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Background: The L-type amino acid transporter (LAT1) exhibits significantly increased expression within tumor cells across various neoplasms. However, the clinical significance of LAT1 expression in patients with pleural mesothelioma (PM) remains unclear. Methods: Eighty patients diagnosed with PM between June 2007 and August 2022, were eligible for this study. LAT1, alanine-serine-cysteine transporter 2 (ASCT2), Ki-67, and VEGFR2 were evaluated by immunohistochemistry. Inflammatory and nutritional indices were also correlated with different variables, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and Glasgow prognostic score (GPS). Results: LAT1 was highly expressed in 57.5 % of patients with PM. Among the 80 patients included in this study, 65 (81.3 %) received chemotherapy, either alone or followed by surgical resection, while 15 (18.7 %) opted for best supportive care. The level of LAT1 significantly correlated with cell proliferation and ASCT2. Factors such as performance status, histology, LAT1 expression, PNI, ALI, and GPS were significant prognostic indicators for progression-free survival (PFS), while Ki-67, LAT1, NLR, SII, PNI, ALI, and GPS were identified as significant predictors for overall survival (OS). LAT1 expression emerged as an independent prognostic factor for predicting PFS and OS in all patients, as well as in the subgroup of 65 patients receiving chemotherapy. Notably, high LAT1 expression proved to be a significant predictor of outcome, particularly in the subgroup with high PLR and SII. Conclusion: LAT1 was a significant predictor of outcomes in patients with PM and was more predictive of worse outcomes in patients with high inflammatory and low nutritional status.

Background and purpose: We investigated the incidence and dose-volume relationships of radiation pneumonitis (RP) after concurrent chemoradiotherapy (CCRT) followed by durvalumab for locally advanced non-small-cell lung cancer (LA-NSCLC). Materials and methods: We retrospectively analyzed records of 36 patients with LA-NSCLC who underwent CCRT followed by durvalumab. Incidence of RP was analyzed for correlations with clinical factors and dose-volume parameters of lung in radiotherapy. Results: All patients received 60 Gy in 30 fractions of radiotherapy with concurrent chemotherapy. Over a median follow-up period of 7 months, incidence of grade ≥2 RP was 36% (including grade 3 RP: 5% and grade 5 RP: 3%). Age, sex, Brinkman index, and blood test results did not significantly differ between patients with grade ≥2 RP and grade ≤1 RP. Dose-volume parameters (lung volumes that received 5 Gy, 10 Gy, 20 Gy, 30 Gy, 40 Gy, 50 Gy, and mean lung dose) were significantly higher among patients with grade ≥2 RP compared with patients with grade ≤1 RP. Conclusion: Incidence of grade ≥2 RP was 36% after CCRT followed by durvalumab for LA-NSCLC, but did not significantly differ from those of patients treated with CCRT alone. Lung dose-volume parameters were significantly correlated with RP.

Abstract Background Although the presence of late gadolinium enhancement (LGE) using cardiovascular magnetic resonance imaging (CMR) is a significant discriminator of events in patients with suspected myocarditis, no data are available on the optimal LGE quantification method. Methods Six hundred seventy consecutive patients (48 ± 16 years, 59% male) with suspected myocarditis were enrolled between 2002 and 2015. We performed LGE quantitation using seven different signal intensity thresholding methods based either on 2, 3, 4, 5, 6, 7 standard deviations (SD) above remote myocardium or full width at half maximum (FWHM). In addition, a LGE visual presence score (LGE-VPS) (LGE present/absent in each segment) was assessed. For each of these methods, the strength of association of LGE results with major adverse cardiac events (MACE) was determined. Inter-and intra-rater variability using intraclass-correlation coefficient (ICC) was performed for all methods. Results Ninety-eight (15%) patients experienced a MACE at a medium follow-up of 4.7 years. LGE quantification by FWHM, 2- and 3-SD demonstrated univariable association with MACE (hazard ratio [HR] 1.05, 95% confidence interval [CI]:1.02–1.08, p = 0.001; HR 1.02, 95%CI:1.00–1.04; p = 0.001; HR 1.02, 95%CI: 1.00–1.05, p = 0.035, respectively), whereas 4-SD through 7-SD methods did not reach significant association. LGE-VPS also demonstrated association with MACE (HR 1.09, 95%CI: 1.04–1.15, p

A PET tracer for tumor imaging, 3-18F-l-α-methyl-tyrosine ([18F]FAMT), has advantages of high cancer-specificity and low physiological background. In clinical studies, FAMT-PET has been proved useful for the detection of malignant tumors and their differentiation from inflammation and benign lesions. The tumor specific uptake of FAMT is due to its high-selectivity to cancer-type amino acid transporter LAT1 among amino acid transporters. In [18F]FAMT PET, kidney is the only organ that shows high physiological background. To reveal transporters involved in renal accumulation of FAMT, we have examined [14C]FAMT uptake on the organic ion transporters responsible for the uptake into tubular epithelial cells. We have found that OAT1, OAT10 and OCTN2 transport [14C]FAMT. The [14C]FAMT uptake was inhibited by probenecid, furosemide and ethacrynic acid, consistent with the properties of the transporters. The amino acid uptake inhibitor, 2-amino-2-norbornanecarboxylic acid (BCH), also inhibited the [14C]FAMT uptake, whereas OCTN2-mediated [14C]FAMT uptake was Na+-dependent. We propose that FAMT uptake by OAT1, OAT10 and OCTN2 into tubular epithelial cells could contribute to the renal accumulation of FAMT. The results from this study would provide clues to the treatments to reduce renal background and enhance tumor uptake as well as to designing PET tracers with less renal accumulation.

Objective: To clarify a rational surgical priority, clinical characteristics were compared between brain metastases (BM) from renal cell carcinoma (RCC) and other cancers., Methods: We reviewed 425 consecutive patients with BM who underwent treatments including surgery between January 2014 and December 2022. Primary cancers included lung (n = 220), breast (n = 46), digestive (n = 65), RCC (n = 25), and others (n = 69). Tumor volume (T), edema volume (E), and edema volume/tumor volume ratio (E/T ratio) were compared between RCC and other primary cancers. Cutoff T values for identifying both symptomatic tumors and tumors suitable for surgery were determined by receiver operating characteristic curves. Factors including E/T ratio, age, Karnofsky Performance Scale score, and tumor characteristics were statistically analyzed., Results: Cutoff values of T and E to determine surgical suitability were 4.973 cm3 (sensitivity, 0.848; specificity, 0.74) and 23.088 cm3 (sensitivity, 0.894; specificity, 0.623), respectively. E/T ratio was significantly higher for RCC than for other cancers (P < 0.01). These results remained consistent after propensity score matching. RCC tended to show a significantly lower frequency of posterior fossa tumor (16%, P < 0.01) and higher rates of single lesions (72%, P = 0.03) and intratumoral hemorrhage (24%, P = 0.02). Subgroup analysis limited to surgical cases showed that E was consistent across tumors, T tended to be smaller, and E/T ratio was significantly higher in RCC., Conclusions: Generally, symptomatic BM were indicated for surgery. BM from RCC were characteristically single, low-volume lesions with expanding edema and intratumoral hemorrhage, causing symptoms. These results suggest that surgery should be a high priority for BM from RCC., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Le Fort I (LF1) osteotomy, a common orthognathic procedure for the maxilla aimed at achieving maxillary mobility by separating the pterygomaxillary suture, poses a risk of bad fracture that may lead to complications and inadequate mobility. Our study analyzed two- and three-dimensional computed tomography images to identify the anatomical factors associated with bad fractures due to an LF1 osteotomy. Point 'a' is where the lateral pterygomaxillary suture on the axial image aligns with the zygomatic alveolar line near the line used for an LF1 osteotomy, with the base line connecting the bilateral 'a' points.Two risk factors were identified on the pterygoid side: (i) when the distance from point 'a' to the intersection of the base line and the medial pterygoid plate was <6.0 mm; and (ii) when the distance from the piriform aperture margin to the base line was <44.78 mm. Six risk factors were identified on the maxillary side, including the distance between the most anterior and most lateral points of the internal surface of the maxillary sinus being <31.9 mm. Our analyses revealed that fractures that occur during pterygomaxillary suture separation in an LF1 osteotomy are influenced by anatomical factors of the maxilla and pterygoid process, which form the pterygomaxillary suture., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Objective: Spondylotic changes in the cervical spine cause degeneration, leading to cervical spinal canal stenosis. This stenotic change can affect cerebrospinal fluid (CSF) dynamics by compressing the dural sac and reducing space in the subarachnoid space. We examined CSF dynamics at the craniovertebral junction (CVJ) using time-spatial labeling inversion pulse magnetic resonance imaging (Time-SLIP MRI) in patients with cervical spinal canal stenosis., Methods: The maximum longitudinal movement of the CSF at the CVJ was measured as length of motion (LOM) in the Time-SLIP MRI of 56 patients. The sum of ventral and dorsal LOM was defined as the total LOM. Patients were classified into 3 groups depending on their spinal sagittal magnetic resonance imaging findings: control (n = 27, Kang classification grades 0 and 1), stenosis (n = 14, Kang classification grade 2), and severe stenosis (n = 15, Kang classification grade 3)., Results: Time-SLIP MRI revealed pulsatile movement of the CSF at the CVJ. The mean total, ventral, and dorsal LOM was 14.2 ± 9, 8.1 ± 5.7, and 3.8 ± 2.9 mm, respectively. The ventral LOM was significantly larger than the dorsal LOM. The total LOM was significantly smaller in the severe stenosis group (6.1 ± 3.4 mm) than in the control (16.0 ± 8.4 mm) or stenosis (11 ± 5.4 mm) groups (P < 0.001, Kruskal-Wallis H-test). In 5 patients, postoperative total LOM was improved after adequate decompression surgery., Conclusions: This study demonstrates that CSF dynamics at the CVJ are influenced by cervical spinal canal stenosis. Time-SLIP MRI is useful for evaluating CSF dynamics at the CVJ in patients with spinal canal stenosis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Thymic carcinoma (TC) is a rare thymic epithelial tumor, and advanced or recurrent TC has limited prognosis. Treatment for chemotherapy-naïve, advanced, or recurrent TC remains unchanged with the combination of carboplatin and paclitaxel; therefore, a new treatment strategy is warranted. Immune checkpoint blockades inhibiting the programmed cell death-1 (PD-1) pathway (PD-1 and its ligand, PD-L1) have shown potential as a monotherapy for TC, although the efficacy of monotherapy was moderate for previously treated TC. We hypothesized that the combination of an anti-PD-L1 antibody, atezolizumab, with carboplatin and paclitaxel, would be effective in inducing immunogenic cell death in patients with advanced or recurrent TC., Methods: We initiated a multicenter, single-arm, open-label phase II study of atezolizumab combined with carboplatin and paclitaxel for metastatic or recurrent TC. Eligible patients will receive atezolizumab plus carboplatin and paclitaxel every 3 weeks for up to 6 cycles, followed by atezolizumab every 3 weeks for up to 2 years until progression or unacceptable toxicity. A total of 47 patients will be enrolled in this study, with a 24-month enrollment period and 12-month follow-up. The primary endpoint is the objective response rate (ORR), based on an independent central review. The secondary endpoints are the investigator-assessed ORR, disease control rate, progression-free survival, duration of response, overall survival, and safety., Results: This study aims to establish the safety and efficacy of atezolizumab combined with carboplatin and paclitaxel in patients with advanced or recurrent TC., Trial Registration: Japan Registry of Clinical Trials (jRCT), jRCT2031220144. Registered on June 18, 2022, https://jrct.niph.go.jp/en-latest-detail/jRCT2031220144., Competing Interests: Disclosure TA reports honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Merck Biopharma, MSD, Nippon Kayaku, Ono, Pfizer, Taiho, and Takeda. T Shukuya reports grant support for the current study from Chugai Pharmaceutical; grant support from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, Novartis; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Taiho, and Takeda. YG reports grant support for the clinical trial group from AstraZeneca, Pfizer, institutional grant support from AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Kyorin, Novartis, Ono, Pfizer, and Preferred Networks; honoraria from Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Merck, MSD, Novartis, Ono, Pfizer, Taiho, and Thermo Fischer; participation on an advisory board for AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Guardant Health, Illumina, MSD, Novartis, Ono, Pfizer, and Taiho; and leadership or fiduciary role at Cancer Net Japan and Japanese Association of Medical Technologists. HT reports institutional grant support from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck Biopharma, MSD, Ono, Taiho, and Takeda; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, Merck Biopharma, MSD, Novartis, Ono, Sun Pharmaceutical, Taiho, and Takeda. K Takayama reports grant support for Chugai Pharmaceutical; honoraria from Chugai Pharmaceutical. YT reports institutional grant support for Ono and Pfizer Health Research Foundation; honoraria from AstraZeneca, Chugai Pharmaceutical, and Daiichi Sankyo. MT reports honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis, Ono, and Takeda. T Suzuki reports honoraria from AstraZeneca and Boehringer Ingelheim. KK reports honoraria from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, Ono, and Taiho. RK reports grant support from AstraZeneca and MSD; honoraria from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly, MSD, Ono, Pfizer, Taiho, and Takeda. YZ reports grant support from Amgen, AstraZeneca, Daiichi Sankyo, Merck Biopharma, and MSD; honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Kyowa Kirin, MSD, Nihon Kayaku, Novartis, Pfizer, Taiho, and Takeda. HA reports grant support from Amgen, Chugai Pharmaceutica, and MSD; honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Taiho and Takeda; data safety monitoring or advisory board participation with Amgen, Janssen, and Sandoz; and a leadership or fiduciary role with World Conference on Lung Cancer Patient Advocate Committee. JT reports honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Janssen Pharmaceutical, MSD, Nihon Medi-Physics, Ono, Nippon Boehringer-Ingelheim, Nippon Kayaku, Taiho, and Pfizer. SI reports institutional grant support for AstraZeneca and Chugai; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Ono, Pfizer, and Takeda. SS reports honoraria from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyowa Kirin, Merck Biopharma, MSD, Nippon Kayaku, Novartis, Ono, Otsuka, Pfizer, Taiho, Takeda, Thermo Fisher Scientific, Towa Pharmaceutical, and Yakult Honsha. KM reports honoraria from Chugai Pharmaceutical, Eli Lilly, and Ono. K Takahashi reports grant support from Asahi Kasei Pharma, Bayer, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Kyorin, Nippon Kayaku, Kyowa Kirin, Nippon Pharma, Nippon Shinyaku, Novartis, Ono, Sanofi, Shionogi, Taiho, Takeda, Teijin, Tsumura, and Pfizer; honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Janssen, Kyorin, Meiji Seika Pharma, Merck Biopharma, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Sumitomo Dainippon Pharma, Taiho, Takeda, Thermo Fisher Scientific and Viatris; patent with Oncolys BioPharma; and leadership or fiduciary role with The Japan Lung Cancer Society and The Japan Respiratory Society. All other authors (HM, TM) declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Cetuximab (Cmab) is a molecularly targeted monoclonal antibody drug for head and neck squamous cell carcinoma (HNSC), although cetuximab resistance is a serious challenge. Epithelial cell adhesion molecule (EpCAM) is an established marker for many epithelial tumors, while the soluble EpCAM extracellular domain (EpEX) functions as a ligand for epidermal growth factor receptor (EGFR). We investigated the expression of EpCAM in HNSC, its involvement in Cmab action, and the mechanism by which soluble EpEX activated EGFR and played key roles in Cmab resistance., Materials and Methods: We first examined EPCAM expression in HNSCs and its clinical significance by searching gene expression array databases. We then examined the effects of soluble EpEX and Cmab on intracellular signaling and Cmab efficacy in HNSC cell lines (HSC-3 and SAS)., Results: EPCAM expression was found to be enhanced in HNSC tumor tissues compared to normal tissues, and the enhancement was correlated with stage progression and prognosis. Soluble EpEX activated the EGFR-ERK signaling pathway and nuclear translocation of EpCAM intracellular domains (EpICDs) in HNSC cells. EpEX resisted the antitumor effect of Cmab in an EGFR expression-dependent manner., Conclusion: Soluble EpEX activates EGFR to increase Cmab resistance in HNSC cells. The EpEX-activated Cmab resistance in HNSC is potentially mediated by the EGFR-ERK signaling pathway and the EpCAM cleavage-induced nuclear translocation of EpICD. High expression and cleavage of EpCAM are potential biomarkers for predicting the clinical efficacy and resistance to Cmab., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A 12-year-old castrated male Beagle dog presented with a 1-month history of progressive loss of appetite and cough. One month after the initial visit, a detailed clinical examination was performed due to weight loss and persistent cough. Computed tomography demonstrated diffuse opacification of the entire right lung and cranial lobe of the left lung. Samples of the pulmonary lesions obtained by fine-needle aspiration (FNA) were highly cellular with scattered and clustered foci of large round cells, suggestive of a round cell tumour. Ten days after the FNA, the dog was euthanized due to decreased activity and severe respiratory symptoms. At necropsy, enlargement of the entire right lung and cranial lobe of the left lung was seen. The external and cut surfaces of the lungs were homogeneously grey-white. Histopathological examination of sections of the right lung and the cranial lobe of the left lung revealed proliferation of large round or polygonal neoplastic cells arranged in nests of variable size separated by a thin fibrous stroma. Neoplastic cells were immunopositive for cytokeratin and thyroid transcription factor-1 but negative for vimentin, CD204, chromogranin A and synaptophysin. On the basis of these findings, the tumour was diagnosed as pulmonary solid adenocarcinoma., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Recently, the prevalence of elderly patients suffering from cervical spinal cord injury (CSCI) without bone injury has been increasing in various countries. Pre-existing factors causing spinal cord compression, such as ossification of the posterior longitudinal ligament (OPLL), can increase the risk of CSCI without bone injury. However, no study has compared the prevalence of pre-existing factors between CSCI with and without bone injury. This study aimed to compare the prevalence of pre-existing factors between CSCI with and without bone injury., Methods: In 168 consecutive patients with CSCI, pre-existing factors including OPLL, posterior spur of the vertebral body, developmental stenosis, disc bulge and calcification of yellow ligament (CYL) were evaluated on imaging studies. The prevalence of each type of pre-existing factors was compared between patients with and without bone injury., Results: The prevalence of pre-existing factors in patients without bone injury (86%) was significantly higher than in those with bone injury (20%) (P < 0.001; odds ratio, 23.9). The most common pre-existing factor was OPLL followed by developmental stenosis, posterior spur, disc bulge and CYL in both groups. OPLL, development stenosis and posterior spur were significantly more common in patients without bone injury compared to those with bone injury (P < 0.01)., Conclusions: Prevalence of pre-existing factors, such as OPLL, development stenosis and posterior spur was significantly higher in patients without bone injury than in those with bone injury. Thus, these pre-existing factors might be a potential risk of CSCI without bone injury., Competing Interests: Declaration of competing interest The submitted manuscript involves no conflicts of interest., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Large amounts of radiocesium were released into marine environments following the Fukushima Daiichi Nuclear Power Plant accident in March 2011. Released radiocesium influenced not only marine environment but also marine biota in Fukushima. Since marine biota as fisheries products is important for Japanese market, it is important to assess the distribution of radiocesium in coastal environment off Fukushima for safety concerns of radioactive contamination. Radiocesium concentrations in sediments are important for understanding fishing ground conditions and for proving the safety of fisheries products in Fukushima. In this study, monthly monitoring data collected from May 2011 to March 2020 were analyzed to describe the temporal variability of 137 Cs concentrations in coastal sediments off Fukushima (total of 3647 samples from eight lines at depths of 7-125 m off Fukushima, and three sites in Matsukawa-ura Lagoon). The 137 Cs concentration in sediment showed a decreasing trend, but our nonlinear model fitting suggested that this rate of decrease had slowed down. Additionally, 137 Cs concentrations were up to 4.08 times greater in shallow sampling sites (7, 10, 20 m depth) following heavy rainfall events (before five months vs. after five months), such as typhoons. These observations were consistent with increasing input from particulate 137 Cs fluxes from rivers and increasing dissolved 137 Cs concentrations in seawater. Finally, our numerical modeling suggested that riverine 137 Cs input could maintain 137 Cs concentrations in coastal sediment. These results indicate that riverine 137 Cs input following heavy rainfall events is the main factor for maintaining 137 Cs concentrations in coastal sediments near the Fukushima Daiichi Nuclear Power Plant., Competing Interests: Declaration of competing interest The authors have no conflict of interest directly relevant to the content of this article., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Over 800 known carotenoids are synthesized from phytoene or 4,4'-diapophytoene (dehydrosqualene) characterized by three conjugated double bonds. In this paper, we report that carotenoid desaturase CrtN from Staphylococcus aureus and Methylomonas can accept oxidosqualene, which is the precursor for plant- or animal-type triterpenoids, yielding the yellow carotenoid pigments with 8, 9, or 10 conjugated double bonds. The resulting pathway is the second nonnatural route for carotenoid pigments and the first pathway for carotenoid pigments not biosynthesized via (diapo)phytoene., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daisuke Umeno reports financial support was provided by Government of Japan Ministry of Education Culture Sports Science and Technology. Yusuke Otani reports financial support was provided by Government of Japan Ministry of Education Culture Sports Science and Technology., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: In Japan, approximately 75% of patients with thoracic myelopathy caused by ossification of the posterior longitudinal ligament (OPLL) are treated by posterior decompression with instrumented spinal fusion (PDF) because of its efficacy and safety. To achieve more effective decompression of the spinal cord using a posterior approach, anterior decompression through a posterior approach was developed. However, this technique has a high risk of postoperative paralysis. We have added a couple of ingenuities to this procedure (modified Ohtsuka procedure). This study was performed to report the surgical results of our modified Ohtsuka procedure and to compare them with the results of PDF., Methods: This was a retrospective case series. From 2008 to 2018, we surgically treated 32 patients: 20 patients treated by PDF (PDF group) and 12 patients by our modified Ohtsuka procedure (modified Ohtsuka group) as the initial surgery. All patients were followed up for at least 12 months. The degree of surgical invasion and patients' neurological condition were assessed., Results: The operative duration and intraoperative blood loss indicated no significant differences (PDF vs. Ohtuska: 507 ± 103 vs. 534 ± 99 min, 1022 ± 675 vs. 1160 ± 685 ml, respectively). The preoperative Japanese Orthopaedic Association (JOA) score was 4.5 ± 2.0 in the PDF group and 3.3 ± 1.4 in the modified Ohtsuka group (p < 0.05). However, the latest JOA score and recovery rate were significantly better in the modified Ohtsuka group than in the PDF group (8.9 ± 1.2 vs. 7.4 ± 2.5 and 70.8 ± 17.6% vs. 44.5 ± 40.2%, respectively). Postoperative paralysis did not occur in the modified Ohtsuka group while four patients had it in the PDF group., Conclusions: The present study clearly indicated the modified Ohtsuka group showed significantly better surgical outcomes than the PDF group with the recovery rate ≥70%., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: The fourth wave of COVID-19 in Osaka Prefecture, Japan, caused a medical crisis. Here, we aim to identify the risk factors for COVID-19 severity and compare patients between the first-third waves and the fourth wave., Methods: We performed an observational retrospective study of COVID-19 cases at the National Hospital Organization Kinki-Chuo Chest Medical Center., Results: We identified 404 patients (median age: 71.0 years [interquartile range: 56.0-80.0]), of whom 199 (49.1%) had mild disease, 142 (35.2%) had moderate disease, and 63 (15.6%) had severe disease. The overall mortality rate was 5.4% (22/404). Based on multivariate logistic regression analysis, cardiovascular disease, fever, dyspnea, and several inflammatory biomarkers were independent risk factors for moderate to severe disease. For every 1 mg/dL increase in C-reactive protein, 10 IU/L increase in lactate dehydrogenase, and 100 ng/mL increase in ferritin, the risk for moderate to severe disease increased by 18.3%, 12.9%, and 8.9%, respectively. Overall disease severity in the fourth wave was higher than in the first-third waves. However, there was no significant difference in mortality. Because of a shortage of beds, four of the 28 severe patients (14.3%) in the fourth wave could not be transferred to the advanced hospital., Conclusions: Cardiovascular disease, fever, dyspnea, and several inflammatory biomarkers were risk factors for moderate to severe COVID-19 in our cohort. During the fourth wave, COVID-19 severity worsened, increasing the number of patients who could not be transferred to beds for severe cases, resulting in a medical crisis in Osaka., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Bone destruction of maxillary and mandibular bone by invasive oral squamous cell cancer (OSCC) raises various problems in the management of patients, resulting in poor outcomes and survival. However, the mechanism behind bone destruction by OSCC remains unclear. High-mobility group box 1 (HMGB1), a highly conserved ubiquitous nuclear non-histone DNA-binding protein, has been demonstrated to be secreted by aggressive cancers and regulate osteoclastogenesis, a central player during bone destruction. We therefore reasoned that HMGB1 secreted by OSCCs contributes to bone destruction. Our results showed that HMGB1 is produced by human cell lines of OSCC and promotes osteoclastogenesis via up-regulation of the expression of receptor activator of nuclear factor kappa-Β ligand in osteoblasts and osteocytes, and consequently osteoclastic bone destruction in mice. Further, we found that these actions of HMGB1 are mediated via the receptor for advanced glycation end products and toll-like receptors. These findings suggest that HMGB1 of OSCC and its down-stream signal pathways are potential targets for the treatment of bone destruction associated with advanced OSCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study investigated the association of cardiovascular cardiac magnetic resonance (CMR) feature tracking (FT) with outcome in a patient cohort with myocarditis and evaluated the possible incremental prognostic benefit beyond clinical features and traditional CMR features., Background: CMR is used to diagnose and risk stratify patients with myocarditis. CMR-FT allows quantitative strain analysis of myocardial function; however, its prognostic benefit in myocarditis is unknown., Methods: Consecutive patients with clinically suspected myocarditis and presence of midmyocardial or epicardial late gadolinium enhancement (LGE) and/or myocardial edema in CMR were included. Clinical and CMR features were analyzed with regard to major adverse cardiovascular events (MACE) (i.e., hospitalization for heart failure, sustained ventricular tachycardia, and all-cause mortality)., Results: Of 740 patients with clinically suspected myocarditis, 455 (61%) met our final diagnostic criteria based on CMR tissue characterization. At a median follow-up of 3.9 years, MACE occurred in 74 (16%) patients. In the univariable analysis, CMR-FT global longitudinal peak strain (GLS) was significantly associated with MACE. In a multivariable model adjusting for clinical variables (age, sex, body mass index, and acuteness of symptoms) and traditional CMR features (left ventricular ejection fraction [LVEF] and LGE extent), GLS remained independently associated with outcome (GLS hazard ratio: 1.21; 95% confidence interval: 1.08 to 1.36; p = 0.001) and incrementally improved prognostication (chi-square increases from 42.6 to 79.8 to 88.5; p < 0.001)., Conclusions: Myocardial strain using CMR-FT provides independent and incremental prognostic value over clinical features, LVEF, and LGE in patients with myocarditis. CMR-FT may serve as a novel marker to improve risk stratification in myocarditis. (CMR Features in Patients With Suspected Myocarditis [CMRMyo]; NCT03470571)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: We conducted a subanalysis of data from the multicentre, retrospective observational Nivolumab Japan Real World (CA209-9CR) study to evaluate nivolumab effectiveness and safety in elderly patients (aged ≥75 years) with advanced/metastatic non-small cell lung cancer., Materials and Methods: Medical record data of patients initiating nivolumab treatment between April 2016 and December 2016 were collected using electronic data capture from 23 cancer hospitals in Japan between March 2017 and August 2018. Nivolumab treatment data were collected to investigate the treatment patterns by age group (<75 and ≥75 years), and the effectiveness and safety of nivolumab treatment., Results: Of the 901 patients evaluated, 178 (19.8%) were aged ≥75 years. Overall, patients received a median of five nivolumab treatments regardless of age group. Comparable progression-free survival was observed, with a median of 2.1 months in patients aged <75 years and 2.1 months in patients aged ≥75 years (p=0.5441). No significant differences were found in duration of response, overall response rate or disease control rate between the two age groups. Median overall survival in patients aged <75 and ≥75 years was 14.7 months and 12.3 months, respectively. Grade ≥3 adverse events (AEs) occurred in 29.2% and 28.1% of patients aged <75 and ≥75 years, respectively. Immune-related AEs decreased slightly with increasing age; time to onset and rates of improvement were similar for patients aged <75 and ≥75 years. The most common grade 3-4 AEs were interstitial lung disease in both age groups (4.0% in patients aged <75 years and 2.8% in those aged ≥75 years). Poor performance status was associated with worse outcomes in both age groups., Conclusion: Based on Japanese real-world data, the effectiveness and safety of nivolumab were confirmed regardless of age., Competing Interests: Competing interests: KO reports personal fees from Ono Pharmaceutical Co, Ltd and MSD K.K. outside the submitted work; JS reports personal fees from Bristol-Myers Squibb K.K. and Ono Pharmaceutical CO, Ltd outside the submitted work; HS reports grants from Chugai Pharmaceutical Co, Ltd, AstraZeneca K.K. and MSD K.K. and personal fees from Ono Pharmaceutical Co, Ltd, Nippon Boehringer Ingelheim Co, Ltd and Novartis Pharma K.K. outside the submitted work; HS reports personal fees from Ono Pharmaceutical Co, Ltd and Bristol-Myers Squibb K.K. during the conduct of the study, personal fees from Chugai Pharmaceutical Co, Ltd and MSD K.K. outside the submitted work; OS reports other from Ono Pharmaceutical Co, Ltd during the conduct of the study, personal fees and other from Novartis Pharma K.K., Nippon Boehringer Ingelheim Co, Ltd and AstraZeneca K.K. and other from Kyorin Pharmaceutical Co, Ltd, Bayer Health, Daiichi Sankyo Co, Ltd, GlaxoSmithKline K.K. and Ono Pharmaceutical Co, Ltd outside the submitted work; MY reports personal fees from Chugai Pharmaceutical Co, Ltd, Ono Pharmaceutical Co, Ltd and AstraZeneca K.K. outside the submitted work; MN reports grants and non-financial support from Ono Pharmaceutical Co, Ltd during the conduct of the study, grants and personal fees from Ono Pharmaceutical Co, Ltd, Bristol-Myers Squibb K.K., Pfizer Japan Inc, Chugai Pharmaceutical Co, Ltd, Eli Lilly Japan K.K., Taiho Pharmaceutical Co, Ltd, AstraZeneca K.K., MSD K.K., Novartis Pharma K.K., Takeda Pharmaceutical Co, Ltd and Daiichi Sankyo Healthcare Co, Ltd and grants from Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) and personal fees from Nippon Boehringer Ingelheim Co, Ltd outside the submitted work; KA reports grants and personal fees from Ono Pharmaceutical Co, Ltd, Bristol-Myers Squibb K.K., AstraZeneca K.K. and Eli Lilly Japan K.K. and grants from MSD K.K. and Novartis Pharma K.K. outside the submitted work; TK reports grants and personal fees from Ono Pharmaceutical Co, Ltd, AstraZeneca K.K., Taiho Pharmaceutical Co, Ltd, MSD K.K., Novartis Pharma K.K., Nippon Boehringer Ingelheim Co, Ltd, Eli Lilly Japan K.K., Pfizer Japan Inc and Chugai Pharmaceutical Co, Ltd, and grants from Takeda Pharmaceutical Co, Ltd, Regeneron Pharmaceuticals, Inc and Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) and personal fees from Teijin Pharma Ltd and Bristol-Myers Squibb K.K. outside the submitted work; SO reports grants and personal fees from Bristol-Myers Squibb K.K. and Ono Pharmaceutical Co, Ltd during the conduct of the study, grants and personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co, Ltd and Taiho Pharmaceutical Co, Ltd and grants from Kyowa Hakko Kirin Co, Ltd (currently Kyowa Kirin Co, Ltd) and Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) and personal fees from MSD K.K. and Eli Lilly Japan K.K. outside the submitted work; DF reports personal fees from Ono Pharmaceutical Co, Ltd and Bristol-Myers Squibb K.K. during the conduct of the study, personal fees from AstraZeneca K.K., Taiho Pharmaceutical Co, Ltd, Chugai Pharmaceutical Co, Ltd, MSD K.K., Nippon Boehringer Ingelheim Co, Ltd and Eli Lilly Japan K.K. outside the submitted work; HT reports grants and personal fees from Bristol-Myers Squibb K.K., Eli Lilly Japan K.K., MSD K.K., Taiho Pharmaceutical Co, Ltd, Pfizer Japan Inc, Chugai Pharmaceutical Co, Ltd, Ono Pharmaceutical Co, Ltd, AstraZeneca K.K. and Nippon Boehringer Ingelheim Co, Ltd and grants from Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) and personal fees from Novartis Pharma K.K. outside the submitted work; TK reports grants and personal fees from Chugai Pharmaceutical Co, Ltd, AstraZeneca K.K., Eli Lilly Japan K.K. and Bristol-Myers Squibb K.K., and personal fees from Taiho Pharmaceutical Co, Ltd, Ono Pharmaceutical Co, Ltd, MSD K.K., Pfizer Japan Inc, Kyowa Hakko Kirin Co, Ltd (currently Kyowa Kirin Co, Ltd), Nippon Boehringer Ingelheim Co, Ltd, and Nippon Kayaku Co, Ltd and grants from Merck Serono Co, Ltd (currently Merck Biopharma Co, Ltd) outside the submitted work; HS reports other from Mebix, Inc during the conduct of the study, personal fees from AstraZeneca K.K. outside the submitted work; IS reports grants from Nippon Boehringer Ingelheim Co, Ltd during the conduct of the study, grants and personal fees from AstraZeneca K.K., Taiho Pharmaceutical Co, Ltd, Nippon Boehringer Ingelheim Co, Ltd, Ono Pharmaceutical Co, Ltd, MSD K.K, Eli Lilly Japan K.K., Bristol-Myers Squibb K.K. and Chugai Pharmaceutical Co, Ltd and grants from Astellas Pharma Inc, Novartis Pharma K.K. and AbbVie GK, and personal fees from Pfizer Japan Inc outside the submitted work; YO reports grants and personal fees from Ono Pharmaceutical Co, Ltd and Bristol-Myers Squibb K.K. during the conduct of the study, grants and personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co, Ltd, Eli Lilly Japan K.K., Pfizer Japan Inc, MSD K.K., Kyorin Pharmaceutical Co, Ltd, Takeda Pharmaceutical Co, Ltd, Novartis Pharma K.K., Taiho Pharmaceutical Co, Ltd, and AbbVie GK, and personal fees from Celltrion Healthcare Co, Ltd, Amgen Inc, and Nippon Boehringer Ingelheim Co, Ltd, and grants from Kissei Pharmaceutical Co, Ltd, Loxo Oncology, Inc, and Janssen Pharmaceutical K.K. outside the submitted work; HH is an employee of Bristol-Myers Squibb K.K.; NY is an employee of Ono Pharmaceutical Co, Ltd; RM, YHK, OS, KK, HT, KM, TM and TH have nothing to declare., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

We conducted this phase I clinical study to examine the pharmacokinetic profiles and safety of lascufloxacin (LSFX), a novel quinolone antibacterial agent, in non-elderly Japanese healthy men and the effects of aging on LSFX pharmacokinetics in elderly Japanese healthy men. 1. After single-dose oral administration of LSFX 100-800 mg (capsules) to six healthy adults in fasting state, the C max and AUC last roughly increased in proportion to the doses. 2. After multiple-dose oral administration of LSFX 75 mg (tablets) once daily for 7 days to six healthy adults, plasma LSFX reached the steady state by Day 7. The cumulative factor of LSFX on Day 7 to Day 1 was 1.65 for the C max and 1.96 for the AUC tau . 3. Regarding pharmacokinetic parameters of plasma LSFX after single-dose administration of LSFX 75 mg tablets (final product) to 24 healthy adults in fed state, the C max was somewhat higher, 1.28 times more than that in fasting state, whereas no changes were found in the AUC last . We therefore proposed that food effects of LSFX on absorption were negligible. 4. No clinically significant safety problems of LSFX were found in a series of studies involving healthy adults conducted this time. 5. After single-dose oral administration of LSFX 200 mg (capsules) to six elderly people in fasting state, its pharmacokinetic parameters were similar to those in non-elderly people, with no significant safety concerns. Therefore, adjustment of dosage and administration was considered to be unnecessary for LSFX administration to elderly individuals., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Recent management after pancreatoduodenectomy recommends either omission of prophylactic drainage or early removal. This potentially makes the diagnosis of postoperative pancreatic fistula (POPF) difficult because the diagnosis is based on the amylase value of drain effluent. The aim of this study was to determine if severe POPF could be predicted independent of drainage information., Methods: Records of consecutive patients who underwent pancreatoduodenectomy between 2012 and 2018 were included for further analysis. The presence of a peripancreatic collection (PC) on routine postoperative (day7) computed tomography (early CT) and perioperative characteristics were analyzed., Results: PC appeared in 82/211 patients (39%) and was associated with clinically relevant POPF (p < 0.001). The C-reactive protein (CRP) on postoperative day5 was a good predictor of severe POPF (needing interventional therapy or Grade C) (area under the receiver operating characteristics curve, 0.802; 95% confidence interval, 0.702-0.875). Presence of a PC and a high CRP value were independent risk factors for severe POPF following multivariate analysis. The combination of CRP<5.0 mg/dL on postoperative day 5 and the absence of a PC had 98% negative predictive value., Conclusion: The combination of CRP measurement and PC evaluation by early CT was useful in predicting severe POPF after pancreatoduodenectomy., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: Giant sacral schwannomas are rare and difficult to treat. Unexpected neurologic deficits after surgery and tumor recurrence should be considered when surgery is performed. We attempt to remove the tumors via piecemeal total or subtotal excision, leaving parts of the capsule adjacent to nerves to preserve the nerves. This study aimed to present the cases of giant sacral schwannoma at our institutions as well as review the relevant literature and to discuss surgical management., Methods: This study included 11 patients (5 male and 6 female, mean age 53 years) with giant sacral schwannoma who were treated surgically. The clinical features, surgical details, and outcomes were investigated retrospectively., Results: The tumors were intraosseous type in 4 cases, dumb-bell type in 3 cases, and retroperitoneal type in 4 cases. The surgeries were performed by a combined anterior and posterior approach in 4 cases, a posterior approach in 4 cases, and an anterior approach in 3 cases. The tumors were removed via piecemeal total or subtotal excision in 7 cases, partial excision in 3 cases, and enucleation in 1 case. After surgery, symptoms improved in all cases. The tumor recurred in 2 patients after partial excision. No patients receiving piecemeal total or subtotal excision showed recurrence. One patient developed motor weakness after piecemeal subtotal excision, but the symptoms resolved., Conclusions: Adopting an appropriate surgical approach based on the location of the tumor is important. Piecemeal total or subtotal excision, with parts of the capsule adjacent to nerves left behind may help achieve a good outcome, avoiding a postoperative neurologic deficit., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: In patients with nonischemic dilated cardiomyopathy (NIDCM), native T1, partition coefficient (λ Gd ), and extracellular volume fraction (ECV) mapping may offer prognostic values beyond late gadolinium enhancement (LGE), by scaling the range of myocardial changes., Background: In patients with NIDCM, LGE is seen in 30% of patients and it indicates adverse prognosis., Methods: The study mapped 6 anatomical locations using all 4 cardiac magnetic resonance (CMR) tissue-characterizing methods and associated with outcome. The authors performed T1 mapping of the myocardium and the blood pool, before and serially after contrast injection, using a Look-Locker cine gradient-echo technique to obtain T1 and the corresponding reciprocal R1 values. λ Gd values were derived from the slopes of the least-squares regression lines for myocardial versus blood R1, then adjusted to serum hematocrit to yield ECV., Results: Consecutive 240 NIDCM patients (49 ± 16 years of age; 38% women) underwent CMR for cardiac function, LGE, native T1, λ Gd , and ECV. After a median of 3.8 years, 36 (15%) experienced major adverse cardiac events (MACE), including 22 heart failure hospitalizations and 14 deaths. Nonischemic LGE was detected in 34%, whereas ECV was elevated (≥1 location) in 58%. Comparing the 4 methods, mean ECV and λ Gd both demonstrated strong association with MACE (both p < 0.001). In contrast to native T1 and LGE, ECV values from all 6 locations were associated with MACE and death, with the anteroseptum being the most significant (p < 0.0001). The number of abnormal ECV locations correlated linearly with annual MACE rates (p = 0.0003). Mean ECV was the only predictor to enter a prognostic model that contained age, sex, New York Heart Association functional class, and left ventricular ejection fraction. For every 10% increase, mean ECV portended to a 2.8-fold adjusted increase risk to MACE (p < 0.001)., Conclusions: In this study of patients with NIDCM, mapping the myocardial extent of abnormality using ECV offers prognostication toward heart failure outcomes incremental to LGE or native T1 mapping., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess the utility of left ventricular (LV) entropy, a novel measure of myocardial heterogeneity, for predicting cardiovascular events in patients with dilated cardiomyopathy (DCM)., Background: Current risk stratification for ventricular arrhythmia in patients with DCM is imprecise. LV entropy is a measure of myocardial heterogeneity derived from cardiac magnetic resonance imaging that assesses the probability distribution of pixel signal intensities in the LV myocardium., Methods: A registry-based cohort of primary prevention implantable cardioverter-defibrillator patients with DCM had their LV entropy, late gadolinium enhancement (LGE) presence, and LGE mass measured on cardiac magnetic resonance imaging. Patients were followed from implantable cardioverter-defibrillator placement for arrhythmic events (appropriate implantable cardioverter-defibrillator therapy, ventricular arrhythmia, or sudden cardiac death), end-stage heart failure events (cardiac death, transplantation, or ventricular assist device placement), and all-cause mortality., Results: One hundred thirty patients (mean age 55 years, 83% men, LV ejection fraction 29%, mean LV entropy 5.58 ± 0.72, LGE present in 57%) were followed for a median of 3.2 years. Eighteen (14.0%) experienced arrhythmic events, 17 (13.1%) experienced end-stage heart failure events, and 7 (5.4%) died. LV entropy provided substantial improvement of predictive ability when added to a model containing clinical variables and LGE mass (hazard ratio: 3.5; 95% confidence interval: 1.42 to 8.82; p = 0.007; net reclassification index = 0.345, p = 0.04). For end-stage heart failure events, LV entropy did not improve the model containing clinical variables and LGE mass (hazard ratio: 2.03; 95% confidence interval: 0.78 to 5.28; p = 0.14). Automated LV entropy measurement has excellent intraobserver (mean difference 0.04) and interobserver (mean difference 0.03) agreement., Conclusions: Automated LV entropy measurement is a novel marker for risk stratification toward ventricular arrhythmia in patients with DCM., (Copyright © 2019. Published by Elsevier Inc.)

Background: Stathmin-1 regulates microtubule dynamics and is associated with malignant phenotypes in non-small cell lung cancer (NSCLC). This study evaluated its diagnostic value for differentiating between NSCLC and high-grade lung neuroendocrine tumor (HGNET)., Methods: Stathmin-1 protein expression was assessed by immunohistochemistry in 414 NSCLC (305 adenocarcinoma [AD], 102 squamous cell carcinoma [SCC], 7 large-cell carcinoma), 5 typical carcinoid (low-grade lung neuroendocrine tumor), and 34 HGNET (17 small-cell carcinoma [SCLC] and 17 large-cell neuroendocrine carcinoma [LCNEC]) surgical specimens and 57 NSCLC (29 AD and 28 SCC) and 42 HGNET (17 LCNEC and 25 SCLC) biopsy specimens. We also analyzed stathmin-1 mRNA levels in 81 NSCLCs and 26 HGNETs with the use of reverse transcription-polymerase chain reaction., Results: Among NSCLC samples, we saw high stathmin-1 protein expression in only three ADs, one SCC, and one large-cell carcinoma surgical samples, all five of which showed neuroendocrine characteristics in pathologic re-review; and low or intermediate expression in all five typical carcinoid surgical samples and all 57 NSCLC biopsy samples. In contrast, all HGNET surgical (n = 34) and biopsy (n = 42) samples showed high stathmin-1 expression. In reverse transcription-polymerase chain reaction, stathmin-1 expression was significantly higher in HGNET tissues than in NSCLC tissues (p < 0.001)., Conclusions: Stathmin-1 expression can help in differentiating NSCLC from HGNET., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Because of aggressive immunosuppression, heart transplant recipients have a high risk of de novo malignancy, which is a major cause of death and worse prognosis, regardless of the type. However, the impact of de novo malignancy on Japanese heart transplant recipients is unknown., Methods: We analyzed 103 Japanese heart transplant recipients over 18-years-old at the time of transplantation between April 1999 and April 2017. Patient characteristics and prognosis were compared between heart transplant recipients with or without de novo malignancy after heart transplantation (HTx). Additionally, univariate and multivariate analyses for the risk factors of de novo malignancy after HTx were performed., Results: De novo malignancy developed in 7 patients (6.8%; post-transplant lymphoproliferative disorders, n=3; Bowen's disease, n=1; colon cancer, n=2; bladder cancer, n=1). Follow-up time and previous antibody mediated rejection (AMR)≥grade 1 were risk factors of de novo malignancy after HTx in multivariate analysis (OR: 1.19, 95% CI: 1.00-1.42, p=0.043; and OR: 10.7, 95% CI: 1.37-83.68, p=0.038, respectively). History of malignancy was a potential risk factor, albeit not significant (OR: 23.05, 95% CI: 0.99-534.53, p=0.071). The survival rates in patients with de novo malignancy was significantly lower than in those without de novo malignancy (3-year survival rate: 100% versus 67%, p=0.0025)., Conclusions: Long follow-up time and previous AMR≥grade 1 were risk factors of de novo malignancy after HTx. Japanese heart transplant recipients with de novo malignancy have worse prognosis; therefore, screening examinations are important for early diagnosis., (Copyright © 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Soluble factors from the primary tumor induce recruitment of bone marrow-derived progenitors to form tumor-supportive microenvironments or pre-metastatic niches in distal organs before metastasis. How tumor-secreted factors condition the sites for tumor progression remains ambiguous. B16 melanoma produces the secreted form of T cell-inhibitory DC-HIL (sDC-HIL) that travels to distal organs and potentiates the metastatic capacity of tumor cells. We studied the molecular mechanisms and found that sDC-HIL binds to select endothelial cells that co-localize with the sites where bone marrow-derived progenitors and tumor cells migrate. sDC-HIL-bound endothelial cells exist at a similar frequency in mice with or without tumors, and they are strongly associated with survival of intravenously injected tumor cells in the lung. sDC-HIL binding conferred T-cell suppressor function on the ECs and awakened the angiogenic property by inducing vascular endothelial growth factor expression, resulting in enhanced transendothelial migration of bone marrow-derived progenitors and tumor cells, but not for T cells. This selectivity is achieved by the T-cell binding of sDC-HIL, which prevents formation of the leading edges required for chemotaxis. Finally, inducing tumor expression of sDC-HIL significantly reduced tumor-infiltrated T cells. Therefore, the highly metastatic attribute of B16 melanoma can be explained by the endothelial gatekeeper function of sDC-HIL that limits lymphocyte transmigration to pre-metastatic niches., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Estimating the risks associated with radiation from long-lived fission products (LLFP) in radioactive waste is essential to ensure the long-term safety of potential disposal sites. In this study, the amount of 93 Zr, a LLFP, was determined by ICP-MS after separating Zr from a spent nuclear fuel solution using a microvolume anion-exchange cartridge (TEDA cartridge). Zirconium in 9.4 M HCl was stably retained on the TEDA cartridge and readily eluted with 0.75 mL of a mixed solution of 9.4 M HCl and 0.01 M HF. The time taken to complete the Zr separation was 1.2 min. Almost all the other elements initially present in the spent nuclear fuel sample were removed, leading to accurate measurement of all six Zr isotopes ( 90 Zr, 91 Zr, 92 Zr, 93 Zr, 94 Zr, and 96 Zr). This demonstrated that the TEDA cartridge allowed highly selective separation of Zr regardless of its small bed volume of 0.08 cm 3 . The concentrations of these isotopes were determined by an isotope-dilution method using a natural Zr standard that has a different isotopic composition from that of the spent nuclear fuel sample. The amount of 93 Zr in an initial spent nuclear fuel pellet was 1081 ± 79 ng per mg of 238 U. The measured concentrations of all Zr isotopes, as well as the isotopic composition, were consistent with values predicted using a burnup calculation code., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Piebaldism is a pigmentary disorder characterized by a white forelock and depigmented patches. Although the loss-of-function mutations in the KIT gene underlie the disease, the intracellular dynamics of the mutant KIT are largely unknown. We herein report a Japanese family with piebaldism in which the affected members showed a mild phenotype., Objective: The objective of this study is to investigate the functions and intracellular dynamics of the mutant KIT protein., Methods: We performed genetic analyses of the KIT gene using peripheral blood cells. We analyzed the intracellular localization of the mutant KIT protein in HEK293T cells transfected with wild-type (Wt) and/or mutant KIT genes. Immunoprecipitation analyses, immunoblotting and immunofluorescence studies were performed using antibodies against KIT and downstream signaling proteins. Glycosidase digestion analysis was performed to clarify the intracellular localization of KIT protein., Results: A genetic analysis revealed a novel heterozygous mutation c.645&#95;650delTGTGTC which results in the in-frame deletion of Val 216 and Ser 217 in the extracellular domain of KIT. Immunoprecipitation analyses confirmed that the wild and mutant KIT formed a heterodimer after treatment with stem cell factor (SCF); however, the phosphorylation of the downstream signaling factors was decreased. In an immunofluorescence study, the mutant KIT accumulated predominantly in the endoplasmic reticulum (ER) and was sparsely expressed on the cell surface. A glycosidase digestion study revealed that the mutant KIT is predominantly localized in the ER., Conclusion: These data reveal an aberrant function and intracellular localization of mutant KIT protein in piebaldism., (Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

In Japan, most tularemia cases occur after contact with hares (hunting, cooking) and involve the glandular or ulceroglandular form. Here, we present a case of typhoidal tularemia in a 72-year-old Japanese male farmer who presented with fever, fatigue, and right lower abdominal pain. Computed tomography revealed intestinal wall thickening at the ascending colon, pleural effusion, and ascites. Following an initial diagnosis of bacterial enteric infection, his symptoms deteriorated after a week-long cephalosporin treatment course. The patient lived in an area endemic for scrub typhus; the antibiotic was changed to a tetracycline on suspicion of scrub typhus infection. His symptoms rapidly improved after initiation of minocycline treatment. Later, blood tests revealed marked increases in serological tests against Francisella tularensis exclusively, and the patient was diagnosed with typhoidal tularemia. Typhoidal tularemia may be characterized by any combination of general symptoms, but does not exhibit the local manifestations associated with other forms of tularemia. The patient, in this case, had no direct contact with hares or other wild animals and did not present with local manifestations of tularemia. Physicians should consider this disease, especially when tick-borne disease is suspected in the absence of local wounds, eschar, ulcers, or lymphadenopathy., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Upon initiation and progression of cancer, α 1 -acid glycoprotein (AGP) possessing highly sialylated and fucosylated glycans appears in the serum, and recently has attracted a great deal of attention, as a potential biomarker of tumorigenesis in humans., Methods: To establish a rapid and precise method for the quantitative assay of fucosylated AGP in serum samples, we developed an enzyme immunoassay (EIA) bearing an anti-AGP antibody and a fucose-binding lectin, Aleuria aurantia (AAL) with additional endeavor to improved sample handling, and antibody preparations., Results: The amounts of fucosylated AGP could be determined by the present method with a good performance feature in all tested samples from both cancer patients and healthy controls. From cancer patients under chemotherapy we show that fucosylated AGP could be a clinically relevant biomarker for cancer progression or prognosis as well as for an early assessment of clinical response and treatment outcomes. Furthermore, in a different setting, fucosylated AGP also showed relevance in patients who received immunotherapy with an anti-programmed cell death-1 (PD-1) antibody., Conclusions: α1,3fucosylated AGP is a potential biomarker of cancer initiation, progression and response to treatment in cancer patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

An efficient method for rare metal recovery from environmental water and urban mines is in high demand. Toward rapid and high-resolution rare metal ion separation, a novel bis(2-ethylhexyl) phosphate (HDEHP)-impregnated graft-type particle as a filler for a chromatography column is proposed. To achieve rapid and high-resolution separation, a convection-flow-aided elution mode is required. The combination of 35 μm non-porous particles and a polymer-brush-rich particle structure minimizes the distance from metal ion binding sites to the convection flow in the column, resulting in minimized diffusional mass transfer resistance and the convection-flow-aided elution mode. The HDEHP-impregnated graft-type non-porous-particle-packed cartridge developed in this study exhibited a higher separation performance for model rare metals, neodymium (III) and dysprosium (III) ions, and a narrower peak at a higher linear velocity, than those of previous HDEHP-impregnated fiber-packed and commercially available Lewatit ® VP OC 1026-packed cartridges., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: It remains unclear whether treatment of dyslipidemia with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) reduces the risk of developing hypertension., Objective: In this post-hoc analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study, a large-scale primary prevention trial with pravastatin, we examined the preventive effect of pravastatin on the future development of hypertension in patients with hypercholesterolemia., Methods: Of the overall (MEGA) Study population, 3397 nonhypertensive patients at baseline were enrolled in this study. The patients were randomly assigned to either the diet alone group (n = 1722) or the diet plus pravastatin group (n = 1675) and then were followed-up for a median of 36 months to determine new-onset hypertension., Results: During the follow-up period, 1595 patients developed hypertension (49.1% in the diet alone group and 44.7% in the diet plus pravastatin group). After adjusting for multiple covariates, the diet plus pravastatin group showed a 10% reduction in the risk of developing hypertension (hazard ratio 0.90, 95% confidence interval 0.81-0.998), compared with the diet alone group. Subgroup analyses revealed that the preventive effect of pravastatin on the development of hypertension was pronounced in patients aged ≥60 years, men, those with chronic kidney disease or diabetes mellitus and those without obesity., Conclusions: Pravastatin reduced the risk of developing hypertension in Japanese patients with hypercholesterolemia. The risk reduction of cardiovascular disease with statins could be partly explained by their preventive effect on the development of hypertension., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: The hypothesis of this retrospective study was that the duration of twice-daily (BID) thoracic radiotherapy (TRT) and time from the start of any treatment to the end of chest irradiation (SER) would predict outcomes in limited-disease small-cell lung cancer., Materials and Methods: All 81 patients received 45 Gy in 30 fractions BID with a ≥ 6-hour interval and concurrent chemotherapy of platinum and etoposide., Results: The median radiotherapy duration was 25 days (range, 21-38 days). The 5-year overall survival rates were 26.2% (95% confidence interval [CI], 14.3%-38.0%), and the median survival time was 30 months (95% CI, 15.5-44.5 months). Using multivariate regression analysis, the significant predictors of survival were the sum of the diameters of the primary tumor and metastatic lymph nodes, male gender, age ≥ 60 years, and the duration of BID-TRT (hazard ratio [HR], 1.15; 95% CI, 1.06-1.25; HR, 2.38; 95% CI, 1.13-5.02; HR, 2.38; 95% CI, 1.10-5.17; and HR, 1.08; 95% CI, 1.01-1.15, respectively). A total of 70 of 81 patients (86%) received radiotherapy during the first chemotherapy cycle. The median SER was 29 days (range, 21-109 days). The 5-year local control rate was 48.7% (95% CI, 33.9%-63.6%). The significant predictors of local control were the sum of the diameters of the primary tumor and metastatic lymph nodes, age ≥ 60 years, and SER (HR, 1.18; 95% CI, 1.06-1.31; HR, 4.18; 95% CI, 1.23-14.24; and HR, 1.02; 95% CI, 1-1.04, respectively)., Conclusions: The duration of BID-TRT and SER were identified as one of the significant predictors of survival and local control in limited-disease small-cell lung cancer treated with concurrent chemoradiotherapy at 45 Gy in 30 fractions, respectively., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atopic dermatitis (AD) is a multifactorial inflammatory skin disease characterized by skin barrier dysfunction, allergic inflammation and intractable pruritus resistant to conventional antipruritic treatments, including H 1 -antihistamines. Granzymes (Gzms) are a family of serine proteases expressed by cytotoxic T lymphocytes and natural killer cells that have been shown to modulate inflammation. However, the relationship between Gzms and pathology in AD remains unclear., Objective: This study assessed the correlation between plasma GzmB levels and severity of pruritus and dermatitis, in AD patients., Methods: Plasma was collected from 46 patients with AD, 24 patients with psoriasis, and 30 healthy controls. AD severity was assessed with the scoring atopic dermatitis (SCORAD) index, psoriasis severity with the psoriasis area and severity index (PASI), and degree of pruritus by visual analogue scale (VAS) score. GzmA, GzmB and gastrin releasing peptide (GRP) levels were measured by enzyme-linked immunosorbent assays., Results: Plasma GzmB concentrations were significantly higher in patients with AD and psoriasis than in healthy controls. Correlation analyses showed that plasma GzmB concentrations positively correlated with SCORAD and serum levels of severity markers such as thymus and activation-regulated chemokine, and lactate dehydrogenase in AD patients. Moreover, plasma levels of GRP, an itch-related peptide, were higher in patients with AD, positively correlating with VAS score and plasma GzmB level. In addition, plasma GzmB concentration was significantly lower in the treatment group than the untreated group with AD. Meanwhile, there were no correlations among GzmB levels, VAS score and PASI score in patients with psoriasis. In contrast to the results of plasma GzmB, plasma GzmA levels were unchanged among AD, psoriasis and healthy groups, and showed no correlations with VAS score and SCORAD index in patients with AD., Conclusion: Plasma GzmB levels may reflect the degree of pruritus and dermatitis in patients with AD., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Pancreatic cancer is a highly lethal disease, for which mortality closely parallels incidence. Most patients with pancreatic cancer remain asymptomatic until the disease reaches an advanced stage. There is no standard programme for screening patients at high risk of pancreatic cancer (eg, those with a family history of pancreatic cancer and chronic pancreatitis). Most pancreatic cancers arise from microscopic non-invasive epithelial proliferations within the pancreatic ducts, referred to as pancreatic intraepithelial neoplasias. There are four major driver genes for pancreatic cancer: KRAS, CDKN2A, TP53, and SMAD4. KRAS mutation and alterations in CDKN2A are early events in pancreatic tumorigenesis. Endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration offer high diagnostic ability for pancreatic cancer. Surgical resection is regarded as the only potentially curative treatment, and adjuvant chemotherapy with gemcitabine or S-1, an oral fluoropyrimidine derivative, is given after surgery. FOLFIRINOX (fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) are the treatments of choice for patients who are not surgical candidates but have good performance status., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Rotational atherectomy (rotablation) has been proposed as a potentially superior strategy for percutaneous coronary intervention (PCI) in complex and severely calcified lesions., Objectives: We hypothesized that a per-lesion coronary artery calcium score determined by multidetector computed tomography (MDCT) would be useful for predicting the requriement for rotablation during PCI., Methods: MDCT was performed in patients with stable angina pectoris who were scheduled for first PCI. In 116 consecutive subjects (168 target lesions) with successful PCI, MDCT and quantitative coronary angiography (QCA) data were retrospectively evaluated regarding their ability to predict rotablation., Results: PCI without rotablation was performed in 105 patients (154 lesions), and rotablation was added in 11 patients (14 lesions). Patients with rotablation had significantly higher SYNTAX scores (p = 0.007) and total calcium scores (p < 0.001) than those without rotablation. Per-lesion, a lesion length ≥20 mm and diameter stenosis ≥74% on QCA as well as a per-lesion calcium score ≥453 and calcification arc ≥270 in MDCT predicted rotablation. After adjustment for potential confounding variables, a high per-lesion calcium score was an independent predictor of rotablation (odds ratio 31.3, 95% confidence interval 2.8-345, p = 0.005, sensitivity 93% and specificity 88%)., Conclusion: The extent of target lesion calcification in MDCT, a simple marker of calcified plaque, is useful for predicting the need for rotablation during PCI., (Copyright © 2016 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Genetic analyses have revealed an important association between A-kinase anchoring proteins (AKAPs) and the intracellular calcium modulating system. AKAP5, also known as AKAP79/150, is an anchoring protein between PKA and voltage-dependent calcium channels, ryanodine receptor-2, phospholamban and other molecules. The aim of the present study was to elucidate the physiological importance of AKAP5 in the creation of cardiac rhythm using AKAP5-null mice. ECG analysis showed a normal sinus rhythm and a decreased responsiveness to isoproterenol in AKAP5-null mice compared with wild-type mice. Analysis of heart rate variability revealed that the R-R interval was unstable in AKAP5-null mutants and that the low-frequency components had decreased, indicating that the tonus of the sympathetic nervous system was affected. Furthermore, the atrium of the AKAP5-null mice showed a decreased positive inotropic response to isoproterenol, indicating the involvement of AKAP5 in a PKA-dependent pathway. Thus, our present study revealed that AKAP5 plays a significant role in the regulation of sympathetic nerve activities., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Whether converting to everolimus (EVL) from mycophenolate mofetil (MMF) during the maintenance period after heart transplantation (HTx) reduces cardiac allograft vasculopathy (CAV) progression remains unclear. We sought to determine the effect of converting from MMF with standard-dose calcineurin inhibitors (CNIs) to EVL with low-dose CNIs on CAV progression., Methods: We retrospectively reviewed the medical records of 63 HTx recipients who survived at least at 1 year after HTx. Twenty-four recipients were converted from MMF to EVL (EVL group, 2.2 ± 2.3 years after HTx), while 39 recipients were maintained on MMF (MMF group, 2.4 ± 2.2 years after HTx). The EVL group underwent three-dimensional intravascular ultrasound (3D-IVUS) analysis before and 1 year after conversion to EVL, and these data were compared with data from 2 consecutive IVUS in the MMF group., Results: IVUS indices in the EVL group at 1 year after conversion did not show increased CAV development, whereas a significant increase in %plaque volume (p=0.006) and decrease in lumen volume (p<0.001) were observed in the MMF group. EVL conversion was significantly associated with smaller increases in %plaque volume (p=0.004) and smaller decreases in lumen volume (p=0.017). IVUS indices in the late EVL conversion group (≥ 2 years) also did not exhibit increased CAV development, while those in the MMF group did., Conclusions: Conversion to EVL from MMF in maintenance periods after HTx may decrease the rate of CAV progression based on IVUS indices., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: This 8-year follow-up cohort study evaluated and compared the degree of coronary atherosclerosis in chronic kidney disease (CKD) according to the Kidney Disease: Improving Global Outcomes (KDIGO) classification using multivessel angioscopy and investigated the impact of the vulnerability of coronary arteries on the relationship between the classification and risk of acute coronary syndromes (ACS)., Methods: We studied 89 coronary artery disease patients who underwent angioscopic observation of multiple coronary arteries. The patients were divided into 3 groups: Risk 0, 1, and 2 were equivalent to low risk, moderately high risk, and high and severely high risk, respectively. We examined the frequencies of complex and yellow plaques. Furthermore, we followed all patients for de novo ACS, dividing into two groups according to the existence of vulnerable coronary atherosclerosis (VCA) based on angioscopic findings., Results: The number of yellow plaques per vessel, maximum yellow grade, number of complex plaques per vessel, and cumulative incidence of ACS in all patients were significantly associated with Risk grade progression (p < 0.05 for trend). Among the patients with VCA, Risk 2 had a higher incidence of ACS than Risk0 (p < 0.014) and Risk 1 (p < 0.007), whereas Risk 0 and Risk 1 had similar outcomes. Among the patients without VCA, no de novo ACS events were seen regardless of the Risk group., Conclusions: Coronary atherosclerosis progressed in the early stages of CKD, and once it reached to a vulnerable stage, advanced CKD patients had a synergistically increased risk of ACS., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

A cassette-microdose (MD) clinical study was performed to demonstrate its usefulness for identifying the most promising compound for oral use. Three Ca-channel blockers (nifedipine, nicardipine, and diltiazem) were chosen as model drugs. In the MD clinical study, a cassette-dose method was employed in which three model drugs were administered simultaneously. Both intravenous (i.v.) and oral (p.o.) administration studies were conducted to calculate the oral bioavailability (BA). For comparison, p.o. studies with therapeutic dose (ThD) levels were also performed. In all studies, blood concentrations of each drug were successfully determined using liquid chromatography-mass spectrometry with the lower limit of quantification of 0.2-2.0 pg/mL. Oral BA of nifedipine in the MD study was approximately 50% and in the same range with that obtained in the ThD study, whereas other two drugs showed significantly lower BA in the MD study, indicating a dose-dependent absorption. In addition, compared with the ThD study, absorption of nicardipine was delayed in the MD study. As a result, nifedipine was considered to be most promising for oral use. In conclusion, a cassette-MD clinical study is of advantage for oral drug development that enables to identify the candidate having desired properties for oral use., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

The Japanese Three Academic Societies Joint Antimicrobial Susceptibility Surveillance Committee has conducted a nationwide surveillance on antimicrobial susceptibility patterns and rates of isolation in 6 otolaryngological diseases. The surveillance program was conducted in the otorhinolaryngological departments of 29 universities, and their 26 affiliated hospitals. Patients suffering from acute otitis media, chronic otitis media, acute nasal sinusitis, chronic nasal sinusitis, acute tonsillitis, and peritonsillar abscess between January 2011 and June 2012 were investigated. The collected swab or incision samples were cultivated for microbial identification, and the drug susceptibility of detected bacteria was measured at the Kitasato University Research Center for Infections and Antimicrobials. The surveillance focused on three gram-positive bacteria (Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus), three gram-negative bacteria (Haemophilus influenzae, Moraxella Catarrhalis, and Pseudomonas aeruginosa), and three anaerobic bacteria (Peptostreptococcus spp., Prevotella spp., and Fusobacterium spp.). Bacterial susceptibility to 39 antimicrobial drugs was investigated. We compared bacterial isolation ratio of each disease in this surveillance from those of past 4 times surveillance which we performed formerly, and we also compared percentage of main drug resistant strains from those of past 4 times surveillance. The age composition between this time and former surveillances was not statistically significant by student-t test. We were unable to completely resolve the rise in resistant bacteria, such as methicillin-resistant S. aureus, penicillin-resistant S. pneumoniae, penicillin-intermediate resistant S. pneumoniae, beta-lactamase non-producing ampicillin-resistant H. influenzae, beta-lactamase producing ampicillin-resistant H. influenzae, and beta-lactamase producing amoxicillin clavulanic acid-resistant H. influenzae. We suggest promoting the proper usage of antimicrobial drugs in order to avoid the spread of these bacteria., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Genetic analyses have revealed an important association between P/Q-type calcium channel activities and hereditary neurological disorders. The P/Q-type channels are composed principally of heterologous multimeric subunits including CaV2.1 and CaVβ4. Of these, the β4 subunit is thought to play a significant role in channel physiology, because a mouse line mutant in that subunit (the lethargic mouse: lh) exhibits a severe ataxic phenotype. The aim of the present study was to elucidate the physiological importance of the β4 subunit. ECG analysis showed that the T wave was high in 8-week-old lh mutants; this may be associated with hyperkalemia. Upon pharmacological ECG analysis, 2-3-week-old lh mutants exhibited reduced responses to a β-blocker and a muscarinic receptor antagonist. Analysis of heart rate variability revealed that the R-R interval was unstable in lh mutants and that both the low- and high-frequency components had increased in extent, indicating that the tonus of both the sympathetic and parasympathetic nervous systems was modified. Thus, our present study revealed that the β4 subunit played a significant role in regulation of sympathetic and parasympathetic nerve activities., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Orexin, also known as hypocretin, is a secreted neuropeptide implicated in the regulation of sleep and food intake. In the present study, we examined the importance of orexin in regulation of the sympathetic nervous system using an orexin/ataxin-3 transgenic (OXTg) rat, which has a minimal number of orexin neurons. RT-PCR analysis identified expression of prepro-orexin and orexin receptor-1 (OX1R) in the superior cervical ganglion (SCG), and expression of another receptor (OX2R) was marginal in the wild-type rat. The orexin/ataxin-3 transgenic rat showed increased expression of OX1R and OX2R, whereas expression of prepro-orexin was undetectable, suggesting a compensatory increase in both receptors. In the ECG recording (R-R interval), orexin/ataxin-3 transgenic rats showed decreased responsiveness to the β-adrenergic blocker propranolol. Furthermore, OXTg rats had deteriorated R-R interval regulation, indicating involvement of the orexin system in sympathetic nerve regulation. This was accompanied by decreased baroreflex and responsiveness to β-adrenergic blocker in blood pressure recording, also suggesting involvement of the orexin system in sympathetic nerve regulation. Histological examination revealed hypotrophic changes in the transgenic heart, suggesting involvement of the orexin system in cardiac development. Taken together, our present results indicate involvement of the orexin system in sympathetic nerve control., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Monilethrix is a hair shaft anomaly characterized by beaded hair with periodic changes in hair thickness. Mutations in the desmoglein 4 (DSG4) gene reportedly underlie the autosomal recessive form of the disease. However, the pathogenesis and cellular basis for the DSG4 mutation-induced monilethrix remained largely unknown. We report a Japanese female patient with monilethrix. Observation of her hair shaft by means of transmission electron microscopy showed fewer desmosomes and abnormal keratinization. Genetic analysis revealed a homozygous mutation, c.2119delG (p.Asp707Ilefs*109), in the DSG4 gene, which was predicted to cause a frameshift and premature termination in the intracellular region of the DSG4 protein. The mutation has not been reported previously. In the patient's hair shaft, we detected reduced but partial expression of the mutant DSG4 protein. Cellular analyses demonstrated that the mutant DSG4 lost its affinity to plakoglobin and accumulated in the endoplasmic reticulum (ER). The amounts of mutant DSG4 were increased by proteasome inhibitor treatment, and the expression of an ER chaperone, GRP78/BiP, was elevated in the patient's skin. Collectively, these results suggest that the dysfunctional mutated DSG4, tethered in the ER, undergoes ER-associated degradation, leading to unfolded protein response induction, and thus ER stress may have a role in the pathogenesis of monilethrix.