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Background: Osgood-Schlatter disease (OSD) is a type of osteochondrosis and traction apophysitis that results from repeated contractions of the quadriceps femoris muscle on the tibial tuberosity. Its prevention, early diagnosis, and treatment are crucial because it causes chronic knee pain and surgical approaches are required if left untreated. Three-dimensional motion analysis is a useful approach for elucidating the pathological factors of OSD; however, it requires advanced cameras, sophisticated facilities, and expensive software. Conversely, the advent of technology has provided affordable video recording devices, and smartphone/tablet-based applications have enabled two-dimensional (2D) motion analysis. This emerging tool and artificial intelligence technology were used to analyze the pivot leg from videos recorded on a tablet device during the instep kicks of adolescent soccer players. Therefore, in this study, we aimed to determine whether the pathological factors for OSD occurring in the pivot foot can be identified through a simple 2D motion analysis using a tablet device., Methods: In total, 94 knees of 47 soccer players (aged 14.1±0.8 years, all male) who belong to a single soccer club were evaluated. OSD was diagnosed using ultrasonography and physical examination (a positive bone fragment on ultrasonography or tenderness at the tibial tuberosity). Lower limb muscle tightness was evaluated using the finger-floor distance, straight leg raising test, heel-buttock distance, Thomas test, and ankle range of motion using a goniometer. We then performed motion analysis, and the instep kicking motion was recorded using a video camera on a tablet device. The joint angles of the hip, knee, and ankle were measured using a real-time human-pose detection system. Data were compared between the OSD and non-OSD groups., Results: Overall, six of the 47 players (12.8%) were diagnosed with OSD. No correlation was found between lower limb tightness and the occurrence of OSD in all indices. However, the 2D motion analysis revealed that the knee flexion angle at the time of plantar placement during the instep kick movement was significantly larger in the OSD group than in the non-OSD group (OSD group: 42.0±7.2˚, non-OSD group: 33.5±6.6˚, *p=0.013)., Conclusion:  A video motion analysis revealed that the knee flexion angle during the instep kicking motion was significantly greater in athletes with OSD of the supporting foot., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Committee of the Faculty of Medicine, Kagawa University Hospital issued approval 2023-156. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Fukuoka et al.)

Progestin therapy is a fertility-sparing treatment option for well-differentiated stage IA endometrioid carcinomas without myometrial invasion. Here, we present a case of successful pregnancy and live birth following long-term progestin therapy in a patient with stage II well-differentiated endometrioid carcinoma. A 30-year-old nulliparous woman with an unremarkable medical history presented with abnormal uterine bleeding. A 45 mm mass was identified in the lower uterine segment. An endometrial biopsy revealed grade 1 endometrioid carcinoma, leading to a diagnosis of stage II uterine corpus cancer based on hysteroscopic findings. The patient refused surgical treatment and underwent oocyte retrieval and cryopreservation at another hospital. A subsequent endometrial biopsy revealed a marked reduction in the Ki-67 index from approximately 60 % to less than 10 %, suggesting the possibility of a hormone-sensitive tumor. The patient persistently refused surgery. Therefore, progestin therapy with medroxyprogesterone acetate (MPA) at a dose of 400 mg/day was initiated as a temporary measure until the patient would accept surgery. The tumor gradually reduced in size and eventually disappeared after 9 months. The MPA therapy was discontinued uneventfully after 20 months. Sixteen months after the discontinuation of MPA therapy, atypical endometrial hyperplasia was detected, and a second round of MPA therapy was initiated. Progestin retreatment was successful and was discontinued at 6 months. Four years after the initial treatment, the patient achieved pregnancy through timed intercourse and delivered a healthy baby at 38 weeks of gestation., (© 2024 The Author(s).)

Peritoneal tuberculosis (TB) is known to mimic advanced ovarian cancer. In this case report, we describe a unique case of ovarian cancer (endometrioid carcinoma grade 3) at the International Federation of Gynecology and Obstetrics (FIGO) stage IC1 with pulmonary and peritoneal TB, which was suspected preoperatively to be a coexistence of advanced ovarian cancer and pulmonary TB. A 68-year-old woman presented with a prominent abdominal mass and fever. Laboratory investigations, imaging, and sputum analysis indicated a probable diagnosis of ovarian cancer at FIGO stage IIIC, characterized by peritoneal dissemination and para-aortic lymph node metastasis, which was further complicated by coexisting pulmonary TB. Surgical management included total abdominal hysterectomy, bilateral salpingo-oophorectomy, and partial omentectomy. Intraoperatively, the tumor was localized to the right ovary with significant peritoneal thickening and adhesions indicative of peritoneal TB. The surgery was completed without apparent complications. Postoperative histopathological evaluation confirmed grade 3 endometrioid carcinoma in the right ovary along with evidence of peritoneal TB. Given the extent of adhesions attributed to TB, lymph node dissection for staging was deemed challenging and was thus not pursued. Initiation of anti-TB treatment on postoperative day 2 resulted in marked regression of the preoperatively identified pulmonary nodules and para-aortic lymph node enlargement, suggesting their inflammatory origin from TB. Although postoperative chemotherapy is typically advocated for patients with stage IC1 endometrioid carcinoma grade 3, the patient opted against it. Consequently, no adjuvant therapy was administered and the patient remained under close observation., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objective: To develop a predictive score for life-threatening severe postpartum hemorrhage in vaginal deliveries following frozen embryo transfer., Materials and Methods: We conducted a retrospective cohort study of 315 singleton vaginal deliveries following frozen embryo transfer from 2017 to 2022. Severe postpartum hemorrhage was defined as hemorrhage exceeding 1500 mL. A predictive score was generated from maternal characteristics and obstetric complications before delivery. We performed multivariable logistic regression analysis using 2017-2020 data and assigned points to identified risk factors. The predictive score's accuracy was evaluated using 2021-2022 data., Results: A large baby (birth weight ≥3500 g), pre-delivery maternal body mass index ≥25 kg/m 2 , marginal or velamentous umbilical cord insertion, and history of postpartum hemorrhage were identified as risk factors. We assigned one point to a large baby, a pre-delivery maternal body mass index ≥25 kg/m 2 , and marginal or velamentous umbilical cord insertion, and two points to a history of postpartum hemorrhage. The sum of the points was defined as the predictive score. The cut-off was set at two points, with a score ≥2 points being the high-risk group and a score ≤1 point being the low-risk group. The predictive score demonstrated a sensitivity of 47.8%, specificity of 85.4%, positive predictive value of 45.8%, and negative predictive value of 86.4% in the 2021-2022 validation cohort., Conclusion: The predictive score identified severe postpartum hemorrhage in approximately half of the high-risk cases. Implementing measures such as autologous blood storage may facilitate rapid response during heavy bleeding and improve maternal prognosis.

Aim: The frequency of postpartum hemorrhage (PPH) is increasing in developed countries, and some reports suggest that assisted reproductive technology (ART) increases various perinatal complications, including PPH. We investigated whether the effect of ART pregnancies on the incidence of PPH is modified by the mode of delivery., Methods: A retrospective cohort study was performed. We analyzed the medical records of 2914 pregnant women, including 411 pregnancies achieved by ART, which were delivered in our hospital from 2017 to 2020. PPH was defined as hemorrhage exceeding the 90th percentile of blood loss per the mode of delivery and number of fetuses. Multivariable logistic regression analysis was used to assess the association between ART and PPH. Propensity score-matched analyses were used to assess the difference in the incidence of PPH by the mode of delivery., Results: As previously reported, multivariable logistic regression analysis showed that ART pregnancy is an independent risk factor for PPH. Propensity score-matched analysis for with and without ART showed a 3.39-fold higher incidence of PPH for ART pregnancy in the vaginal delivery group (p < 0.001)., Conclusions: The effect of ART pregnancies on the incidence of PPH differed depending on the mode of delivery. Only in vaginal delivery, ART pregnancy increased the incidence of PPH., (© 2023 Japan Society of Obstetrics and Gynecology.)

The dynamic and static properties of structured surfaces have important functions in nature. In particular, wrinkles have important static roles, for example, increasing surface area, but dynamic roles of wrinkles remain poorly understood. Specifically, to understand and utilize the dynamic functions of wrinkles, it is necessary to observe wrinkle formation directly. In this study, a polyion complex (PIC) is formed on a hydrogel surface by electrophoresis, and the process of wrinkle formation through a transparent electrode is directly observed. By quantitative analysis of the wavelength and amplitude of wrinkles, it is found that the wrinkles move randomly in a wavy pattern in the initial stage of growing process. Furthermore, the direction of wavy motion of wrinkles is controlled by the compression of hydrogels in the in-plane direction. The present study provides important insights into the fabrication of wrinkled surfaces with a controlled flow direction; opening the possibility for active wrinkles used in the development of functional surface structures as actuators that are capable of transporting small objects in water., (© 2022 Wiley-VCH GmbH.)

Background: Theophylline, a xanthine derivative drug, is used for the treatment of respiratory diseases, such as asthma, and is primarily eliminated by hepatic metabolism. There is marked interindividual variability in theophylline clearance. Therefore, the aim of this study was to evaluate the influence of chronic hepatitis (CH), liver cirrhosis (LC), and other covariates on theophylline clearance by population pharmacokinetic (PPK) analysis., Methods: The authors retrospectively obtained 496 trough concentrations of theophylline at steady state from 226 adult patients with bronchial asthma. The liver functions of the patients were classified into 3 categories: normal hepatic function, CH, and LC. The PPK analysis was performed using the NONMEM program. CH, LC, age, smoking status, coadministration of clarithromycin (CAM), and sex were considered as covariates that affected theophylline clearance., Results: Theophylline clearance (CL/F per kg) was significantly influenced by CH, LC, smoking, and CAM. The final model of theophylline clearance was as follows: CL/F (L/h·kg) = 0.0484 × 1.40 × 0.861 × 0.889 × 0.557. Smoking is a well-known factor that markedly enhances CL/F through the induction of CYP1A enzymes, whereas CAM has been reported to inhibit CYP3A4. The final model for hepatic function showed that CL/F in CH and LC patients was 0.043 and 0.027 L/h/kg, respectively, and it was lower than that in patients with normal hepatic function. As theophylline clearance depends on intrinsic hepatic clearance, lower CL/F in patients with LC than in those with CH may be due to a decrease in the metabolic enzymatic capability of LC patients., Conclusions: Differences exist in theophylline clearance between CH and LC patients as per the PPK analysis.

Surface geometries in nature such as wrinkle structures have various functions. Attention has been paid to the fabrication method of the geometry and geometry control by external stimuli. This is because surface geometries as an active interface are able to contribute to the control of interactions with the external environment. In this study, aligned wrinkles were fabricated on the surface of stretched hydrogels in aqueous conditions by the electrophoretic formation of a polyion complex layer. The geometry of wrinkles was controlled by the stretching ratio and Young's modulus of hydrogels, and hierarchical wrinkle structures were fabricated after unloading the stretched hydrogels. Therefore, it can be a new wrinkle-formation method capable of transferring the initial elastic anisotropy of the substrate material to the wrinkle structure. Creation of thermoresponsive wrinkles that can transform their geometrical configuration reversibly was achieved by fabrication of aligned wrinkles on the surface of thermoresponsive hydrogels.

Background: Fosphenytoin, the diphosphate ester salt of phenytoin, is widely used to treat status epilepticus. The aim of this study was to develop a population pharmacokinetic (PPK) model to describe serum phenytoin concentrations after the intravenous administration of fosphenytoin in adult and elderly epileptic patients., Methods: Patient backgrounds, laboratory tests, and prescribed drugs were retrospectively collected from electronic medical records. Patients who received fosphenytoin were enrolled. The PPK analysis was performed using NONMEM 7.3.0 with the first-order conditional estimation method with interaction. Age, sex, laboratory tests, and coadministered drugs were selected as candidates for covariates. Significance levels for forward inclusion and backward elimination were set at 0.05 and 0.01, respectively. The study protocol was approved by the Fukuoka Tokushukai Ethics Committee., Results: A total of 340 serum phenytoin concentrations from 200 patients treated with fosphenytoin were available. The median age and body weight of the population were 71 years and 53.4 kg, respectively. A linear 1-compartment model with the conversion rate of fosphenytoin to phenytoin clearly described the pharmacokinetics of phenytoin after the intravenous administration of fosphenytoin. Age was detected as a covariate of clearance (CL): CL (L/h) = 1.99 × (body weight/53.4) × (age/71). Goodness-of-fit plots revealed the high-predictive performance of the final PPK model, and systematic deviations were not observed. The final model was validated by a prediction-corrected visual predictive check and bootstrap analysis., Conclusions: We herein developed a PPK model to describe phenytoin concentrations after the intravenous administration of fosphenytoin. Age was identified as a significant covariate for CL.

Background: Magnesium oxide (MgO) is often co-prescribed with L-dopa/carbidopa (LDCD) to improve constipation in Parkinson's disease patients. The mixing of L-dopa and MgO has been shown to degrade L-dopa; however, there is no interaction study on humans. We proposed mechanisms for the interaction between LDCD and MgO and conducted pharmacokinetic studies on rats and humans. To assess pharmacodynamic changes with the MgO treatment, we applied a model-based meta-analysis (MBMA)., Methods: The effects of MgO on the stabilities of L-dopa and carbidopa were evaluated in in vitro studies. We conducted pharmacokinetic interaction studies of MgO and LDCD on rats and healthy volunteers. A clinical study was conducted with an open-label, non-randomized, single-arm, and two-phase study. In MBMA, we constructed a population pharmacokinetic/pharmacodynamic model of L-dopa and predicted the effects of the MgO treatment on the pharmacodynamics of L-dopa., Results: In vitro results suggested that carbidopa was unstable under alkaline pH conditions. Reductions in plasma LDCD concentrations were observed after oral-MgO/oral-LDCD, but not in oral-MgO/i.v.-LDCD treatments in rats, suggesting that the gastrointestinal tract is an interaction site. A healthy volunteer study showed that MgO was also associated with significant decreases of 35.3 and 80.9% in the AUC 0-12 of L-dopa and carbidopa, respectively. A model-based simulation suggested that the MgO treatment was undesirable for the effectiveness of L-dopa., Conclusions: This is the first study to show a clear pharmacokinetic interaction between LDCD and MgO in humans. Further investigations to confirm the effects of MgO on the pharmacodynamics of L-dopa are required.

Aims: The aim of the present study was to quantitate the hypoglycaemic effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1r) and sodium glucose cotransporter 2 inhibitors (SGLT2i) as add-on treatments to metformin monotherapy in patients with type 2 diabetes mellitus (T2DM) using a model-based meta-analysis (MBMA)., Methods: A systematic literature search of public databases was conducted to develop models that describe the time courses of the fasting plasma glucose (FPG)- and haemoglobin A1c (HbA1c)-lowering effects of three antidiabetic classes using NONMEM 7.3.0., Results: Seventy-six publications were eligible for this study, and 873 FPG and 1086 HbA1c values were collected. We developed a physiological indirect response model that described the time courses of FPG and HbA1c and simulated reductions in these values 90 days after the initiation of add-on treatments. FPG and HbA1c reductions with once weekly exenatide, liraglutide and dulaglutide were greater than those with other drugs. Mean changes from baseline FPG and HbA1c with these drugs were as follows: exenatide (-22.5 and -16.6%), liraglutide (-22.1 and -16.3%), and dulaglutide (-19.3 and -14.3%). The hypoglycaemic effects of DPP-4i and SGLT2i were similar., Conclusions: Once weekly exenatide, liraglutide and dulaglutide provided better hypoglycaemic effects among the antidiabetic drugs analysed. Long-acting GLP-1r appears to be more useful for T2DM patients inadequately controlled with metformin monotherapy., (© 2018 The British Pharmacological Society.)

This study aimed to elucidate the impact of OATP1B1 genotype (*1b/*1b, *1b/*15, and *15/*15) on plasma concentrations of endogenous OATP1B1 substrates. Healthy volunteers with OATP1B1 *1b/*1b (n = 10), *1b/*15 (n = 7), or *15/*15 (n = 2) received oral administration of a cocktail of statins (atorvastatin, pitavastatin, rosuvastatin, and fluvastatin). Mean area under the plasma concentration of atorvastatin, pitavastatin, and rosuvastatin in OATP1B1 *15/*15 were 2.2, 1.7 and 1.58-times greater than the corresponding values in OATP1B1 *1b/*1b, respectively, whereas that of fluvastatin was identical to those in other OATP1B1 genotypes. OATP1B1 *15/*15 also showed higher mean plasma concentrations of OATP1B1 endogenous substrates compared with the other OATP1B1 genotypes, such as coproporphyrin I, glycochenodeoxycholate sulfate (GCDCA-S), lithocholate sulfate (LCA-S), glycolithocholate sulfate (GLCA-S) and taurolithocholate sulfate (TLCA-S), but not total or direct bilirubin, chenodeoxycholate-24-glucuronide, or ω-dicarboxylic long-chain fatty acids. Area under the plasma concentration-time curves of plasma coproporphyrin I and GLCA-S discriminated OATP1B1 genotype *15/*15 from the other genotypes. In combination with previously published clinical studies, these results support the notion that coproporphyrin I, and GLCA-S and GCDCA-S could be a surrogate probe for assessing human in vivo OATP1B1 activities., (Copyright © 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

The objective of the present study was to develop a population pharmacodynamic (PPD) model to describe the glycated hemoglobin (HbA1c)-lowering effects of metformin in type 2 diabetes mellitus patients with and without secondary failure and to characterize changes in HbA1c levels in the two subpopulations using a mixture model. Information on patients was collected retrospectively from electronic medical records. In this study, the mixture model was used to characterize the bimodal effects of metformin. A PPD analysis was performed using NONMEM 7.3.0. A physiological indirect response model, based on 829 HbA1c levels of 69 patients, described the time course for the HbA1c-lowering effects of metformin. Evidence for the different effectiveness of metformin subpopulations was provided using the mixture model. In the final PPD model, the inhibition effect was constant over a study duration in a patient subpopulation without secondary failure. In contrast, the inhibition effect decreased as a function of time after start of metformin treatment in a subpopulation with secondary failure. These results indicated that HbA1c improvements appeared to deteriorate over time in patients with secondary failure. In a PPD analysis of metformin, it was possible to assign patients with secondary failure using the mixture model., (Copyright © 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Pulmonary hypertension (PH) is a disease with poor prognosis, caused by the obstruction/stenosis of small pulmonary arteries. Statin is known to have vasodilating and anti-inflammatory property and is considered to be a candidate of therapeutic agents for the treatment of PH, but its efficacy has not been verified in clinical trials. We have formulated pitavastatin incorporating nanoparticles composed of poly (lactic-co-glycolic acid) (NK-104-NP) to improve drug delivery to the pulmonary arteries and evaluated their safety and pharmacokinetics in healthy volunteers. To accomplish this purpose, phase I clinical trials were conducted. In the single intravenous administration regimen, 40 healthy subjects were enrolled and PK (pharmacokinetic) parameters in 4 groups (1, 2, 4, and 8 mg as pitavastatin calcium) were as follows: 1.00 hour after the administration, the plasma concentration of pitavastatin reached C max (the maximum drug concentration) in all groups. C max , AUC 0-t (area under the curve from time 0 to the last measurable concentration) and AUC 0-∞ (area under the curve from time 0 extrapolated to infinite time) were increased in a dose-dependent manner. Population pharmacokinetic analysis based on these results indicated no accumulation of pitavastatin after repeated administration of NK-104-NP for 7 days. In this 7-day administration trial, the mean C max and AUC 0-∞ of pitavastatin were not significantly different between days 1 and 7, suggesting that pitavastatin is unlikely to accumulate after repeated administration. In these trials, three adverse events (AEs) were reported, but they were resolved without any complications and judged to have no causal relationships with NK-104-NP. These results indicate that the innovative nanotechnology-based medicine NK-104-NP exhibited dose-dependent pharmacokinetics and was well tolerated with no significant AEs in healthy volunteers.

The aims of this study were (1) to investigate the effects of atorvastatin (10 mg, therapeutic dose) and grapefruit juice (GFJ), inhibitors of OATP2B1, on the pharmacokinetics of substrates for OATP2B1 and BCRP under oral small-dosing conditions (300 μg sulfasalazine, 250 μg rosuvastatin, 300 μg glibenclamide, 1200 μg celiprolol, and 600 μg sumatriptan), and (2) to evaluate the contribution of SLCO2B1*3 and ABCG2 c.421C>A polymorphisms to the pharmacokinetics of the 5 test drugs in 23 healthy volunteers. In the 3 phases, the test drugs were administered to volunteers with either water (control phase), atorvastatin, or GFJ. GFJ but not atorvastatin reduced the exposure of the test drugs significantly more than the control phase, suggesting that all 5 test drugs are substrates for OATP2B1. The SLCO2B1*3 genotype had no effect on the pharmacokinetics of the test drugs. In contrast, the exposure of sulfasalazine and rosuvastatin was significantly higher in ABCG2 421C/A than in ABCG2 421C/C individuals at all 3 phases, even under small-dosing conditions., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Although some studies have examined platelet reactivity (PR) during prasugrel treatment, little is known about PR during the early treatment period and its clinical significance in Japan., Methods: We investigated the early and medium-term efficacy and safety of prasugrel in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI). Seventy-eight patients were enrolled and PR was measured (in P2Y 12 reaction units; PRU) by the VerifyNow P2Y 12 assay (Accumetrics, San Diego, CA, USA)., Results: In 44 patients, serial measurement revealed that PR was significantly higher at 2h after administration of the 20-mg loading dose of prasugrel than on the morning of the second day at 17.6±6.6h after administration (191.6±75.5 vs. 138.5±68.9PRU). During the 8-month follow-up period, bleeding events occurred in 18 patients (23.1%) (GUSTO minor: 15 patients). Multivariate regression analysis identified oral anticoagulant use as a significant predictor of bleeding events during admission [odds ratio (OR): 4.214, 95% confidence interval (CI): 1.005-17.669, p=0.049]. Administration of prasugrel via a nasogastric tube was a significant predictor of high on-treatment platelet reactivity (HTPR) (PRU≥230) (OR: 43.100, 95% CI: 4.517-411.251, p=0.001). In addition, HTPR was a significant predictor of major adverse cardiac events (cardiovascular death, non-fatal myocardial infarction, stent thrombosis, stroke, and sustained ventricular tachycardia) during the 8-month follow-up period (OR: 4.911, 95% CI: 1.164-20.722, p=0.030)., Conclusions: It is feasible to treat AMI patients with prasugrel. HTPR is a significant independent risk factor for adverse events in AMI patients receiving prasugrel after primary PCI., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

The usefulness of coronary magnetic resonance angiography (cMRA) has been reported, although the difference in the diagnostic accuracy of different protocols has not been established.We compared conventional coronary angiography (CAG) and cMRA, conducted within 6 months in 24 consecutive patients between September 2012 and July 2014. Three cMRA protocols were examined, cMRA1, free-breathing wholeheart coronary angiography (WHCA) without contrast; cMRA2, free-breathing WHCA with contrast; and cMRA3, breath-hold steady-state free precession with contrast using a 3.0 T scanner. Image quality was graded on a 4-point scale: 1) nonassessable; 2) assessable, fair vessel contrast; 3) assessable, good vessel contrast; and 4) assessable, excellent vessel contrast. Significant narrowing of the coronary arteries was visually assessed.Stenosis was observed in 34 segments, with a prevalence of 10.3%. For cMRA1, cMRA2, and cMRA3, the numbers of assessable segments were 245 (74.2%), 287 (87.0%), and 164 (49.7%), respectively (P < 0.001 by the McNemar test). For assessable segments, the sensitivity, specificity, positive predictive value, and negative predictive value were 89.3%, 99.1%, 92.6%, and 98.6% for cMRA1, 90.0%, 98.1%, 84.4%, and 98.8% for cMRA2, and 76.5%, 93.9%, 59.1%, and 97.1% for cMRA3, respectively. For the assessable segments, the image quality score was better with cMRA2 than with the other two protocols.cMRA is a useful modality to rule out coronary artery disease, especially the cMRA2 protocol, which performed better than the other two protocols.

The objective of this study was to identify factors affecting on errors in carbohydrate (CHO) content estimation during CHO counting. Thirty-seven type 1 diabetes patients and 22 of their parents and 28 physicians/dieticians were enrolled in this study. CHO counting was counted in "Carb", with 1 Carb defined as 10 g of CHO. To evaluate the accuracy of CHO counting, 80 real-size photographs of cooked meals were presented to the subjects for Carb estimation. Carbs tended to be overestimated for foods containing relatively small amounts of Carbs. On the other hands, Carbs tended to be underestimated for foods with higher than 6 Carbs. Accurate estimation of the Carbs in food containing a large amount of rice was particularly difficult even in the subjects having the CHO counting experience. The Carb contents of high-calorie foods such as meats, fried foods, and desserts tended to be overestimated. This error was smaller in subjects having the CHO counting experience. In conclusion, misunderstanding of high-calorie dishes containing high amounts of CHO was observed in inexperienced subjects, indicating the efficacy of the current methodology of CHO counting. On the other hand it was difficult even for experienced subjects to assess the amount of seasoned rice, suggesting the need for a new methodology for accurate estimation.

RNA silencing (RNAi) induced by virus-derived double-stranded RNA (dsRNA), which is in a sense regarded as a pathogen-associated molecular pattern (PAMP) of viruses, is a general plant defense mechanism. To counteract this defense, plant viruses express RNA silencing suppressors (RSSs), many of which bind to dsRNA and attenuate RNAi. We showed that the tobacco calmodulin-like protein, rgs-CaM, counterattacked viral RSSs by binding to their dsRNA-binding domains and sequestering them from inhibiting RNAi. Autophagy-like protein degradation seemed to operate to degrade RSSs with the sacrifice of rgs-CaM. These RSSs could thus be regarded as secondary viral PAMPs. This study uncovered a unique defense system in which an rgs-CaM-mediated countermeasure against viral RSSs enhanced host antiviral RNAi in tobacco.

Unlabelled: Aims/Introduction:  The daily basal insulin doses/body weight and the daily basal insulin doses/total daily insulin doses of Japanese type 1 diabetes mellitus patients are less than those of Western type 1 diabetes mellitus patients. It is known that Western meals are richer in fat than Japanese meals. We speculated that fat intake might be associated with basal insulin dose in type 1 diabetes mellitus patients., Materials and Methods:   Forty-one outpatients with type 1 diabetes mellitus (20 males, 21 females, mean age 15.9) were enrolled. Variables investigated included: gender, SDS-BMI, HbA1c, duration of diabetes, therapy (MDI or CSII), insulin doses and meal contents. Meal contents were recorded for 3 days using a digital camera. Correlation and multiple regression analyses were performed for all subjects and each age group., Results:   The mean daily basal insulin doses/total daily insulin doses was 0.35. In the multiple regression analysis among all subjects, when daily basal insulin doses/body weight was used as a dependent variable, fat energy ratio of the meal was obtained as an entered variable (P = 0.001). This tendency was particularly strong among the patients aged 14 or above (P < 0.001, standardized coefficient β = 0.683)., Conclusions:   In the type 1 diabetes patients who are aged 14 or above, an association between daily basal insulin doses/body weight and fat energy ratio of meal was suggested. This may explain the aforementioned expectation of increased fat intakes making higher basal insulin doses. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00171.x, 2011).

The interactions between Cu(II) complexes with heterocyclic azo compounds and several anions were studied by equilibrium analysis of ion-pair extraction, RP-HPLC of metal complexes, and ion chromatography of anions on an ODS column coated with Cu(II) complexes of the long alkyl derivatives. Both ion-pair extraction and HPLC studies demonstrated that a dicationic complex with 8-(3,5-dibromo-2-pyridylazo)-5-aminoquinoline interacted with anions stronger than a monocationic complex with 2-(2-pyridylazo)methylphenol. Anions were more retained on the column coated with dicationic Cu(II) complex. Such differences were quantitatively ascribed to the first ion-pair formation of the dicationic complex giving a monocationic species.

The aim of the present study was to elucidate the pathogenic role of endogenous 5-HT in pancreatitis. Injections of cerulein at hourly intervals caused edematous pancreatitis in mice characterized by hyperenzymemia and histological alterations. While the cerulein-induced hyperenzymemia was attenuated in mice pretreated with p-CPA, a 5-HT depletor, it was exaggerated by the preferential 5-HT2A agonist (DOI), but not by the preferential 5-HT2B agonist (BW723C86) or the preferential 5-HT2C agonist (mCPP). Selective 5-HT2A antagonists (risperidone, spiperone, ketanserin, AMI-193, and MDL 11,939) dose-dependently attenuated the hyperenzymemia; and their potency order, excepting that of ketanserin which has considerable affinity at the 5-HT2C receptor as well, paralleled their reported pKi values at the 5-HT2A receptor. Selective 5-HT2B (SB204741) and 5-HT2C (SB242084) antagonists hardly affected the hyperenzymemia. Although the non-selective 5-HT2A/2B/2C antagonists (metergoline, ritanserin, and methysergide) dose-dependently attenuated the hyperenzymemia, they were relatively less potent compared to their high pKi values at the 5-HT2A receptor. In another set of experiments, risperidone, but not SB204741 and SB242084, dose-dependently reversed the cerulein-induced histological alteration of the pancreas (inflammatory cell infiltration). These results suggest that endogenously released 5-HT activates 5-HT2A receptors to aggravate cerulein-induced pancreatitis. We propose that selective 5-HT2A antagonists may provide a new therapy for acute pancreatitis.

Background: Patients with recurrent soft tissue sarcoma (STS) are seldom curable, with 5-year survival rates of less than 10% in all large series. The role of high-dose chemotherapy (HDC) with hematopoietic stem cell support in this disease has not been established., Case Report: We report on two patients with recurrent STS who were treated with tandem HDC supported by autologous peripheral blood stem cell transplantation (PBSCT). One patient with malignant fibrous histiocytoma recurred with multiple lung metastases. This patient achieved a partial response after two cycles of induction chemotherapy consisting of ifosfamide and epirubicin. During four cycles of induction chemotherapy, peripheral blood stem cells (PBSCs) were harvested. Tandem high-dose ICE regimen (ifosfamide 3 g/m2 on days-7 to -3, carboplatin 400 mg/m2 on days-7, -5 and 3, etoposide 500 mg/m2 on days-7, -5 and 3) supported by autologous PBSCT gave rise to further regression of the tumors. Another patient with malignant hemangiopericytoma was treated by tandem high-dose ICE regimen supported by autologous PBSCT after the 3rd removal of abdominal tumors. Relapse-free intervals until the 1st, 2nd and 3rd relapses were 40, 19 and 22 months, respectively. Tandem high-dose ICE regimen might delay the relapse., Conclusion: These observations suggest that a tandem high-dose ICE regimen with autologous PBSCT is feasible with some clinical efficacy in the control of refractory STS.

The rotated-inclined double-crystal monochromator (RIDCM) has been adopted to reduce the heat load from third-generation undulator radiation. The position of the exit X-rays from RIDCM has been calculated as a function of X-ray energy on the basis of diffraction theory including refraction effects. The results show that the positions of the exit X-rays vary over a wide range due to asymmetric reflection. Methods of fixing the exit position in RIDCM are also discussed.

In the present study, we isolated five murine LIM-homeodomain (LH) genes including a novel gene designated as L3 which is expressed specifically in the medial ganglionic eminence of the embryonic brain and the mesenchyme surrounding the oral cavity. The comparison of the expression domains in the embryonic forebrain using in situ hybridization histochemistry proved that three LH genes (LH-2, lim-1, and L3) share sharp boundaries. In addition to the prosomeric boundaries in the diencephalon, this gene family defines novel boundaries in the basal telencephalon, the mesencephalon, and the rhombencephalon. These mutually exclusive expression domains suggest that this family might be involved in controlling the early compartmentalization and boundary formation of the developing central nervous system.

1. IRL 1620 (0.01-0.1 mg kg-1, i.v.), a selective endothelin B (ETB) receptor agonist, induced a dose-dependent biphasic increase in total lung resistance and a decrease in dynamic compliance in anaesthetized and artificially ventilated guinea-pigs. After intravenous injection of IRL 1620 (0.03 mg kg-1), the first phase was observed within 2 min whereas the second phase started between 5 and 10 min after injection and was long lasting. 2. In order to characterize which endothelin receptors are involved in both phases of bronchoconstriction, we studied the effect of ETA and ETB receptor antagonists (BQ 123 and BQ 788, respectively). BQ 788 (0.1-1 mg kg-1, i.v.) inhibited, in a dose-dependent manner, both phases of bronchoconstriction. BQ 123 (3 mg kg-1, i.v.) markedly inhibited (by 76%) the second phase of bronchoconstriction but had no effect on the early component of the response. 3. The effect of atropine, neurokinin-I (NK1) and neurokinin-2 (NK2) receptor antagonists (SR140333 and SR48968, respectively) were tested to investigate the possible involvement of cholinergic and sensory nerve activation, respectively, in the response to IRL 1620. Likewise, the role of arachidonic acid metabolites (leukotriene D4 antagonist, ONO-1078 and thromboxane A2 (TXA2) inhibitor, OKY-046) in this response was also investigated. OKY-046 (1 mg kg-1, i.v.) and atropine (1 mg kg-1, i.v.) partially inhibited the first phase (by 80% and 20%, respectively) without affecting the late phase of bronchoconstriction. Neither ONO-1078 (1 mg kg-1, i.v.) nor the combination of SR140333 (0.2 mg kg-1, i.v.) and SR 48968 (0.2 mg kg-1, i.v.) modified IRL 1620-induced bronchoconstriction. 4. A low dose of IRL 1620 (0.005 mg kg-1, i.v.) induced a monophasic bronchoconstriction. Pretreatment by phosphoramidon (100 mumol kg-1, i.v.) restored the second phase of bronchoconstriction. In this condition, BQ 123 (3 mg kg-1, i.v.) was able to inhibit partially the second phase of bronchoconstriction. 5. These results suggest that both phases of bronchoconstriction induced by IRL 1620 were mediated primarily by ETB receptor activation, the first phase being a consequence of TXA2 and acetylcholine release. The inhibition by an ETA receptor antagonist and the restoration by a neutral endopeptidase (NEP) inhibitor of the second phase of bronchoconstriction suggests that primary activation of ETB receptors leads to autocrine/paracrine endothelin-1 (ET-1) release that would subsequently cause profound bronchoconstriction through both ETA and ETB receptor activation.

Homeobox-containing genes are associated with the control of various stages in embryogenesis. LIM-homeodomain genes have been implicated in the control of differentiation of specific cell types in both neuronal and non-neuronal tissues, yet there have been few studies comparing the expression domains of these genes in the developing brain of a single species. In the present study, we isolated murine LIM-homeodomain genes (LH-2, lim-1, and L3) by reverse transcription-polymerase chain reaction (RT-PCR) method and investigated their expression domains in the embryonic brain by in situ hybridization analysis. These mRNAs showed mutually exclusive expression patterns suggesting that these factors may be involved in region-specific differentiation in the developing brain.

The metastatic phenotype of tumor cells is thought to be induced by an aberrant signaling cascade or cascades that are different from those required for tumorigenicity. Oncogene-transfected cells with different tumorigenicities and metastatic potentials have been used to identify such pathways and responsible molecules. However, oncogenes that can induce tumorigenicity in recipient cells also frequently induce the metastatic phenotype at the same time. The difficulty in obtaining cell lines that are tumorigenic but not metastatic has hampered such studies. In this report, we transfected the activated c-Ha-ras oncogene into BALB/c 3T3 A31 variant cells and found that the transfectants were tumorigenic but they did not form metastatic lung modules in the experimental metastasis assay. The phenotype was very stable and was maintained during cultivation. On the other hand, the metastatic potentials of either the transfected cells or the original variant cells could be induced by transfection of the v-src oncogene. The src transfectants formed extensive nodules in lung when injected into the tail veins of congeneric mice. The cell motility of the metastatic src transfectants on Matrigel-coated dishes was greater than that of the ras transfectants. The src transfectants were also invasive in Matrigel when analyzed on a filter. These variant cells transformed by the ras and src oncogenes will be a useful system for identifying the signaling cascades responsible for the metastatic potential of tumors.

By reverse-transcription polymerase chain reaction method, we isolated a novel murine LIM-homeodomain gene, L3. In situ hybridization analyses revealed that L3 mRNA was localized to the ventral telencephalon and the mesenchyme surrounding the oral cavity of mouse embryo, suggesting that L3 may be involved in the region-specific differentiation of these areas.

The survival of motoneurons requires a trophic factor derived from the target muscles, but the nature of this trophic factor is not known. We examined whether skeletal muscle expresses mRNAs encoding survival-promoting factors for motoneurons. Messenger RNAs were purified from hindlimbs of chick embryos and injected into Xenopus oocytes for translation. The media conditioned by incubation of the injected oocytes were applied to chick embryos during the natural cell death period of lumbar motoneurons. This procedure significantly reduced the magnitude of natural motoneuronal death. The conditioned media also promoted the survival of motoneurons cultured from chick embryos.

Acute renal failure in rats was induced by transient occlusion of bilateral renal arteries and veins to investigate whether insulin-like growth factor-I (IGF-I) has an effect on the damaged renal function or not. Administration of IGF-I at 0.01, 0.1 and 1 mg/kg by s.c. injection caused a 18.7, 33.0 and 66.5% increase of glomerular filtration rate and 54.8, 61.2 and 84.1% decrease of blood urea nitrogen, respectively, compared with the values in the saline-treated group 2 days after ischemia. Other renal parameters tested such as fractional excretion of sodium, N-acetyl-beta-D-glucosaminidase and tubular reabsorptance of phosphorus which are thought to represent renal function of proximal and distal tubules, respectively, were also improved by IGF-I treatment. A histochemical study also supported these observations. Severe epithelial necrosis of proximal tubules and decrease of brush borders were observed 2 days after transient ischemia in the saline-treated group, whereas marked histochemical alterations were not observed in the IGF-I-treated group. L-NG-nitroarginine, an inhibitor of nitric oxide synthetase, prevented the improvement of glomerular filtration rate and blood urea nitrogen by IGF-I at 1 mg/kg, suggesting that the ameliorative action on renal function by IGF-I is mediated via nitric oxide, possibly its vasodilating action. These findings provide the first evidence for the efficacy of IGF-I in the model of acute renal failure, suggesting that IGF-I may be useful for the treatment of acute renal failure.

Calcitonin gene-related peptide (CGRP) in skeletal muscle is of neural origin. After degeneration of sensory fibers induced by removal of the lumbar dorsal root ganglia (DRG), the CGRP content in the rat soleus muscle was reduced to about 5% of the normal level. In contrast, degeneration of motor fibers induced by sectioning of the lumbar ventral roots markedly increased the CGRP content in the soleus muscle and CGRP levels in the lumbar DRG. It is suggested that the expression of CGRP in sensory neurons is up-regulated by some humoral factor induced by degeneration of motor nerve fibers.

Calcitonin gene-related peptide (CGRP) is present in both motor and sensory neurons and transported in the somatofugal direction. CGRP levels in sensory neurons are assumed to be regulated by NGF supplied from their peripheral targets. In cultured sensory neurons, however, a basal level of CGRP persists even without NGF. This suggests that some additional factors may be involved in regulation of CGRP levels of sensory neurons. The present study shows that chronic section of the sciatic nerve in the rat reduces CGRP levels in the lumbar dorsal root ganglia (DRG), whereas section of dorsal roots increases CGRP levels in the DRG. This increased CGRP level by dorsal rhizotomy was associated with enhancement of the CGRP mRNA expression in the DRG. Thus, CGRP expression in DRG appears to be regulated reciprocally via their central and peripheral processes. When the sciatic nerve had been cut 1 week previously, however, dorsal rhizotomy no longer increased CGRP levels in the lumbar DRG. Therefore, stimulation of CGRP synthesis in the DRG by dorsal rhizotomy may require the integrity of the peripheral processes. When NGF had been infused into the central stump of the cut sciatic nerve, dorsal rhizotomy again increased CGRP levels in the DRG, despite prior section of the peripheral processes. We conclude that CGRP expression in sensory neurons may be regulated by cooperative action of some factors derived via their central processes and NGF supplied from the peripheral targets.

1. The amount of calcitonin gene-related peptide (CGRP) released from the isolated rat soleus muscle was measured by enzyme immunoassay. 2. When the soleus muscle was exposed to a solution containing high K+ (20-100 mM) in the presence of tetrodotoxin, the amount of CGRP released into the bathing medium increased with an increase in the K+ concentration. 3. The exposure to 100 mM-K+ did not increase CGRP release from chronically denervated soleus muscles or from pieces of the soleus nerve separated from the muscle. 4. The amount of CGRP released from the isolated muscle by 100 mM-K+ depended on the external Ca2+ concentration. The slope of the relation between the amount of CGRP release and the Ca2+ concentration was less than one on double logarithmic co-ordinates. 5. Following chronic section of the lumbar ventral roots, the mean amount of CGRP released from the soleus muscle by 100 mM-K+ was reduced by 28%, compared with that observed in normal muscle. 6. Antidromic stimulation of the lumbar dorsal roots at an intensity three times the threshold for most excitable sensory fibres failed to induce CGRP release from the soleus muscle, whereas stimulation at intensities 50-100 times the threshold increased significantly the amount of CGRP release from the muscle. 7. Stimulation of the muscle nerve at an intensity sufficient to activate the alpha-motor fibres did not release CGRP from the soleus muscle or from the diaphragm. 8. It is concluded that the major source of CGRP released from skeletal muscle is A delta- and/or C sensory terminals and that the Ca2+ dependence of CGRP release is less steep than that reported for acetylcholine release at neuromuscular junctions.

Calcitonin gene-related peptide (CGRP) has been found in both sensory and motor neurons. It has been suggested that CGRP is transported from neuron cell bodies to their terminals, where it may act as an anterograde trophic factor. However, it is not known how fast CGRP is transported or whether CGRP found in the innervated target organ indeed originated in neural tissues. We have quantified endogenous CGRP in the rat peripheral nerve by a newly developed enzyme immunoassay. The CGRP immunoreactive material obtained from neural tissues coincided with synthetic rat CGRP in fractional distributions separated by gel filtration. After ligation of the sciatic nerve, tissue CGRP accumulated in the segment central to the ligature. The rate of anterograde transport of CGRP was about 1 mm/hr in both sensory and motor fibers. In the sciatic nerve, only a small fraction of CGRP measured was found to originate from the motor nerve fibers. This may be due in part to the disproportionately large number of sensory fibers in the sciatic nerve and in part to the possible presence of CGRP in sympathetic nerve fibers. The CGRP content in the dorsal root fibers was significantly lower than that in the peripheral processes of the sensory neurons. The CGRP content in the hind leg muscle was much higher than that expected from the amount of CGRP per nerve fiber in the sciatic nerve. Most CGRP in muscle disappeared following denervation. It is concluded that CGRP highly concentrated in nerve terminals is supplied by axonal transport from the neuron cell bodies.

Sensory neurons with small diameters (A delta and C cells) are known to be responsive to exogenous NGF even at postnatal stages. We have examined whether large Group Ia sensory neurons (A alpha cells) arising from muscle spindles are also responsive to NGF in neonatal rats. For this purpose, monosynaptic excitatory postsynaptic potentials (EPSPs) were evoked in spinal motoneurons by Group Ia muscle afferent volleys. When a muscle nerve was crushed on the day after birth, the monosynaptic EPSPs elicited by afferent volleys from the muscle were depressed within several weeks. This synaptic depression was partially reversed by daily treatment with NGF. NGF treatment also enhanced the EPSPs evoked by stimulation of intact muscle nerves, but this effect was less marked than that on the EPSPs produced by stimulation of the previously crushed muscle nerve. Exogenous NGF was effective for the EPSPs when the treatment began on the day after birth but not when the treatment began 4 d after birth. Following crush of a muscle nerve on the day after birth, about 45% of the sensory neurons derived from the muscle were lost. The cell death of small sensory neurons was prevented by daily treatment with NGF, whereas the NGF treatment was ineffective in preventing the cell death of large sensory neurons. The results indicate that Group Ia sensory neurons are responsive to NGF during early postnatal life.

1. Motoneurone death induced by axotomy in the rat was studied following section of the medial gastrocnemius nerve near the muscle 4 days after birth. 2. The maximum twitch tension of the medial gastrocnemius muscle achieved by motor reinnervation after section of its nerve was about 70% of that measured on the contralateral, intact side. 3. The number of motor units counted at 35-45 days of age in the animals whose medial gastrocnemius nerves had been sectioned on day 4 was 62% of that observed in normal rats. 4. The number of medial gastrocnemius motoneurones retrogradely labelled with horseradish peroxidase (HRP) 30-40 days after section of the medial gastrocnemius nerve was 77% of that labelled on the contralateral, intact side. 5. When the medial gastrocnemius nerve had been sectioned on day 4 and prevented from peripheral reinnervation, the number of medial gastrocnemius motoneurones labelled with HRP was, on the average, only 18% of that labelled on the control side. 6. Decreased number of medial gastrocnemius motoneurones labelled with HRP following prevention of peripheral reinnervation was associated with a decrease in the neurone density of the motor cell column, indicating the occurrence of motoneurone death. 7. The majority of medial gastrocnemius motoneurones axotomized 4 days after birth appear to maintain their survival for about 2 weeks without target contact. 8. The area of the compound action potential of medial gastrocnemius motor fibres once decreased after axotomy on day 4 began to recover from the 12th day after the operation if reinnervation by the cut peripheral nerve had been allowed, whereas the compound action potential continued to decrease in those axotomized motoneurones whose reinnervation had been prevented. 9. It is concluded that target dependence of motoneurone survival previously observed at embryonic stages is still present during the early post-natal period.

Recovery from destruction by sodium deoxycholate (DOC) was studied with the receptor membrane of the blowfly, Phormia regina. The recovery can be divided into two processes, colchicine dependent and colchicine independent. The colchicine-dependent process was completely depressed by pretreatment with colchicine at 5 mM for 2 min (partially at 0.1 mM for 10 min), but the colchicine-independent one persisted. Vinblastine also caused depression but lumicolchicine did not. Records of responses obtained from the DOC-treated sugar receptor showed long response latencies that gradually became indistinct with recovery. Colchicine also affected this change in response latency after the DOC treatment. These results suggest that the colchicine-dependent recovery process is related to microtubules in the distal process of the receptor cell. The recovery time course and the change in response latency could be quantitatively explained by the simple assumptions that DOC underwent desorption from the receptor membrane (colchicine-independent recovery process) and that regeneration of the disrupted distal process of the receptor cell accompanied recovery in the number of available receptor sites (colchicine-dependent recovery process).

Electron micrographs of sections of the labellar chemosensilla of the blowfly, Phormia regina, showed that treatment with sodium deoxycholate (DOC; 7.2 mM for 2 min) destroyed the distal processes of the receptors from up to 10 microns from the tip of the sensillum, but these processes regenerated almost completely within 0.5 h. However, when DOC treatment was preceded by colchicine treatment (25 mM for 2 min), greater than 10 h was required for complete regeneration. Sugar receptor responses supported these findings and disclosed a more detailed time course of regeneration after DOC treatment: without colchicine pretreatment, the destroyed distal process completely regenerated in 0.3-1.0 h, but with pretreatment, regeneration began at 3 h and reached the chemosensillar tip at 8 h at the earliest. Hardly any depression of the response was observed for 8 h after treatment with colchicine alone, but a transient depression was detected at 12 h. Based on these results, the role of microtubules in the maintenance of the receptor membrane is discussed.