The administration of a single dose of all-trans retinoic acid on day 8 of gestation to pregnant mice, ICR strain, led to malformed fetuses in all of the litters. All-trans retinoic acid (RA) was dissolved in olive oil and given in doses of 60 or 40 mg/kg of body weight. The control mice were given vehicle alone. Examination on day 18 of gestation of the fetuses exposed to 60 mg/kg showed various malformations, such as exencephaly, exophthalmus, micrognathia, agnathia, cleft palate, cleft lower lip, spina bifida, atresia ani, tail anomalies, agenesis of the kidneys, or hydronephrosis. In the fetuses exposed to 40 mg/kg, isolated cleft palate was much more common than in those exposed to 60 mg/kg. Double-stained preparations of bone and cartilage showed cranio-facial anomalies and axial skeletal anomalies: a- or hypogenesis of palatine or maxillary bones, tympanic ring, squamosal temporal bone or otic ossicles in cartilage, and fusion of basioccipital to basisphenoid and maxilla, zygomatic and mandibular bones; a- or hypogenesis of caudal vertebrae and supernumerary thoracic and lumbar vertebrae. These results indicate that anomalies comparable to those seen in the infants of mothers treated with isotretinoin, 13-cis retinoic acid, during pregnancy can also be induced in mice and suggest that the site affected by RA may be neural crest cells, including those in the cephalic and caudal regions, and cells committed to somitic mesoderm in the trunk region.

ObjectiveThis post hoc, pooled, subgroup analysis of two randomised studies evaluated baseline characteristics that may influence the efficacy and safety of naldemedine in patients with opioid-induced constipation (OIC) and cancer.MethodsData for patients who received 0.2 mg naldemedine or placebo were pooled from randomised, placebo-controlled, phase IIb and phase III studies. Proportions of spontaneous bowel movement (SBM) responders and patients with diarrhoea were assessed for each treatment group. For the patient subgroups with or without possible blood–brain barrier (BBB) disruptions, changes in Numerical Rating Scale (NRS) and Clinical Opioid Withdrawal Scale (COWS) scores were assessed.ResultsA total of 307 patients were included in this analysis (naldemedine: n=155; placebo: n=152). The pooled proportion of SBM responders was 73.5% with naldemedine versus 35.5% with placebo. There was a significant increase in the proportion of SBM responders with naldemedine versus placebo (38.0% (95% CI 27.6% to 48.4%); p<0.0001). Greater proportions of SBM responders and patients who experienced diarrhoea were observed with naldemedine versus placebo in all subgroups. Changes from baseline in NRS and COWS scores were similar with naldemedine or placebo in patients with or without brain metastases.ConclusionsAlthough not powered to detect statistically significant differences in treatment effect among subgroups, this study demonstrated that naldemedine appeared to benefit patients with OIC and cancer, irrespective of baseline characteristics, and did not seem to affect analgesia or withdrawal–even in patients with potential BBB disruptions. Baseline characteristics did not appear to affect the incidence of diarrhoea in patients who received naldemedine.Trial registration numbersJapicCTI-111510 and JapicCTI-132340.

~ T o analyze hot-gas flows in puffer-type gas circuit breakers (GCBs), a program was developed by adding functions for dealing with opening process, gas compression, and arcing t o an axially-symmetric compressive fluid analysis program.Accuracy of the program is provekl by comparing the results of computation by this program with the results of two different tests: the observation of hot-gas backflows by using the Schlieren method and the measurement of breakdown voltage drops resulting from hot gas generated by curient interruptions. The results of both tests show trends similar to calculated results obtained by simulating the tests, proving that this program is applicable to interruption phenomena associated with hot gas t o a certain extent.The program is applied to the calculation of pressure rise phenomena in a puffer chamber caused by hot-gas backflows and dielectric strength to ground in a tank-type GCB. The program is expected to be useful as a means of estimating test results.

Objective To evaluate the opioid-induced constipation burden in the subgroup of patients with lung cancer who participated in the observational Opioid-Induced Constipation in Patients with Cancer Pain in Japan (OIC-J) study. Methods The prospective, observational study, OIC-J, included 212 patients with various tumour types, 33% of whom had lung cancer. The incidence of opioid-induced constipation was evaluated using several diagnostic criteria, as well as the physician’s diagnosis and patient’s subjective assessment. Following initiation of opioids, patients recorded details of bowel movements (i.e. date/time, Bristol Stool Scale form, sensations of incomplete evacuation or anorectal obstruction/blockage and degree of straining) in a diary for 2 weeks. Relationships between patient characteristics and opioid-induced constipation onset and effects of opioid-induced constipation on quality of life were explored. Results In total, 69 patients were included in this post hoc analysis. The incidence of opioid-induced constipation varied (39.1–59.1%) depending on which diagnostic criteria was used. Diagnostic criteria that included a quality component or a patient’s feeling of bowel movement as an evaluation item (i.e. Rome IV, physician’s diagnosis, Bowel Function Index, patient’s assessment) showed higher incidences of opioid-induced constipation than recording the number of spontaneous bowel movements alone. Opioid-induced constipation occurred rapidly after initiating opioids and had a significant impact on Patient Assessment of Constipation Symptoms total score (P = 0.0031). Patient baseline characteristics did not appear to be predictive of opioid-induced constipation onset. Conclusions In patients with lung cancer, opioid-induced constipation can occur quickly after initiating opioids and can negatively impact quality of life. Early management of opioid-induced constipation, with a focus on quality-of-life improvement and patient’s assessments of bowel movements, is important for these patients.

Abstract-itwas found that salmon calcitonin-I (sCT) inhibited in vitro 45Ca2+-uptake by rat brain hypothalamus blocks in a dose-dependent manner. The minimum effective concentration was estimated to be 10 nM or less. The effect appeared to be specific to the hypothalamus and was not observed with the pons plus medulla oblongata or the cerebral cortex. Two C-terminal fragments of the fish hormone, sCT (10-32) and sCT (22 32), and porcine calcitonin failed to inhibit the ion-uptake though tested in concentrations abolishing 1275I-sCT binding to these brain tissues, in dicating that the whole structure of sCT is essential for the inhibitory effect but not for the binding. Another finding to be noted was a possible de pendency of this effect on the integrity of the cell membrane structure. A crude synaptosomal fraction subsequently prepared from sCT-exposed hypothalamus blocks exhibited a decreased uptake of 45Ca2+, while a corresponding fraction from unexposed tissue did not respond to the hormone. These characteristics of this novel in vitro effect of sCT suggest its possible relevancy to the anorectic effect which also appears to be specific to the fish hormone.Recently, the calcitonin-specific binding sites were characterized in the rat brain (1-4) and based on the regional and hormonal specificities of the sites, a functional relevancy to some in vivo effects of the hormone (e.g. anorectic) (5, 6) has been suggested. Thus far, an elegant study by Miyahara and Oomura (7) seems to have succeeded in pinpointing the hypothalamic glucoreceptor as one of the sites.Peripherally, calcitonin regulates the blood Ca2+-level by changing the Ca-metabolism of bone and kidney tissues (8). An assumption was made that also in the central nervous system, the hormone would exert such behavioral effects by directly affecting the ion-metabolism, and using tissue blocks obtained from some brain regions, its effect on 45Ca2+-uptake was examined in vitro . We report herein that sCT specifically modified the ion-uptake of the rat hypothalamus, and