: Headaches and long working hours are important issues for workers. This study investigated the association between hours worked and the prevalence of headaches, and how that association varies with physical activity. STUDY DESIGN: Cross-sectional study with two-stage cluster sampling. METHODS: Using data from a nationally representative sample of households in Japan, people aged 20-65 years who worked ≥35 h/week were studied, and the cross-sectional association between the number of hours worked per week (35-45, 46-55 and >55 h/week) and the prevalence rates of headaches of different severity was evaluated. RESULTS: Of 721 workers, 307 reported experiencing at least one headache per month. Compared with working 35-45 h/week, the prevalence ratios of severe or disabling headaches among individuals working >55 h/week were 1.38 [95% confidence interval (CI) 1.06-1.78] and 1.63 (95% CI 1.09-2.43), respectively. After stratification by the level of physical activity, the prevalence ratios were greater in the low-physical-activity group: 1.56 (95% CI 1.11-2.19) for severe headaches and 2.20 (95% CI 1.31-3.68) for disabling headaches. The number of hours worked was not associated with headaches in the high-physical-activity group. CONCLUSIONS: Among workers in the general population, long working hours were associated with the prevalence of headaches, and the association may depend on a lack of physical activity.

Role of osteopontin, a multifunctional protein, in allergy and asthma.

Osteopontin (OPN) is an extracellular matrix protein and immune modulator with a wide range of functions. OPN is recognized as a key cytokine in Th1 immune responses, yet its potential involvement in allergic/asthmatic responses has been investigated only recently. Current data from molecular and cellular studies and studies of OPN-deficient mice provide evidence that OPN plays multiple roles in the regulation of allergic responses, including regulation of IgE response, inflammatory cell migration, and the development of airway fibrosis and angiogenesis. These results suggest that OPN is a pleiotropic cytokine that functions both systemically and locally in tissue mucosa. Notably, OPN is able to exert its effects through different functional domains, and the secreted and intracellular forms of OPN may have distinct functions. Future research to elucidate all aspects of OPN function is needed to ultimately establish its role in the regulation of immune responses and various disease processes, including those critically involved in the development of allergies and asthma.

Periodic rotation of magnetization in a non-centrosymmetric soft magnet induced by an electric field.

The control of magnetism with an electric field is a challenging area with the potential to affect fields related to magnetic data storage, sensors and magnetic random access memory. Although there are some successful examples of such control based on the use of magnetic metals and semiconductors, energy loss caused by current flow is a problem that needs to be addressed. In particular, the repeatable control of magnetization with an electric field can be disturbed by joule heat loss. In this regard, non-centrosymmetric insulating magnets are good candidates for controlling magnetization without energy loss, in which the linear magnetoelectric effect has an essential role. Moreover, such magnets exhibit an unconventional magneto-optical effect, which allows the time-resolved detection of the magnetization direction. Here, we show a periodic oscillation of the magnetization direction by +/-20 degrees in a non-centrosymmetric soft magnet (Cu,Ni)B(2)O(4), which is induced by an a.c. electric field of 2 kHz. The present study provides a strategy for identifying materials in which the magnetization direction can be modulated at high speed with an electric field.

Chance fracture of the lumbar spine in an amateur snowboarder: a case report.

"Chance fracture" is an unusual type of spinal fracture caused by flexion-distraction of the back. We describe herein a rare case of a male amateur snowboarder who suffered lumbar Chance fracture caused by a fall after freestyle jumping. Radiological findings of plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI) showed a loss of vertebral height in the anterior L1 vertebral body with a horizontal splitting fracture extending across the vertebral body, bilateral pedicles, and lamina. On the basis of the aforementioned findings, the diagnosis of Chance fracture of the L1 vertebra was established. The fracture healed without any subsequent disabilities following conservative medical management with a thoracolumbar orthosis, and no impairments to activities of daily living were encountered, including job or sports performance. Although Chance fracture caused by a fall is rare, particularly in sports, the possibility of this fracture should be considered when diagnosing spinal injuries in snowboarders.

Osteopontin is involved in migration of eosinophils in asthma.

BACKGROUND: Osteopontin (OPN) is an extracellular matrix protein with a wide range of functions, and is involved in various inflammatory diseases. However, the role of OPN in eosinophilic airway inflammation is unclear. OBJECTIVE: To elucidate the role of OPN in eosinophilic airway inflammation. METHODS: OPN protein levels in induced sputum from asthmatic patients and healthy controls were measured. Eosinophil migration assays were performed in the presence or absence of OPN, a blocking antibody (Ab) recognizing its integrin-binding domain (2K1) and an anti-integrin alpha 4 Ab (P1H4). In the mouse asthma model, the levels of eosinophilia were examined in bronchoalveolar lavage fluids (BALFs) from ovalbumin (OVA)-sensitized and -challenged mice with or without administration of an Ab (M5) corresponding to human 2K1. RESULTS: Levels of OPN in induced sputum were significantly higher in asthmatic patients when compared with healthy controls. In addition, levels of OPN were correlated with the percentage of sputum eosinophils. OPN induced significant migration of human eosinophils and this effect was inhibited by 2K1 and P1H4. M5 significantly attenuated OVA-induced eosinophilia in BALFs. CONCLUSION: These results indicate that OPN plays a role in the migration of eosinophils into the airways and may be involved in the pathogenesis of asthma.

Functional single nucleotide polymorphisms of the CCL5 gene and nonemphysematous phenotype in COPD patients.

It was previously reported that the gain-of-function -28 guanine allele of the promoter single nucleotide polymorphism (SNP; cytosine to guanine substitution of nucleotide -28 (-28C>G)) in the CC chemokine ligand 5 gene (CCL5) was associated with susceptibility to late-onset asthma in patients who developed asthma at age > or =40 yrs. The clinical diagnosis of chronic obstructive pulmonary disease (COPD) includes emphysema and small airway disease, and upregulation of CCL5 has been described in the airways of patients with COPD. It was hypothesised that CCL5 has a genetic impact upon the variable expression of emphysema in patients with COPD. Patients with COPD were studied (n = 267). All of the patients underwent pulmonary high-resolution computed tomography (CT), and visual scoring (CT score) was performed to determine emphysema severity. Three SNPs of CCL5 were genotyped, including -403G>A, -28C>G and 375T>C. A significant difference was found in CT score according to CCL5 genotype; the -28G allele was inversely associated with CT score. When the analysis was confined to 180 patients with bronchial reversibility of <15%, even stronger evidence for this association was noted. Functional single nucleotide polymorphisms in the CC chemokine ligand 5 gene were associated with milder emphysema. Together with previous findings, the present study may identify the CC chemokine ligand 5 gene as part of a common pathway in the pathogenesis of late-onset asthma and chronic obstructive pulmonary disease with milder emphysema.

Complications after proximal gastrectomy with jejunal pouch interposition: report of a case.

We report a rare case of proximal gastrectomy complication as a result of a severe dilatation of a jejunal pouch interposed for reconstruction. A 44-year-old man who had early gastric cancer underwent proximal gastrectomy with a jejunal pouch interposition at our department. Fourteen months after the procedure, he began to complain of left hypochondrial fullness and reflux symptoms. He had difficulty eating and his quality of life (QOL) was markedly impaired. Barium meal revealed severe dilatation of the jejunal pouch. Decompression using a stomach tube and other measures only achieved temporary improvement. 4.5 years later, the dilated jejunal pouch was resected together with apyloroplasty and double tract reconstruction. Six months after this secondary surgery, the patient recorded no further complications. Food intake increased and QOL improved.

Effect of the alternative magnetic stimulation on peripheral circulation for regenerative medicine.

Regenerative medicine for patients with peripheral atherosclerosis attracts considerable attention around the world. However, ethical problems persist in gene therapy. This study evaluates the effect of alterative magnetic stimulation on peripheral circulation. The effect of magnetic stimulation as a medical treatment was examined using a thermograph for 11 healthy volunteers. The thermograph was used to measure the rise in skin temperature. The experimental results suggested an improvement in the peripheral circulation. The results of our study suggest the effectiveness of alternative magnetic stimulation on atherosclerosis. We intend to extend our study in order to establish a methodology for regenerative medical treatment for patients with peripheral atherosclerosis. Further, we wish to advance the current research in the field of angiogenesis.

Cardio-ankle vascular index (CAVI) for the monitoring of the atherosclerosis after heart transplantation.

Atherosclerosis has been reported to progress rapidly after heart transplantation. A quantitative diagnosis is required for the diagnosis of atherosclerosis after heart transplantation. In this study, we compared brachial-ankle pulse wave velocity (baPWV) and cardio-ankle vascular index (CAVI) for the diagnosis. The average values of both baPWV and CAVI in the seven cases after heart transplantation were found to be signif-icantly large in comparison to the average values of the normal healthy people of the same age group. When comparisons were made before and after the heart transplantation in a particular case, CAVI was stable and baPWV changed sharply. A lot of parameters such as blood pressure, blood volume, etc. have been reported to influence baPWV. The results of this study suggested that CAVI was a stable parameter in comparison to baPWV even after heart transplantation. Thus, CAVI may be useful in the diagnosis of arteriosclerosis after heart transplantation.

Chaos analysis of electro encephalography and control of seizure attack of epilepsy patients.

In order to evaluate the EEG of patients with epilepsy, chaos analysis was performed for the subdural EEG time series data. The chaos attractor was reconstructed in the phase space and the correlation dimension. KS entropy calculated from the Lyapunov exponents was evaluated. Before the seizure attack, the KS entropy showed a lower value when compared with the time series data recorded during healthy condition. The results of our study suggest that it is possible to predict the seizure attack by the chaos analysis of the EEG signal. Further, we aim at developing an automatic control system for predicting a seizure attack by the use of local cooling of the focus with Peltier elements.

Constriction/dilatation of the cerebral microvessels by intravascular endothelin-1 in cats.

The effects of intracarotidly injected endothelin (ET)-1 (0.01-3 nmol) on the local cerebral blood volume (CBV) in the parietotemporal cortex were examined by the photoelectric method in 17 anesthetized cats. CBV reflects the cumulative dimensions of the cerebral microvessels. Low doses of ET-1 (0.01 and 0.1 nmol) elicited mild but significant reductions in CBV without changes in the systemic arterial blood pressure (SABP). High doses of ET-1 (3 nmol) initially induced marked declines of CBV, which were attributable to the significant falls in SABP. CBV subsequently exhibited significant increases. The CBV increases were not secondary to the accompanying elevations of SABP, since they were unaffected by inhibition of the SABP changes after preinjection of BQ-123 (1 mg/kg), an ET antagonist specific to the ETA receptors. The CBV increases, however, were prevented by continuous administration of NG-mono-methyl-L-arginine (0.35 mg/kg/min), an inhibitor of nitric oxide synthesis, plus BQ-123. We conclude that while low doses of intravascular ET-1 constrict the cerebral microvessels, high doses of ET-1 dilate the cerebral microvessels through the induction of nitric oxide probably in the cerebrovascular endothelium.