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This randomized, single‐blind, 3‐way crossover study assessed the effect of edaravone on QT interval, including an exposure‐response analysis. Twenty‐seven healthy Japanese male volunteers, aged 20 to 49 years, were randomly assigned to receive a single intravenous dose of each treatment in 1 of 3 sequences (n = 9 each): ACB, BAC, and CBA, where A was edaravone 60 mg (therapeutic dose), B was edaravone 300 mg (supratherapeutic dose), and C was normal saline (placebo). Electrocardiographs were collected to assess treatment effects. In an exposure‐response analysis, a linear model was determined to be valid and indicated no statistically significant positive slope for the relationship between change from baseline in QTcF (ΔQTcF) and edaravone concentration (0.000155 ms/(ng/mL); P = .1478); upper bounds of 2‐sided 90% confidence intervals after placebo adjustment (ΔΔQTcF) were

Background Although the cell cycle and cell differentiation should be coordinately regulated to generate a variety of neurons in the brain, the molecules that are involved in this coordination still remain largely unknown. In this study, we analyzed the roles of a nuclear protein Cfdp1, which is thought to be involved in chromatin remodeling, in zebrafish neurogenesis. Results Zebrafish cfdp1 mutants maintained the progenitors of granule cells (GCs) in the cerebellum, but showed defects in their differentiation to GCs. cfdp1 mutants showed an increase in phospho-histone 3 (pH 3)-positive cells and apoptotic cells, as well as a delayed cell cycle transition from the G2 to the M phase in the cerebellum. The inhibition of tp53 prevented apoptosis but not GC differentiation in the cfdp1 mutant cerebellum. A similar increase in apoptotic cells and pH 3-positive cells, and defective cell differentiation, were observed in the cfdp1 mutant retina. Although mitotic spindles formed, mitosis was blocked before anaphase in both the cerebellum and retina of cfdp1 mutant larvae. Furthermore, expression of the G2/mitotic-specific cyclin B1 gene increased in the cfdp1 mutant cerebellum. Conclusions Our findings suggest that Cfdp1 regulates the cell cycle of neural progenitors, thereby promoting neural differentiation in the brain.

Chronic widespread pain conditions are more prevalent in women than men, suggesting a role for gonadal hormones in the observed differences. Previously, we showed that female mice, compared to male, develop widespread, more severe, and longer-duration hyperalgesia in a model of activity-induced muscle pain. We hypothesized testosterone protects males from developing the female pain phenotype. We tested whether orchiectomy of males before induction of an activity-induced pain model produced a female phenotype and whether testosterone administration produced a male phenotype in females. Orchiectomy produced longer-lasting, more widespread hyperalgesia, similar to females. Administration of testosterone to females or orchiectomized males produced unilateral, shorter-lasting hyperalgesia. Prior studies show that the serotonin transporter (SERT) is increased in the nucleus raphe magnus (NRM) in models of chronic pain, and that blockade of SERT in the NRM reduces hyperalgesia. We examined potential sex differences in the distribution of SERT across brain sites involved in nociceptive processing using immunohistochemistry. A sex difference in SERT was found in the NRM in the activity-induced pain model; females had greater SERT immunoreactivity than males. This suggests that testosterone protects against development of widespread, long-lasting muscle pain and that alterations in SERT may underlie the sex differences.

Background/purpose It is known that the elderly and adult women with reduction in sebum secretion have reduced skin barrier function, drying of the skin in a low humidity environment is accompanied by physiological distress. As our hypothesis, when fine water particles are sprayed on the skin, the water content of the corneal layer is significantly increased. In the present study, we examined the ability of fine water particles to improve facial skin moisture levels in adult women. Methods We examined skin conductance, transepidermal water loss (TEWL), and skin elasticity as an index of skin barrier function at the cheek in 17 healthy adult women in the spraying of fine water particles, in the environment temperature at 24°C and 34.5% relative humidity. Results The skin conductance of stratum corneum after 120 minute of spraying, A condition (peak particle size below 0.5 μm) was 119.7 ± 25.1%, B condition (peak particle size 1.8 μm) was 100.4 ± 31.7%, C condition (peak particle size 5.4 μm) was 110.1 ± 25.0%, and the A condition was significantly higher than the B condition. Also, skin elasticity in the A condition tended to be higher value than in the other conditions. Transepidermal water loss (TEWL) after 120 minute of spraying showed a lower value in the A condition than in the other conditions. In the A condition, the skin conductance steadily maintained their initial levels up to 360 minute after spraying. Conclusion Especially, by spraying smallest fine water particles, skin barrier function at the cheek was improved. These data indicated that non‐charged fine water particles played an important role on moisten skin in a low humidity environment.

Low back pain (LBP) is the most common cause of chronic pain. Numerous clinical scales are available for evaluating pain, but their objective criteria in the management of LBP patients remain unclear. This study aimed to determine an objective cutoff value for a change in the Pain Intensity Numerical Rating Scale (ΔPI-NRS) three months after LBP treatment. Its utility was compared with changes in six commonly used clinical scales in LBP patients: Pain Disability Assessment Scale (PDAS), Pain Self-Efficacy Questionnaire (PSEC), Pain Catastrophizing Scale (PCS), Athens Insomnia Scale (AIS), EuroQoL 5 Dimension (EQ5D), and Locomo 25. We included 161 LBP patients treated in two representative pain management centers. Patients were partitioned into two groups based on patient’s global impression of change (PGIC) three months after treatment: satisfied (PGIC = 1, 2) and unsatisfied (3–7). Multivariate logistic regression analysis was performed to explore relevant scales in distinguishing the two groups. We found ΔPI-NRS to be most closely associated with PGIC status regardless of pre-treatment pain intensity, followed by ΔEQ5D, ΔPDAS, ΔPSEC, and ΔPCS. The ΔPI-NRS cutoff value for distinguishing the PGIC status was determined by ROC analysis to be 1.3–1.8 depending on pre-treatment PI-NRS, which was rounded up to ΔPI-NRS = 2 for general use. Spearman’s correlation coefficient revealed close relationships between ΔPI-NRS and the six other clinical scales. Therefore, we determined cutoff values of these scales in distinguishing the status of ΔPI-NRS≥2 vs. ΔPI-NRS

Background This study marks the first epidemiological evaluation of the prevalence and burden of chronic neuropathic pain (NeP) in an Asian population. The objective of this nationwide cross-sectional study was to identify the characteristics of individuals with NeP, detect the NeP features that affect their quality of life (QOL), and demonstrate the negative effects of NeP on social and daily living as well as comorbidities including depression, anxiety and sleep disorders. Methods We mailed a cross-sectional, population-based epidemiological survey to a random nationwide sample of 10,000 Japanese adults over 20 years old. Results The response rate was 54.4% (2445 men, 2992 women; mean age, 53.4 years). Prevalence of chronic pain was 16.6%, and prevalence of NeP was 3.2% as detected by the PainDETECT. Participants with NeP showed significantly lower quality of life according to scores on the EuroQol-5 Dimensions scale (p

Background and Purpose We conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT-1303), a second-generation sphingosine 1-phosphate (S1P) receptor modulator, designed to reduce the bradycardia associated with fingolimod and other S1P receptor modulators. Experimental Approach The selectivity of the active metabolite amiselimod phosphate (amiselimod-P) for human S1P receptors and activation of G-protein-coupled inwardly rectifying K+ (GIRK) channels in human atrial myocytes were assessed. Its cardiac distribution was determined in rats, and cardiovascular telemetry was assessed in monkeys. We also examined the pharmacokinetics, pharmacodynamics and safety of amiselimod in healthy humans. Key Results Amiselimod-P showed potent selectivity for S1P1 and high selectivity for S1P5 receptors, with minimal agonist activity for S1P4 and no distinct agonist activity for S1P2 or S1P3 receptors and approximately five-fold weaker GIRK activation than fingolimod-P. After oral administration of amiselimod or fingolimod at 1 mg·kg−1, the concentration of amiselimod-P in rat heart tissue was lower than that of fingolimod-P, potentially contributing to the minimal cardiac effects of amiselimod. A telemetry study in monkeys confirmed that amiselimod did not affect heart rate or ECG parameters. In healthy human subjects, peripheral blood lymphocyte counts gradually reduced over the 21 day dosing period, with similar lymphocyte count profiles with the highest doses by day 21, and no clinically significant bradycardia observed on day 1 or during the study. Conclusions and Implications Amiselimod exhibited potent therapeutic efficacy with minimal cardiac effects at the anticipated clinical dose and is unlikely to require dose titration.

The absorption, metabolism and excretion of MT-1303 were investigated in healthy male subjects after a single oral dose of 0.4 mg [14C]-MT-1303 (ClinicalTrials.gov NCT02293967).The MT-1303 concentration in the plasma reached a maximum at 12 h after administration. Thereafter, the concentration declined with a half-life of 451 h. At the final assessment on Day 57, 91.16% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 35.32% and 55.84%, respectively.The most abundant metabolite in plasma was MT-1303-P, which accounted for 42.6% of the area under the plasma concentration–time curve (AUC) of the total radioactivity. The major component excreted in urine was Human Urine (HU)4 (3066434), accounting for 28.1% of radioactivity in the sample (4.05% of the dose), whereas MT-1303 was a major component in the faeces, accounting for 89.8% of radioactivity in the sample (25.49% of the dose) up to 240 h after administration.This study indicates that multiple metabolic pathways are involved in the elimination of MT-1303 from the human body and the excretion of MT-1303 and MT-1303-P via the kidney is low. Therefore, MT-1303 is unlikely to cause conspicuous drug interactions or alter pharmacokinetics in patients with renal impairment. The absorption, metabolism and excretion of MT-1303 were investigated in healthy male subjects after a single oral dose of 0.4 mg [14C]-MT-1303 (ClinicalTrials.gov NCT02293967). The MT-1303 concentration in the plasma reached a maximum at 12 h after administration. Thereafter, the concentration declined with a half-life of 451 h. At the final assessment on Day 57, 91.16% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 35.32% and 55.84%, respectively. The most abundant metabolite in plasma was MT-1303-P, which accounted for 42.6% of the area under the plasma concentration–time curve (AUC) of the total radioactivity. The major component excreted in urine was Human Urine (HU)4 (3066434), accounting for 28.1% of radioactivity in the sample (4.05% of the dose), whereas MT-1303 was a major component in the faeces, accounting for 89.8% of radioactivity in the sample (25.49% of the dose) up to 240 h after administration. This study indicates that multiple metabolic pathways are involved in the elimination of MT-1303 from the human body and the excretion of MT-1303 and MT-1303-P via the kidney is low. Therefore, MT-1303 is unlikely to cause conspicuous drug interactions or alter pharmacokinetics in patients with renal impairment. Trial registration:ClinicalTrials.gov identifier: NCT02293967.

Aim Amiselimod (MT-1303) is a selective sphingosine 1-phosphate 1 (S1P1) receptor modulator which is currently being developed for the treatment of various autoimmune diseases. Unlike some other S1P receptor modulators, amiselimod seemed to show a favourable cardiac safety profile in preclinical, phase I and II studies. The aim of the current study was to characterize the cardiac effects of amiselimod by directly comparing it with fingolimod and placebo. Methods A total of 81 healthy subjects aged 18–55 years were equally randomized to receive amiselimod 0.4 mg, amiselimod 0.8 mg, placebo or fingolimod 0.5 mg once daily for 28 days. The chronotropic/dromotropic and inotropic effects were evaluated using intensive Holter electrocardiogram and echocardiography. Results Unlike fingolimod, neither amiselimod dose exerted acute (1–6 h) negative chronotropic effects on Days 1 and 2. The lowest nadir mean hourly heart rate was observed on Day 14 in the amiselimod 0.4 mg group (least squares mean difference: −4.40 bpm, 95% confidence interval −7.15, −1.66) and Day 7 in the 0.8 mg group [−3.85 bpm (−6.58, −1.11)] compared with placebo, but these changes were smaller than those with fingolimod on Day 1 [−6.49 bpm (−8.95, −4.02)]. No clinically significant bradyarrhythmia or cardiac functional abnormalities were observed in either amiselimod group. Both amiselimod doses were well tolerated and no serious adverse events were reported. Fingolimod was also generally well tolerated, although one subject was withdrawn owing to highly frequent 2:1 atrioventricular blocks on Day 1. Conclusion The study demonstrated a more favourable cardiac safety profile for amiselimod than fingolimod when administered over 28 days in healthy subjects.

Shinsuke Inoue,1,2 Mitsuhiro Kamiya,2 Makoto Nishihara,1 Young-Chang P Arai,1,3 Tatsunori Ikemoto,1,3 Takahiro Ushida1,3 1Multidisciplinary Pain Center, 2Department of Orthopaedic Surgery, 3Institute of Physical Fitness, Sports Medicine and Rehabilitation, Aichi Medical University, Aichi, Japan Abstract: We conducted a cross-sectional, Internet-based survey with a nationally representative sample of Japanese adults to assess the prevalence and characteristics of failed back surgery syndrome (FBSS). Data regarding the residual symptoms and patient satisfaction from an online survey of 1842 lumbar surgery patients revealed the prevalence of FBSS to be 20.6% (95% confidence interval [CI], 18.8–22.6). The prevalence of low back pain, dull ache, numbness, cold sensations, and paresthesia after surgery was 94.0%, 71.1%, 69.8%, 43.3%, and 35.3%, respectively. With a logistic regression model, severe residual low back pain (numerical rating scale 8–10), higher pain intensity, and multiple low back surgeries were strongly associated with FBSS, with odds ratios of 15.21 (95% CI, 7.79–29.7), 1.40 (95% CI, 1.32–1.49), and 1.87 (95% CI, 1.25–2.81), respectively. Respondents with FBSS had significantly lower EuroQol-5D (P

Background Numerous reports indicate that multifaceted pain management programs based on cognitive-behavioral principles are associated with clinically meaningful long-term improvements in chronic pain. However, this has not yet been investigated in Japan. This study investigated the effects of a multifaceted pain management program in Japanese patients with chronic pain, both immediately after the program and 6 months thereafter. Methods A total of 96 patients, 37 male and 59 female (mean age 63.8 years) experiencing treatment difficulties and suffering from intractable pain for more than 6 months were enrolled in the study. The programs were conducted with groups of 5–7 patients who met weekly for 9 weeks. Weekly sessions of approximately 2 h in duration incorporating a combination of lectures and exercise were conducted. Several measures related to pain and physical function were assessed at the start of the program, the end of the program, and 6 months after completion of the program. The resulting data were analyzed via Wilcoxon signed-rank test, and ‘r’ estimated by effect size was also assessed. Results Of the 96 initial participants, 11 dropped out during the program and 85 completed it. Thereafter, we evaluated 62 subjects at 6 months after the program, while 23 could not be evaluated at that time-point. Pain intensity upon moving, catastrophizing scores, and pain disability scores showed good improvements at the 6-month follow-up, with large efficacy (r > 0.5). Moving capacity and 6-min walking distance also showed good improvements with large efficacy, both at the end of the program and at the 6-month follow-up (r > 0.5). Conclusions A multifaceted pain-management program based on cognitive-behavioral principles was effective in Japanese patients with chronic pain, resulting in improved long-term clinical outcomes.

Background: Short duration massage of the lower limbs reduces fatigue sensation in working adults. However, the effects of lower limb vibrations on autonomic activity, which potentially could improve sleep onset, have not been fully investigated. This study aimed to examine the effects of lower limb vibrations on heart rate variability (HRV) as a marker of autonomic activity. Methods: The study involved two aspects. In the first experiment, the optimal frequency of vibration was determined in five healthy adults (one male and four females; mean age, 20.4 ± 0.5 years). The second experiment involved assessing the effects of vibration at the optimal frequency on nine healthy adults (four males and five females; mean age, 26.3 ± 16.8 years). Electrocardiograms (recorded with bipolar lead CM5) were obtained in the supine position, and HRV was used as an index for autonomic activity. The power spectra at 0.04-0.15 Hz (low frequency (LF) power) and 0.15-0.40 Hz (high frequency (HF) power) were quantified, and HF power and LF/HF ratio were calculated. In the first experiment, vibrations at four different frequencies (i.e., 25, 30, 35, and 40 Hz) were randomly applied for 10 minutes. In the second experiment, HF power and LF/HF ratio were measured at a vibration frequency of 35 Hz for 10 minutes and for 10 minutes of interruption. As a control, HF power and LF/HF ratio were recorded for 20 minutes without vibration. Findings: The percent change in HF power tended to be higher at a vibration frequency of 35 Hz compared to vibrations at frequencies of 25, 30, and 40 Hz. Vibrations at this frequency significantly increased HF power and reduced the LF/HF ratio compared to when vibrations were not applied. Conclusion: Our findings suggest that the lower limbs vibration in the supine position at the frequency of 35 Hz may increase parasympathetic activity and presumably promote the rapid onset of sleep.

Objective Neuropathic pain is difficult to manage and treat. Spinal cord stimulation (SCS) has become an established procedure for treating chronic neuropathic pain that is refractory to pharmacological therapy. In order to achieve better analgesia, a number of studies have evaluated the effectiveness of combining drug therapy with SCS. Cholecystokinin antagonists, such as proglumide, enhance the analgesic efficacy of endogenous opioids in animal models of pain. We previously reported that both systemic and spinal administration of proglumide enhances analgesia produced by both low- and high-frequency transcutaneous electrical nerve stimulation (TENS). Since SCS produces analgesia through endogenous opioids, we hypothesized that the analgesic effect of SCS would be enhanced through co-administration with proglumide in animals with neuropathic pain. Materials and methods Male Sprague-Dawley rats (n = 40) with spared nerve injury were given proglumide (20 mg/kg, i.p.) or saline prior to treatment with SCS (sham, 4 Hz, and 60 Hz). Mechanical withdrawal thresholds of the paw were measured before and after induction of nerve injury, and after SCS. Physical activity levels were measured after SCS. Results Both proglumide and SCS when given independently significantly increased withdrawal thresholds two weeks after nerve injury. However, there was no additional effect of combining proglumide and SCS on mechanical withdrawal thresholds or activity levels in animals with nerve injury. Discussion and conclusions Proglumide may be a candidate for achieving analgesia for patients with refractory neuropathic pain conditions, but does not enhance analgesia produced by SCS.

Background and Purpose We conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT‐1303), a second‐generation sphingosine 1‐phosphate (S1P) receptor modulator, designed to reduce the bradycardia associated with fingolimod and other S1P receptor modulators. Experimental Approach The selectivity of the active metabolite amiselimod phosphate (amiselimod‐P) for human S1P receptors and activation of G‐protein‐coupled inwardly rectifying K+ (GIRK) channels in human atrial myocytes were assessed. Its cardiac distribution was determined in rats, and cardiovascular telemetry was assessed in monkeys. We also examined the pharmacokinetics, pharmacodynamics and safety of amiselimod in healthy humans. Key Results Amiselimod‐P showed potent selectivity for S1P1 and high selectivity for S1P5 receptors, with minimal agonist activity for S1P4 and no distinct agonist activity for S1P2 or S1P3 receptors and approximately five‐fold weaker GIRK activation than fingolimod‐P. After oral administration of amiselimod or fingolimod at 1 mg·kg−1, the concentration of amiselimod‐P in rat heart tissue was lower than that of fingolimod‐P, potentially contributing to the minimal cardiac effects of amiselimod. A telemetry study in monkeys confirmed that amiselimod did not affect heart rate or ECG parameters. In healthy human subjects, peripheral blood lymphocyte counts gradually reduced over the 21 day dosing period, with similar lymphocyte count profiles with the highest doses by day 21, and no clinically significant bradycardia observed on day 1 or during the study. Conclusions and Implications Amiselimod exhibited potent therapeutic efficacy with minimal cardiac effects at the anticipated clinical dose and is unlikely to require dose titration.

Vasodilation profiles following a short-term infusion of nitric oxide (NO), acetylcholine (ACh), and sodium nitroprusside (SNP) into an isolated perfused mesenteric artery bed were analyzed in rats to examine their vasodilatory efficacy under physiological conditions. These compounds commonly increase the intracellular NO concentration to exert vasodilatory activity. In an experiment with exogenous NO infusion where 100 µl of 1 : 300 diluted NO-saturated solution (approx. 53 pmol of NO) was applied, the infusion caused transient vasodilation in a dose-dependent manner, with the peak vasodilation value being 74.7% of the maximum relaxation value. In experiments with ACh, the peak vasodilation value was 81.5% of the maximum at a dose of 60 pmol. The vasodilation profile of ACh was similar to that of NO infusion, but the ACh-induced vasodilation reduced at a slower rate than that induced by NO infusion. The vasodilatory activity of SNP was less potent than that of ACh, and its peak value was 62.8% of the maximum at a dose of 2000 pmol. However, SNP activity was augmented by removing the vascular endothelia of the mesenteric artery bed, and the peak value reached 67.3% of the maximum at a dose of 60 pmol. Pharmacodynamic analysis indicated that NO and ACh are equivalent regarding their vasodilatory efficacy, while the efficacy of SNP was less than 1% of theirs, as the arterial vascular endothelium impeded intracellular SNP-related NO generation, by which 95% of SNP's vasodilatory efficacy was negated. These findings will be helpful to understand factors influencing the therapeutic efficacy of vasodilators.

A new molecular design concept for colorless and multicolor light-emitting polyimides (PIs) based on excited-state proton transfer is proposed. The ultraviolet−visible optical absorption spectra and fluorescence spectra of PIs containing hydroxy groups in their anhydride moieties and their corresponding imide compounds were extensively investigated. N-Cyclohexyl-3-hydroxyphthalimide (3HNHPI), which forms intramolecular hydrogen bonding between the hydroxy group and imide carbonyl group, exhibited an excited-state intramolecular proton transfer (ESIPT) emission at 534 nm with excitation at 332 nm having a large Stokes’ shift of 11394 cm−1. The highly fluorescent PIs, prepared from 4,4′-oxidiphthalic dianhydride (ODPA) and 4,4′-diaminocyclohexylmethane (DCHM) end-capped with 3-hydroxyphthalic anhydride, are colorless and exhibited two characteristic fluorescence peaks at 400 and 530 nm with excitation at 340 nm. These PIs showed gradated multicolor emission (blue, light-blue, white, and light-green) dependi...

The purpose of this study was to examine the cost-effectiveness of pain treatments in two pain centers in Japan. The study population comprised 91 patients receiving various treatments for chronic pain, which were divided into three categories: (1) medication, (2) medication + nerve block, and (3) other modalities (exercise and/or pain education). Pain was assessed using the Pain Disability Assessment Scale (PDAS) score, Hospital Anxiety and Depression Scale (HADS) score, Pain Catastrophizing Scale (PCS) score, and EQ-5D score. First, the reliability of the EQ-5D score first assessed by evaluating the correlation this score with those of the other pain-related evaluation instruments, and then the cost effectiveness of the pain treatments was evaluated. Evaluation of medical costs was based on data provided from the Management Services of the hospital, which in turn were based on national health scheme medical treatment fees. The quality-adjusted life year (QALY) value was calculated from the EQ-5D score, converted to 12 months, and then used for cost-benefit analysis along with medical treatment fees. According to the recent IASP classification, more patients had chronic neuropathic pain (41) than chronic primary pain (37 patients) or chronic musculoskeletal pain (27 patients). There was a significant correlation between the EQ-5D score and the PDAS, HADS, and PCS scores, which demonstrated the reliability of the EQ-5D score. Significant improvement in the HADS, PCS, and EQ-5D scores was noted after 3 months of pain treatment. Calculation of the cost-effectiveness based on the estimated annual medical treatment cost and QALY revealed a mean value of US $45,879 ± 103,155 per QALY (median US $16,903), indicating adequate socioeconomic utility. Based on our results, the EQ-5D is reliable for evaluating chronic pain in patients. The medico-economic balance was appropriate for all treatments provided in two comprehensive pain centers in Japan.

Objective: Frozen shoulder is a common disorder in general orthopedic practice, characterized by spontaneous onset of pain in the shoulder and accompanied by limitation of glenohumeral movement. Treatments for frozen shoulder include shoulder exercise, manual therapy, corticosteroid injection, manipulation under anesthesia, and arthroscopic capsular release. Several patients suffer from some degree of pain and range of motion limitation for up to 10 years even when these treatments are applied. Kampo, a traditional Japanese herbal medicine based on traditional Chinese herbal medicine, has been used for the treatment of pain in Japan. Nijutsuto has been a Kampo formula used to effectively treat frozen shoulder. Methods: Thirteen patients suffering from long-term frozen shoulder refractory to Western medical treatment were administered Nijututo. Results: Almost all patients experienced sound pain relief after Nijutsuto admnistration. There were no severe side effects reported. Conclusion: Nijutsuto combined with an exercise program improved pain intensity in 13 patients with long-term frozen shoulder.

There are patients who suffer from persistent dentoalveolar pain disorder (PDAP) which is a pain of the teeth, either dentoalveolar pain or nonodontogenic toothache, and its cause has not yet been identified. An effective intervention for PDAP has not yet been established. Interventions for patients with PDAP are generally pharmacological treatments such as antidepressants, anticonvulsants, and pregabalin. However, these medicines are not always effective for patients. The pain disorder in the orofacial region including temporomandibular disorder (TMD) and PDAP was effectively treated with our original exercise therapy. However, we did observe some intractable cases of PDAP even when our original exercise therapy was used. This paper presents our findings in which Kamishoyosan improved the pain intensity in 14 out of 15 PDAP patients refractory to our original exercise therapy.

‘Tonewase’ Japanese persimmon fruit (Diospyros kaki Thunb.) grown in a heated plastic-house softens rapidly within several days of harvest, which is a major problem in marketing of this cultivar. In this study, we elucidated the involvement of water stress-induced ethylene in fruit softening and investigated the induction mechanism of this ethylene biosynthesis occurring in specific tissues at the molecular level. Two instances of increase in ethylene production were observed in fruit held in ambient low humidity conditions (40–60% RH), an initial increase on the 1st and 2nd days and a second increase on the 6th and 8th days after harvest. Increase in ethylene production was accompanied by rapid softening in these fruit. Fruit held in high humidity conditions (>95%) neither produced detectable levels of ethylene nor softened rapidly. Moreover, treatment of the fruit held in low humidity with 1-methylcyclopropene (1-MCP), a strong inhibitor of ethylene action, inhibited fruit softening remarkably. These results suggest the involvement of water stress-induced ethylene in fruit softening. 1-MCP also suppressed the second increase in ethylene production but not the initial increase, indicating that the initial increase is induced directly in response to the primary water stress signal while the second is induced autocatalytically by the ethylene produced during the initial phase. During the initial increase in ethylene, the calyx produced more than 5 nl g−1 h−1 of ethylene accompanied by increased accumulation of 1-aminocyclopropane-1-carboxylic acid (ACC) and expression of DK-ACS2. In pulp, 0.5 nl g−1 h−1 of ethylene was detected but no increase in ACC content or expression of any ethylene biosynthetic genes was observed. During the second increase in ethylene, ethylene production in the calyx was not detected whereas the pulp produced 0.2–0.4 nl g−1 h−1 of ethylene with a marked increase in ACC content and expression of the two ACC synthase (DK-ACS1, DK-ACS2) and one ACC oxidase (DK-ACO1) genes. These results suggest that in plastic-house ‘Tonewase’ persimmon fruit, ethylene production is initiated in the calyx in response to water stress through activated expression of DK-ACS2, and this ethylene in turn induces autocatalytic ethylene production in the pulp. As the flesh firmness decreased markedly just after the initial ethylene production, the results also indicate that the fruit softening is due to the action of ethylene produced in the calyx.

Sharks of the genus Cephaloscyllium from Taiwan were reviewed. After extensive survey of the specimens deposited in useums, universities and fisheries institutions in Taiwan and Japan, the following four species were recognized as valid n Taiwanese waters: C. umbratile JordanFowler, 1903, C. fasciatum Chan, 1966, C. sarawakensis Yano, AhmadGambang, 2005, and C. formosanum Teng, 1962. Cephaloscyllium formosanum is resurrected herein. Four species (C. circulopullum Yano, AhmadGambang, 2005, C. parvum InoueNakaya, 2006, C. pardelotum Schaaf-da SilvaEbert, 2008, C. maculatum Schaaf-da SilvaEbert, 2008) are concluded to be junior synonyms. The four valid species here recognized are fully described, and a key to Taiwanese species is provided. The original description of C. formosanum was translated into English from Japanese and is included as an Appendix.

Background Chronic pain is recognized as a public health problem that affects the general population physically, psychologically, and socially. However, there is little knowledge about the associated factors of chronic pain, such as the influence of weather, family structure, daily exercise, and work status. Objectives This survey had three aims: 1) to estimate the prevalence of chronic pain in Japan, 2) to analyze these associated factors, and 3) to evaluate the social burden due to chronic pain. Methods We conducted a cross-sectional postal survey in a sample of 6000 adults aged ≥20 years. The response rate was 43.8%. Results The mean age of the respondents was 57.7 years (range 20–99 years); 39.3% met the criteria for chronic pain (lasting ≥3 months). Approximately a quarter of the respondents reported that their chronic pain was adversely influenced by bad weather and also oncoming bad weather. Risk factors for chronic pain, as determined by a logistic regression model, included being an older female, being unemployed, living alone, and no daily exercise. Individuals with chronic pain showed significantly lower quality of life and significantly higher psychological distress scores than those without chronic pain. The mean annual duration of absence from work of working-age respondents was 9.6 days (range 1–365 days). Conclusions Our findings revealed that high prevalence and severity of chronic pain, associated factors, and significant impact on quality of life in the adult Japanese population. A detailed understanding of factors associated with chronic pain is essential for establishing a management strategy for primary care.

葛野川ダムでは, コストダウン, 工期短縮の観点から, 中高標高部に単位結合材量110kg/m3の配合を初めて採用するとともに, リフト厚さも1mと厚くしたRCD工法で施工した. 施工に先立ってRCD用コンクリートの施工試験を行い, 施工仕様を検討するとともに, 締固め中のRCD用コンクリート内の加速度や圧力を計測し, 締固め挙動や振動ローラの振動輪加速度の把握を行った. 本論は施工試験の結果に基づいてRCD用コンクリートの締固め時の挙動を把握するとともに, RCD用コンクリートの締固めをリアルタイムに打込み面全域に亘って管理できるシステムの開発について述べるものである.

The possible involvement of stress-induced ethylene in softening of 'Saijo' persimmon fruit with or without>95% CO2 treatment for 16 hr at 25°C, a technique widely used for the removal of astringency (Constant Temperature Short Duration (CTSD) method) was investigated. To confirm the role of ethylene in fruit softening, fruit were treated with 1-methylcyclopropene (MCP), a strong inhibitor of ethylene perception. The softening of treated fruit was inhibited markedly compared with non-treated fruit. Fruits, with or without CO2 treatment, were held in high (>95% RH) or low humidity (40-60% RH) at 20°C to determine the effects of water and CO2 stresses on postharvest ethylene production and fruit softening. Without CO2 treatment, ethylene production and fruit softening were retarded significantly by high humidity. Whereas, with CO2 treatment, a considerable amount of ethylene was produced and fruit softened, irrespective of humidity. These results indicate that ethylene is involved in fruit softening and that its evolution is stimulated not only by water stress but also by CO2 stress in 'Saijo' persimmon fruit.

Background This was a randomized, open-label, three-way crossover study to assess the effects of AST-120 (an orally administered spherical carbon adsorbent acting in the gastrointestinal tract without systemic circulation) on the single-dose pharmacokinetics of metoprolol in an extended-release formulation (metoprolol ER) in healthy volunteers. Methods A total of 34 subjects were singly administered metoprolol ER alone (A), and metoprolol ER in combination with AST-120 simultaneously (B) and 1 h later (C). Results The total exposure was more significantly reduced in both treatments B and C than that in treatment A; the geometric mean ratios of area under the curve extrapolated to infinity (AUC0-∞) for B/A and C/A were reduced by approximately 30% in both treatments B and C. Maximum observed plasma concentration (Cmax) of metoprolol in treatment B significantly decreased, whereas Cmax in treatment C was slightly decreased. AST-120 treatment was unlikely to affect apparent first-order terminal elimination half-life (T1/2) of metoprolol significantly. Reduction in heart rate and blood pressure readings were similar across the treatment periods. Coadministration of AST-120 and metoprolol ER was safe and was well tolerated. Conclusions Because AST-120 reduced gastrointestinal absorption of metoprolol ER, careful monitoring of heart rate and blood pressure is recommended in coadministration of AST-120 with metoprolol ER.

Kampo, or traditional Japanese herbal medicine, has been used for clinical practice in Japan. The most appropriate Kampo formula should be chosen for each individual based on specific diagnostic procedures. Fuku shin, the abdominal exam, is one of the most important diagnostic procedures. There are several Fukushos (abdominal conformations). Depression and anxiety have been shown to be related to Shin ka hi koh, epigastric obstructive hardness, and neuroses have an association with Kyoh kyoh ku man, hypochondriac distress. The aim of our study was to compare Fukushos at each level of depression and anxiety symptoms and to assess the associations between occurrence and pain catastrophizing. Two hundred and twenty-nine patients were assigned to high-, moderate-, or low-level anxiety-depression groups based on the hospital anxiety and depression scale and were investigated for occurrence of major Fukushos. Moreover, the associations between occurrence and the pain catastrophizing scale (PCS) were analyzed. The moderate and high anxiety-depression groups showed a higher occurrence of Shin ka hi koh [low, 29%; moderate, 51%; high, 67%] (P < 0.0001). In contrast, the relationship between the occurrence of Kyoh kyoh ku man and the PCS showed a significant albeit small correlation (r s = 0.1296, n = 229, P = 0.0491).

Purpose Apparent organic abnormalities are sometimes not identified among patients suffering from chronic pain in the craniocervical region. In some cases, parafunctional activities (PAs) are recognized. PAs are nonfunctional oromandibular activities that include jaw clenching and bruxism, but are considered as factors that contribute to craniomandibular disorders (CMDs). It is now recognized that PAs and CMDs influence musculoskeletal conditions of the upper quarter. Exercise therapy (ET) to improve jaw movement and psychological intervention (PI) to reduce PAs are useful for PAs and CMDs. We hypothesized that ET and PI would be effective for craniocervical pain without organic abnormalities. Methods Thirty-nine subjects suffering from craniocervical chronic pain were allocated into 3 groups: The control group received only pharmacological treatment; the ET group received jaw movement exercise (JME); and the ET-PI group received JME and PI. Pain and jaw movement were evaluated using a numerical rating scale (NRS). Results After interventions, the NRS scores were significantly lower in the ET-PI group, compared with those in the other groups. Jaw movement improved 100% in the ET group, 92% in the ET-PI group, and 0% in the control group. Conclusion A combination of jaw exercise and psychological intervention to reduce parafunctional activities is more effective than jaw exercise alone for the improvement of craniocervical pain without apparent organic abnormalities.

Pain drawings have frequently been used for documentation of pain and a convenient diagnosis tool. Pain drawings were found to be associated with psychological states in chronic patients with low back pain. Few researchers have investigated pain drawings except in low back pain. The aim of this study was to investigate the pain, pain drawings, psychological characteristics, and pain interference in the head, neck-shoulder (NS), and low-back/lower-limb (LB-LL) regions among patients with chronic pain.We included a total of 291 patients with new chronic pain (headache, 62; NS pain, 87; LB-LL pain, 142). The pain drawings and scores of 10-cm Visual Analogue Scale (VAS), Hospital Anxiety and Depression Scale (HADS), Pain Catastrophizing Scale (PCS), Short-Form McGill Pain Questionnaire (SF-MPQ), and Pain Disability Assessment Scale (PDAS) were extracted from medical records. A subset of 60 pain drawings was scored by senior and junior evaluators to assess inter-rater agreement. We investigated the correlation between pain drawings and VAS, HADS, PCS, SF-MPQ, and PDAS in each body region group at the initial visit. Moreover, almost all patients received nonsurgical treatment as a follow-up and were investigated using VAS after treatment.The reliability of pain drawings was substantial with an interevaluator reliability in headache, NS, and LB-LL pain. Nonorganic pain drawings were associated with psychological disturbances in NS and LB-LL pain, but not headache. Poor outcomes were associated with nonorganic drawings in LB-LL pain, but not in the case of headache or NS pain.Our results suggest that the characteristics of patients with nonorganic drawings differ according to body regions.

Musculoskeletal disorders are the most common causes of severe long-term pain and physical disability, affecting hundreds of millions of people around the world. In industrialized countries, which have increasingly aging populations, chronic musculoskeletal pain has become a significant health care burden and major issue in the 1980s and 1990s. On January 13, 2000, The Bone and Joint Decade was formally launched at the headquarters of the World Health Organization in Geneva, Switzerland. This global campaign aimed to improve the quality of life for people who have musculoskeletal conditions. Complying with this trend, large-scale surveys have been conducted in Europe and the US in recent years to evaluate the effect of chronic pain on society, but in Japan, there has been a paucity of basic information on the status of chronic musculoskeletal pain. We organized a postal survey designed to quantify and describe the prevalence and distribution of chronic pain in the Japanese community. We found that chronic pain of moderate to severe intensity occurs in 17.2%. Chronic pain had a significant impact on the occupational and social relationships, and it seriously affected their psychological conditions and quality of life. Such disabling chronic pain is regarded as the result of interrelated physical, psychological, and social or occupational factors requiring multidisciplinary intervention. We introduce a multidisciplinary clinical approach and report on novel multimodal methodologies -- for patients with chronic musculoskeletal pain.

Celiac plexus block (CPB) can be used for treating intra-abdominal visceral pain syndromes. The celiac plexus is the largest plexus of the sympathetic nervous system. Several nerve blocks have a marked effect on autonomic nervous activity. Furthermore, stellate ganglion block changes cardiac autonomic nervous activity. Thus, CPB could influence the sympathetic activity of the cardiac plexus. The aim of the present study was to see whether CPB modulated heart rate variability (HRV) in patients with pancreatic cancer.Twelve patients received neurolytic CPB using 14 ml absolute alcohol. Data recorded in a palm-sized electrocardiographic unit were analyzed for HRV.CPB using a neurolytic solution did not induce any significant changes in the low-frequency (LF)/high-frequency (HF) ratio of HRV (LF/HF, P = 0.4642). Furthermore, the procedure did not induce any significant changes in blood pressure (systolic, P = 0.5051; diastolic, P = 0.5180).CPB did not induce any significant changes in HRV or hemodynamics.

Neuraxial blockade causes arterial hypotension. Transcutaneous electrical nerve stimulation (TENS) at the Neiguan (PC-6) and Jianshi (PC-5) reduces the severity of hypotension after spinal anaesthesia, but did not clarify the optimal stimulus frequency. We hypothesized that the stimulus frequency of TENS at the PC-6 and PC-5 points would influence the severity of hypotension after epidural anaesthesia. 65 ASA I or II male patients presenting for inguinal hernia repair were randomized to five groups: the control group received no treatment; the 2 Hz, 10 Hz, 20 Hz, and 40 Hz groups received TENS at a frequency of 2 Hz, 10 Hz, 20 Hz, and 40 Hz, respectively. The lowest SBP was significantly higher in the 40 Hz group [the control, 84 (74–110) mmHg; the 2 Hz, 96 (62–116) mmHg; the 10 Hz, 100 (68–110) mmHg; the 20 Hz, 96 (64–115) mmHg; the 40 Hz, 104 (75–140) mmHg:P=0.004]. Significantly less patients experienced hypotension in the 40 Hz group [the control, 78%; the 2 Hz, 43%; the 10 Hz, 38%; the 20 Hz, 38%; the 40 Hz, 8%:P=0.008]. TENS on the PC-6 and PC-5 points reduced the severity and incidence of hypotension after epidural anaesthesia, depending on the stimulus frequency.

In the management of clinical low back pain (LBP), actual damage to lower back areas such as muscles, intervertebral discs etc. are normally targeted for therapy. However, LBP may involve not only sensory pain, but also underlying affective pain which may also play an important role overall in painful events. Therefore we hypothesized that visualization of a painful event may trigger painful memories, thus provoking the affective dimension of pain. The present study investigated neural correlates of affect processing in subjects with LBP (n = 11) and subjects without LBP (n = 11) through the use of virtual LBP stimuli. Whole brain functional magnetic resonance imaging (MRI) was performed for all subjects while they were shown a picture of a man carrying luggage in a half-crouching position. All subjects with LBP reported experiencing discomfort and 7 LBP subjects reported experiencing pain. In contrast to subjects without LBP, subjects with LBP displayed activation of the cortical area related to pain and emotions: the insula, supplementary motor area, premotor area, thalamus, pulvinar, posterior cingulate cortex, hippocampus, fusiform, gyrus, and cerebellum. These results suggest that the virtual LBP stimuli caused memory retrieval of unpleasant experiences and therefore may be associated with prolonged chronic LBP conditions.