Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Tomohiko Akahoshi Last modified date:2024.01.25

Professor / Department of Emergency medicine, Advanced medicine and disaster medicine / Department of Clinical Medicine / Faculty of Medical Sciences

1. Daisuke Yoshida, Tomohiko Akahoshi, Hirofumi Kawanaka, Shohei Yamaguchi, Nao Kinjo, Akinobu Taketomi, Morimasa Tomikawa, Ken Shirabe, Yoshihiko Maehara, Makoto Hashizume, Roles of Vascular Endothelial Growth Factor and Endothelial Nitric Oxide Synthase During Revascularization and Regeneration After Partial Hepatectomy in a Rat Model, SURGERY TODAY, 10.1007/s00595-010-4484-9, 41, 12, 1622-1629, 2011.12, Purpose. Angiogenesis is an essential process in liver regeneration. Nitric oxide (NO) and vascular endothelial growth factor (VEGF) are the main regulators of normal and pathological angiogenesis. This study aimed to determine the roles of NO derived from endothelial nitric oxide synthase (eNOS) and VEGF in sinusoidal endothelial cell (SEC) proliferation during liver regeneration.
Methods. Sprague-Dawley rats underwent a 70% partial hepatectomy (PHx), and were euthanized 0, 24, 48, 72, or 168 h later. Liver regeneration and SEC proliferation were evaluated. The protein expression of VEGF and eNOS was examined by a Western blot analysis. The rats were also treated with the NO synthase inhibitor NG-nitro-l-arginine-methyl ester (L-NAME) to examine its effects on liver regeneration and SEC proliferation.
Results. The proliferating cell nuclear antigen (PCNA) labeling index of hepatocytes was significantly increased at 24 h after PHx. The eNOS protein expression and NO production were significantly increased from 72 to 168 h. The expression of VEGF protein was significantly increased at 72 h. L-NAME significantly inhibited the increases in the liver mass and decreased the PCNA labeling index of hepatocytes at 24 h. L-NAME also inhibited the induction of VEGF protein at 72 h.
Conclusions. Endothelial NOS and VEGF coordinately regulate SEC proliferation during liver regeneration. Sinusoidal endothelial cell proliferation is necessary and is an important step in liver regeneration..
2. Hideo Uehara, Tomohiko Akahoshi, Hirohumi Kawanaka, Naotaka Hashimoto, Yoshihiro Nagao, Morimasa Tomikawa, Akinobu Taketomi, Ken Shirabe, Makoto Hashizume, Yoshihiko Maehara, Endothelin-1 derived from spleen-activated Rho-kinase pathway in rats with secondary biliary cirrhosis, HEPATOLOGY RESEARCH, 10.1111/j.1872-034X.2012.01021.x, 42, 10, 1039-1047, 2012.10, Aim: Splenectomy or partial splenic embolism has been reported to improve liver function in patients with hypersplenism and liver dysfunction. The aim of this study was to investigate the mechanism of improvement after splenectomy. Methods: Liver cirrhosis was induced by bile duct ligation (BDL). Rats underwent sham operation, splenectomy (Sp group), BDL, or BDL plus splenectomy (BDL + Sp group), and were subjected to experiments at 2 weeks after the operation. Portal venous pressure (PVP) and hepatic tissue blood flow (HTBF) were measured in each group. The plasma concentration of endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS), RhoA and Rho-kinase expressions were studied. Results: There were significant differences in PVP (17.9 +/- 0.91 vs 23.3 +/- 3.91 cmH2O; P < 0.01) and HTBF (16.6 +/- 1.72 vs 13.3 +/- 1.82 mL/min; P < 0.01) between the BDL + Sp and BDL groups. In the liver of BDL rats, eNOS phosphorylation and NOx levels were decreased, accompanied by RhoA activation compared with the BDL + Sp group. Splenectomy decreased serum ET-1 levels, RhoA activation and consequently increased eNOS phosphorylation. Conclusion: ET-1 derived from the spleen might increase intrahepatic resistance by downregulating Rho signaling in liver cirrhosis. Splenectomy for splenomegaly in liver cirrhosis might partially improve liver function by enhancing intrahepatic microcirculation..
3. Takashi Motomura, Ken Shirabe, Norihiro Furusyo, Tomoharu Yoshizumi, Toru Ikegami, Yuji Soejima, Tomohiko Akahoshi, Morimasa Tomikawa, Takasuke Fukuhara, Jun Hayashi, Yoshihiko Maehara, Effect of laparoscopic splenectomy in patients with Hepatitis C and cirrhosis carrying IL28B minor genotype, BMC GASTROENTEROLOGY, 10.1186/1471-230X-12-158, 12, 158, 2012.11, Background: IL28B and ITPA genetic variants are associated with the outcome of pegylated-interferon and ribavirin (PEG-IFN/RBV) therapy. However, the significance of these genetic variants in cirrhotic patients following splenectomy has not been determined.
Methods: Thirty-seven patients with HCV-induced cirrhosis who underwent laparoscopic splenectomy (Spx group) and 90 who did not (non-Spx group) were genotyped for IL28B and ITPA. The outcome or adverse effects were compared in each group. Interferon-stimulated gene 15 (ISG15) and protein kinase R expression in the spleen was measured using total RNA extracted from exenterate spleen.
Results: Sustained virological response (SVR) rate was higher in patients carrying IL28B major genotype following splenectomy (50% vs 27.3%) and in patients carrying minor genotype in the Spx group compared to non-Spx group (27.3% vs 3.6%, P<0.05). Pretreatment splenic ISG expression was higher in patients carrying IL28B major. There was no difference in progression of anemia or thrombocytopenia between patients carrying each ITPA genotype in the Spx group. Although splenectomy did not increase hemoglobin (Hb) level, Hb decline tended to be greater in the non-Spx group. In contrast, splenectomy significantly increased platelet count (61.1 x 10(3)/mu l vs 168.7 x 10(3)/mu l, P<0.01), which was maintained during the course of PEG-IFN/RBV therapy.
Conclusions: IL28B genetic variants correlated with response to PEG-IFN/RBV following splenectomy. Splenectomy improved SVR rate among patients carrying IL28B minor genotype and protected against anemia and thrombocytopenia during the course of PEG-IFN/RBV therapy regardless of ITPA genotype..
4. Tetsuo Ikeda, Tomohiko Akahoshi, Hirofumi Kawanaka, Hideaki Uchiyama, Yo-ichi Yamashita, Masaru Morita, Eiji Oki, Hiroshi Saeki, Keishi Sugimachi, Toru Ikegami, Tomoharu Yoshizumi, Yuji Soejima, Ken Shirabe, Koshi Mimori, Masayuki Watanabe, Makoto Hashizume, Yoshihiko Maehara, Evaluation of a transection method for distal pancreatectomy: A comparative study on the use of electrosurgical and stapling devices in swine., Fukuoka igaku zasshi = Hukuoka acta medica, 10.15017/1440930, 104, 12, 515-22, 2013.12, BACKGROUND: Despite marked improvements in pancreatic surgery, the high incidence of pancreatic fistula and high morbidity after resection persists. PURPOSES: The objective of this study was to evaluate the role of electrosurgical and stapling devices as an alternative to traditional methods of stump closure in an animal model of distal pancreatectomy. METHODS: Four devices were used for transection of the pancreatic body : a bi-polar thermofusion system attached to an automatic irrigation function (BI, n = 3), a bi-polar tissue sealer (BS, n = 3), an ultrasonic scissor (US, n = 3), and an endoscopic stapling device (ES, n = 3). For each group, burst pressure was tested using an electronic manometer, with a focus on the location (s) of the first disruption (s). Histological examination was performed for the dissected surfaces. The transection line, including staples, was embedded in a polyester resin, and histological examination was performed for these polished sections of the resin. RESULTS: Pressure was significantly higher for BI (P
5. Tomohiko Akahoshi, Hirofumi Kawanaka, Morimasa Tomikawa, Hiroshi Saeki, Hideaki Uchiyama, Tetsuo Ikeda, Ken Shirabe, Makoto Hashizume, Yoshihiko Maehara, Effect of proton pomp inhibitor (PPI : Rabeprazole) on reflux esophagitis after endoscopic injection sclerotherapy (EIS), a randomized control study (24 hour-pH monitoring)., Fukuoka igaku zasshi = Hukuoka acta medica, 10.15017/1440926, 104, 12, 483-9, 2013.12, BACKGROUND: Transient esophageal ulceration is a common finding after sclerotherapy of varices. These ulcers sometimes cause pain, ulcer bleeding, and stricture formation. Gastroesophageal reflux (GER) after Endoscopic injection sclerotherapy (EIS) is a known cause of worsening ulcer formation. Therefore, an efficient drug for GER is desirable to improve the quality of life of patients with esophageal varices. METHODS: We randomized 18 Japanese cirrhotic patients who had risky esophageal varices. The patients were randomly allocated into two groups, and during EIS sessions, one group was administered proton pump inhibitor(PPI) (Rabeprazole 20 mg a person once a day), while the other received histamine H2 receptor antagonist (H2-blocker) (famotidine 20 mg a person, twice a day). Gastroesophageal reflux was monitored by a 24-h pH-monitoring catheter introduced into the distal esophagus. Ulcer formation was evaluated using an endoscopic examination. The subjective and objective symptoms were also compared between the two groups. RESULTS: All patients in the H2-blocker group showed an increased percentage of time with pH
6. Megumu Mori, Toru Chiba, Akira Nakamizo, Ryuichi Kumashiro, Masaharu Murata, Tomohiko Akahoshi, Morimasa Tomikawa, Yuichiro Kikkawa, Koji Yoshimoto, Masahiro Mizoguchi, Tomio Sasaki, Makoto Hashizume, Intraoperative visualization of cerebral oxygenation using hyperspectral image data: a two-dimensional mapping method, INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY, 10.1007/s11548-014-0989-9, 9, 6, 1059-1072, 2014.11, Superficial temporal artery (STA)-middle cerebral artery (MCA) bypass is an important technique for cerebrovascular reconstruction. Intraoperative hemodynamic imaging is needed to perform cerebrovascular reconstruction safely and effectively. Optical intrinsic signal (OIS) imaging is commonly used for assessing cerebral hemodynamics in experimental studies, because it can provide high-resolution mapping images. However, OIS is not used clinically due to algorithm, instrumentation and spectral resolution limitations. We tested the feasibility of a hyperspectral camera (HSC) for assessment of cortical hemodynamics with spectral imaging of the cerebral cortex in rats and in vivo humans.
A hyperspectral camera (HSC) was tested in a rat model of cerebral ischemia (middle cerebral artery occlusion) and during human revascularization surgery (STA-MCA anastomosis). Changes in cortical oxygen saturation were derived from spectral imaging data (400-800 nm) collected by exposing the cortex to Xenon light. Reflected light was sampled using the HSC. The system was then tested intraoperatively during superficial temporal artery to middle cerebral artery anastomosis procedures. Comparison with single-photon emission computed tomography (SPECT) imaging data was done.
During middle cerebral artery occlusion in rats, the HSC technique showed a significant decrease in cortical oxygen saturation in the ischemic hemisphere. In clinical cases, the cortical oxygen saturation was increased after STA-MCA anastomosis, which agreed with the SPECT imaging data.
Continuous collection of imaging spectroscopic data is feasible and may provide reliable quantification of the hemodynamic responses in the brain. The HSC system may be useful for monitoring intraoperative changes in cortical surface hemodynamics during revascularization procedures in humans..
7. Wei-Ping Tang, Tomohiko Akahoshi, Jing-Shu Piao, Sayoko Narahara, Masaharu Murata, Takahito Kawano, Nobuhito Hamano, Tetsuo Ikeda, Makoto Hashizume, Basic fibroblast growth factor-treated adipose tissue-derived mesenchymal stem cell infusion to ameliorate liver cirrhosis via paracrine hepatocyte growth factor, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 10.1111/jgh.12893, 30, 6, 1065-1074, 2015.06, Background and AimRecent studies show that adipose tissue-derived mesenchymal stem cells have potential clinical applications. However, the mechanism has not been fully elucidated yet. Here, we investigated the effect of basic fibroblast growth factor-treated adipose tissue-derived mesenchymal stem cells infusion on a liver fibrosis rat model and elucidated the underlying mechanism.
MethodsAdipose tissue-derived mesenchymal stem cells were infused into carbon tetrachloride-induced hepatic fibrosis rats through caudal vein. Liver functions and pathological changes were assessed. A co-culture model was used to clarify the potential mechanism.
ResultsBasic fibroblast growth factor treatment markedly improved the proliferation, differentiation, and hepatocyte growth factor expression ability of adipose tissue-derived mesenchymal stem cells. Although adipose tissue-derived mesenchymal stem cells infusion alone slightly ameliorated liver functions and suppressed fibrosis progression, basic fibroblast growth factor-treatment significantly enhanced the therapeutic effect in association with elevated hepatocyte growth factor expression. Moreover, double immunofluorescence staining confirmed that the infused cells located in fibrosis area. Furthermore, co-culture with adipose tissue-derived mesenchymal stem cell led to induction of hepatic stellate cell apoptosis and enhanced hepatocyte proliferation. However, these effects were significantly weakened by knockdown of hepatocyte growth factor. Mechanism investigation revealed that co-culture with adipose tissue-derived mesenchymal stem cells activated c-jun N-terminal kinase-p53 signaling in hepatic stellate cell and promoted apoptosis.
ConclusionsBasic fibroblast growth factor treatment enhanced the therapeutic effect of adipose tissue-derived mesenchymal stem cells, and secretion of hepatocyte growth factor from adipose tissue-derived mesenchymal stem cells plays a critical role in amelioration of liver injury and regression of fibrosis..
8. Wei-Ping Tang, Tomohiko Akahoshi, Jing-Shu Piao, Sayoko Narahara, Masaharu Murata, Takahito Kawano, Nobuhito Hamano, Tetsuo Ikeda, Makoto Hashizume, Splenectomy enhances the therapeutic effect of adipose tissue-derived mesenchymal stem cell infusion on cirrhosis rats, LIVER INTERNATIONAL, 10.1111/liv.12962, 36, 8, 1151-1159, 2016.08, Background & AimsClinical studies suggest that splenectomy improves liver function in cirrhotic patients, but the influence of splenectomy on stem cell transplantation is poorly understood. This study investigated the effect ofsplenectomy on stem cell infusion and elucidated its mechanism.
MethodsRat adipose tissue-derived mesenchymal stem cells were infused into cirrhosis rats with or without splenectomy, followed by the assessment of the invivo distribution of stem cells and pathological changes. Stromal cell-derived factor-1 and hepatocyte growth factor expression were also investigated in splenectomized cirrhosis patients and rats.
ResultsSplenectomy, prior to cell infusion, improved liver function and suppressed fibrosis progression more efficiently than cell infusion alone in the experimental cirrhosis model. Stromal cell-derived factor-1 and hepatocyte growth factor levels after splenectomy were increased in patients and rats. These upregulated cytokines significantly facilitated stem cell motility, migration and proliferation invitro. C-X-C chemokine receptor type 4 neutralization weakened the promotion of cell migration by these cytokines. The infused cells integrated into liver fibrosis septa and participated in regeneration more efficiently in splenectomized rats. Direct coculture with stem cells led to inhibition of hepatic stellate cell proliferation. In addition, hepatocyte growth factor induced hepatic stellate cell apoptosis via the c-jun N-terminal kinase-p53 pathway.
ConclusionsSplenectomy prior to cell infusion enhanced the therapeutic effect of stem cells on cirrhosis, which involved upregulation of stromal cell-derived factor-1 and hepatocyte growth factor after splenectomy..
9. Takahito Kawano, Masaharu Murata, Fuminori Hyodo, Hinako Eto, Nuttavut Kosem, Ryosuke Nakata, Nobuhito Hamano, Jing Shu Piao, Sayoko Narahara, Tomohiko Akahoshi, Makoto Hashizume, Noninvasive mapping of the redox status of dimethylnitrosamine-induced hepatic fibrosis using in vivo dynamic nuclear polarization-magnetic resonance imaging, SCIENTIFIC REPORTS, 10.1038/srep32604, 6, 32604, 2016.09, Hepatic fibrosis is a chronic disorder caused by viral infection and/or metabolic, genetic and cholestatic disorders. A noninvasive procedure that enables the detection of liver fibrosis based on redox status would be useful for disease identification and monitoring, and the development of treatments. However, an appropriate technique has not been reported. This study describes a novel method for assessing the redox status of the liver using in vivo dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) with the nitroxyl radical carbamoyl-PROXYL as a molecular imaging probe, which was tested in dimethylnitrosamine-treated mice as a model of liver fibrosis. Based on the pharmacokinetics of carbamoyl-PROXYL in control livers, reduction rate mapping was performed in fibrotic livers. Reduction rate maps demonstrated a clear difference between the redox status of control and fibrotic livers according to the expression of antioxidants. These findings indicate that in vivo DNP-MRI with a nitroxyl radical probe enables noninvasive detection of changes in liver redox status..
10. Ryuichi Kumashiro, Kozo Konishi, Tohru Chiba, Tomohiko Akahoshi, Shotaro Nakamura, Masaharu Murata, Morimasa Tomikawa, Takayuki Matsumoto, Yoshihiko Maehara, Makoto Hashizume, Integrated Endoscopic System Based on Optical Imaging and Hyperspectral Data Analysis for Colorectal Cancer Detection, ANTICANCER RESEARCH, 36, 8, 3925-3932, 2016.08, Background/Aim: Two-dimensional hyperspectral data systems with enhanced area detection and diagnostic abilities are now available in gastrointestinal endoscopy for colorectal cancer. We evaluated a new hyperspectral system for diagnosis of colorectal cancer. Patients and Methods: A resected-specimen spectrum observation module (stereoscopic macroscope, hyperspectral camera, and xenon lamp) was used to evaluate 21 resected colorectal cancer specimens (ex vivo experiment). A colonoscopy spectrum observation module (imaging fiberscope and hyperspectral camera) was used to perform 24 colonoscopic spectroscopy evaluations (in vivo experiment). Results: An approximately 525-nm increase in spectral absorption occurred between normal mucosa and adenoma, with a tendency toward decreased absorption rates with aggravation of other tumor types. In vivo discrimination between tumorous and non-tumorous tissues showed 72.5% sensitivity and 82.1% specificity. Conclusion: This in vivo hyperspectral diagnostic system showed that reflectance spectra intensity may discriminate between normal and abnormal colonic mucosa..
11. Ryosuke Nakata, Fuminori Hyodo, Masaharu Murata, Hinako Eto, Tomoko Nakaji, Takahito Kawano, Sayoko Narahara, Keiji Yasukawa, Tomohiko Akahoshi, Morimasa Tomikawa, Makoto Hashizume, In vivo redox metabolic imaging of mitochondria assesses disease progression in non-alcoholic steatohepatitis., Scientific reports, 10.1038/s41598-017-17447-2, 7, 1, 17170-17170, 2017.12, Given the rising incidence of non-alcoholic fatty liver disease (NAFLD) in both adults and children, the development of a non-invasive diagnostic method for assessing disease progression to non-alcoholic steatohepatitis (NASH) has become an important research goal. Currently available non-invasive imaging technologies are only able to assess fat accumulation in the liver. Therefore, these methods are not suitable for a precise diagnosis of NASH. The standard diagnostic technique for NASH, liver biopsy, has several drawbacks, including the higher risk of complications that accompanies invasive procedures. Here, we demonstrated that in vivo mitochondrial redox metabolism was dramatically altered at an early stage, before histopathological changes, and NASH could be accurately diagnosed by in vivo dynamic nuclear polarization-magnetic resonance imaging, with carbamoyl-PROXYL as a molecular imaging probe. In addition, this technique was feasible for the diagnosis of NASH compared with histopathological findings from biopsies. Our data reveal a novel method for monitoring the dynamics of redox metabolic changes in NAFLD/NASH..
12. Yuji Shono, Tomohiko Akahoshi, Satomi Mezuki, Kenta Momii, Noriyuki Kaku, Jun Maki, Kentaro Tokuda, Tetsuro Ago, Takanari Kitazono, Yoshihiko Maehara, Clinical characteristics of type A acute aortic dissection with CNS symptom., The American journal of emergency medicine, 10.1016/j.ajem.2017.06.011, 35, 12, 1836-1838, 2017.12, BACKGROUND AND PURPOSE: Accurate diagnosis of acute aortic dissection (AAD) is sometimes difficult because of accompanying central nervous system (CNS) symptoms. The purpose of this study was to investigate the clinical characteristics of Type A AAD (TAAAD) with CNS symptoms. METHODS: We retrospectively reviewed the medical records of 8403 patients ambulanced to our emergency and critical care center between April 2009 and May 2014. RESULTS: We identified 59 TAAAD patients for the analysis (mean age, 67.3±10.5years; 37 (62.0%) male). Eleven patients (18.6%) presented CNS symptoms at the onset of TAAAD, and these patients complained less frequently of typical chest and back pain than those without CNS symptoms (p
13. Tsutomu Iwasa, Ryu Nakadate, Shinya Onogi, Yasuharu Okamoto, Jumpei Arata, Susumu Oguri, Haruei Ogino, Eikichi Ihara, Kenoki Ohuchida, Tomohiko Akahoshi, Tetsuo Ikeda, Yoshihiro Ogawa, Makoto Hashizume, A new robotic-assisted flexible endoscope with single-hand control: endoscopic submucosal dissection in the ex vivo porcine stomach., Surgical endoscopy, 10.1007/s00464-018-6188-y, 32, 7, 3386-3392, 2018.07, BACKGROUND: Difficulties in endoscopic operations and therapeutic procedures seem to occur due to the complexity of operating the endoscope dial as well as difficulty in performing synchronized movements with both hands. We developed a prototype robotic-assisted flexible endoscope that can be controlled with a single hand in order to simplify the operation of the endoscope. The aim of this study was to confirm the operability of the robotic-assisted flexible endoscope (RAFE) by performing endoscopic submucosal dissection (ESD). METHODS: Study 1: ESD was performed manually or with RAFE by an expert endoscopist in ex vivo porcine stomachs; six operations manually and six were performed with RAFE. The procedure time per unit circumferential length/area was calculated, and the results were statistically analyzed. Study 2: We evaluated how smoothly a non-endoscopist can move a RAFE compared to a manual endoscope by assessing the designated movement of the endoscope. RESULTS: Study 1: En bloc resection was achieved by ESD using the RAFE. The procedure time was gradually shortened with increasing experience, and the procedure time of ESD performed with the RAFE was not significantly different from that of ESD performed with a manual endoscope. Study 2: The time for the designated movement of the endoscope was significantly shorter with a RAFE than that with a manual endoscope as for a non-endoscopist. CONCLUSIONS: The RAFE that we developed enabled an expert endoscopist to perform the ESD procedure without any problems and allowed a non-endoscopist to control the endoscope more easily and quickly than a manual endoscope. The RAFE is expected to undergo further development..
14. Takashi Nagata, Tomohiko Akahoshi, Michiko Sugino, Wataru Ishii, Ryoji Iizuka, Takafumi Shinjo, Yoshimitsu Izawa, Michiaki Hata, Alan Kawarai Lefor, The importance of simulation education for the management of traumatic cardiac injuries: a case series., Surgical case reports, 10.1186/s40792-019-0762-y, 5, 1, 202-202, 2019.12, BACKGROUND: The management of cardiac trauma requires rapid intervention in the emergency room, facilitated by a surgeon with prior experience to have good outcomes. Many surgeons have little experience in the requisite procedures. We report here 4 patients who suffered cardiac trauma, and all 4 patients survived with good neurologic outcomes. CASE PRESENTATIONS: Patient 1 suffered blunt cardiac trauma from a motor vehicle accident and presented in shock. Cardiac tamponade was diagnosed and a cardiac rupture repaired with staples through a median sternotomy after rapid transport to the operating room. Patient 2 suffered blunt cardiac trauma and presented in shock with cardiac tamponade. Operating room median sternotomy allowed extraction of pericardial clot with recovery of physiologic stability. Patient 3 presented with self-inflicted stab wounds to the chest and was unstable. She was brought to the operating room and thoracotomy allowed identification of a left ventricle wound which was repaired with a suture. Patient 4 presented in cardiac arrest with multiple self-inflicted stab wounds to the chest. Emergency room thoracotomy allowed repair of a right ventricle laceration with recovery of vital signs. CONCLUSIONS: The management of all 4 patients was according to the principles taught in the ATOM course. Three of the 4 surgeons had no prior experience with management of cardiac trauma and credited the good outcomes to taking the ATOM course. These are uncommon injuries and formal training in their management is beneficial to patients..
15. Yoshihiko Maehara, Yuji Soejima, Tomoharu Yoshizumi, Naoyuki Kawahara, Eiji Oki, Hiroshi Saeki, Tomohiko Akahoshi, Toru Ikegami, Yo-Ichi Yamashita, Tadashi Furuyama, Keishi Sugimachi, Noboru Harada, Tetsuzo Tagawa, Norifumi Harimoto, Shinji Itoh, Hideto Sonoda, Koji Ando, Yuichiro Nakashima, Yoshihiro Nagao, Nami Yamashita, Yuta Kasagi, Takafumi Yukaya, Takeshi Kurihara, Ryosuke Tsutsumi, Shinkichi Takamori, Shun Sasaki, Tetsuo Ikeda, Yoshikazu Yonemitsu, Takasuke Fukuhara, Hiroyuki Kitao, Makoto Iimori, Yuki Kataoka, Takeshi Wakasa, Masami Suzuki, Koji Teraishi, Yasuto Yoshida, Masaki Mori, The evolution of surgical treatment for gastrointestinal cancers., International journal of clinical oncology, 10.1007/s10147-019-01499-7, 24, 11, 1333-1349, 2019.11, INTRODUCTION: According to the latest Japanese nationwide estimates, over a million Japanese people are newly diagnosed with cancer each year. Since gastrointestinal cancers account for more than 40% of all cancer-related deaths, it is imperative to formulate effective strategies to control them. MATERIALS AND METHODS, AND RESULTS: Basic drug discovery research Our research has revealed that the abnormal expression of regulators of chromosomal stability is a cause of cancers and identified an effective compound against cancers with chromosomal instability. We revealed the molecular mechanism of peritoneal dissemination of cancer cells via the CXCR4/CXCL12 axis to CAR-like cells and identified an MEK inhibitor effective against these tumors. Residual tumor cells after chemotherapy in colorectal cancer are LGR5-positive cancer stem cells and their ability to eliminate reactive oxygen species is elevated. The development of surgical procedures and devices In cases of gastric tube reconstruction for esophageal cancer, we determined the anastomotic line for evaluating the blood flow using ICG angiography and measuring the tissue O2 metabolism. We established a novel gastric reconstruction method (book-binding technique) for gastric cancer and a new rectal reconstruction method focusing on the intra-intestinal pressure resistance for rectal cancer. We established a novel tissue fusion method, which allows contact-free local heating and retains tissue viability with very little damage, and developed an understanding of the collagen-related processes that underpin laser-induced tissue fusion. Strategy to prevent carcinogenesis We succeeded in cleaving hepatitis B virus DNA integrated into the nucleus of hepatocytes using genome editing tools. The development of HCC from non-alcoholic steatohepatitis (NASH) may be prevented by metabolic surgery. CONCLUSION: We believe that these efforts will help to significantly improve the gastrointestinal cancer treatment and survival..
16. Ryosuke Tsutsumi, Tomohiko Akahoshi, Tetsuo Ikeda, Yoshihiko Maehara, Makoto Hashizume, Successful use of flexible silicone mesh for management of prolonged open abdomen., Acute medicine & surgery, 10.1002/ams2.438, 6, 4, 400-403, 2019.10, Background: Open abdomen management (OAM) is used not only for trauma but also for treatment of peritonitis. However, the rate of successful fascial closure in patients with OAM remains low. Case Presentation: The patient was a 38-year-old morbidly obese man who underwent laparoscopic sleeve gastrectomy. Twenty days after surgery, postoperative leakage resulted in panperitonitis. In this case, we undertook drainage by open laparotomy. The patient's status was generally unstable and he was treated with OAM. We used flexible silicone mesh as the dressing material for negative-pressure wound therapy. Open abdominal management continued until status improvement (32 days). Fascial closure was eventually successful because of good granulation growth. Conclusion: When combined with negative-pressure wound therapy, silicone mesh prevents wound adhesions and infection after surgery. Silicone mesh is useful for patients with increased risk of infection, such as those with diffuse peritonitis..
17. Satoko Ohfuji, Yoshihiro Furuichi, Tomohiko Akahoshi, Masayoshi Kage, Katsutoshi Obara, Makoto Hashizume, Tomoka Matsuura, Wakaba Fukushima, Yosikazu Nakamura, Japanese periodical nationwide epidemiologic survey of aberrant portal hemodynamics., Hepatology research : the official journal of the Japan Society of Hepatology, 10.1111/hepr.13343, 49, 8, 890-901, 2019.08, AIM: Idiopathic portal hypertension (IPH), extrahepatic portal obstruction (EHO), and Budd-Chiari syndrome (BCS) are characterized by aberrant portal hemodynamics of unknown etiology. The aim of this study was to explore trends in the descriptive epidemiology of these diseases through periodical nationwide surveys. METHODS: Nationwide epidemiologic surveys were undertaken in 1999, 2005, and 2015 using the same protocol. The survey targets were selected from all departments of gastrointestinal medicine, surgery, pediatrics, and pediatric surgery in Japan by stratified random sampling according to the number of beds. We asked each department to complete a mail-back questionnaire on the annual numbers of patients with IPH, EHO, and BCS during the preceding year. RESULTS: The estimated number of BCS patients increased from 280 (95% confidence interval, 200-360) in 1999 survey to 410 (300-530) in 2015 survey, whereas the number of IPH and EHO patients has remained largely unchanged during the 15 years (IPH was approximately 1000; EHO was approximately 770 in 2015 survey). The mean age at symptom onset was approximately 45 years for IPH, 30 years for EHO, and 40 years for BCS over the past 15 years. Those who described disease aggravation from the time of diagnosis accounted for approximately 10% of IPH, 15% of EHO, and 20% of BCS patients in each of the three surveys. CONCLUSIONS: In Japan, the prevalence of BCS is increasing, while those of IPH and EHO appear to be stable. Clinical characteristics, including prognoses, have remained largely unchanged in the past 15 years..
18. Yasuharu Okamoto, Ryu Nakadate, Shotaro Nakamura, Jumpei Arata, Susumu Oguri, Tomohiko Moriyama, Motohiro Esaki, Tsutomu Iwasa, Kenoki Ohuchida, Tomohiko Akahoshi, Tetsuo Ikeda, Takanari Kitazono, Makoto Hashizume, Colorectal endoscopic submucosal dissection using novel articulating devices: a comparative study in a live porcine model., Surgical endoscopy, 10.1007/s00464-018-6408-5, 33, 2, 651-657, 2019.02, BACKGROUND AND AIMS: Colonic endoscopic submucosal dissection (ESD) is time-consuming and bears a high risk of perforation. The aim of the present study was to compare the safety and efficacy between novel articulating devices and conventional ESD in live porcine colon models. METHODS: Thirty ESDs in ten pigs were carried out at three different locations (15, 25, and 35 cm from the anus) by the conventional method (n = 15) and by the new method (n = 15). Procedure times, adverse events (perforation, bleeding), and damage to the muscular layer were recorded, and the ESD time per unit area of the specimens was calculated. RESULTS: The perforation rate using the conventional method was 6.7% (1/15), whereas that using the new method was 0.0%. The number of sites of muscular damage was significantly lower in the new than conventional method (6 vs. 37, respectively; P = 0.024). The mean procedure time was significantly shorter in the new than conventional method (4.6 ± 2.0 vs. 7.0 ± 4.1 min/cm2, respectively; P = 0.042). CONCLUSIONS: Use of the new ESD method allows for reduced adverse events and a shortened resection time..
19. Toru Chiba, Yoshimi Obara, Masaharu Murata, Tomohiko Akahoshi, Advanced multispectral image-processing endoscopy system for visualizing two-dimensional hemoglobin saturation and relative hemoglobin concentration., Endoscopy international open, 10.1055/a-0990-9189, 7, 11, E1442-E1447, 2019.11, Background and study aims  The association of tumor hypoxia and vascularization with malignant progression is recognized, and detection by measuring tissue hemoglobin (Hb) saturation and concentration has attracted attention. In this study, we designed a simple algorithm and multispectral image-processing endoscopy system to map relative Hb concentration and Hb saturation for detection of tumors in small animal viscera in vivo. Materials and methods  We designed and validated an optical filter-equipped endoscope system for two-dimensional visualization of Hb concentration and saturation maps and used it in a real-time video examination. A simplified method based on spectral data capture and analysis of defuse reflection of mucosa, including image capture and data processing of the spectral features of Hb oxygenation, was developed. Results  An Hb saturation calibration curve was obtained. Then, differences in oxygenation levels between normal mucosa and in vivo tumors in a small animal model were determined by using the new method and endoscope system. Conclusions  A multispectral image-processing endoscopic system with a mapping frame rate comparable to that of white light imaging systems (7.5 frames/second) was developed..
20. Jie Guo, Kazuhiro Shirozu, Tomohiko Akahoshi, Yukie Mizuta, Masaharu Murata, Ken Yamaura, The farnesyltransferase inhibitor tipifarnib protects against autoimmune hepatitis induced by Concanavalin A., International immunopharmacology, 10.1016/j.intimp.2020.106462, 83, 106462-106462, 2020.06, No effective treatment has been established for autoimmune hepatitis (AIH), except for liver transplantation in the fatal stage. Little is known about the roles and mechanisms of farnesyltransferase inhibitors (FTIs) in treating AIH. Thus, we investigated the specific role of the FTI, tipifarnib, in a Concanavalin A (Con A)-induced model of hepatitis. The effects of tipifarnib (10 mg/kg, intraperitoneal injection) were studied in Con A (20 mg/kg, intravenous injection)-challenged mice by histological, biochemical, and immunological analyses. Tipifarnib-treated mice were compared to phosphate-buffered saline (PBS)-treated mice. Con A caused liver injury characterized by increased plasma alanine aminotransferase (ALT) levels and marked histological changes. The increased serum ALT, interleukin-6, or interferon-γ (IFN-γ) levels were observed at 2 or 8 h; tumor necrosis factor-α levels at 2 h post-Con A administration decreased significantly in the tipifarnib group. Tipifarnib also suppressed Con A-induced activation of CD4+ cells (but not CD8+ T cells) in the liver and spleen, and also reversed the Con A-induced decrease of natural killer T (NKT) cells in the liver. Tipifarnib significantly inhibited IFN-γ production and STAT1 phosphorylation from CD4+ T cells (but not CD8+ T and NKT cells) in the liver at 2 h post-Con A administration. Tipifarnib significantly inhibited IFN-γ production by splenic CD4+ T cells at 48 h post-Con A injection in vitro. Tipifarnib also inhibited the expression of farnesylated proteins induced by Con A administration. In conclusion, tipifarnib inhibited IFN-γ derived from Con A-induced CD4+ T cell activation due to downregulated STAT1 phosphorylation, suggesting that Tipifarnib can protect against AIH..
21. Yukie Mizuta, Kentaro Tokuda, Jie Guo, Shuo Zhang, Sayoko Narahara, Takahito Kawano, Masaharu Murata, Ken Yamaura, Sumio Hoka, Makoto Hashizume, Tomohiko Akahoshi, Sodium thiosulfate prevents doxorubicin-induced DNA damage and apoptosis in cardiomyocytes in mice., Life sciences, 10.1016/j.lfs.2020.118074, 257, 118074-118074, 2020.09, AIM: Doxorubicin (DOX) induces dose-dependent cardiotoxicity due to reactive oxygen species (ROS)-mediated oxidative stress and subsequent apoptosis of cardiomyocytes. We aimed to assess whether sodium thiosulfate (STS), which has antioxidant and antiapoptotic properties, exerts cardioprotective effects on DOX-induced cardiomyopathy. MAIN METHODS: Male C57BL/6N mice were divided into four groups, control, DOX, STS, and DOX + STS, and administered DOX (20 or 30 mg/kg) or normal saline intraperitoneally, followed by an injection of STS (2 g/kg) or normal saline 4 h later. KEY FINDINGS: The DOX group showed a poorer 6-day survival and decreased cardiac function than the DOX + STS group. The DOX group showed a marked increase in the plasma creatine kinase isoenzyme myocardial band (CK-MB) and lactate dehydrogenase (LDH) levels 10 h after DOX injection, while the DOX + STS group showed suppression of DOX-induced elevation of CK-MB and LDH levels. The DOX group showed increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the heart, whereas the DOX + STS group showed increased catalase and superoxide dismutase (SOD) activities and decreased 8-OHdG levels in the heart compared with DOX group, suggesting that STS reduces DOX-induced DNA damage by improving antioxidant enzymes activities in cardiomyocytes. Additionally, the DOX + STS group showed attenuation of cleaved caspase-3 and DNA fragmentation in cardiomyocytes compared with the DOX group, suggesting that STS suppresses DOX-induced apoptosis in cardiomyocytes. SIGNIFICANCE: STS exerts cardioprotective effects against DOX-induced cardiac dysfunction partly by improving antioxidant defense and suppressing apoptosis, indicating the therapeutic potential of STS against DOX-induced cardiomyopathy..
22. Toshifumi Fujiwara, Kentaro Tokuda, Kenta Momii, Kyohei Shiomoto, Hidetoshi Tsushima, Yukio Akasaki, Satoshi Ikemura, Jun-Ichi Fukushi, Jun Maki, Noriyuki Kaku, Tomohiko Akahoshi, Tomoaki Taguchi, Yasuharu Nakashima, Prognostic factors for the short-term mortality of patients with rheumatoid arthritis admitted to intensive care units., BMC rheumatology, 10.1186/s41927-020-00164-1, 4, 1, 64-64, 2020.12, BACKGROUND: Patients with rheumatoid arthritis (RA) have high mortality risk and are frequently treated in intensive care units (ICUs). METHODS: This was a retrospective observational study. This study included 67 patients (20 males, 47 females) with RA who were admitted at the ICU of our institution for ≥48 h between January 2008 and December 2017. We analyzed the 30-day mortality of these patients and the investigated prognostic factors in RA patients admitted to our ICU. RESULTS: Upon admission, the median age was 70 (range, 33-96) years, and RA duration was 10 (range, 0-61) years. The 5-year survival after ICU admission was 47%, and 30-day, 90-day, and 1-year mortality rates were 22, 27, and 37%, respectively. The major reasons for ICU admission were cardiovascular complications (24%) and infection (40%) and the most common ICU treatments were mechanical ventilation (69%), renal replacement (25%), and vasopressor (78%). In the 30-day mortality group, infection led to a fatal outcome in most cases (67%), and nonsurvival was associated with a significantly higher glucocorticoid dose, updated Charlson's comorbidity index (CCI), and acute physiology and chronic health evaluation (APACHE) II score. Laboratory data obtained at ICU admission showed that lower platelet number and total protein and higher creatinine and prothrombin time international normalized ratio (PT-INR) indicated significantly poorer prognosis. The multivariate Cox proportional hazard model revealed that nonuse of csDMARDs, high updated CCI, increased APACHE II score, and prolonged PT-INR were associated with a higher risk of mortality after ICU admission. CONCLUSION: Our study demonstrated that the nonuse of csDMARDs, high updated CCI, elevated APACHE II score, and coagulation abnormalities predicted poorer prognosis in RA patients admitted to the ICU..
23. Yukie Mizuta, Tomohiko Akahoshi, Jie Guo, Shuo Zhang, Sayoko Narahara, Takahito Kawano, Masaharu Murata, Kentaro Tokuda, Masatoshi Eto, Makoto Hashizume, Ken Yamaura, Exosomes from adipose tissue-derived mesenchymal stem cells ameliorate histone-induced acute lung injury by activating the PI3K/Akt pathway in endothelial cells., Stem cell research & therapy, 10.1186/s13287-020-02015-9, 11, 1, 508-508, 2020.11, BACKGROUND: Mesenchymal stem cells (MSCs), including adipose-derived mesenchymal stem cells (ADSCs), have been shown to attenuate organ damage in acute respiratory distress syndrome (ARDS) and sepsis; however, the underlying mechanisms are not fully understood. In this study, we aimed to explore the potential roles and molecular mechanisms of action of ADSCs in histone-induced endothelial damage. METHODS: Male C57BL/6 N mice were intravenously injected with ADSCs, followed by histones or a vehicle. The mice in each group were assessed for survival, pulmonary vascular permeability, and histological changes. A co-culture model with primary human umbilical vein endothelial cells (HUVECs) exposed to histones was used to clarify the paracrine effect of ADSCs. Overexpression and inhibition of miR-126 ADSCs were also examined as causative factors for endothelial protection. RESULTS: The administration of ADSCs markedly improved survival, inhibited histone-mediated lung hemorrhage and edema, and attenuated vascular hyper-permeability in mice. ADSCs were engrafted in the injured lung and attenuated histone-induced endothelial cell apoptosis. ADSCs showed endothelial protection (via a paracrine effect) and Akt phosphorylation in the histone-exposed HUVECs. Notably, increased Akt phosphorylation by ADSCs was mostly mediated by exosomes in histone-induced cytotoxicity and lung damage. Moreover, the expression of miR-126 was increased in exosomes from histone-exposed ADSCs. Remarkably, the inhibition of miR-126 in ADSCs failed to increase Akt phosphorylation in histone-exposed HUVECs. CONCLUSION: ADSC-derived exosomes may exert protective effects on endothelial cells via activation of the PI3K/Akt pathway..
24. Md Zahangir Hosain, Fuminori Hyodo, Takeshi Mori, Koyo Takahashi, Yusuke Nagao, Hinako Eto, Masaharu Murata, Tomohiko Akahoshi, Masayuki Matsuo, Yoshiki Katayama, Development of a novel molecular probe for the detection of liver mitochondrial redox metabolism., Scientific reports, 10.1038/s41598-020-73336-1, 10, 1, 16489-16489, 2020.10, Redox status influences the course of the inflammatory, metabolic, and proliferative liver diseases. Oxidative stress is thought to play a crucial and sustained role in the pathological progression of early steatosis to severe hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Oxidative stress induced by reactive oxygen species which are generated in the mitochondria can lead to chronic organelle damage in hepatocytes. Currently, the diagnosis of liver disease requires liver biopsy, which is invasive and associated with complications. The present report describes the development of a novel molecular probe, EDA-PROXYL, with higher reactivity and mitochondrial selectivity than standard carboxyl-PROXYL and carbamoyl-PROXYL probes. The membrane permeability of our probe improved in aqueous environments which led to increased accumulation in the liver and interaction of EDA-PROXYL with the carnitine transporter via the amine (NH3+) group further increased accumulation. This increased mitochondrial sensitivity and enhanced accumulation highlight the potential of EDA-PROXYL as a molecular probe for determining metabolic reactions of the mitochondria. Thus, this novel probe could be a tool for the evaluation of redox status of the mitochondria to assess the degree of liver injury and, ultimately, the response to pharmacological therapy..
25. Sho Iwasaka, Yuji Shono, Kentaro Tokuda, Kosuke Nakashima, Yuzo Yamamoto, Jun Maki, Yoji Nagasaki, Nobuyuki Shimono, Tomohiko Akahoshi, Tomoaki Taguchi, Clinical improvement in a patient with severe coronavirus disease 2019 after administration of hydroxychloroquine and continuous hemodiafiltlation with nafamostat mesylate., Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 10.1016/j.jiac.2020.08.001, 26, 12, 1319-1323, 2020.12, The number of people infected with severe acute respiratory syndrome coronavirus 2 is increasing globally, and some patients have a fatal clinical course. In light of this situation, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic on March 11, 2020. While clinical studies and basic research on a treatment for COVID-19 are ongoing around the world, no treatment has yet been proven to be effective. Several clinical studies have demonstrated the efficacy of chloroquine phosphate and nafamostat mesylate with COVID-19. Here, we report the case of a Japanese patient with COVID-19 with severe respiratory failure who improved following the administration of hydroxychloroquine and continuous hemodiafiltlation with nafamostat mesylate. Hence, hydroxychloroquine with nafamostat mesylate might be a treatment option for severe COVID-19..
26. Kenta Momii, Yuji Shono, Kanji Osaki, Yoshinori Nakanishi, Takeshi Iyonaga, Masaaki Nishihara, Tomohiko Akahoshi, Yasuharu Nakashima, Use of venovenous extracorporeal membrane oxygenation for perioperative management of acute respiratory distress syndrome caused by fat embolism syndrome: A case report and literature review., Medicine, 10.1097/MD.0000000000024929, 100, 8, e24929, 2021.02, INTRODUCTION: Fat embolism syndrome (FES) is a known complication of long bone fracture and can affect multiple organs. The organ most commonly affected with FES is the lung. Severe cases of FES from long bone fracture can cause acute respiratory distress syndrome (ARDS). Although the treatment of ARDS remains challenging, it is reported that a lung protection strategy and prone positioning are effective. In addition, early fixation is reported to be beneficial in respiratory failure due to FES, though it may exacerbate respiratory failure during the perioperative period. We report the use of venovenous extracorporeal membrane oxygenation (VV-ECMO) for the successful perioperative management of a patient diagnosed with ARDS due to FES. PATIENT CONCERNS: A 24-year-old man injured in a traffic accident was brought to our emergency department due to shock and consciousness disorder. DIAGNOSIS: After examining the patient, we noted bilateral pneumothorax, liver and spleen injuries, and multiple long bone fractures. Four days after admission, he was diagnosed with FES due to a prolonged consciousness disorder, progressive hypoxia with diffuse lung damage, and cutaneous and mucosal petechiae. INTERVENTION: As respiratory failure progressed, VV-ECMO was initiated on the 6th day. To improve the respiratory failure caused by ARDS, prone position therapy was necessary. Thus, we performed osteosynthesis on the 9th day under ECMO. Prone position therapy was started after surgery. OUTCOMES: Subsequently, his respiratory condition and chest radiographs improved steadily. VV-ECMO was discontinued on the 17th day and the ventilator was removed on the 28th day. His consciousness levels improved without residual central nervous system complications. CONCLUSION: Our study reveals the successful improvement of FES-induced ARDS by osteosynthesis and prone positioning under VV-ECMO. This strategy prioritizes supportive treatment over pharmacologic interventions..
27. Masahiko Sugiyama, Yoshihiro Nagao, Hideo Uehara, Masaki Kagawa, Yuki Shin, Keiichi Shiokawa, Mitsuhiko Ota, Tomohiko Akahoshi, Masaru Morita, Wireless Light-emitting Marker Using Magnetic Field Resonance for Laparoscopic Gastrointestinal Surgery., Surgical laparoscopy, endoscopy & percutaneous techniques, 10.1097/SLE.0000000000000929, 2021.03, BACKGROUND: In laparoscopic gastrointestinal surgery, the location of the tumor is identified mainly with marking methods, such as ink tattooing and intraoperative gastrointestinal endoscopy and marking with a metal clip followed by confirmation with intraoperative x-ray fluoroscopy. Each method has disadvantages, such as complexity, instability of ink sticks, and radiation exposure. Thus, a simple and less-invasive marking method is needed. METHODS: We developed a wireless light-emitting marker with a miniature light-emitting diode that uses a magnetic field resonance mechanism. It emits 4 individual colors-red, blue, green, and white. We confirmed the usefulness of this marker system in ex vivo and in vivo animal experiments. RESULTS: In the ex vivo experiment in porcine intestines, use of the wireless marker was successful, as each color of emitted light was recognized from outside the intestine. In the live animal experiment, it was confirmed that the light emitted by the marker system was visible in the porcine intestinal tract during laparoscopic surgery. The light emitted by the wireless marker in the intestinal tract was confirmed with a laparoscope in a simulated animal surgery. CONCLUSION: We have developed an innovative, radiation-free and reliable light-emitting marker system that uses a magnetic field resonance mechanism that emits four colors of light during laparoscopic surgery..
28. Toru Chiba, Masaharu Murata, Takahito Kawano, Makoto Hashizume, Tomohiko Akahoshi, Reflectance spectra analysis for mucous assessment., World journal of gastrointestinal oncology, 10.4251/wjgo.v13.i8.822, 13, 8, 822-834, 2021.08, This review report represents an overview of research and development on medical hyperspectral imaging technology and its applications. Spectral imaging technology is attracting attention as a new imaging modality for medical applications, especially in disease diagnosis and image-guided surgery. Considering the recent advances in imaging, this technology provides an opportunity for two-dimensional mapping of oxygen saturation (SatO2) of blood with high accuracy, spatial spectral imaging, and its analysis and provides detection and diagnostic information about the tissue physiology and morphology. Multispectral imaging also provides information about tissue oxygenation, perfusion, and potential function during surgery. Analytical algorithm has been examined, and indication of accurate map of relative hemoglobin concentration and SatO2 can be indicated with preferable resolution and frame rate. This technology is expected to provide promising biomedical information in practical use. Several studies suggested that blood flow and SatO2 are associated with gastrointestinal disorders, particularly malignant tumor conditions. The use and analysis of spectroscopic images are expected to potentially play a role in the detection and diagnosis of these diseases..
29. Fuminori Hyodo, Hinako Eto, Tatsuya Naganuma, Norikazu Koyasu, Abdelazim Elsayed Elhelaly, Yoshifumi Noda, Hiroki Kato, Masaharu Murata, Tomohiko Akahoshi, Makoto Hashizume, Hideo Utsumi, Masayuki Matsuo, In Vivo Dynamic Nuclear Polarization Magnetic Resonance Imaging for the Evaluation of Redox-Related Diseases and Theranostics., Antioxidants & redox signaling, 10.1089/ars.2021.0087, 36, 1-3, 172-184, 2021.07, Significance: In vivo molecular and metabolic imaging is an emerging field in biomedical research that aims to perform noninvasive detection of tissue metabolism in disease states and responses to therapeutic agents. The imbalance in tissue oxidation/reduction (Redox) states is related to the onset and progression of several diseases. Tissue redox metabolism provides biomarkers for early diagnosis and drug treatments. Thus, noninvasive imaging of redox metabolism could be a useful, novel diagnostic tool for diagnosis of redox-related disease and drug discovery. Recent Advances: In vivo dynamic nuclear polarization magnetic resonance imaging (DNP-MRI) is a technique that enables the imaging of free radicals in living animals. DNP enhances the MRI signal by irradiating the target tissue or solution with the free radical molecule's electron paramagnetic resonance frequency before executing pulse sequence of the MRI. In vivo DNP-MRI with redox-sensitive nitroxyl radicals as the DNP redox contrast agent enables the imaging of the redox metabolism on various diseases. Moreover, nitroxyl radicals show antioxidant effects that suppress oxidative stress. Critical Issues: To date, considerable progress has been documented preclinically in the development of animal imaging systems. Here, we review redox imaging of in vivo DNP-MRI with a focus on the recent progress of this system and its uses in patients with redox-related diseases. Future Directions: This technique could have broad applications in the study of other redox-related diseases, such as cancer, inflammation, and neurological disorders, and facilitate the evaluation of treatment response as a theranostic tool..
30. Jie Guo, Tomohiko Akahoshi, Yukie Mizuta, Masaharu Murata, Sayoko Narahara, Takahito Kawano, Yoshihiro Nagao, Shuo Zhang, Morimasa Tomikawa, Hirofumi Kawanaka, Makoto Hashizume, Histidine-Rich Glycoprotein Alleviates Liver Ischemia/Reperfusion Injury in Mice With Nonalcoholic Steatohepatitis., Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 10.1002/lt.25960, 27, 6, 840-853, 2021.06, Hepatic ischemia/reperfusion injury (IRI) is a major complication of liver surgery and transplantation, especially in patients with nonalcoholic steatohepatitis (NASH). The mechanism of NASH susceptibility to IRI has not been fully clarified. We investigated the role of liver-produced histidine-rich glycoprotein (HRG) in NASH IRI. A NASH mouse model was established using C57BL/6J mice fed a methionine-choline-deficient diet (MCDD) for 6 weeks. The MCDD and standard diet groups were exposed to 60 minutes of partial hepatic ischemia/reperfusion (I/R). We further evaluated the impact of HRG in this context using HRG knockdown (KD) mice. IRI increased HRG expression in the standard diet group, but not in the MCDD group after I/R. HRG expression was inversely correlated with neutrophil infiltration and the formation of neutrophil extracellular traps (NETs). HRG KD mice showed severe liver injury with neutrophil infiltration and the formation of NETs. Pretreatment with supplementary HRG protected against I/R with the inhibition of neutrophil infiltration and the formation of NETs. In vitro, hepatocytes showed that the expression of HRG was upregulated under hypoxia/reoxygenation conditions, but not in response to oleic acid-treated hepatocytes. The decrease in HRG expression in fatty hepatocytes was accompanied by decreased farnesoid X receptor and hypoxia inducible factor 2 alpha subunit expression. HRG is a hepatoprotective factor during hepatic IRI because it decreases neutrophil infiltration and the formation of NETs. The decrease in HRG is a cause of susceptibility to IRI in steatotic livers. Therefore, HRG is a new therapeutic target for minimizing liver damage in patients with NASH..
31. Fuminori Hyodo, Shinji Ito, Hinako Eto, Abdelazim Elsayed Elhelaly, Masaharu Murata, Tomohiko Akahoshi, Hideo Utsumi, Masayuki Matuso, Free radical imaging of endogenous redox molecules using dynamic nuclear polarization magnetic resonance imaging., Free radical research, 10.1080/10715762.2020.1859109, 55, 4, 343-351, 2021.04, Redox reactions accompanied by the oxidation-reduction of endogenous molecules play important roles in maintaining homeostasis in living organisms. In humans, numerous endogenous molecules that contribute toward maintaining physiological conditions form free radicals via electron transfer. A typical example of this is the mitochondrial electron transport chain, which is involved in energy production. If free radicals derived from endogenous molecules could be visualized and exploited as biological and functional probes, redox reactions mediated by endogenous molecules could be detected non-invasively. We succeeded in visualizing the free radicals derived from endogenous molecules using an in vivo dynamic nuclear polarization (DNP) magnetic resonance imaging (MRI) system. In this review, we describe the visualization of endogenous redox molecules, such as flavins and ubiquinones, which are mitochondrial electron carriers, as well as vitamin E and vitamin C (ascorbate). In addition, we describe the application of melanin free radicals for the in vivo visualization of metabola without using probes via in vivo DNP-MRI..
32. Ryosuke Nakashima, Masaaki Nishihara, Takeshi Iyonaga, Sho Iwasaka, Yuzo Yamamoto, Yuji Shono, Jun Maki, Kentaro Tokuda, Tomohiko Akahoshi, Taiki Higo, Takanari Kitazono, Hiroyuki Tsutsui, Efficacy of thromboelastography in the management of anticoagulation for veno-venous extracorporeal membrane oxygenation in a coronavirus disease 2019 patient: A case report., Medicine, 10.1097/MD.0000000000026313, 100, 23, e26313, 2021.06, RATIONALE: In coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome refractory to optimal conventional management, we should consider the indication for veno-venous extracorporeal membrane oxygenation (V-V ECMO). Growing evidence indicates that COVID-19 frequently causes coagulopathy, presenting as hypercoagulation and incidental thrombosis. For these reasons, a multifactorial approach with several anticoagulant markers should be considered in the management of anticoagulation using heparin in COVID-19 patients on V-V ECMO. PATIENT CONCERNS: A 48-year-old man was infected with COVID-19 with a worsening condition manifesting as acute respiratory distress syndrome. DIAGNOSES: He was refractory to conventional therapy, thus we decided to introduce V-V ECMO. We used heparin as an anticoagulant therapy for V-V ECMO and adjusted the doses of heparin by careful monitoring of the activated clotting time (ACT) and activated partial thromboplastin time (APTT) to avoid both hemorrhagic and thrombotic complications. We controlled the doses of heparin in the therapeutic ranges of ACT and APTT, but clinical hemorrhaging and profound elevation of coagulant marker became apparent. INTERVENTIONS: Using thromboelastography (TEG; Haemonetics) in addition to ACT and APTT, we were able to clearly detect not only sufficient coagulability of COVID19 on V-V ECMO (citrated rapid thromboelastography-R 0.5 min, angle 75.5°, MA 64.0 mm, citrated functional fibrinogen-MA 20.7 mm) but also an excessive effect of heparin (citrated kaolin -R 42.7 min, citrated kaolin with heparinase 11.7 min). OUTCOMES: Given the TEG findings indicating an excessive heparin effect, the early withdrawal of ECMO was considered. After an evaluation of the patient's respiratory capacity, withdrawal from V-V ECMO was achieved and then anticoagulation was stopped. The hemorrhagic complications and elevated thrombotic marker levels dramatically decreased. LESSONS: TEG monitoring might be a useful option for managing anticoagulation in COVID-19 patients on V-V ECMO frequently showing a hypercoagulative state and requiring massive doses of heparin, to reduce both hemorrhagic and thrombotic complications..
33. Hinako Eto, Tatuya Naganuma, Motonao Nakao, Masaharu Murata, Abdelazim Elsayed Elhelaly, Yoshifumi Noda, Hiroki Kato, Masayuki Matsuo, Tomohiko Akahoshi, Makoto Hashizume, Fuminori Hyodo, Development of 20 cm sample bore size dynamic nuclear polarization (DNP)-MRI at 16 mT and redox metabolic imaging of acute hepatitis rat model., Free radical biology & medicine, 10.1016/j.freeradbiomed.2021.04.017, 169, 149-157, 2021.06, Tissue redox metabolism is involved in various diseases, and an understanding of the spatio-temporal dynamics of tissue redox metabolism could be useful for diagnosis of progression and treatment. In in vivo dynamic nuclear polarization (DNP)-MRI, electron paramagnetic resonance (EPR) irradiation at the resonance frequency of nitroxyl radicals administered as a redox probe for induction of DNP, increases the intensity of MRI signals. For electron spin, it is necessary to apply a resonant frequency 658 times higher than that required for nuclear spin because of the higher magnetic moment of unpaired electrons. Previous studies using a disease model of small animals and in vivo DNP-MRI have revealed that an abnormal redox status is involved in many diseases, and that it could be used to visualize the dynamics of alterations in redox metabolism. To use the current methods in clinical practice, the development of a prototype DNP-MRI system for preclinical examinations of large animals is indispensable for clarifying the problems peculiar to the increase in size of the DNP-MRI device. Therefore, we developed a in vivo DNP-MRI system with a sample bore size of 20 cm and a 16-mT magnetic field using a U-shaped permanent magnet. Because the NMR frequency is very low, we adopted a digital radiofrequency transmission/reception system with excellent filter and dynamic range characteristics and equipped with a digital eddy current compensation system to suppress large eddy currents. The pulse sequence was based on the fast spin-echo sequence, which was improved for low frequency and large-eddy current equipment. The in vivo DNP-MRI system developed was used to non-invasively image the redox reaction of a carbamoyl-PROXYL probe in the livers of large rats weighing 800 g. Furthermore, DNP-MRI analysis was able to capture significant changes in redox metabolism in hepatitis-model rats..
34. Yukie Mizuta, Tomohiko Akahoshi, Hinako Eto, Fuminori Hyodo, Masaharu Murata, Kentaro Tokuda, Masatoshi Eto, Ken Yamaura, Noninvasive Diagnosis of the Mitochondrial Function of Doxorubicin-Induced Cardiomyopathy Using In Vivo Dynamic Nuclear Polarization-Magnetic Resonance Imaging., Antioxidants (Basel, Switzerland), 10.3390/antiox11081454, 11, 8, 2022.07, Doxorubicin (DOX) induces dose-dependent cardiotoxicity via oxidative stress and abnormal mitochondrial function in the myocardium. Therefore, a noninvasive in vivo imaging procedure for monitoring the redox status of the heart may aid in monitoring diseases and developing treatments. However, an appropriate technique has yet to be developed. In this study, we demonstrate a technique for detecting and visualizing the redox status of the heart using in vivo dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) with 3-carbamoyl-PROXYL (CmP) as a molecular imaging probe. Male C57BL/6N mice were administered DOX (20 mg/kg) or saline. DNP-MRI clearly showed a slower DNP signal reduction in the DOX group than in the control group. Importantly, the difference in the DNP signal reduction rate between the two groups occurred earlier than that detected by physiological examination or clinical symptoms. In an in vitro experiment, KCN (an inhibitor of complex IV in the mitochondrial electron transport chain) and DOX inhibited the electron paramagnetic resonance change in H9c2 cardiomyocytes, suggesting that the redox metabolism of CmP in the myocardium is mitochondrion-dependent. Therefore, this molecular imaging technique has the potential to monitor the dynamics of redox metabolic changes in DOX-induced cardiomyopathy and facilitate an early diagnosis of this condition..
35. Akahoshi T, Sarcopenia is a predictive factor for prolonged intensive care unit stays in high-energy blunt trauma patients, Acute Medicine & Surgery, 2016.08.
36. Akahoshi T, Hashizume et al., Comparison of recombinant human thrombomodulin and gabexate mesylate for treatment of disseminated intravascular coagulation(DIC) with sepsis following emergent Gastrointestinal surgery: a retrospective study. , 10.1007/s00068-014-0478-4, 20, 2014.11.
37. Tomohiko Akahoshi, Hirofumi Kawanaka, MORIMASA TOMIKAWA, Hiroshi Saeki, Hideaki Uchiyama, Tetsuo Ikeda, Ken Shirabe, Makoto Hashizume, Yoshihiko Maehara, The Effect of Proton Pomp Inhibitor(PPI : Rabeprazole) on Reflux Esophagitis after Endoscopic Injection Sclerotherapy(EIS), a Randomized Control Study(24 hour-pH monitoring), 104, 12, 483-489, 2013.12.
38. Kinjo N, Kawanaka H, Akahoshi T, Maehara Y, Hepatic vein waveform and splenomegaly predict improvement of prothrombin time after splenectomy in hepatitis C virus-related cirrhotic patients., Hepatol Res, 10.1111/hepr.12040, 43, 9, 933-941, 2013.09.
39. Sumida K, Shimoda S, Iwasaka S, Hisamoto S, Kawanaka H, AKahoshi T, Ikegami T, Akashi K, Characteristics of splenic CD8+ T cell exhaustion in patients with hepatitis C, Clin Exp Immunol, 10.1111/cei., 174, 1, 172-178, 2013.08.
40. Akahoshi T, Merits of prophylactic sclerotherapy for esophageal varices concomitant unresectable hepatocellular carcinoma: Prospective randomized study., Dig Endosc., 10.1111/den.12119, 2013.05.
41. Hashimoto N, Akahoshi T, Kamori M, Tomikawa M, Yoshida,D, Nagao Y, Morita K, Kayashima H, Ikegami T, Yoshizumi T, Taketomi A, Shirabe K, Maehara Y. , Treatment of Bleeding Rectal Varices With Transumbilical Venous Obliteration of the Inferior Mesenteric Vein, Surg Laparosc Endosc Percutan Tech, In press, 2013.02.
42. Tsutsumi N, Tomikawa M, Uemura M, Akahoshi T, Image-guided laparoscopic surgery in an open MRI operating theater., Surg Endosc. , 1007/s00464-012-2737, 27, 6, 2178-2184, 2013.01.
43. Tomikawa M, Akahoshi T, Kinjo N, Uehara H, Hashimoto N, Nagao Y, Kamori M, Kumashiro R, Maehara Y, Hashizume M., Rigid and flexible endoscopic rendezvous in spatium peritonealis may be an effective tactic for laparoscopic megasplenectomy: significant implications for pure natural orifice translumenal endoscopic surgery., Surg Endosc, 26, 12, 3573-9, 2012.12.
44. Tomikawa M, Korenaga D, Akahoshi T, Kohshi K, Sugimachi K, Nagao Y, Tsutsumi N, Takenaka K, Kakeji Y, Hashizume M, Maehara Y., Quality of life after laparoscopy-assisted pylorus-preserving gastrectomy: an evaluation using a questionnaire mailed to the patients. , Surg Today, 42, 7, 625-32, 2012.07.
45. AKAHOSHI T, Laparoscopic splenectomy with peginterferon and ribavirin therapy for patients with hepatitis C virus cirrhosis and hypersplenism, Surg Endosc., 24, 680-685, 2010.08.
46. Akahoshi T, Higashi H, Takeuchi H, Muto Y., Neuroendocrine carcinoma in liver , a case report and literature review. Surgery Today Surg Today., Surg Today., 2010;40(2):185-9., 2010.01.
47. Tomohiko Akahoshi, Selective cyclooxygenase(COX)inhibition causes damage to portal hypertensive gastric mucosa Role of nitric oxide and NF-kapperB, The FASEB Journal, 19, 9, 1163-1165, 2005.07.
48. Tomohiko Akahoshi, Role of the spleen in liver fibrosis in rats may be mediated by transforming growth factor beta-1., Journal of Gastroenterlogy and Hepatology, 10.1046/j.1440-1746.2002.02667.x, 17, 1, 59-65, 17(1): 59-65, 2002.01.
49. Akahoshi T, Long-term results of endoscopic Histoacryl injection sclerotherapy for gastric variceal bleeding: a 10-year experience., Surgery, 10.1067/msy.2002.119501, 131, 1, S176-S181, 131(1): 176-181, 2002.01.
50. Akahoshi T, Tanoue K, Tomikawa M, Hashizume M, Sugimachi K., Rupture of jejunal varices treated by percutaneous transhepatic obliteration and endoscopic injection sclerotherapy with n-butyl-2-cyanoacrylate., Endoscopy, 10.1055/s-2001-17919, 33, 11, 998-998, 33(11):998, 2001.11.
51. AkahoshiT, Nishizaki T, Wakasugi K, Mastuzaka T, Kume K, Yamamoto I, Sugimachi K., Portal-systemic encephalopathy due to a congenital extrahepatic portosystemic shunt: three cases and literature review., Hepatogastroenterology, 47, 34, 1113-1116, 47(34):1113-6, 2000.07.