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The anticancer drug, Lenvima (lenvatinib), has severe side effects. Therapeutic drug monitoring helps ensure its efficacy and safety. Regular and optimally timed blood sampling is tough, especially when lenvatinib is self-medicated. Microsampling using the easy to handle Microsampling Wing (MSW) may help circumvent this problem. However, current lenvatinib detection methods are not sensitive enough to detect its concentrations in microsamples (50-250 μL). Thus, the aim of this study was 2-fold (1) develop an analytic method to estimate plasma lenvatinib concentrations in microsamples and (2) verify whether this method works on micro (5.6 μL) blood plasma samples obtained clinically through MSW from patients with unresectable hepatocellular carcinoma (HCC).A simple, highly sensitive, and specific liquid chromatography-electrospray ionization tandem mass spectrometry method was developed. Using this novel protocol, the trough blood plasma concentration of lenvatinib was measured for both blood sampled conventionally and that using MSW. Thirty-five venous whole blood samples were obtained from 11 patients with HCC. Furthermore, the stability of lenvatinib in MSW samples during storage was evaluated.The mean plasma lenvatinib concentration estimates were not significantly different between the MSW and conventional venous blood samples. CV for interday and intraday assays was low. Up to day 5, the lenvatinib concentration in the MSW samples was 85%-115% of the initial day concentration (when stored at 25°C or 4°C). The interference of endogenous matrix components in the human plasma was low.These results indicate that the novel mass spectrometry protocol accurately measures lenvatinib in human plasma and is reproducible. Thus, MSW could be a useful microsampling device for lenvatinib therapeutic drug monitoring in patients with HCC when used in combination with this novel liquid chromatography-electrospray ionization tandem mass spectrometry detection method.

To compare the initial fixation strength of osteochondral fragment fixations using osteochondral plugs, bioabsorbable pins, and knotless suture anchors.Eighteen fresh-frozen immature (6 month old) porcine knees were used. An osteochondral fragment, cut from the articular surface of the medial femoral condyle to achieve a thickness of 5 mm, was used to mimic the unstable osteochondral fragment. It was fixed using three techniques, including two osteochondral plugs (osteochondral plug group), four full-threaded poly l-lactic acid pins (bioabsorbable pin group), and three suture anchors with a 2-0 tape (suture anchor group). Tensile loads at displacements of 1 and 2 mm and ultimate failure load were measured at a cross-head speed of 100 mm/min, and the variables of the three groups were compared statistically using a one-way ANOVA with Tukey's honestly significant difference test.There was no significant difference in the tensile load to achieve 1-mm displacement. The load to achieve 2-mm displacement and the ultimate failure load were significantly greater in the suture anchor group than the osteochondral plug group and the bioabsorbable pin group.Single-pull destructive testing of a fixed articular osteochondral fragment with the force perpendicular to the articular surface, demonstrated no statistical difference in the tensile load to achieve 1-mm displacement, but the load to achieve 2-mm displacement was significantly greater for the three suture anchor-interlocking 2-0 tape constructs than the dual osteochondral plug fixation and the four bioabsorbable pin fixation constructs. Additionally, the three suture anchor-interlocking 2-0 tape construct's mean single-pull failure load was greater than other two fixation procedures.To achieve osteochondral fragment union, sufficient fixation strength is critical. However, the initial fixation strength of osteochondral plugs, bioabsorbable pins, and knotless suture anchors for unstable osteochondral lesions remains unclear.

本稿の目的は，従来の「別れ」に関連する知見を整理した上で，「別れ」の概念がどのような事象として認識されてきたのかについて問い直し，それを踏まえながら，今後の「別れ」研究への展望と新たな発展について検討することであった。先行研究では，「別れ」という枠組みからの包括的な検討は見られていない。そこで，本稿では，従来の悲嘆研究や死別研究などを手がかりに，「別れ」の概念整理を行った。その結果，これまで，様々な別れは「対象喪失」として理解されてきたと考えられるが，「別れは関係性の変容である」と理解することも可能であることが示唆された。これを踏まえて，関係性の変容が起きるのかどうかには，「別れ観」の個人差が影響を与えている可能性があると考え，この点に着目した実証的な研究を展開していくことが，今後の「別れ」研究には重要なのではないかとの考察を行った。, This article aimed to reconsider how the concept of parting was understood and treated as a research object, after the knowledge concerning conventional parting was organized. Then, the prospects of future parting research and new developments were examined accordingly. In the preceding research, comprehensive research within the framework of parting has not been observed. In this paper, the concept arrangement of parting was carried out based on conventional grief and bereavement researches. The results showed that it was possible to encompass various parting in the framework of “loss,” and it was important to notice the parting which cannot only be captured in the frame. Further, it was indicated that the understanding of the “transformation of the relationship” was also possible. Hence, it was considered that individual differences in “views of parting” might affect whether the transformation of the relationship occurs. In future parting research, it is important to develop empirical research focusing on this aspect.

Osteochondritis dissecans (OCD) of the knee is a subchondral bone abnormality that results in the separation of the articular cartilage and bone with subsequent progression to osteoarthritis. Unstable OCD lesions should undergo fixation to preserve the natural contour of the articular surface. Although several fixation procedures have been reported, the appropriate procedure remains unknown. Because the bony portion of the OCD lesion is usually thin, it is difficult to fix firmly with conventional methods. We began fixing OCD lesions with knotless PushLock anchors and sutures and have obtained satisfactory results. This report describes this fixation method that uses the PushLock suture anchor to treat unstable OCD lesions. This procedure also can be applied for traumatic osteochondral fractures., Technique Video Video 1 This video shows internal fixation using PushLock suture anchor for (OCD) of the knee. This patient is a 14-year-old male with juvenile OCD in the medial femoral condyle. Magnetic resonance imaging shows high signal rim and cystic lesion behind the OCD lesion indicating synovial fluid infiltration. Following the induction of anesthesia, the patient is placed in the supine position on a standard operating table. A tourniquet is placed on the proximal thigh, and support plates are placed at the thigh and foot to maintain the knee in approximately 90° of flexion. Diagnostic arthroscopy shows the OCD lesion located in the medial femoral condyle, and the OCD lesion looks unstable. After arthroscopic examination, medial parapatellar arthrotomy is performed. This is the OCD lesion located on the medial femoral condyle. In this case, the articular cartilage was cut along the border of OCD lesion, and the lesion was turned like an open door to expose the base of the lesion. The base of the lesion should be debrided using a curette until the underlying healthy subchondral bone is exposed, and then, microfracture is performed. The osteochondral fragment is reduced into the condyle, and the OCD lesion is temporarily fixed with a 2.4-mm K-wire. First, a bone socket is made by a drill for the PushLock, and then the spear with the suture tape is advanced into the bone socket until the anchor body contacts the bone. The orange packaging clip is removed and the metal button on the driver handle is tapped to advance the anchor body. A second PushLock anchor is inserted in the same manner. It is necessary to adjust the suture tension appropriately while the anchor is in contact with the bone. The K-wire is removed, and the drill hole is used for the third PushLock anchor. Under appropriate tensioning of the suture, the PushLock anchor is inserted. The suture is cut flush using a FiberWire suture cutter, and the stability of the OCD lesion is confirmed. This is the arthroscopic view after PushLock fixation. (OCD, osteochondritis dissecans.)

Floating offshore structures are attracting increasing attention as a method for addressing problems such as rising sea levels due to global warming and the increasing global populations. However, unlike ground structures, floating offshore structures must consider the effects of waves. The movement characteristics of the floating offshore structure have been reported. However, no studies have compared variations in motion response characteristics according to the scale of floating structures or buildings atop them, so it is currently difficult during the initial planning and design stages to estimate the size of superstructures that can be designed for a given marine area. Therefore, with the aim of obtaining basic data for planning floating offshore structures, in this study we developed floating structure modules (a square 36m on a side) according to their superstructure and investigated the basic motion response characteristics for each. We furthermore derived tendencies for horizontal acceleration and inclination occurring in individual modules according to design waves for Tokyo Bay.

As toxic substances can enter the circulating blood and cross endothelial monolayers to reach parenchymal cells in organs, vascular endothelial cells are an important target compartment for such substances. Reactive sulfur species protect cells against oxidative stress and toxic substances, including heavy metals. Reactive sulfur species are produced by enzymes, such as cystathionine &gamma, lyase (CSE), cystathionine &beta, synthase, 3-mercaptopyruvate sulfurtransferase, and cysteinyl-tRNA synthetase. However, little is known about the regulatory mechanisms underlying the expression of these enzymes in vascular endothelial cells. Bio-organometallics is a research field that analyzes biological systems using organic-inorganic hybrid molecules (organometallic compounds and metal coordinating compounds) as molecular probes. In the present study, we analyzed intracellular signaling pathways that mediate the expression of reactive sulfur species-producing enzymes in cultured bovine aortic endothelial cells, using copper diethyldithiocarbamate (Cu10). Cu10 selectively upregulated CSE gene expression in vascular endothelial cells independent of cell density. This transcriptional induction of endothelial CSE required both the diethyldithiocarbamate scaffold and the coordinated copper ion. Additionally, the present study revealed that ERK1/2, p38 MAPK, and hypoxia-inducible factor (HIF)-1&alpha, /HIF-1&beta, pathways mediate transcriptional induction of endothelial CSE by Cu10. The transcription factors NF-&kappa, B, Sp1, and ATF4 were suggested to act in constitutive CSE expression, although the possibility that they are involved in the CSE induction by Cu10 cannot be excluded. The present study used a copper complex as a molecular probe to reveal that the transcription of CSE is regulated by multiple pathways in vascular endothelial cells, including ERK1/2, p38 MAPK, and HIF-1&alpha, Bio-organometallics appears to be an effective strategy for analyzing the functions of intracellular signaling pathways in vascular endothelial cells.

High-fat diet (HFD) is associated with impairment of insulin sensitivity. We investigated the effects of Bangle (Zingiber purpureum) extract (Ba) with exercise training (Ex) on phosphorylation of Akt and mammalian target of rapamycin (mTOR), and autophagy flux in the gastrocnemius (GM) of HFD-fed rats. The rats, on a diet providing 45% of energy from fat, were divided into four groups: untreated (HFD), 1.5% Ba-treated (HFD + Ba), 1.5% Ba with Ex-treated (HFD + Ba + Ex), and Ex-treated (HFD + Ex) groups. The controls were fed a normal diet. The homeostatic model assessment of insulin resistance index and non-esterified fatty acid levels were decreased in the HFD + Ba + Ex. The HFD + Ba + Ex showed decreased phosphorylated Akt and mTOR levels, and increased levels of autophagy flux markers, LC3B-II and Beclin 1, compared to the HFD. In conclusion, the combination of Ba and Ex modulates Akt/mTOR phosphorylation and the autophagy flux in the GM and may attenuate insulin resistance induced by a HFD.

e18562 Background: Although patients with locoregional advanced maxillary sinus squamous cell carcinoma (MSSCC) are often treated with surgery followed by postoperative radiotherapy (RT), the cosmetic and functional outcomes are unsatisfactory. Moreover, the efficacy and safety of intra-arterial chemoradiotherapy are controversial. Methods: In this study, we investigated the efficacy and safety of low-dose cisplatin administration through the superficial temporal artery (STA) combined with definitive RT in patients with MSSCC. Between January 2009 and December 2018, 57 patients were administered weekly intra-arterial infusions of cisplatin (30–50 mg/m2/5h) through the STA with simultaneous intravenous infusions of sodium thiosulfate. Overall response rate (ORR), local progression-free survival (LFS), maxillectomy-free survival (MFS), progression-free survival (PFS), overall survival (OS), and safety were evaluated retrospectively. The impact of clinical factors on survival was investigated using the Cox proportional hazard models. Results: The median follow-up time was 44 months (range, 10–80 months). There were 4, 26, 23, and 4 patients with cT2, cT3, cT4a, and cT4b, respectively. All patients completed the planned treatment except for one patient who discontinued owing to facial palsy. The ORR was 98% with 51 and 5 patients having complete and partial responses, respectively. The 3-year LFS, PFS, and OS were 74%, 63%, and 81%, respectively for all patients and 100%, 81%, and 94%, respectively for 22 patients received 70 Gy irradiation. Notably, the 3-year MFS was 95% for all patients and 100% in patients received 70 Gy RT. The most common grade 3 or more toxic event was oral mucositis (22.8%). Additionally, 4 (7.0%) patients had catheter-related infections. Late grade 3 or more adverse events included optic nerve disorder (8.8%), osteonecrosis (7.0%), encephalopathy (1.8%), and increased creatinine levels (1.8%). Salvage surgery including hard palate resection and orbital exenteration were performed in 2 and 1 patients, respectively. No clinical factor was correlated with survival outcomes in our study cohort. Conclusions: Low-dose cisplatin through STA combined with RT, especially 70 Gy RT, was associated with promising tumor response, high organ preservation rate, and tolerable adverse events in MSSCC patients. Further prospective studies are warranted to compare these outcomes with primary surgery.

Aims/Introduction Though there are many differences in dietary habits and in the metabolic basis between Western and Asian people, the actual dietary intake in Asian patients with diabetes has not been investigated in a nationwide setting, unlike in Western countries. We aimed to clarify dietary intake among Japanese individuals with type 2 diabetes, and identify differences in dietary intake between Japanese and Western diabetic patients. Materials and Methods Nutritional and food intakes were surveyed and analyzed in 1,516 patients with type 2 diabetes aged 40–70 years from outpatient clinics in 59 university and general hospitals using the food frequency questionnaire based on food groups (FFQg). Results Mean energy intake for all participants was 1737 ± 412 kcal/day, and mean proportions of total protein, fat, and carbohydrate comprising total energy intake were 15.7, 27.6 and 53.6%, respectively. They consumed a ‘low-fat energy-restricted diet’ compared with Western diabetic patients, and the proportion of fat consumption was within the suggested range that has been traditionally recommended in Western countries. As a protein source, consumption of fish (100 g) and soybean products (71 g) was larger than that of meat (50 g) and eggs (29 g). These results imply that dietary content and food patterns among Japanese patients with type 2 diabetes are quite close to those reported as suitable for prevention of obesity, type 2 diabetes, cardiovascular disease, and total mortality in Europe and America. Conclusions A large difference was shown between dietary intake by Japanese and Western patients. These differences are important to establish ethnic-specific medical nutrition therapy for diabetes.

The 2007 Noto Hanto earthquake (Mj 6.9) occurred off northwest of Noto Peninsula, Japan on March 25, 2007. Associated with this earthquake, a tsunami was excited off northwest of Noto. And a mysterious small tsunami was also observed at Toyama off southeast of Noto Peninsula. This small tsunami arrived soon after the earthquake occurrence, and the wave height was about 10cm. First we estimated normal tsunami by the simulation considering vertical displacement of fault movement. Calculated waveforms roughly agree with the observed one except. for early arrival tsunami at Toyama. Next we assume the source region of the tsunami at Toyama from inverse propagation diagrams and finally attempt. to simulate this mysterious tsunami by considering horizontal displacement of the sea-bed in Toyama Bay.

To report outcomes for men treated with iodine-125 ((125)I) prostate brachytherapy (BT) at a single institution in Japan.Between 2003 and 2009, 1313 patients (median age, 68 years) with clinically localized prostate cancer were treated with (125)I BT. Median prostate-specific antigen level was 7.6 ng/mL (range, 1.1-43.3). T-stage was T1c in 60%, T2 in 39%, and T3 in 1% of patients. The Gleason score was7, 7, and7 in 49%, 45%, and 6% of patients, respectively. Neoadjuvant androgen deprivation therapy was used in 40% of patients and combined external beam radiotherapy of 45 Gy in 48% of patients. Postimplant dosimetry was performed after 30 days after implantation, with total doses converted to the biologically effective dose. Survival functions were calculated by the Kaplan-Meier method and Cox hazard model.Median followup was 67 months (range, 6-126). The 7-year biochemical freedom from failure for low-, intermediate-, and selected high-risk prostate cancers were 98%, 93%, and 81%, respectively (p0.001). Multivariate analysis identified the Gleason score, initial prostate-specific antigen level, positive biopsy rate, dose, and neoadjuvant androgen deprivation therapy as predictors for biochemical freedom from failure. The 7-year actuarial developing Grade 3+ genitourinary and gastrointestinal toxicity was 2% and 0.3%, respectively. Forty-four percent patients with normal baseline potency retained normal erectile function at 5 years.(125)I prostate BT is a highly effective treatment option for low-, intermediate-, and selected high-risk prostate cancers. Side effects were tolerable. An adequate dose may be required to achieve successful biochemical control.

on normalized EPIC QOL scores were used to compare clinical and dynamic changes over time between the two treatment groups (p!0.05). Results: Eighty-four and 125 patients were treated on the SBRT and HDR boost studies, with a median followup of 51 and 61 months, respectively. There were no significant differences in any of the domains at baseline between the two treatment groups (pO0.05). There was a significant difference in MCIC between treatments in the urinary (17% vs 58%, p! 0.0001) and sexual domains (50% vs 71%, p50.007) (figure 1). Overall, no significant difference was noted in the bowel domain (32% vs 44%, p50.25). Of patients who reported no problem with their sexual function at baseline, 6% and 23% respectively considered it to be a moderate to big problem on followup (p50.007). On univariate and multivariate analysis, higher baseline scores (ie. better QOL) predicted for greater chance of MCIC in the sexual domain (p!0.0001). Conclusions: Long-term followup data suggests that a greater percentage of patients with localized prostate cancer treated with HDR-boost reported deterioration of QOL particularly in sexual domains in comparison with SBRT alone. The relative contribution of the brachytherapy and external beam components of treatment to this is unknown.