Electric Quadrupolar Contributions in the Magnetic Phases of UNi_{4}B.

We present acoustic signatures of the electric quadrupolar degrees of freedom in the honeycomb-layer compound UNi_{4}B. The transverse ultrasonic mode C_{66} shows softening below 30 K both in the paramagnetic phase and antiferromagnetic phases down to ∼0.33 K. Furthermore, we traced magnetic field-temperature phase diagrams up to 30 T and observed a highly anisotropic elastic response within the honeycomb layer. These observations strongly suggest that Γ_{6}(E_{2g}) electric quadrupolar degrees of freedom in localized 5f^{2} (J=4) states are playing an important role in the magnetic toroidal dipole order and magnetic-field-induced phases of UNi_{4}B, and evidence some of the U ions remain in the paramagnetic state even if the system undergoes magnetic toroidal ordering.

All-suture anchor pullout results in decreased bone damage and depends on cortical thickness.

PURPOSE: To evaluate the influence of cortical and cancellous bone structure on the biomechanical properties of all-suture and conventional anchors and compare the morphological bone damage after their failure. The hypothesis of the study is that all-suture anchor pullout is less invasive and that the pullout force is influenced by the cortical thickness. METHODS: Thirty human humeri were biomechanically tested as follows: starting with a load cycle from 20 to 50 N, a stepwise increase of the upper peak force by 0.05 N for each cycle at a rate of 1 Hz was performed. Analysis included maximum pullout strength for three different anchor implantation angles (45°, 90°, 110°) of the two anchor types. After anchor pullout, every sample underwent micro-CT analysis. Bone mineral density (BMD) and cortical thickness were determined at the anchor implantation site. Furthermore, the diameter of the cortical defect and the volume of the bone cavity were identified. RESULTS: The maximum pullout strength of all-suture anchors demonstrates a strong correlation to the adjacent cortical thickness (r = 0.82, p ≤ 0.05) with at least 0.4 mm needed to withstand 200 N. No correlation could be seen in conventional anchors. Moreover, no correlation could be detected for local BMD in both anchors. All-suture anchors show a significantly narrower cortical defect as well as a smaller bone cavity following pullout (4.3 ± 1.3 mm vs. 5.3 ± 0.9 mm, p = 0.037; 141 mm3 vs. 212 mm3; p = 0.009). The cortical defect is largest if the anchors are placed at a 45° angle. CONCLUSION: In contrast to conventional anchors, the pullout force of all-suture anchors depends on the thickness of the humeral cortex. Furthermore, all-suture anchors show a significantly smaller cortical defect as well as decreased bone damage in the case of pullout. Therefore, the clinical implication of this study is that all-suture anchors are advantageous due to their bone preserving ability. Also, intraoperative decortication should not be performed and cortical thickness should be preoperatively evaluated to decrease the risk of anchor failure.

New physician specialty training system impact on distribution of trainees in Japan.

OBJECTIVES: The problem of uneven distribution of medical services and inequitable distribution of physicians is drawing much attention worldwide. Revealing how changes in the specialty training system in Japan have affected the distribution of doctors could help us understand this problem. In 2018, a new and standardized specialty training system was implemented by the Japanese Medical Specialty Board, which is recognized by the Ministry of Health, Labor and Welfare. The purpose of this study was to investigate how this new system has affected the geographical distribution of doctors commencing specialty training (trainees) and choice of specialty in Japan. STUDY DESIGN: Retrospective observational study. METHODS: The change in the number of trainees between the control period (2012-2014) and 2018 was investigated, taking into account the prefecture and specialty selected. Population, the proportion of residents aged 65 years or older (aging rate), and the total number of overall doctors in each prefecture were considered as the background characteristics of each prefecture. We created a Lorenz curve and calculated the Gini coefficient for the distribution of trainees. RESULTS: In 2018, the number of trainees per 100,000 population increased to 6.6 nationwide compared with 5.5 during the control period. The number of trainees per 100,000 population in 2018 increased in prefectures with a large population of ≧ 2,000,000, a low aging rate (<27%), and a high doctor density (≧ 250 doctors per 100,000 population). The Gini coefficient showed an increase to 0.226 in 2018 compared with only 0.160 during the control period. CONCLUSIONS: After the implementation of the new training system, there was an increase in the number of doctors enrolling in specialty programs, and the specialties other than internal medicine and surgery have attracted more trainees. Inequality in the distribution of doctors between urban and rural prefectures worsened. This indicates the need to explore new ways of balancing distribution while maintaining optimal opportunities for specialist training.

Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer.

BACKGROUND: Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data. PATIENTS AND METHODS: Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan-Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model. RESULTS: OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 [95% confidence interval (CI): 0.883-1.775, P = 0.2070]. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312-0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively. CONCLUSION: G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.

An update on stem cell biology and engineering for brain development.

Two recent technologies, induced-pluripotent stem cells (iPSCs) and direct somatic reprogramming, have shown enormous potential for cell-based therapies against intractable diseases such as those that affect the central nervous system. Already, methods that generate most major cell types of the human brain exist. Whether the cell types are directly reprogrammed from human somatic cells or differentiated from an iPSC intermediate, the overview presented here demonstrates how these protocols vary greatly in their efficiencies, purity and maturation of the resulting cells. Possible solutions including micro-RNA switch technologies that purify target cell types are also outlined. Further, an update on the transition from 2D to 3D cultures and current organoid (mini-brain) cultures are reviewed to give the stem cell and developmental engineering communities an up-to-date account of the progress and future perspectives for modeling of central nervous system disease and brain development in vitro.

Complex networks for tracking extreme rainfall during typhoons.

Reconciling the paths of extreme rainfall with those of typhoons remains difficult despite advanced forecasting techniques. We use complex networks defined by a nonlinear synchronization measure termed event synchronization to track extreme rainfall over the Japanese islands. Directed networks objectively record patterns of heavy rain brought by frontal storms and typhoons but mask out contributions of local convective storms. We propose a radial rank method to show that paths of extreme rainfall in the typhoon season (August-November, ASON) follow the overall southwest-northeast motion of typhoons and mean rainfall gradient of Japan. The associated eye-of-the-typhoon tracks deviate notably and may thus distort estimates of heavy typhoon rainfall. We mainly found that the lower spread of rainfall tracks in ASON may enable better hindcasting than for westerly-fed frontal storms in June and July.

Effect of serotonin transporter genotype on self-reported efficacy and activity changes of brain prefrontal area in response to placebo.

Patients benefit from drug therapy not only through pharmacological mechanisms, but also through non-pharmacological action (placebo effect), which may be mediated in part by the prefrontal area of the brain. We consider that the difference between responders and non-responders to placebo might be related to polymorphisms in the serotonin transporter-linked polymorphic region (5-HTTLPR). To study this idea, we performed a randomized double-blind clinical trial using caffeine and lactose (placebo). Activity in the prefrontal area of the brain was measured in terms of blood flow by means of near-infrared spectroscopy (NIRS) as an objective indicator. Self-reported feelings of drowsiness on established scales were used as subjective indicators. Twenty-one subjects in block A took caffeine on the first day and placebo on the third day, and 21 in block B took placebo on the first day and placebo on the third day. After placebo administration, improvement of sleepiness was significantly enhanced, a similar extent to that after caffeine medication. Among the 42 subjects, 22 showed S/S type polymorphism in the serotonin transporter (52.4 %), 17 showed S/L type (40.5 %) and 3 showed L/L type (7.10 %). Statistical analysis of the results indicate that subjects with L/L genotype showed a significantly greater placebo response in terms of both self-reported feeling of drowsiness and blood flow in the prefrontal area of the brain associated with working memory (46 area). Our results indicate that the L/L genotype of 5-HTTLPR, which is rare in Japanese (3.2 %) but common in Americans (32.2 %), may be associated with a greater placebo effect.

A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer.

Background: Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods: We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35 mg/m2 on days 1-3 every 3 weeks) or docetaxel (60 mg/m2 on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results: Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P = 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥3 leukopenia occurred in 63.3% and 70.7%, and grade ≥3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions: This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel. Clinical trial registration: NCT01207011 (ClinicalTrials.gov).

No increased risk of major congenital anomalies or adverse pregnancy or neonatal outcomes following letrozole use in assisted reproductive technology.

STUDY QUESTION: Does letrozole use increase the risk of major congenital anomalies and adverse pregnancy and neonatal outcomes in fresh, single-embryo transfer? SUMMARY ANSWER: Letrozole significantly decreases the risk of miscarriage and does not increase the risk of major congenital anomalies or adverse pregnancy or neonatal outcomes compared with natural cycles in patients undergoing ART. WHAT IS KNOWN ALREADY: Letrozole is the most commonly used aromatase inhibitor for mild ovarian stimulation in ART. However, its safety in terms of pregnancy and neonatal outcomes is unclear. STUDY DESIGN SIZE, DURATION: This retrospective cohort study used data from the Japanese national ART registry from 2011 to 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 3136 natural cycles and 792 letrozole-induced cycles associated with fresh, single-embryo transfer and resulting in a clinical pregnancy were included in the analysis. The main pregnancy outcomes were miscarriage, ectopic pregnancy and still birth, and the neonatal outcomes were preterm delivery, low birth weight, small/large for gestational age and major congenital anomalies. Terminated pregnancies were included in the analysis of major congenital anomalies. Odds ratios (ORs) and 95% CIs were calculated using multivariate logistic regression analysis adjusted for maternal age and calendar year. MAIN RESULTS AND THE ROLE OF CHANCE: The risk of miscarriage was significantly lower in women administered letrozole (adjusted OR [aOR], 0.37, 95% CI, 0.30-0.47, P < 0.001). There was no significant difference in the overall risk of major congenital anomalies between the two groups (natural cycle 1.5% vs letrozole 1.9%, aOR, 1.24, 95% CI, 0.64-2.40, P = 0.52), and no increased risk for any specific organ system. Subgroup analysis demonstrated that the risk of major congenital anomalies was not increased in patients who underwent either in vitro fertilization or ICSI, or in those who received early cleavage stage or blastocyst embryo transfer. All other pregnancy and neonatal outcomes were comparable between the two groups. LIMITATIONS REASONS FOR CAUTION: Despite the large sample size, we were only able to rule out the possibility that letrozole might cause large increases in birth-defect risks in ART patients. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest that letrozole stimulation reduces the risk of miscarriage, with no increase in the risk of major congenital anomalies or adverse pregnancy or neonatal outcomes compared with natural cycles in women undergoing ART. Letrozole may thus be a safe option for mild ovarian stimulation. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable.

Pregnancy and neonatal outcomes following letrozole use in frozen-thawed single embryo transfer cycles.

STUDY QUESTION: Are pregnancy and neonatal outcomes following letrozole use comparable with natural and HRT cycles in patients undergoing single frozen-thawed embryo transfer (FET)? SUMMARY ANSWER: Letrozole use was significantly associated with higher rates of clinical pregnancy, clinical pregnancy with fetal heart beat and live birth, and with a lower rate of miscarriage, compared with natural and HRT cycles. WHAT IS KNOWN ALREADY: Letrozole is the most commonly used aromatase inhibitor for mild ovarian stimulation in ART. However, the effect of letrozole on pregnancy and neonatal outcomes in FET are not well known. STUDY DESIGN SIZE, DURATION: A retrospective cohort study was conducted using data from the Japanese national ART registry between 2012 and 2013. PARTICIPANTS/MATERIALS SETTING METHODS: A total of 110 722 single FET cycles with letrozole (n = 2409), natural (n = 41 470) or HRT cycles (n = 66 843) were included. The main outcomes were the rates of clinical pregnancy, clinical pregnancy with fetal heart beat, miscarriage and live birth. Adjusted odds ratios and relative risks (RRs) were calculated using a generalized estimating equation adjusting for correlations within clinics. MAIN RESULTS AND THE ROLE OF CHANCE: The rates of clinical pregnancy, clinical pregnancy with fetal heart beat, and live birth were significantly higher, while the rate of miscarriage was significantly lower in the letrozole group compared with the natural and HRT groups. In blastocyst stage transfers, the adjusted RRs for clinical pregnancy with fetal heart beat of letrozole compared with natural and HRT cycles were 1.48 (95% CI: 1.41-1.55) and 1.62 (95% CI: 1.54-1.70), respectively. Similarly, the adjusted RRs of letrozole for miscarriage compared with natural and HRT cycles were 0.91 (95% CI: 0.88-0.93) and 0.84 (95% CI: 0.82-0.87), respectively. Neonatal outcomes were mostly similar in letrozole, natural and HRT cycles. LIMITATIONS REASONS FOR CAUTION: Important limitations of this study included the lack of information concerning the reasons for selecting the specific FET method, parity, the number of previous ART failures, embryo quality and the dose and duration of letrozole intake. WIDER IMPLICATIONS OF THE FINDINGS: These results suggest that letrozole use may improve clinical pregnancy, clinical pregnancy with fetal heart beat, and live births and reduce the risk of miscarriage in patients undergoing single FET cycles. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable.

A phase III clinical trial of a mixture agent of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors.

INTRODUCTION: MC710, a 1:10 protein weight ratio mixture of plasma-derived activated factor VII (FVIIa) and factor X (FX), is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. We evaluated the haemostatic efficacy and safety of one to two administrations of MC710 in 21 joint, muscle, and subcutaneous bleeding episodes in 14 male patients, in a multi-centre, open-label, non-randomized clinical trial. METHODS: Subjects were intravenously administered one or two doses of 60 or 120 µg kg-1 MC710 (as FVIIa) once or twice (to a maximum of 180 µg kg-1 ) over up to five bleeding episodes per subject. The haemostatic efficacy of MC710 was determined for each episode by investigator evaluation, using changes in visual analogue scale (VAS) for pain relief, and/or knee joint or muscle circumference for swelling reduction, and range of motion (ROM) for improvement of joint mobility. RESULTS: In 21 treatments for bleeding episodes, 19 were rated "excellent" or "effective" 8 h after the last treatment. VAS significantly decreased over time, and ROM significantly improved over time compared with the values before treatment. One mild adverse reaction, decreased blood potassium, and two serious adverse events, both knee joint bleeding, were observed within 1 week after first administration, with no significant effect on safety. Furthermore, diagnostic markers did not show any signs of disseminated intravascular coagulation (DIC). CONCLUSION: These results show that MC710 has sufficient haemostatic efficacy and safety, and can be used as a potential bypassing agent to control bleeding in haemophilia patients with inhibitors.

Effects of fertility education on knowledge, desires and anxiety among the reproductive-aged population: findings from a randomized controlled trial.

STUDY QUESTION: What are the effects of fertility education on knowledge, childbearing desires and anxiety? SUMMARY ANSWER: Providing fertility information contributed to greater knowledge, but increased anxiety. WHAT IS KNOWN ALREADY: Past studies have found that exposure to educational material improved fertility awareness and changed desires toward childbearing and its timing. Existing educational websites with evidence-based medical information provided in a non-judgmental manner have received favorable responses from reproductive-aged men and women. STUDY DESIGN, SIZE, DURATION: This three-armed (one intervention and two control groups), randomized controlled trial was conducted using online social research panels (SRPs) in Japan in January 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1455 participants (726 men and 729 women) between 20 and 39 years of age who hoped to have (more) children in the future were block-randomized and exposed to one of three information brochures: fertility education (intervention group), intake of folic acid during pregnancy (control group 1) or governmental financial support for pregnancy and childbirth (control group 2). Fertility knowledge was measured with the Japanese version of the Cardiff Fertility Knowledge Scale (CFKS-J). Knowledge, child-number and child-timing desires, subjective anxiety (i.e. whether participants felt anxiety [primary outcome]), and scores on the State-Trait Anxiety Inventory were assessed immediately after exposure. Non-inferiority comparisons were performed on subjective anxiety with non-inferiority declared if the upper limit of the two-sided 95% confidence interval (CI) for risk difference did not exceed a margin of 0.15. This test for non-inferiority was only performed for subjective anxiety; all the other variables were tests of superiority. MAIN RESULTS AND THE ROLE OF CHANCE: Posttest scores on the CFKS-J (mean, SD) were higher in the intervention group than that of the control groups: intervention versus Control 1 and versus Control 2: 52.8 (28.8) versus 40.9 (26.2) (P< 0.001) versus 45.1 (27.1) (P = 0.003) among men and 64.6 (26.0) versus 50.8 (26.9) (P< 0.001) versus 53.0 (26.4) (P< 0.001) among women.The percentage of participants who felt subjective anxiety after exposure to the intervention brochure was significantly higher than that of the control groups: intervention versus Control 1 and versus Control 2: 32.6 versus 17.8% (risk difference [RD] = 0.149, 95% CI: 0.073-0.225) versus 14.5% (RD = 0.182, 95% CI: 0.108-0.256) among men, and 50.2 versus 26.3% (RD = 0.239, 95% CI: 0.155-0.322) versus 14.0% (RD = 0.362, 95% CI: 0.286-0.439) among women. Non-inferiority of the intervention was inconclusive (i.e. the CI included 0.15) among men whereas inferiority was declared among women. The incidence of anxiety was higher in the intervention group than that of the control groups especially among men aged 30 and older and among women aged 25 and older. No difference existed in childbearing desires between groups after exposure. LIMITATIONS, REASONS FOR CAUTION: The possibility of selection bias associated with the use of SRPs (higher socioeconomic status and education) and volunteer bias toward those more interested in fertility may limit the generalizability of these findings. WIDER IMPLICATIONS OF THE FINDINGS: In addition to education targeting a younger generation, psychological approaches are needed to alleviate possible anxiety caused by fertility information. STUDY FUNDING/COMPETING INTERESTS: This study was funded by National Center for Child Health and Development, Seiiku Medical Study Grant (24-6), the Daiwa Foundation Small Grants and Grant-in-Aid for JSPS Fellows (26-1591). No competing interest declared. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry. Trial registration number, 000016168. TRIAL REGISTRATION DATE: 13 January 2015. DATE OF FIRST PATIENT'S ENROLMENT: 15 January 2015.

Long-distance propagation of a surface plasmon on the surface of a ferromagnetic metal.

A method for the reduction of the propagation loss of surface plasmons was proposed and experimentally demonstrated. A plasmonic structure, which contains a metal and two dielectric layers of different refractive indexes, is proposed in order to optimize the optical confinement and to reduce the propagation loss of the surface plasmons. Long-distance propagation of a surface plasmon on the surface of a ferromagnetic metal was demonstrated. A low propagation loss of 0.17 dB/µm for a surface plasmon in a Fe/MgO/AlGaAs plasmonic structure was achieved.

Efficacy of combined treatment with alendronate (ALN) and eldecalcitol, a new active vitamin D analog, compared to that of concomitant ALN, vitamin D plus calcium treatment in Japanese patients with primary osteoporosis.

UNLABELLED: Combined treatment with alendronate and eldecalcitol was found to be more effective in reducing the bone turnover markers and increasing bone mineral density than alendronate treatment with vitamin D3 and calcium supplementation in the osteoporotic patients. INTRODUCTION: We compared the clinical efficacy and safety of combined treatment with alendronate plus eldecalcitol (ALN + ELD) with those of treatment with ALN plus vitamin D and calcium (ALN + VitD). METHODS: Osteoporotic 219 patients were randomly assigned to the ALN + ELD, or the ALN + VitD group. Primary endpoint was the inter-group differences in lumbar spine BMD (L-BMD) at patient's last visit. Secondary endpoints included the differences in BMD at other sites and the bone turnover marker (BTM) levels. RESULTS: L-BMD, total hip BMD and femoral neck (FN-BMD) increased from baseline by 7.30, 2.41, and 2.70 % in the ALN + ELD group, and by 6.52, 2.27, and 1.18% in the ALN + VitD group, respectively. Inter-group differences of the L-BMD and total hip BMD values were not significant. The increase of the FN-BMD was larger in the ALN + ELD group than the ALN + VitD group. Reductions of the BTMs were greater in the ALN + ELD group than the ALN + VitD group. Interaction of the percent increase of the L-BMD with the baseline values of the BTMs was observed in the ALN + VitD group only. The increases of the FN-BMD in patients with lower baseline values of type-I-collagen C-telopeptide (sCTX) and serum 25(OH) D levels <20 ng/mL were significantly larger in the ALN + ELD group than the other group. CONCLUSION: Combination treatment of ALN plus ELD was more effective in reducing the BTMs and increasing the FN-BMD than ALN treatment with vitamin D3 and calcium.

Total serum IgE level influences oral food challenge tests for IgE-mediated food allergies.

Probability curves predicting oral food challenge test (OFC) results based on specific IgE levels are widely used to prevent serious allergic reactions. Although several confounding factors are known to affect probability curves, the main factors that affect OFC outcomes are currently unclear. We hypothesized that an increased total IgE level would reduce allergic reactivity. Medical records of 337 and 266 patients who underwent OFCs for 3.5 g boiled hen's egg white and 3.1 ml raw cow's milk, respectively, were examined retrospectively. We subdivided the patients into three groups based on total IgE levels and age by percentile (<25th, 25-75th, and >75th percentiles), and logistic regression analyses were performed on each group. Patients with higher total IgE levels were significantly less responsive. In addition, age did not significantly affect the OFC results. Therefore, total IgE levels should be taken into account when predicting OFC results based on food-specific IgE levels.

MRI findings of radiation-induced myocardial damage in patients with oesophageal cancer.

AIM: To evaluate radiation-induced myocardial damage after mediastinal radiotherapy using MRI. MATERIALS AND METHODS: Between May 2010 and April 2011, delayed contrast-enhanced MRI was performed for patients who had maintained a complete response to curative radiotherapy for oesophageal cancer for more than 6 months. The patients received radiotherapy with a median total dose of 66 Gy (60-70 Gy) for the primary tumour and metastatic lymph nodes. Images of MRI were analysed by a 17-segment method recommended by the American Heart Association. A segment included mainly in the 40 Gy dose line was defined as Segment 40 Gy, a segment included mainly in the 60 Gy dose line as Segment 60 Gy, and a segment out of the radiation fields as Segment OUT. The percentage of late gadolinium enhancement (LGE) was examined in those categories. The layer in which LGE was predominantly distributed was evaluated for each patient. RESULTS: Four hundred and eight segments in 24 patients were analysed. The median interval from completion of radiotherapy to MRI was 23.5 months (range 6-88 months). LGE was detected in 12 of the 24 patients. LGE was detected in 15.38% of Segment 40 Gy cases, 21.21% of Segment 60 Gy cases, and 0% of Segment OUT cases. LGE in mid-myocardial and subendocardial layers was detected in 11 patients and one patient, respectively. CONCLUSION: LGE suggesting radiation induced myocardial fibrosis was observed by performing delayed contrast-enhanced MRI. Care should be taken when planning radiotherapy to avoid late cardiac damage.

Identification of insulin-like growth factor 2 mRNA-binding protein 3 as a radioresistance factor in squamous esophageal cancer cells.

Identification of reliable markers of radiosensitivity and the key molecules that donate susceptibility to anticancer treatments to esophageal cancer cells would be highly desirable. We found that the mRNA expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) was higher in radioresistant TE-5 and TE-9 cells than in radiosensitive TE-12 cloneA1 cells. Conversely, knocking down expression of IGF2BP3 mRNA in TE-5 and TE-9 cells using small interfering RNA significantly enhanced their radiosensitivity. Furthermore, patients with squamous cell esophageal cancers strongly expressing IGF2BP3 tended to respond poorly to chemoradiation. These data suggest that IGF2BP3 may be a key marker of radiosensitivity that diminishes the susceptibility of squamous cell esophageal cancer cells to radiotherapy. IGF2BP3 may, thus, be a useful target for improving radiotherapy for patients with esophageal squamous cell carcinoma.

Longitudinal monitoring of CYP3A activity in patients receiving 3 cycles of itraconazole pulse therapy for onychomycosis.

WHAT IS KNOWN AND OBJECTIVE: Itraconazole, a CYP3A inhibitor, is used for the treatment for onychomycosis with a three-cycle pulse therapy over 3 months, but its effects on in vivo CYP3A activity during the entire course remain unknown. METHODS: Urinary 6ß-hydroxycortisol/cortisol ratios were determined in 19 patients with onychomycosis, before therapy, during three cycles of itraconazole pulse therapy (200 mg twice daily for a week in each monthly cycle) and at 3 month after completion of therapy. RESULTS AND DISCUSSION: The mean 6ß-hydroxycortisol/cortisol ratio was reduced by 68% from baseline (P < 0·05) after the 1st pulse dosing, but the inhibitory effect appeared to be resolved before the next pulse dosing and at 3 months post-treatment. The magnitude of inhibition appeared in proportion to the baseline CYP3A activity. WHAT IS NEW AND CONCLUSION: The inhibitory effect of itraconazole pulse therapy on the in vivo CYP3A activity appears clinically relevant at the end of each cycle, but the inhibition resolves, on average, within 3 weeks.

Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: We evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone. PATIENTS AND METHODS: Patients receiving chemotherapy including cisplatin (≥70 mg/m(2)) were eligible. A total of 347 patients (21% had received cisplatin with vomiting) were enrolled in this trial to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 µg/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1-3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). The primary end point was the percentage of patients who had a complete response (no emesis and no rescue therapy) over the entire treatment course (0-120 h). RESULTS: The percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% versus 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0-24 h postchemotherapy) phase (94% versus 81%, P = 0.0006) and the delayed (24-120 h postchemotherapy) phase (65% versus 49%, P = 0.0025). CONCLUSIONS: Single-dose fosaprepitant used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin.

Cell type-dependent effects of corticosteroid on periostin production by primary human tissue cells.

Overproduction of periostin, an IL-13-inducible matricellular protein, despite corticosteroid treatment is thought to be involved in the chronicity of allergic inflammation seen in corticosteroid-refractory tissue fibrosis. Therefore, we hypothesized that some tissue cells must produce periostin in a corticosteroid-insensitive manner. Here, we show that IL-4 and IL-13 each induced comparable levels of periostin production by primary normal human fibroblasts and microvascular endothelial cells derived from lung and skin. Dexamethasone, a corticosteroid, completely inhibited IL-4/13-induced, but did not affect TGF-ß-induced, periostin production by fibroblasts. In contrast, dexamethasone synergistically enhanced IL-4/13-induced periostin production by microvascular endothelial cells. TGF-ß did not induce periostin production by microvascular endothelial cells. Our novel findings suggest that IL-4/13-induced microvascular endothelium-derived and/or TGF-ß-induced fibroblast-derived periostin might play a pivotal role in corticosteroid-refractory tissue fibrosis, leading to chronic allergic inflammation in the lung and/or skin.