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Junya Kojima,1 Masanori Ono,1 Koichiro Tasaki,2 Takeshi Nagai,2 Toshitaka Nagao,2 Sho Rinno,3 Yoshihiko Kanno,3 Rie Yoshida,1 Tomoo Suzuki,1 Naoaki Kuji,1 Hirotaka Nishi1 1Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo, Japan; 2Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan; 3Department of Nephrology, Tokyo Medical University, Tokyo, JapanCorrespondence: Masanori Ono, Department of Obstetrics and Gynecology, Tokyo Medical University, 6-7-1, Nishishinjuku, Shinjuku, Tokyo, 160-0023, Japan, Tel +81-3-3342-6111, Email masaoriono@gmail.comBackground: Pregnancy-related acute kidney injury (Pr-AKI) is associated with significant maternal and fetal morbidity and mortality, with a three- to four-fold increase in perinatal mortality. Pr-AKI can arise from various obstetric complications, such as hyperemesis gravidarum, septic abortion, hypertensive disorders of pregnancy, pyelonephritis, and antiphospholipid antibody syndrome. Therefore, early diagnosis and appropriate intervention, including the identification of the underlying etiology, are important to effectively manage Pr-AKI. Therefore, we report a case of Pr-AKI after early miscarriage in a patient without hyperemesis gravidarum or septic abortion whose renal function gradually improved postoperatively for miscarriage.Case Presentation: A 34-year-old primigravid woman was referred to us for perinatal management at 6 weeks of gestation. Unfortunately, she was diagnosed with miscarriage 1 week later. The patient had no history of hyperemesis gravidarum or septic abortion; however, she developed oliguria, and her serum creatinine and blood urea nitrogen levels were abnormally increased. Consequently, she underwent a renal biopsy to evaluate renal dysfunction, which indicated tubulointerstitial damage. The patient also underwent manual vacuum aspiration for a miscarriage. Postoperatively, her urine output increased, and her renal function improved. She was determined to have experienced Pr-AKI due to her miscarriage.Conclusion: Our patient had Pr-AKI after a miscarriage in the absence of other causes. This case report highlights the presence of unknown causes of Pr-AKI, warranting further research for the development of preventive interventions.Keywords: pregnancy-related acute kidney injury, miscarriage, missed abortion, creatinine, renal insufficiency

Chihiro Kawasoe,1,2 Yoshi Miyamoto,1,3 Kaoru Ito,1 Takaya Murashima,1 Takahiro Nagai,1 Hiroki Takamori,1 Takumi Kiwaki,4 Toshio Kamimura,1 Shoichiro Mukai,1 Toshiyuki Kamoto1 1Department of Urology, Faculty of Medicine, Miyazaki University Hospital, Miyazaki, Japan; 2Department of Urology, Koga General Hospital, Miyazaki, Japan; 3Department of Urology, Miyazaki Prefectural Nichinan Hospital, Miyazaki, Japan; 4Section of Oncopathology and Regenerative Biology, Faculty of Medicine, Miyazaki University, Miyazaki, JapanCorrespondence: Shoichiro Mukai, Department of Urology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan, Tel +81-985-85-2968, Fax +81-985-85-6958, Email syoichiro_mukai@med.miyazaki-u.ac.jpAbstract: Epithelioid angiomyolipoma (EAML) is a rare variant of AML with malignant potential. It is occasionally difficult to distinguish EAML from renal cell carcinoma (RCC) on imaging. A 72-year-old woman was admitted to our hospital for the treatment of a left renal tumor with relatively high blood flow and a tumor thrombus extending to the inferior vena cava, suggesting RCC. The patient underwent presurgical combination therapy with axitinib and pembrolizumab. This treatment significantly shortened the thrombus, and radical nephrectomy was performed. The pathological findings were compatible with EAML, and the treatment effects were observed. We report a case treated pre-surgically with a combined therapy of pembrolizumab and axitinib, with a favorable response as a treatment option for EAML.Keywords: epithelioid angiomyolipoma, axitinib, pembrolizumab, tumor thrombus, presurgical treatment

Norihiko Sukenaga,1 Yuka Matsuki,2 Lynn Maeda,3 Takako Nagai,1 Kazuma Hashimoto,1 Yumiko Takao,1 Munetaka Hirose1 1Department of Anesthesiology and Pain Medicine, Hyogo College of Medicine, Hyogo, Japan; 2Department of Anesthesiology and Reanimatology, Faculty of Medicine Sciences, University of Fukui, Fukui, Japan; 3Department of Anesthesiology and Pain Management, Nishinomiya Municipal Central Hospital, Hyogo, JapanCorrespondence: Munetaka HiroseDepartment of Anesthesiology and Pain Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, JapanTel +81-798-45-6392Email mhirose@hyo-med.ac.jpBackground: Persistent idiopathic facial pain (PIFP) is a subtype of painful cranial neuropathies and other facial pains. The involvement of neuropathic mechanisms in PIFP, however, remains controversial. Using the Douleur Neuropathique 4 (DN4) questionnaire, the present study examined neuropathic characteristics in patients with PIFP.Methods: The multi-institutional retrospective study collected the following clinical data from 205 consecutive patients with adult chronic pain: gender, age, BMI, diseases causing chronic pain, disease duration, visual analogue scale score of pain strength, and DN4 score. To compare neuropathic characteristics between PIFP and postherpetic neuralgia (PHN), we selected patients with PIFP (n=19) and patients with PHN (n=33), and performing a case–control study in which each patient with PHN or PIFP was matched by age and gender (n=16 in each group).Results: DN4 score was significantly lower in the PIFP group than in the PHN group before and after matching. The incidence when DN4 was ≥4 was 10.5% before matching and 12.5% after matching in the PIFP group, both of which were significantly lower than those in the PHN group before and after matching (66.7% and 75.0%).Conclusion: Ten percent of the PIFP patients likely show neuropathic pain characteristics.Keywords: DN4, neuropathic pain, orofacial pain

Koki Tsuchiya,1 Koji Ishikawa,1 Soji Tani,1 Yusuke Oshita,2 Takuma Kuroda,1 Ryo Yamamura,1 Haruka Emori,1 Hiroshi Maruyama,1 Akira Matsuoka,1 Yoshifumi Kudo,1 Toshiyuki Shirahata,1 Tomoaki Toyone,1 Takashi Nagai,1 Katsunori Inagaki11Department of Orthopaedic Surgery, Showa University School of Medicine, Tokyo 142-8666, Japan; 2Department of Orthopaedic Surgery, Yamanashi Red Cross Hospital, Yamanashi, JapanAbstract: Discontinuation of denosumab during osteoporosis treatment leads to rapid loss of bone mineral density and induces a bone turnover rebound effect. Previous studies have reported analysis based on dual-energy X-ray absorptiometry scanning (DXA). Here, we report the first case involving analysis of three-dimensional bone mineral density and bone strength, measured by quantitative computed tomography (QCT) after discontinuation of denosumab. An 82-year-old woman who discontinued denosumab because of patient’s wish was administered the fifth dose after a gap of 14 months. Her bone mineral density evaluated by DXA and QCT, bone strength, and bone turnover marker levels showed significant rebound phenomenon. The levels of the cortical parameters of the hip were also decreased indicating an increased risk of femoral fractures after denosumab interruption. Our case highlights the increased risk of fractures after discontinuation of denosumab. Therefore, denosumab must be used judiciously without interruption in the dosage schedule.Keywords: lumbar spine, femoral neck, bone turnover markers, cortical bone, biomechanical analysis

Kozue Nakahara,1 Koji Yamasaki,1 Takahiro Nagai,1 Masato Fujii,1 Takahiro Akioka,1 Hiroki Takamori,1 Naoki Terada,1 Shoichiro Mukai,1 Yuichiro Sato,2 Toshiyuki Kamoto11Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; 2Section of Diagnostic Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, JapanBackground: Matriptase, which is a Type II transmembrane serine protease, has the potential to activate several growth factors, including pro-hepatocyte growth factor (HGF). A G protein-coupled transmembrane cell-surface receptor and a protease-activated receptor 2 (PAR-2) are also required for activation by matriptase. Activation of PAR-2 has been reported to induce the progression of various cancers. In a previous study, we evaluated the correlation between upregulation of MET phosphorylation with high matriptase expression and worse prognosis in patients with muscle invasive bladder cancer; however, expression of PAR-2, matriptase and MET in non-muscle invasive bladder cancer (NMIBC) has not been evaluated.Materials and methods: We retrospectively analyzed the expression of PAR-2, matriptase and MET using 55 paraffin-embedded specimens obtained from patients with NMIBC by immunohistochemistry.Results: MET was significantly expressed in high-grade urothelial carcinoma (UC) and pathological T1 cancers. High expression of PAR-2 was significantly associated with a worse recurrence rate in NMIBC. In subgroup analysis, the expression of PAR-2 was also correlated with high recurrence rate in low-grade UC. In addition, expression of matriptase tended to correlate with worse recurrence rate in high-grade UC.Conclusion: Increased expression of PAR-2 was significantly correlated with worse recurrence rate in patients with NMIBC. In addition, expression of matriptase also indicated a tendency toward recurrence in high-grade UC, suggesting an important role of matriptase-induced PAR-2 activation in NMIBC.Keywords: PAR-2, matriptase, MET, NMIBC

Koji Ishikawa,1–3 Takashi Nagai,1 Koki Tsuchiya,1 Yusuke Oshita,3 Takuma Kuroda,1 Hiroshi Ito,1 Soji Tani,1 Yusuke Dodo,1 Tomoaki Toyone,1 Katsunori Inagaki1 1Department of Orthopaedic Surgery, Showa University School of Medicine, Tokyo, Japan; 2Department of Orthopaedic and Spine Surgery, Sanraku Hospital, Tokyo, Japan; 3Department of Orthopaedic Surgery, Yamanashi Red Cross Hospital, Yamanashi, Japan Abstract: Denosumab is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL) that is used for the treatment of osteoporosis. Denosumab-induced hypocalcemia is a rare but important adverse event, which is usually asymptomatic in patients with osteoporosis. It is also known that hypocalcemia is common in patients with bone metastases and severe renal impairment. Here we report a case of symptomatic hypocalcemia following administration of 60 mg of denosumab in a patient with high bone turnover and no renal impairment (estimated glomerular filtration rate [eGFR], 71 mL/min), despite prophylactic oral vitamin D administration. This report supports our observation that there is a risk of protracted and marked denosumab-induced hypocalcemia in patients with high bone turnover, irrespective of their degree of renal impairment. Keywords: denosumab, symptomatic hypocalcemia, high bone turnover, no renal impairment

Toyoharu Kamibeppu, Koji Yamasaki, Kozue Nakahara, Takahiro Nagai, Naoki Terada, Hiromasa Tsukino, Shoichiro Mukai, Toshiyuki Kamoto Department of Urology, Faculty of Medicine, University of Miyazaki, Kiyotake, Japan Background: Caveolin (Cav)-1 and Cav-2 are cell membrane proteins, which are structural proteins of caveolae and are reported to be positive regulators of cell survival and metastasis in prostate cancer (PC). In a previous study, we reported that elevated levels of Cav-1 and Cav-2 were significantly associated with PC progression. However, their functions in PC have not yet been clarified. In this study, we examined the function of Cav-1 and Cav-2 in PC cell invasiveness and motility.Materials and methods: We introduced Cav-1- and Cav-2-specific small interfering into PC3 cells to knock-down (KD) both molecules. We also performed cell proliferation assay, wound healing assay, migration assay, and invasion assay using PC3 cells and compared the results between Cav-1-KD, Cav-2-KD, and negative control PC3 cells. In addition, we performed real-time quantitative PCR (RT-qPCR) and RT2 Profiler PCR Array analysis to identify factors influencing migration.Results: We observed no significant difference in the proliferative and invasive activities of Cav-1-KD and Cav-2-KD PC3 cells; however, the cell motility was significantly decreased compared with negative control PC3 cells. RT-qPCR revealed that the expression of vimentin and N-cadherin was downregulated in Cav-1-KD PC3 cells. In addition, PCR array revealed a decreased expression of MGAT5, MMP13, and MYCL in Cav-1-KD PC3 and ETV4, FGFR4, and SRC in Cav-2-KD PC3.Conclusion: Cav-1 and Cav-2 may positively contribute to the upregulation of castration-resistant PC cell migration. Cav-induced regulation of several molecules including vimentin, N-cadherin, MGAT5, MMP13, MYCL, ETV4, FGFR4, and SRC may have an important role in PC3 cell motility. However, further examination will be required. Keywords: caveolin-1, caveolin-2, CRPC, cell motility

Taku Naiki,1 Keitaro Iida,1 Toshiki Etani,1 Takashi Nagai,2 Yutaro Tanaka,1 Yosuke Sugiyama,3 Ryosuke Ando,1 Shuzo Hamamoto,1 Rika Banno,4 Daisuke Nagata,4 Noriyasu Kawai,1 Takahiro Yasui1 1Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan; 2Department of Urology, Anjo Kosei Hospital, Anjo, Japan; 3Department of Pharmacy, Nagoya City University Hospital, Nagoya, Japan; 4Department of Urology, Konan Kosei Hospital, Konan, Japan Background: The objective of this study was to evaluate the efficacy of a combination of gemcitabine and docetaxel (GD) as a second-line treatment for elderly patients with metastatic urothelial carcinoma (mUC).Patients and methods: A total of 122 patients with mUC who were previously treated with platinum-based chemotherapy received second-line GD therapy from July 2010 to June 2016. This consisted of 800 mg/m2 gemcitabine and 40 mg/m2 docetaxel on days 1 and 8 in each 21-day cycle. Using pooled cumulative data, we divided patients into the following three groups based on age:

Koji Ishikawa,1 Takashi Nagai,1 Keizo Sakamoto,1 Kenji Ohara,2 Takeshi Eguro,1,2 Hiroshi Ito,1 Yoichi Toyoshima,1 Akatsuki Kokaze,3 Tomoaki Toyone,1 Katsunori Inagaki1 1Department of Orthopaedic Surgery, Showa University School of Medicine, Tokyo, 2Department of Orthopaedic Surgery, Yamanashi Red Cross Hospital, Yamanashi, 3Department of Public Health, Showa University School of Medicine, Tokyo, Japan Abstract: Hypocalcemia is the most common major adverse event in patients with osteoporosis receiving the bone resorption inhibitor denosumab; however, limited information is available regarding risk factors of hypocalcemia. Therefore, this study aimed to identify the risk factors of hypocalcemia induced by denosumab treatment for osteoporosis. We retrospectively reviewed the records of patients who had received initial denosumab supplemented with activated vitamin D for osteoporosis. Serum levels of the following bone turnover markers (BTMs) were measured at baseline: bone-specific alkaline phosphatase (BAP), total N-terminal propeptide of type 1 procollagen (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and urinary cross-linked N-telopeptide of type 1 collagen (NTX). Of the 85 denosumab-treated patients with osteoporosis studied, 22 (25.9%) developed hypocalcemia. Baseline serum total P1NP, TRACP-5b, and urinary NTX were significantly higher in patients with hypocalcemia than in those with normocalcemia following denosumab administration (all P76.5 µg/L, TRACP-5b >474 mU/dL, or urinary NTX >49.5 nmol bone collagen equivalent/mmol creatinine had a higher risk of hypocalcemia (P

Takashi Nagai, Keizo Sakamoto, Koji Ishikawa, Emi Saito, Takuma Kuroda, Katsunori Inagaki Department of Orthopaedic Surgery, Showa University School of Medicine, Shinagwa-ku, Tokyo, Japan Abstract: Bisphosphonate excessively inhibits bone resorption and results in pathological fracture of the femur or ilium. The subject of this study was administered risedronate for 7 years; we suspected an easy fracture of the femoral diaphysis. In this study, we report the results of this patient's bone biopsy and bone morphometric analysis. A 76-year-old female patient presented with right femoral pain. Bone mineral density of the anteroposterior surface of the 2nd to 4th lumbar vertebrae (L2-L4) was decreased and levels of bone turnover markers were high. Therefore, we initiated treatment with risedronate. As she continued the medication, urinary levels of cross-linked N-terminal telopeptides of type I collagen and alkaline phosphatase (bone-type isozyme) were found to be within the normal ranges. After 7 years of administration, the patient experienced pain when she put weight on the right femur and right femoral pain while walking. Plain radiographic examination revealed polypoid stress fracture-like lesions on the right femoral diaphysis and on the slightly distal-lateral cortical bone. Similar lesions were observed on magnetic resonance imaging and bone scintigraphy. We suspected severely suppressed bone turnover. Bone biopsy was obtained after labeling with tetracycline, and bone morphometric analysis was performed. On microscopic examination, slight double tetracycline labeling was observed. The trabeculae were narrow, and the numbers of osteoblasts and osteoclasts were decreased. Further, rates of bone calcification and bone formation were slow. Hence, we diagnosed fracture as a result of low turnover osteopathy. Risedronate was withdrawn, and Vitamin D3 was administered to improve the bone turnover. At 6 months, abnormal signals on magnetic resonance imaging had decreased and her pain while walking or undergoing the stress test disappeared as well. Thus, long-term administration of bisphosphonates may lead to easy fracture, although bone turnover markers were observed to be within the normal range. During bisphosphonate administration, physicians need to monitor closely and treat their patients for any pain experienced in the femoral region while walking or undergoing a stress test. Keywords: bisphosphonate, severely suppressed bone turnover, risedronate

Yoshihiro Nishimura1,2, Maiko Taguchi1, Takafumi Nagai1, Masashi Fujihara1,2, Shigeru Honda2, Mamoru Uenishi11Department of Ophthalmology, Mitsubishi Kobe Hospital, Kobe, Japan; 2Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, JapanPurpose: To compare the effect of pegaptanib versus ranibizumab on exudative age-related macular degeneration (AMD) with small lesion size.Methods: This is a retrospective study of 81 eyes from 78 patients with exudative AMD treated and followed up over 12 months. Patients with baseline best corrected visual acuity (BCVA) under 20/400 and with a greatest linear dimension of lesion over 4500 µm were excluded from the study. Twenty-six eyes from 25 patients were treated with three consecutive intravitreal injections of pegaptanib (IVP group) and 55 eyes from 54 patients were treated with three consecutive ranibizumab injections (IVR group). Each therapy was repeated as needed. The alteration in BCVA was evaluated in the IVP and IVR groups.Results: No differences were detected in baseline parameters between the IVP and IVR groups. The mean BCVA (logMAR) at month 1, 3, 6 and 12 after the initial treatment was improved from baseline in the IVP group (-0.095, -0.17, -0.18 and -0.18, respectively) and in the IVR group (-0.077, -0.15, -0.17 and -0.11, respectively), which was statistically significant. There was no difference in the change in mean BCVA between IVP and IVR groups at the same time periods.Conclusions: The visual outcome of IVP was equivalent with IVR in exudative AMD with small lesion size.Keywords: pegaptanib, ranibizumab, age-related macular degeneration, small lesion size

Although mesenchymal stem cells (MSCs) play pivotal supportive roles in hematopoiesis, how they interact with hematopoietic stem cells (HSCs) is not well understood. We investigated the interaction between HSCs and surrogate MSCs (C3H10T1/2 stromal cells), focusing on the molecular events induced by cell contact of these bipartite populations. C3H10T1/2 is a mesenchymal stromal cell line that can be induced to differentiate into preadipocytes (A54) and myoblasts (M1601). The stromal cell derivatives were cocultured with murine HSCs (Lineage-Sca1+), and gene expression profiles in stromal cells and HSCs were compared before and after the coculture. HSCs gave rise to cobblestone areas only on A54 cells, with ninefold more progenitors than on M1601 or undifferentiated C3H10T1/2 cells. Microarray-based screening and a quantitative reverse transcriptase directed-polymerase chain reaction showed that the levels of Notch ligands (Jagged1 and Delta-like 3) were increased in A54 cells upon interaction with HSCs. On the other hand, the expression of Notch1 and Hes1 was upregulated in the HSCs cocultured with A54 cells. A transwell assay revealed that the reciprocal upregulation was dependent on cell-to-cell contact. The result suggested that in the hematopoietic niche, HSCs help MSCs to produce Notch ligands, and in turn, MSCs help HSCs to express Notch receptor. Such a reciprocal upregulation would reinforce the downstream signaling to determine the fate of hematopoietic cell lineage. Clarification of the initiating events on cell contact should lead to the identification of specific molecular targets to facilitate HSC engraftment in transplantation therapy.

A down-scattered neutron detector operating in the multichannel counting mode was developed for areal density (ρR) measurement. Equipped with a newly developed 6Li glass scintillator (APLF80), the detector was tested in a fusion experiment at the GEKKO XII facility, Osaka University, Osaka, Japan. For a low-ρR fusion shot, the detector clearly discriminated the γ-rays, primary neutrons, γ-rays produced via (n, γ) reactions from the target chamber, and neutrons scattered by the target chamber. Furthermore, the observed signal was in good agreement with predictions made by Monte Carlo simulation.

A fast-decay and low-afterglow liquid scintillator was developed for the fast ignition experiment at the Institute of Laser Engineering (ILE). The liquid scintillator was coupled to a gated photomultiplier (PMT), and the gating performance under high-intensity γ-rays was experimentally checked. In 2010, a detector with a high detection efficiency of 10−4 was developed and installed in this experiment. The neutron yield in the fast heating experiment was successfully measured using this detector.

The FIREX-1 project, the goal of which is to demonstrate fuel heating up to 5 keV by fast ignition scheme, has been carried out since 2003 including construction and tuning of LFEX laser and integrated experiments. Implosion and heating experiment of Fast Ignition targets have been performed since 2009 with Gekko-XII and LFEX lasers. A deuterated polystyrene shell target was imploded with the 0.53- μm Gekko-XII, and the 1.053- μm beam of the LFEX laser was injected through a gold cone attached to the shell to generate hot electrons to heat the imploded fuel plasma. Pulse contrast ratio of the LFEX beam was significantly improved. Also a variety of plasma diagnostic instruments were developed to be compatible with harsh environment of intense hard x-rays (γ rays) and electromagnetic pulses due to the intense LFEX beam on the target. Large background signals around the DD neutron signal in time-of-flight record of neutron detector were found to consist of neutrons via (γ,n) reactions and scattered gamma rays. Enhanced neutron yield was confirmed by carefully eliminating such backgrounds. Neutron enhancement up to 3.5 × 107 was observed. Heating efficiency was estimated to be 10–20% assuming a uniform temperature rise model.

Metallic delafossites, ABO2 (A = Pd or Pt), are layered oxides that are as conductive as elemental metals. The high conductivity and surface polarity make metallic delafossites fascinating electrode materials for heterostructure devices. Here, we report the successful growth of c-axis-oriented PdCoO2 thin films on Al2O3 (001) substrates by magnetron sputtering that is widely used in industries. The observation of the PdCoO2 thin films through scanning transmission electron microscopy revealed layered crystal structures. A sharp interface exhibiting a layer stacking sequence of Pd/CoO2/Al2O3 was observed clearly, similar to the interfaces obtained with other growth methods such as pulsed laser deposition and molecular beam epitaxy. This layer stacking is particularly interesting because it can induce a high work function at the interface. The in-plane resistivity of the as-grown PdCoO2 thin film was 73 μΩ cm at room temperature, which decreased to 11 μΩ cm after post-annealing. The residual resistivity ratio of the annealed thin films was approximately 2.9. The impurity phases of PdOx were observed using x-ray diffraction and scanning transmission electron microscopy. The sputtering deposition of c-axis-oriented thin films could lead to the practical application of the polar surface of PdCoO2 in semiconductor devices. [ABSTRACT FROM AUTHOR]