Background and PurposeWe 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 ApproachThe 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 ResultsAmiselimod‐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 ImplicationsAmiselimod exhibited potent therapeutic efficacy with minimal cardiac effects at the anticipated clinical dose and is unlikely to require dose titration.

Static and dynamic factors were related to the development of myelopathy in OPLL.

AimAmiselimod (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.MethodsA 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.ResultsUnlike 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.ConclusionThe study demonstrated a more favourable cardiac safety profile for amiselimod than fingolimod when administered over 28 days in healthy subjects.

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 0 -oxidiphthalic dianhydride (ODPA) and 4,4 0 -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) depending on the amount of fluorescent termini while maintaining colorless and transparence. It was clarified that ESIPT emission is a useful tool for controlling the absorption and fluorescence properties of PIs.

Study Design. Retrospective clinical review and prospective report of postoperative delirium after cervical spine surgeries.Objective. To investigate factors contributing to the development of delirium after cervical surgery and see whether amended therapeutic protocols could improve or alter postoperative outcomes.Summary of Background Data. Important consequences of postoperative delirium for the orthopedic patients include impaired recovery and increased morbidity and mortality. Although its risk factors have been reported in orthopedic surgery, there are a very few reports regarding postoperative delirium in spine surgery.Methods. Eighty-one cervical myelopathy patients were retrospectively examined about the incidence of postoperative delirium and the risk factors. Similarly, 41 patients who received postoperative care under modified protocols were prospectively examined.Results. Postoperative delirium occurred more commonly in patients over 70 years and those with hearing impairment. Patients who received high-dose methylprednisolone (Ͼ1000 mg) demonstrated an increased incidence of postoperative delirium. Under modified protocol, we reduced the usage of methylprednisolone and encouraged free body movement with cervical orthosis immediately after surgery. The incidence of postoperative delirium was significantly lower under the modified protocol.Conclusion. Early commencement of mobilization after cervical spine surgery would be crucial to the prevention of postoperative delirium in the elderly.Key words: postoperative delirium, cervical spine surgery, hearing impairments, methylprednisolone. Spine 2009;34: 2500-2504Delirium is an acute and relatively sudden decline in attention-focus, perception, and cognition and known to occur usually in the elderly people.1 Its incidence is known to increase during the perioperative period and it can cause major medical management problems. Several previous reviews indicate that delirium may affect a large proportion of orthopedic patients and report prevalence rates of 28% to 61%. 2,3 Although the incidence in hip and knee joint surgery has been widely reported, there are few studies regarding postoperative delirium in spine surgery. 4,5 Increasing age, blood urea levels, cardiothoracic index, hypertension, smoking habits, blood replacement during bypass, atrial fibrillation (AF), pneumonia, and blood fluid balance in the postoperative period were found to be significant risk factors for delirium by logistic regression analysis.6 Previous reports also suggest that prior cognitive impairment and reduced hemoglobin and hematocrit levels are significant risk factors for postoperative delirium. With the development of modern medicine, the percentage of elderly people in the population is increasing and thus the incidence of postoperative delirium would increase. Spinal surgery in general and cervical spinal surgery in particular entail specific management problems and risk factors. During the postoperative phase of cervical spine surgery, it is essential to maintain spina...

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Despite recent interest in amorphous ceramics for a variety of nuclear applications, many details of their structure before and after irradiation/implantation remain unknown. Here we investigated the short-range order of amorphous silicon oxycarbide (SiOC) alloys by using the atomic pair-distribution function (PDF) obtained from electron diffraction. The PDF results show that the structure of SiOC alloys are nearly unchanged after both irradiation up to 30 dpa and He implantation up to 113 at%. TEM characterization shows no sign of crystallization, He bubble or void formation, or segregation in all irradiated samples. Irradiation results in a decreased number of Si-O bonds and an increased number of Si-C and C-O bonds. This study sheds light on the design of radiation-tolerant materials that do not experience helium swelling for advanced nuclear reactor applications.

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 <10 milliseconds at the geometric mean maximum concentration for each edaravone dose. Overall estimated values by time point of ΔΔQTcF ≤0.9 milliseconds, no outlier values, and no morphologic changes suggestive of repolarization abnormalities were observed. Analysis of heart rate, PR interval, and QRS duration also revealed no adverse findings. These data indicate that edaravone, even at supratherapeutic doses, does not produce clinically meaningful QT prolongation and has no clinically relevant cardiac effects.