A Retrospective Observational Study of Factors Affecting the Efficacy of Concurrent Prescription of Naldemedine for Opioid-Induced Constipation Caused by Oxycodone Tablets.

Naldemedine is indicated for the treatment of opioid-induced constipation (OIC), but reports on its efficacy in preventing OIC are few. Therefore, we retrospectively investigated factors affecting the efficacy of concurrent prescription of naldemedine on OIC. Outpatients with cancer who were started on oxycodone 10 mg/d were included in the study. The eligible patients were classified by their physicians into the following three groups: Group A used regular laxatives before the introduction of oxycodone and initiated naldemedine treatment simultaneously with oxycodone administration, Group B did not take laxatives before the introduction of oxycodone and started naldemedine simultaneously with oxycodone administration, and Group C had been administering regular laxatives before the introduction of oxycodone and were not prescribed naldemedine simultaneously with oxycodone treatment. The Support Team Assessment Schedule Japanese edition score for constipation, frequency of defecation, Bristol Stool Form Scale, sense of incomplete rectal evacuation, and development or worsening of straining to pass bowel movements were compared among the three groups before and after oxycodone administration. In Group B, there was significant worsening of the four parameters except for the sense of incomplete rectal evacuation, whereas Groups A and C did not present any changes. In logistic regression analysis, body weight ≥51.8 kg was a factor significantly decreasing the preventive effect of naldemedine on OIC, and regular use of laxatives was a factor significantly increasing the preventive effect of naldemedine on OIC. Thus, the initiation of naldemedine should be considered depending on the body weight and regular laxative use.

Relationship between Pain Scores and EORTC QLQ-C15-PAL Scores in Outpatients with Cancer Pain Receiving Opioid Therapy.

Cancer pain is one of the most frequent and distressing symptoms associated with cancer and has a serious impact on the QOL of patients. However, inadequate pain treatment has also been reported in outpatients with cancer pain. The aims of this study were (1) to evaluate the relationship between pain intensity using the Numerical Rating Scale (NRS) and QOL scores using the Japanese version of the European Organization for Research and Treatment of Cancer (QOL Questionnaire Core 15 for Palliative Care (QLQ-C15-PAL)), and (2) to investigate their association with various pain patterns, especially with baseline and breakthrough pain. Forty outpatients who were receiving opioid therapy and obtained informed consent participated. We collected a total of 222 pharmacist consultations during the study period. Global QOL scores and pain scores (PA) in the QLQ-C15-PAL (PA score, 0-100) at the first visit were significantly correlated with worst pain intensity. In addition, the scores for the worst pain were significantly correlated with not only physical functioning scores but also with emotional functioning scores. The correlations between the worst pain NRS and PA scores were positive. Specifically, patients tended to report large variability of NRS scores when the PA score was less than 40 and also when they exhibited pain patterns with "baseline and breakthrough cancer pain in the same day" or "baseline pain throughout the day." Reducing the worst pain NRS and relieving breakthrough pain appear to be important measures to improve the QOL of outpatients receiving opioid therapy for cancer pain.

Clinical utility of thoracoscopy in elderly tuberculous pleurisy patients under local anesthesia.

INTRODUCTION: Diagnosing tuberculous pleurisy is important in Japan because it currently has a moderate tuberculosis prevalence. However, physicians often have difficulty making a diagnosis. It was reported that thoracoscopy under local anesthesia is useful for the diagnosis of tuberculous pleurisy, but there are no reports focusing on elderly patients. METHODS: In this study, the usefulness of thoracoscopy under local anesthesia was evaluated in elderly patients. Among 170 patients who underwent thoracoscopy under local anesthesia at our hospital during 11 years from January 2008 to December 2018, those aged 75 years or older (n = 75) were investigated retrospectively. RESULTS: A total of 55 patients underwent thoracoscopy under local anesthesia for detailed examination of pleural effusion of unknown cause. Of these, 18 were diagnosed as tuberculous pleurisy. The median age was 82 years (range: 75-92 years). The diagnosis of tuberculous pleurisy was made in 11 patients in whom Mycobacterium tuberculosis was detected and in four patients whose pathological findings indicated epithelioid granuloma accompanied by caseous necrosis. Clinical diagnosis was made in the remaining three patients based on thoracoscopic findings of the pleural cavity and a high level of adenosine deaminase in pleural fluid. No serious complications attributable to the examination were observed in any patient. CONCLUSIONS: Thoracoscopy under local anesthesia was useful for the diagnosis of tuberculous pleurisy in elderly patients, with useful information being also obtained for the treatment of tuberculosis.

Development of a novel and rapid measurement system for growth differentiation factor-15, progranulin, and osteopontin in uterine sarcoma.

Uterine sarcomas are rare and aggressive gynecologic tumors with poor prognosis; therefore, early diagnosis is crucial for therapy. However, it is very difficult to distinguish uterine sarcomas from leiomyomas which are common benign uterine tumors. Therefore, the development of a diagnostic method that utilizes reliable biomarkers to distinguish uterine sarcomas from leiomyomas is important so as to identify the rare tumors. The candidate factors as novel biomarkers were searched for in public databases and a pilot study was performed for confirmation. Growth differentiation factor-15 (GDF15), progranulin, and osteopontin were identified as candidate biomarkers for diagnosing uterine sarcoma. Thus, developing a rapid and easy method to measure these factors could help establish a screening system for uterine sarcomas. In this study, we developed a novel measurement system for these factors using a compact chemical luminescence immunological automatic analyzer POCubeTM. This assay system, which is based on the flow-through membrane immunoassay, completes the whole process and generates results within 15 min. Serum concentrations of these factors measured via POCubeTM correlated well with those measured using enzyme-linked immunosorbent assay (r = 0.994 for GDF15, r = 0.992 for progranulin, and r = 0.976 for osteopontin). The POCubeTM system provides rapid and easy measurement of these factors, thereby facilitating uterine sarcoma diagnosis.

Effect of Continuous Pharmacist Interventions on Pain Control and Side Effect Management in Outpatients with Cancer Receiving Opioid Treatments.

For improving the QOL of patients diagnosed with cancer, early palliative care is recommended, aiming to minimize pain and opioid-induced side effects. Herein, we evaluated the effect of continuous interventions for pain management and opioid-induced side effects in outpatients with cancer. Pharmacists continuously performed interventions on patients on their hospital visits, starting from the first visit for opioid introduction to intervention via telephone. We recorded their pain patterns and intensities, use of rescue doses, and types and degrees of side effects during these interventions. The physicians were suggested appropriate recommendations for increased doses or alternative opioids when the pharmacists considered the analgesic dose should be titrated. During the study period, palliative care pharmacists conducted 105 interviews for 27 patients (male: 19 and female: 8) with cancer pain. Pain intensities significantly decreased after the pharmacists' continuous intervention, including those from telephone interviews, with their appropriate recommendations and increased opioid doses. Side effects such as nausea and constipation increased or remained unaffected even after the intervention, likely due to the increased opioid doses. Approximately 90% of recommendations for pain control were accepted by the physicians and helped to control the pain intensities. Before starting physician consultations, pharmacists informed the patients that adequate pain control and side effect management were achievable through regular interviews, wherein patient symptoms were monitored and patients received detailed explanations of pharmaceutical care and courteous and continuous counseling.

Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part II: Optimization of 4-(pyrrolidin-1-yl)benzonitrile derivatives.

We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us to further modifications, which improved metabolic stability while maintaining potent androgen agonistic activity. Among the synthesized compounds, (2S,3S)-2,3-dimethyl-3-hydroxylpyrrolidine derivative 1c exhibited a suitable PK profile and improved metabolic stability. Compound 1c demonstrated significant efficacy in levator ani muscle without increasing the weight of the prostate in an in vivo study. In addition, compound 1c showed agonistic activity in the CNS, which was detected using sexual behavior induction assay.

[A CASE OF SUBPHRENIC ABSCESS WITH PARADOXICAL RESPONSE CAUSED BY MYCOBACTERIUM TUBERCULOSIS].

A 40-year-old woman was admitted to our hos- pital with cough and sputum production. A chest computed tomography (CT) scan revealed a diffuse nodular shadow in the upper lung. The patient was diagnosed with pulmonary tuberculosis, based on a positive T-SPOT®.TB test result of peripheral blood and a positive polymerase chain reaction (PCR) test result for Mycobacterium tuberculosis in gastric aspirates. M.tuberculosis was subsequently isolated from the gastric aspirate specimen. After 2 months of treatment with antituberculous medication, the patient developed a low grade fever and left-sided chest pain. A CT scan revealed a left pleural effusion and a right subphrenic abscess. Tuber- culous pleurisy with paradoxical response was diagnosed on the basis of an increased lymphocyte count and increased adenosine deaminase activity in the pleural fluid exudate. A percutaneous ultrasound-guided needle biopsy of the sub- phrenic abscess was performed. Histological analysis revealed epithelioid cell granulomas with necrosis and PCR for M. tuberculosis using puncture needle washing fluid returned positive results. Based on these findings, a diagnosis of subphrenic abscess with paradoxical response, caused by M. tuberculosis, was made. Subphrenic abscess caused by M. tuberculosis is an important consideration during antituber- culous therapy.

Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors-Part 2.

Peripherally selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Herein, we describe our medicinal chemistry approach to discover peripheral-selective noradrenaline reuptake inhibitors to avert the risk of P-gp-mediated DDI at the blood-brain barrier. We observed that steric shielding of the hydrogen-bond acceptors and donors (HBA and HBD) of compound 1 reduced the multidrug resistance protein 1 (MDR1) efflux ratio; however, the resulting compound 6, a methoxyacetamide derivative, was mainly metabolized by CYP2D6 and CYP2C19 in the in vitro phenotyping study, implying the risk of PK variability based on the genetic polymorphism of the CYPs. Replacement of the hydrogen atom with a deuterium atom in a strategic, metabolically hot spot led to compound 13, which was mainly metabolized by CYP3A4. To our knowledge, this study represents the first report of the effect of deuterium replacement for a major metabolic enzyme. The compound 13, N-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-[(2H(3))methyloxy]acetamide hydrochloride, which exhibited peripheral NET selective inhibition at tested doses in rats, increased urethral resistance in a dose-dependent manner.

Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors - Part 3.

Peripheral-selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Here, we describe our medicinal chemistry approach to discover a novel series of highly potent, peripheral-selective, and orally available noradrenaline reuptake inhibitors with a low multidrug resistance protein 1 (MDR1) efflux ratio by cyclization of an amide moiety and introduction of an acidic group. We observed that the MDR1 efflux ratio was correlated with the pKa value of the acidic moiety. The resulting compound 9 exhibited favorable PK profiles, probably because of the effect of intramolecular hydrogen bond, which was supported by a its single-crystal structure. The compound 9, 1-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride, which exhibited peripheral NET-selective inhibition at tested doses in rats by oral administration, increased urethral resistance in a dose-dependent manner.

Characteristics of Colonic Diverticulitis and Factors Associated With Complications: A Japanese Multicenter, Retrospective, Cross-Sectional Study.

BACKGROUND: Little is known about the epidemiology of diverticulitis in Japan. Additional information is needed about its clinical characteristics and the factors associated with complications of diverticulitis. OBJECTIVE: This study was designed to determine the clinical characteristics of diverticulitis and factors associated with its complications in Japanese patients. DESIGN: This was a retrospective, multicenter, large-scale, cross-sectional study. SETTINGS: All of the consecutive patients in 21 Japanese hospitals with a final diagnosis of acute colonic diverticulitis were included in this study. PATIENTS: A total of 1112 patients, including 658 men and 454 women, with a mean age of 54.8 years, who were diagnosed by CT and/or ultrasonography between January 2006 and May 2011, were included in this study. INTERVENTIONS: Data on medical history, investigations, treatments, and prognosis were collected using a standard form to create a dedicated database. MAIN OUTCOME MEASURES: Clarification of the clinical characteristics of Japanese patients with acute diverticulitis was the main outcome measured. RESULTS: Diverticulitis was detected mainly in men and women aged 40 to 60 years. Although diverticulitis more frequently affected the right colon (70.1%), diverticulitis of the left colon was significantly more frequent (61.0%) in elderly patients. Of the 1112 patients with diverticulitis, 179 (16.1%) developed complications, including abscess formation, perforation, stenosis, and/or fistula, some of which required surgical treatment, such as drainage or colonic resection. The duration of hospitalization (24.1 ± 19.5 days) and mortality rate (2.8%) were significantly higher in patients with versus without complications. Factors associated with complications were fever (>38.5°C), involvement of the left colon, higher age, and delayed diagnosis. LIMITATIONS: Limitations included the nonconsideration of diverticulitis treatment, the effect of dietary fiber, and the retrospective design of the study. CONCLUSIONS: Complications were more frequent in elderly men with left-sided diverticulitis, although diverticulitis was more common in middle-aged people and on the right side of the colon. Factors associated with complications were fever, site of involvement, older age, and longer time until diagnosis.

Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor.

Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites.

mNUDC is required for plus-end-directed transport of cytoplasmic dynein and dynactins by kinesin-1.

Lissencephaly is a devastating neurological disorder caused by defective neuronal migration. The LIS1 (or PAFAH1B1) gene was identified as the gene mutated in lissencephaly patients, and was found to regulate cytoplasmic dynein function and localization. In particular, LIS1 is essential for anterograde transport of cytoplasmic dynein as a part of the cytoplasmic dynein-LIS1-microtubule complex in a kinesin-1-dependent manner. However, the underlying mechanism by which a cytoplasmic dynein-LIS1-microtubule complex binds kinesin-1 is unknown. Here, we report that mNUDC (mammalian NUDC) interacts with kinesin-1 and is required for the anterograde transport of a cytoplasmic dynein complex by kinesin-1. mNUDC is also required for anterograde transport of a dynactin-containing complex. Inhibition of mNUDC severely suppressed anterograde transport of distinct cytoplasmic dynein and dynactin complexes, whereas motility of kinesin-1 remained intact. Reconstruction experiments clearly demonstrated that mNUDC mediates the interaction of the dynein or dynactin complex with kinesin-1 and supports their transport by kinesin-1. Our findings have uncovered an essential role of mNUDC for anterograde transport of dynein and dynactin by kinesin-1.

Self-reported faster eating is positively associated with accumulation of visceral fat in middle-aged apparently healthy Japanese men.

PURPOSE: Faster eating is positively associated with body mass index in apparently healthy Japanese populations. In the present study, we examined the associations between self-reported rate of eating and visceral and subcutaneous fat areas in apparently healthy middle-aged Japanese men. METHODS: We conducted a cross-sectional study of men who participated in health checkups in Japan. We removed participants who were diagnosed with metabolic diseases by the time of their health checkups. A total of 320 subjects aged 30-64 years (mean ± standard deviation, 47.4 ± 8.6 years) were selected. We compared the associations between rate of eating and various clinical parameters including visceral and subcutaneous fat areas, using analysis of covariance (ANCOVA), which was adjusted by age and lifestyle factors such as alcohol intake, energy intake, smoking, and physical activity. Multivariate logistic regression analyses (MLRA) were performed with visceral fat area (cm(2)) as the dependent variable and independent variables that included self-reported rate of eating. RESULTS: Tukey's multiple test following ANCOVA showed that self-reported rate of eating was positively associated with visceral fat area (cm(2)), but not with subcutaneous fat area (cm(2)). MLRA showed that the odds ratio of rate of eating for visceral fat area in tertile (T) 3 (>100 cm(2)) compared with T1 (≤70 cm(2)) was 1.99 (95% CI 1.40-2.90, P < 0.01), and the association remained after adjustment for the subcutaneous fat area. CONCLUSIONS: The present results show that self-reported faster eating is positively associated with visceral fat accumulation, independently of subcutaneous fat accumulation, in apparently healthy Japanese men.

A Kpna1-deficient psychotropic drug-induced schizophrenia model mouse for studying gene-environment interactions.

KPNA1 is a mediator of nucleocytoplasmic transport that is abundantly expressed in the mammalian brain and regulates neuronal differentiation and synaptic function. De novo mutations in Kpna1 have been identified using genome-wide association studies in humans with schizophrenia; however, it remains unclear how KPNA1 contributes to schizophrenia pathogenesis. Recent studies have suggested a complex combination of genetic and environmental factors that are closely related to psychiatric disorders. Here, we found that subchronic administration of phencyclidine, a psychotropic drug, induced vulnerability and behavioral abnormalities consistent with the symptoms of schizophrenia in Kpna1-deficient mice. Microarray assessment revealed that the expression levels of dopamine d1/d2 receptors, an RNA editing enzyme, and a cytoplasmic dynein component were significantly altered in the nucleus accumbens brain region in a gene-environment (G × E) interaction-dependent manner. Our findings demonstrate that Kpna1-deficient mice may be useful as a G × E interaction mouse model for psychiatric disorders and for further investigation into the pathogenesis of such diseases and disorders.

Ultrasonic humidifier lung with a reversed halo sign: A case report.

The reversed halo sign was initially reported as a representative computed tomography scan finding of cryptogenic organizing pneumonia. Since then, however, it has been reported in various diseases and is now considered a nonspecific finding. However, there are no cases of humidifier lung with the reversed halo sign. An 82-year-old Japanese male patient presented with moving difficulties 48 days after starting darolutamide treatment for prostate cancer. He was admitted to the hospital due to acute pneumonia, which presented as bilateral extensive nonsegmental ground-glass opacities in the peripheral regions and extensive areas of ground-glass opacity with a circumferential halo of consolidation, with the reversed halo sign on computed tomography scan. After darolutamide discontinuation with the concomitant administration of antibiotics, the patient's pneumonia improved, and he was discharged from the hospital. However, within a few days, he was again admitted to the hospital due to pneumonia. He was found to have been using an ultrasonic humidifier at home and was then diagnosed with humidifier lung based on the bronchoscopy and provocative testing findings. Hence, ultrasonic humidifier lung should be considered as a differential diagnosis in patients presenting with the reversed halo sign, and a detailed medical history must be taken.

Escherichia coli DNA polymerase III is responsible for the high level of spontaneous mutations in mutT strains.

Reactive oxygen species induce oxidative damage in DNA precursors, i.e. dNTPs, leading to point mutations upon incorporation. Escherichia coli mutT strains, deficient in the activity hydrolysing 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP), display more than a 100-fold higher spontaneous mutation frequency over the wild-type strain. 8-oxo-dGTP induces A to C transversions when misincorporated opposite template A. Here, we report that DNA pol III incorporates 8-oxo-dGTP ≈ 20 times more efficiently opposite template A compared with template C. Single, double or triple deletions of pol I, pol II, pol IV or pol V had modest effects on the mutT mutator phenotype. Only the deletion of all four polymerases led to a 70% reduction of the mutator phenotype. While pol III may account for nearly all 8-oxo-dGTP incorporation opposite template A, it only extends ≈ 30% of them, the remaining 70% being extended by the combined action of pol I, pol II, pol IV or pol V. The unique property of pol III, a C-family DNA polymerase present only in eubacteria, to preferentially incorporate 8-oxo-dGTP opposite template A during replication might explain the high spontaneous mutation frequency in E. coli mutT compared with the mammalian counterparts lacking the 8-oxo-dGTP hydrolysing activities.

Interlaboratory trial of the rat Pig-a mutation assay using an erythroid marker HIS49 antibody.

The peripheral blood Pig-a assay has shown promise as a tool for evaluating in vivo mutagenicity. In this study five laboratories participated in a collaborative trial that evaluated the transferability and reproducibility of a rat Pig-a assay that uses a HIS49 antibody reacts with an antigen found on erythrocytes and erythroid progenitors. In preliminary work, flow cytometry methods were established that enabled all laboratories to detect CD59-negative erythrocyte frequencies (Pig-a mutant frequencies) of <10×10(-6) in control rats. Four of the laboratories (the in-life labs) then treated male rats with a single oral dose of N-nitroso-N-ethylurea, 7,12-dimethylbenz[a]anthracene (DMBA), or 4-nitroquinoline-1-oxide (4NQO). Blood samples were collected up to 4 weeks after the treatments and analyzed by flow cytometry for the frequency of CD59-negative cells among total red blood cells (RBCs; RBC Pig-a assay). RBC Pig-a assays were conducted in the four in-life laboratories, plus a fifth laboratory that received blood samples from the other laboratories. In addition, three of the five laboratories performed a Pig-a assay on reticulocytes (RETs; PIGRET assay), using blood from the rats treated with DMBA and 4NQO. The four in-life laboratories detected consistent, time- and dose-related increases in RBC Pig-a mutant frequency (MF) for all three test articles. Furthermore, comparable results were obtained in the fifth laboratory that received blood samples from other laboratories. The three laboratories conducting the PIGRET assay also detected consistent, time- and dose-related increases in Pig-a MF, with the RET MFs increasing more rapidly with time than RBC MFs. These results indicate that rat Pig-a assays using a HIS49 antibody were transferable between laboratories and that data generated by the assays were reproducible. The findings also suggest that the PIGRET assay may detect the in vivo mutagenicity of test compounds earlier than the RBC Pig-a assay.

[Dose estimation for exposure conditions of diagnostic radiology acquired by a 2011 questionnaire in a phantom study].

Using a 2011 questionnaire, the Japanese Society of Radiological Technology conducted a nationwide survey on the exposure conditions in diagnostic radiography. The purpose of this study was to measure the entrance surface dose and absorbed dose for each organ dose and to calculate the effective dose using a human phantom with the 2011 exposure conditions. We estimated the patient exposure doses during skull (antero-posterior), chest (postero-anterior), abdomen (antero-posterior), and lumbar vertebrae (antero-posterior, left-right, and right-left) radiographs. The radiation doses were determined by placing 255 thermoluminescence dosimeters at various positions on and in the phantom, including the surface of the skin, head, thyroid, lung, breast, esophagus, stomach, liver, and gonads. The maximum entrance surface dose was 7.83 mGy, which occurred to the lateral lumbar spine. In addition, the minimum entrance surface dose was 0.24 mGy, to the chest. The maximum organ dose was 3.15 mGy, to the stomach of the lateral lumbar vertebrae (LR). Meanwhile, the maximum effective dose was 0.63 mSv, to the lateral lumbar vertebrae (LR). On the contrary, the minimum effective dose was 0.03 mSv, to the head. We could evaluate the entrance surface dose, absorbed dose for each organ dose, and effective doses using the 2011 exposure conditions in Japan. The entrance surface dose of 5 examinations with these exposure conditions was below the guidance level of the IAEA. In the future, it can be said that the entrance surface dose as well as the effective dose require diagnostic reference levels in radiography.

Carcinogenic risk of food additive AF-2 banned in Japan: a case study on reassessment of genotoxicity.

BACKGROUND: Carcinogenic risk assessment studies have been repeatedly improved and are still being debated to find a goal. Evaluation might be changed if new approaches would be applied to some chemicals which means that new approaches may change the final assessment. In this paper, the risk assessment of a chemical, in particular the proper carcinogenicity, is examined using the long-banned food additive, 2-(2-furyl)-3-(5-nitro-2-furyl)-acrylamide, AF-2, as a case study. RESULTS: First, Ames tests were carried out using strains TA1535, TA100, TA1538, and TA98 and their nitroreductase-deficient strains YG7127, YG7128, YG7129, and YG7130. The results showed that mutagenic activity was reduced by about 50% in the nitroreductase-deficient strains, indicating that part of the mutagenic activity shown in Ames test was due to bacterial metabolism. Second, in vivo genotoxicity tests were conducted, including the one that had not been developed in 1970's. Both a micronucleus test and a gene mutation assay using transgenic mice were negative. Third, assuming it is a genotoxic carcinogen, the virtual safety dose of 550 µg/day was calculated from the TD50 in rats with a probability of 10-5. CONCLUSION: AF-2 has been shown to be carcinogenic to rodents and has previously been indicated to be genotoxic in vitro. However, the present in vivo genotoxicity study, it was negative in the forestomach, a target organ for cancer, particularly in the gene mutation assay in transgenic mice. Considering the daily intake of AF-2 in the 1970s and its virtually safety dose, the carcinogenic risk of AF-2 could be considered acceptable.

A cysteine proteinase inhibitor ALLN alleviates bleomycin-induced skin and lung fibrosis.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease that is characterized by fibrosis in the skin and internal organs, such as the lungs. Activated differentiation of progenitor cells, which are mainly resident fibroblasts, into myofibroblasts is considered a key mechanism underlying the overproduction of extracellular matrix and the resultant tissue fibrosis in SSc. Calpains are members of the Ca2+-dependent cysteine protease family, whose enzymatic activities participate in signal transduction and tissue remodeling, potentially contributing to fibrosis in various organs. However, the roles of calpain in the pathogenesis of SSc remain unknown. This study aimed to examine the anti-fibrotic properties of N-acetyl-Leu-Leu-norleucinal (ALLN), one of the cysteine proteinase inhibitors that primarily inhibit calpain, in vitro and in vivo, to optimally translate into the therapeutic utility in human SSc. METHODS: Normal human dermal and lung fibroblasts pretreated with ALLN were stimulated with recombinant transforming growth factor beta 1 (TGF-ß1), followed by assessment of TGF-ß1/Smad signaling and fibrogenic molecules. RESULTS: ALLN treatment significantly inhibited TGF-ß1-induced phosphorylation and nuclear transport of Smad2/3 in skin and lung fibroblasts. TGF-ß1-dependent increases in α-smooth muscle actin (αSMA), collagen type I, fibronectin 1, and some mesenchymal transcription markers were attenuated by ALLN. Moreover, our findings suggest that ALLN inhibits TGF-ß1-induced mesenchymal transition in human lung epithelial cells. Consistent with these in vitro findings, administering ALLN (3 mg/kg/day) three times a week intraperitoneally remarkably suppressed the development of skin and lung fibrosis in a SSc mouse model induced by daily subcutaneous bleomycin injection. The number of skin- and lung-infiltrating CD3+ T cells decreased in ALLN-treated mice compared with that in control-treated mice. Phosphorylation of Smad3 and/or an increase in αSMA-positive myofibroblasts was significantly inhibited by ALLN treatment on the skin and lungs. However, no adverse effects were observed. CONCLUSIONS: Our results prove that calpains can be a novel therapeutic target for skin and lung fibrosis in SSc, considering its inhibitor ALLN.