Publications by authors named "Takaaki Murata"

31 Publications

Endovascular aortic repair for abdominal aortic injury complicated with bowel injury due to blunt abdominal trauma: A case report.

Int J Surg Case Rep 2021 Aug 18;85:106216. Epub 2021 Jul 18.

Department of General Surgery, Shonan Kamakura General Hospital, Kanagawa, Japan.

Introduction And Importance: Blunt abdominal aortic injury (BAAI) resulting from blunt abdominal trauma is rare; therefore, there are no standard guidelines for its treatment. Herein, we report the successful treatment of BAAI via endovascular aortic repair (EVAR) performed immediately after emergency laparotomy to repair a bowel injury.

Case Presentation: A 78-year-old man was injured after being caught between a shovel car and the bumper of his own car for approximately 15 s. Upon arrival at the hospital, the patient was conscious and had stable vital signs, abdominal and low back pain, and numbness in the right lower limb. Computed tomography revealed contrast medium leakage into the mesentery, as well as aortic dissection and rupture. Hemostasis and intestinal resection were completed, and EVAR was performed immediately after abdominal closure. The patient was discharged from the hospital at 35 days after surgery.

Clinical Discussion: In this case, there existed a risk of artificial blood vessel infection if reconstruction was simultaneously performed with intestinal resection. Symptoms of lower limb ischemia that were observed prior to surgery resolved. After open surgery, bleeding was controlled, and the patient's vital signs were stable. EVAR was performed as treatment for aortic injury, thereby reducing the risk of direct implant infection and enabling minimally invasive treatment.

Conclusion: EVAR may be useful for the treatment of BAAI in the presence of intestinal injuries, reduce the risk of implant infection, and allow for a one-time, minimally invasive treatment.
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http://dx.doi.org/10.1016/j.ijscr.2021.106216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319751PMC
August 2021

Anti-transcription intermediary factor 1 gamma (TIF1γ) antibody-positive dermatomyositis associated with ascending colon cancer: a case report and review of the literature.

J Med Case Rep 2021 Mar 22;15(1):142. Epub 2021 Mar 22.

Department of General Internal Medicine, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-8533, Japan.

Background: Anti-transcriptional intermediary factor 1 gamma (TIF1γ) antibody is a marker for predicting cancer association in patients with dermatomyositis (DM). The overall survival rate in DM patients with cancer was reported to be considerably worse than that in DM patients without cancer. However, the treatment for cancer-associated DM remains controversial, because the treatment priority between surgical resection for the tumor and internal treatments, including glucocorticoids, immunosuppressive agents, and intravenous immune globulin, has not been established.

Case Presentation: We report the case of a 57-year-old Japanese man diagnosed with anti-TIF1γ antibody-positive DM associated with ascending colon cancer. His clinical symptoms included facial and brachial edema, muscle weakness, dysphagia, myalgia, and rash. Physical examination revealed periorbital edema and Gottron's papules over his knuckles with brachial edema, and tenderness and weakness of the proximal limb muscles. The findings of hyperintense muscles in T2-weighted sequences of brachial contrast-enhanced magnetic resonance imaging and the infiltration of lymphocytic cells and CD4-positive lymphocytes from muscle biopsy were compatible with the diagnostic criteria for dermatomyositis. Anti-TIF1γ antibody was positive by immunoprecipitation assay. He first started internal treatment including intravenous immunoglobulin, steroid pulse, prednisolone, and azathioprine, followed by surgical resection for the tumor because of the elevation of creatine kinase and progression of dysphagia. However, clinical symptoms did not improve, and the patient died 6 months later.

Conclusions: We faced difficulties in determining the treatment priority between surgical resection and internal treatment for our case; therefore, this case would be educational for readers. We searched PubMed to identify English-language case reports of anti-TIF1γ antibody-positive dermatomyositis with malignancy and found 21 reported cases. We herein review and summarize previously reported cases of anti-TIF1γ antibody-positive DM with malignancy. Cancer screening is essential in patients with anti-TIF1γ antibody-positive dermatomyositis because it is associated with a high prevalence of malignancies. Our review revealed that initial surgical treatment should be recommended for better prognosis if the general condition allows.
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http://dx.doi.org/10.1186/s13256-021-02664-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983382PMC
March 2021

Intraoperative angiography with indocyanine green injection for precise localization and resection of small bowel bleeding.

Acute Med Surg 2020 Jan-Dec;7(1):e549. Epub 2020 Aug 13.

Department of Surgery Shonan Kamakura General Hospital Kamakura Japan.

Aim: Bleeding in the small bowel rarely occurs, and its treatment is challenging. Surgery is sometimes required in unstable patients; however, intraoperative identification of the bleeding site is extremely difficult. Many methods have been reported, but no standard strategy has been established yet. Here, we aimed to assess the safety and feasibility of intraoperative angiography with indocyanine green staining to accurately identify small bowel bleeding sites.

Methods: This retrospective study analyzed contrast-enhanced computed tomography images of patients ( = 8) with small bowel extravasation who underwent surgery. If extravasation or other vessel abnormalities that were potential bleeding sites were detected on intraoperative angiography, a microcatheter was placed as close as possible to the extravasation site. Laparotomy was carried out, and 3-5 mL indocyanine green was injected through the microcatheter. The green-stained segment of the small bowel was resected.

Results: Seven of the eight patients had positive angiographic findings and underwent bowel resection. The eighth patient had no abnormalities and hence did not undergo laparotomy. The rate of hemostatic success among the resected cases was 85.7% (six of seven cases). The resected specimens showed pathologic features in six of the seven patients (85.7%), all of whom achieved hemostasis. One patient had pneumonia and congestive heart failure that required longer hospital stay, but no mortality occurred.

Conclusions: Intraoperative angiography with indocyanine green injection, followed by resection for massive small bowel bleeding is effective. This can be a therapeutic option for hemodynamically unstable patients.
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http://dx.doi.org/10.1002/ams2.549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426192PMC
August 2020

Novel ACTG1 mutations in patients identified by massively parallel DNA sequencing cause progressive hearing loss.

Sci Rep 2020 04 27;10(1):7056. Epub 2020 Apr 27.

Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan.

Human ACTG1 mutations are associated with high-frequency hearing loss, and patients with mutations in this gene are good candidates for electric acoustic stimulation. To better understand the genetic etiology of hearing loss cases, massively parallel DNA sequencing was performed on 7,048 unrelated Japanese hearing loss probands. Among 1,336 autosomal dominant hearing loss patients, we identified 15 probands (1.1%) with 13 potentially pathogenic ACTG1 variants. Six variants were novel and seven were previously reported. We collected and analyzed the detailed clinical features of these patients. The average progression rate of hearing deterioration in pure-tone average for four frequencies was 1.7 dB/year from 0 to 50 years age, and all individuals over 60 years of age had severe hearing loss. To better understand the underlying disease-causing mechanism, intracellular localization of wild-type and mutant gamma-actins were examined using the NIH/3T3 fibroblast cell line. ACTG1 mutants p.I34M p.M82I, p.K118M and p.I165V formed small aggregates while p.R37H, p.G48R, p.E241K and p.H275Y mutant gamma-actins were distributed in a similar manner to the WT. From these results, we believe that some part of the pathogenesis of ACTG1 mutations may be driven by the inability of defective gamma-actin to be polymerized into F-actin.
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http://dx.doi.org/10.1038/s41598-020-63690-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184572PMC
April 2020

Association of pre-operative chronic kidney disease and acute kidney injury with in-hospital outcomes of emergency colorectal surgery: a cohort study.

World J Emerg Surg 2020 03 26;15(1):22. Epub 2020 Mar 26.

Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kanagawa, Japan.

Background: Pre-operative kidney function is known to be associated with surgical outcomes. However, in emergency surgery, the pre-operative kidney function may reflect chronic kidney disease (CKD) or acute kidney injury (AKI). We examined the association of pre-operative CKD and/or AKI with in-hospital outcomes of emergency colorectal surgery.

Methods: We conducted a retrospective cohort study including adult patients undergoing emergency colorectal surgery in 38 Japanese hospitals between 2010 and 2017. We classified patients into five groups according to the pre-operative status of CKD (defined as baseline estimated glomerular filtration rate < 60 mL/min/1.73 m or recorded diagnosis of CKD), AKI (defined as admission serum creatinine value/baseline serum creatinine value ≥ 1.5), and end-stage renal disease (ESRD): (i) CKD(-)AKI(-), (ii) CKD(-)AKI(+), (iii) CKD(+)AKI(-), (iv) CKD(+)AKI(+), and (v) ESRD groups. The primary outcome was in-hospital mortality, while secondary outcomes included use of vasoactive drugs, mechanical ventilation, blood transfusion, post-operative renal replacement therapy, and length of hospital stay. We compared these outcomes among the five groups, followed by a multivariable logistic regression analysis for in-hospital mortality.

Results: We identified 3002 patients with emergency colorectal surgery (mean age 70.3 ± 15.4 years, male 54.5%). The in-hospital mortality was 8.6% (169/1963), 23.8% (129/541), 15.3% (52/340), 28.8% (17/59), and 32.3% (32/99) for CKD(-)AKI(-), CKD(-)AKI(+), CKD(+)AKI(-), CKD(+)AKI(+), and ESRD, respectively. Other outcomes such as blood transfusion and post-operative renal replacement therapy showed similar trends. Compared to the CKD(-)AKI(-) group, the adjusted odds ratio (95% confidence interval) for in-hospital mortality was 2.54 (1.90-3.40), 1.29 (0.90-1.85), 2.86 (1.54-5.32), and 2.76 (1.55-4.93) for CKD(-)AKI(+), CKD(+)AKI(-), CKD(+)AKI(+), and ESRD groups, respectively. Stratified by baseline eGFR (> 90, 60-89, 30-59, and < 30 mL/min/1.73 m) and AKI status, the crude in-hospital mortality and adjusted odds ratio increased in patients with baseline eGFR < 30 mL/min/1.73 m among patients without AKI, while these were constantly high regardless of baseline eGFR among patients with AKI. Additional analysis restricting to 2162 patients receiving the surgery on the day of hospital admission showed similar results.

Conclusions: The differentiation of pre-operative CKD and AKI, especially the identification of AKI, is useful for risk stratification in patients undergoing emergency colorectal surgery.
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http://dx.doi.org/10.1186/s13017-020-00303-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098074PMC
March 2020

Successful treatment of hepatic gas gangrene by open drainage: A case report and review of the Japanese literature.

Int J Surg Case Rep 2018 30;49:121-125. Epub 2018 Jun 30.

Department of Surgery, Shonan Kamakura General Hospital, Japan.

Introduction: Liver gas gangrene is rare and has a low prognosis. This case, reports a successful treatment of hepatic gas gangrene using an open drainage technique, followed by antibiotics and hyperbaric oxygen therapy (HBO).

Presentation Of The Case: An 82-year-old male with a history of left hepatectomy and bile duct resection for hilar cholangiocarcinoma presented with chilling, lethargy and dyspnea. He had a history of diabetes mellitus, hypertension, atrial fibrillation, and angina pectoris. Physical examination revealed scleric icterus, right hypochondrium tenderness and percussion tenderness of the liver, with warm extremities. Laboratory findings revealed leukocytosis and increased levels of hepatobiliary enzymes. A computed tomography (CT) scan showed gas accumulation in an S8 lesion with portal vein gas. Percutaneous drainage was performed immediately, and broad-spectrum antibiotics were started, but the drainage was insufficient. Consequently, laparotomy drainage was carried out, followed by HBO. No abscess was detected at one-year of follow-up.

Discussion: Hepatic gas gangrene progresses rapidly and has a high mortality rate. Malignant disease and diabetes mellitus may be predisposing factors. While half of non-clostridial cases survive, most cases of hepatic gas gangrene are associated with clostridial infection and have a fatal outcome.

Conclusion: All survival cases of hepatic gas gangrene were treated by laparotomy drainage, thus immediate laparotomy seems essential to prevent a fatal outcome.
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http://dx.doi.org/10.1016/j.ijscr.2018.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037661PMC
June 2018

Small intestinal metastases from esophageal carcinoma presenting as a perforation: A case report and review of the literature.

Int J Surg Case Rep 2018 5;48:104-108. Epub 2018 Jun 5.

Department of Surgery, Shonan Kamakura General Hospital, Japan.

Introduction: Small intestinal metastasis from oesophageal carcinoma is rare. We report a case of small intestinal metastases from oesophageal carcinoma presenting as a perforation and discuss the aetiology with other cases of small intestinal metastasis from oesophageal carcinoma reported in previous literature.

Presentation: An 86-year-old man presented with fever and coughing. He had choked while eating and had history of weight loss. He was diagnosed with aspiration pneumonia. Two days after the admission, he complained of abdominal pain. Physical examination revealed guarding and rebound tenderness in the upper abdomen. A contrast computed tomography of the abdomen showed ascites, free air, and irregular thickness of the small intestinal walls. Small intestinal perforation was noted, and surgical resection of the small intestine was performed. The pathological findings of the resected small intestine revealed ulcers with squamous cell carcinoma, and upper gastrointestinal endoscopy demonstrated oesophageal tumour, whose biopsy revealed squamous cell carcinoma. A diagnosis of small intestinal metastases from oesophageal carcinoma was made, but the patient died one month after the diagnosis.

Discussion: Most cases found in the literature of oesophageal tumour involve squamous cell carcinoma with male patients, and specific symptoms are divided into obstruction and perforation. All patients with small intestinal metastasis from oesophageal carcinoma who survived were treated by a combination of resection and radiation and/or chemotherapy; thus, immediate treatments seem essential to improve the prognosis.

Conclusion: Physicians should keep in mind the possibility of small intestinal metastasis when patients with a history of oesophageal cancer have abdominal symptoms.
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http://dx.doi.org/10.1016/j.ijscr.2018.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041422PMC
June 2018

Lumbar Arterial Bleeding Treated with Endovascular Aneurysm Repair: A Report of 4 Patients.

Ann Vasc Surg 2018 May 1;49:316.e11-316.e15. Epub 2018 Mar 1.

Department of Surgery, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan.

Background: Lumbar arterial bleeding is a severe condition. Surgical exploration is not indicated because of its rich collateral flow. Transarterial embolization (TAE) is reportedly effective, but there have been cases of failure. It may be a time-consuming procedure for patients with multiple bleeding sources or those with poor vital signs. In this case series, we used endovascular aneurysm repair (EVAR) instead of TAE.

Method: In this case series, we described 4 male patients (2 with traumatic injury, 1 with iatrogenic injury, and 1 with drug-induced hypocoagulability) with lumbar arterial bleeding. The reasons we chose EVAR are because 2 patients had poor vital signs, one patient was a technically difficult case for selective cannulation, and one patient had accompanying aortic dissection.

Result: In all patients, EVAR was performed successfully, and hemostasis was obtained although one patient died of pneumonia on postoperative day 23.

Conclusions: EVAR is an effective alternative for lumbar arterial bleeding although TAE is a first choice of treatment.
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http://dx.doi.org/10.1016/j.avsg.2017.12.018DOI Listing
May 2018

POU4F3 mutation screening in Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis identified novel variants associated with autosomal dominant hearing loss.

PLoS One 2017 17;12(5):e0177636. Epub 2017 May 17.

Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan.

A variant in a transcription factor gene, POU4F3, is responsible for autosomal dominant nonsyndromic hereditary hearing loss, DFNA15. To date, 14 variants, including a whole deletion of POU4F3, have been reported to cause HL in various ethnic groups. In the present study, genetic screening for POU4F3 variants was carried out for a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA15 in the Japanese population. Massively parallel DNA sequencing of 68 target candidate genes was utilized in 2,549 unrelated Japanese HL patients (probands) to identify genomic variations responsible for HL. The detailed clinical features in patients with POU4F3 variants were collected from medical charts and analyzed. Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants) were successfully identified in 15 probands (2.5%) among 602 families exhibiting autosomal dominant HL, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown HL. To obtain the audiovestibular configuration of the patients harboring POU4F3 variants, we collected audiograms and vestibular symptoms of the probands and their affected family members. Audiovestibular phenotypes in a total of 24 individuals from the 15 families possessing variants were characterized by progressive HL, with a large variation in the onset age and severity with or without vestibular symptoms observed. Pure-tone audiograms indicated the most prevalent configuration as mid-frequency HL type followed by high-frequency HL type, with asymmetry observed in approximately 20% of affected individuals. Analysis of the relationship between age and pure-tone average suggested that individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants. The present study showed that variants in POU4F3 were a common cause of autosomal dominant HL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177636PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435223PMC
September 2017

Differences between acoustic trauma and other types of acute noise-induced hearing loss in terms of treatment and hearing prognosis.

Acta Otolaryngol 2017 10;137(sup565):S48-S52. Epub 2017 Apr 10.

c Department of Otorhinolaryngology , Shinshu University School of Medicine , Matsumoto , Japan.

Objectives: To evaluate the differences between acoustic trauma (AT) and other types of acute noise-induced hearing loss (ANIHL), we performed a literature search and case reviews.

Methods: The literature search based on online databases was completed in September 2016. Articles on ANIHL and steroid treatment for human subjects were reviewed. The source sounds and treatment sequelae of our accumulated cases were also reviewed. Hearing loss caused by gun-shots and explosions was categorized into the AT group, while hearing loss caused by concerts and other noises was categorized into the ANIHL group.

Results: Systemic steroid treatment did not appear to be effective, at least in the AT group, based on both the literature and our case reviews. However, effective recovery after treatment including steroids was observed in the ANIHL group. The difference in hearing recovery between the AT and ANIHL groups was statistically significant (p = .030), although differences in age, days from the onset to treatment and pretreatment hearing levels were not significant.

Conclusions: Hearing recovery from AT is very poor, whereas, ANIHL is recoverable to some extent. Therefore, it is essential to differentiate between these two groups for accurate prediction of the hearing prognosis and evaluation of treatment effects.
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http://dx.doi.org/10.1080/00016489.2017.1297899DOI Listing
March 2018

Nationwide epidemiological survey of idiopathic sudden sensorineural hearing loss in Japan.

Acta Otolaryngol 2017 10;137(sup565):S8-S16. Epub 2017 Apr 10.

a Department of Otorhinolaryngology , Shinshu University School of Medicine , Matsumoto , Japan.

Objectives: Using a large-scale nationwide survey database, we investigated the epidemiological characteristics for idiopathic SSNHL in Japan.

Methods: The subjects for this analysis were patients registered in a Japanese multicentre database between April 2014 and March 2016. A total of 3419 idiopathic SSNHL patients were registered in the database, and the clinical characteristics of the idiopathic SSNHL patients were obtained. Several factors associated with the severity of hearing impairment and prognosis were then investigated. Statistical analysis was performed to clarify the factors associated with the severity of hearing impairment and prognosis.

Results: There were significant correlations between the severity of hearing loss and diabetes mellitus, kidney disease, past history of brain infarction, heart disease, age (under 16 years/elderly), and symptoms of vertigo/dizziness. We also analyzed the prognostic factors for idiopathic SSNHL, and found that the severity of hearing loss (Grade 3 or 4), heart disease, aged 65 years or over, time from onset to treatment (over 7 days), and symptoms of vertigo/dizziness were all significantly related to poor prognosis.

Conclusion: The present large-scale clinical survey revealed current epidemiological trends for idiopathic sudden sensorineural hearing loss (SSNHL) and various factors associated with the severity of hearing impairment and prognosis.
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http://dx.doi.org/10.1080/00016489.2017.1297537DOI Listing
March 2018

Idiopathic sudden sensorineural hearing loss and acute low-tone sensorineural hearing loss: a comparison of the results of a nationwide epidemiological survey in Japan.

Acta Otolaryngol 2017 1;137(sup565):S38-S43. Epub 2017 Apr 1.

y Department of Otolaryngology, Faculty of Medicine , University of Tokyo , Tokyo , Japan.

Objectives: The aim of this study was to investigate the differences between idiopathic sudden sensorineural hearing loss (SSNHL), and acute low-tone sensorineural hearing loss (ALHL) using the results of a nationwide survey database in Japan and to analyze the variables associated with their clinical features and the severity of hearing impairment, treatment, and prognosis.

Methods: Participants were patients registered between April 2014 and March 2016 in a multicenter epidemiological survey database involving 30 university hospitals and medical centers across Japan. Statistical analysis was performed to clarify the factors associated with their clinical characteristics and the severity of hearing impairment, treatment, and prognosis.

Results: Idiopathic SSNHL and ALHL differed significantly in terms of male-to-female ratio, age distribution, and time from onset to start of treatment. The treatment methods and hearing prognosis also differed markedly between the two diseases. A majority (92%) of idiopathic SSNHL patients were administered some type of corticosteroid, while half of the ALHL patients received corticosteroids and a diuretic agent.

Conclusion: The results suggested that idiopathic SSNHL and ALHL belonged to different categories of inner ear disease.
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http://dx.doi.org/10.1080/00016489.2017.1297539DOI Listing
March 2018

Relationships among drinking and smoking habits, history of diseases, body mass index and idiopathic sudden sensorineural hearing loss in Japanese patients.

Acta Otolaryngol 2017 1;137(sup565):S17-S23. Epub 2017 Apr 1.

z Department of Otolaryngology, Faculty of Medicine , University of Tokyo , Tokyo , Japan.

Objectives: To present the cardiovascular risk factors in idiopathic sudden sensorineural hearing loss (SSNHL) patients enrolled in a nationwide epidemiological survey of hearing disorders in Japan.

Materials And Methods: We compiled the cardiovascular risk factors in 3073 idiopathic SSNHL subjects (1621 men and 1452 women) and compared their proportions with controls as part of the National Health and Nutrition Survey in Japan, 2014. The cardiovascular risk factors consisted of drinking and smoking habits, a history of five conditions related to cardiovascular disease and body mass index.

Results: The proportion of current smokers was significantly higher among men aged 50-59, 60-69 and 70+ and among women aged 30-39, 40-49 and 60-69. The proportion of patients with a history of diabetes mellitus was significantly higher among men aged 50-59, 60-69 and 70+, but not in women. In addition, male and female SSNHL subjects aged 60-69 showed lower proportions of current drinking; and female SSNHL subjects aged 60-69 showed higher proportions of overweight (BMI ≥25 kg/m).

Conclusions: The present cross-sectional study revealed showed significantly higher proportions of current smokers among both men and women as well as those with a history of diabetes mellitus among men across many age groups in patients with idiopathic SSNHL compared with the controls.
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http://dx.doi.org/10.1080/00016489.2017.1297898DOI Listing
March 2018

Epidemiological survey of acute low-tone sensorineural hearing loss.

Acta Otolaryngol 2017 1;137(sup565):S34-S37. Epub 2017 Apr 1.

b Department of Otorhinolaryngology , Shinshu University School of Medicine , Matsumoto , Japan.

Objectives: A nationwide epidemiological survey involving 23 hospitals in Japan was conducted and the predictive values of demographic data were examined statistically.

Methods: A total of 642 patients from 23 hospitals, including 20 university hospitals, in Japan were enrolled in the study. Age ranged from 8 to 87 years, and all were diagnosed with acute low-tone sensorineural hearing loss (ALHL) between 1994 and 2016. Demographic data for the patients, such as symptoms, gender, mean age, and distribution of ALHL grading, were collected and analyzed in relation to prognosis using Student's t-test, χ test and logistic regression.

Results: Female gender (p < .013), younger age (p < .001), low-grade hearing loss (p < .001), and shorter interval between onset and initial visit (p < .004) were significantly predictive of a good prognosis. The prognosis for definite ALHL was significantly better than that for probable ALHL (p < .007).

Conclusions: The severity of initial hearing loss, interval between onset and initial visit and age were important prognostic indicators for ALHL, while female gender was an important prognostic indicator peculiar to ALHL.
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http://dx.doi.org/10.1080/00016489.2017.1297538DOI Listing
March 2018

The effect of initial treatment on hearing prognosis in idiopathic sudden sensorineural hearing loss: a nationwide survey in Japan.

Acta Otolaryngol 2017 31;137(sup565):S30-S33. Epub 2017 Mar 31.

y Department of Otolaryngology, Faculty of Medicine , University of Tokyo , Tokyo , Japan.

Objective: To investigate the hearing prognosis of idiopathic sudden sensorineural hearing loss (SSNHL) treated with different initial therapies.

Methods: Subjects consisted of patients diagnosed with idiopathic SSNHL within 7 days from onset and showing severe hearing loss (≥60 dB), who were registered in a Japanese multicenter database between April 2014 and March 2016. Subjects were divided into four groups according to initial therapy: (1) steroids, (2) steroids + Prostaglandins (PGs), (3) intratympanic steroids (ITS), and (4) no steroids. Hearing outcomes were compared among the groups.

Results: In total, 1305 patients were enrolled. The final hearing level and hearing gain of patients treated with steroids + PGs were significantly higher than those of patients treated with steroids alone or no steroids. The ratio of good prognosis (complete recovery or marked improvement) in patients treated with steroids + PGs was higher than that in patients treated with steroids alone or no steroids. There was no difference in the prognosis of patients treated with steroids alone or no steroids.

Conclusion: A large number of patients with idiopathic SSNHL were registered in a multicenter database. PG use in combination with steroid administration was associated with a good hearing prognosis in patients with severe hearing loss.
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http://dx.doi.org/10.1080/00016489.2017.1296970DOI Listing
March 2018

The clinical features and prognosis of mumps-associated hearing loss: a retrospective, multi-institutional investigation in Japan.

Acta Otolaryngol 2017 24;137(sup565):S44-S47. Epub 2017 Mar 24.

b Department of Otorhinolaryngology , Shinshu University School of Medicine , Matsumoto, Nagano , Japan.

Conclusions: The majority of hearing loss due to mumps presents as unilateral profound sensorineural hearing loss, which is refractory to treatment. In rare cases of bilateral total deafness, cochlear implants were beneficial for speech perception. Vaccination against mumps is recommended to prevent mumps-associated hearing loss.

Objective: The objective of this study is to investigate the clinical characteristics of hearing loss due to mumps and to evaluate hearing outcomes.

Subjects And Methods: The clinical parameters were analyzed under a retrospective multi-institutional study design in patients diagnosed with hearing loss due to mumps at the Otolaryngology departments of 19 hospitals between 1987 and 2016.

Results: Sixty-seven patients with hearing loss due to mumps were enrolled. The study population consisted of 35 males and 32 females, ranging in age from 1 to 54, with a median age of 9.5 years. Sixty-three patients presented with unilateral, and 4 with bilateral hearing loss. Profound hearing loss was observed in 65 ears. Only one ear with severe hearing loss showed complete recovery. Four patients with bilateral hearing loss received cochlear implant surgery. Most of the patients with hearing loss due to mumps had no history of vaccination.
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http://dx.doi.org/10.1080/00016489.2017.1290826DOI Listing
March 2018

Impact of a Multidisciplinary Round Visit for the Management of Dysphagia Utilizing a Wi-Fi-Based Wireless Flexible Endoscopic Evaluation of Swallowing.

Ann Otol Rhinol Laryngol 2017 Jan 23;126(1):47-53. Epub 2016 Oct 23.

Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Objectives: The management of dysphagia requires a multidisciplinary approach, especially in large-scale hospitals. We introduce a novel protocol using a Wi-Fi-based flexible endoscopic evaluation of swallowing (FEES) system and aim to verify its effectiveness in evaluation and rehabilitation of inpatients with dysphagia.

Method: We conducted novel Wi-Fi-based FEES at the bedside using 3 iPads as monitors and recorders. Functional outcomes of swallowing in 2 different hospitals for acute care with conventional wired or wireless FEES were compared retrospectively.

Results: Using the wireless system, we could visit more patients in a short period of time. Furthermore, a large multidisciplinary team was able to be present at the bedside, which made it easy to hold discussions and rapidly devise appropriate rehabilitation strategies. Aspiration pneumonia recurred in a few cases following our intervention with wireless FEES. Functional oral intake score was significantly increased following the intervention. Moreover, the number of deaths during hospitalization using wireless FEES evaluation was lower than those observed using the conventional system.

Conclusion: Wi-Fi-based wireless FEES system, the first of its kind, allowed our multidisciplinary team to easily and effectively assess inpatients with dysphagia by facilitating simple examinations and intensive transprofessional discussions for patient rehabilitation.
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http://dx.doi.org/10.1177/0003489416674223DOI Listing
January 2017

[Sequential Chemoradiotherapy for Advanced Head and Neck Cancer: A Clinical Study with 33 Cases].

Nihon Jibiinkoka Gakkai Kaiho 2016 May;119(5):734-40

A total of 33 patients with advanced head and neck cancer (AHNC) treated with sequential chemoradiotherapy (SCRT) were retrospectively evaluated at Gunma University Hospital between 2009 and 2011. The regimen of SCRT was docetaxel, cisplatin, and fluorouracil (TPF)-based induction chemotherapy (ICT), accompanied by docetaxel and cisplatin-based concurrent chemoradiotherapy (CCRT), and oral administration of TS-1 after that. The response rate was 61%, the 3-year overall survival rate was 42%, the non-tumor-bearing survival rate was 27%, and the tumor-bearing survival rate was 15%. Fourteen of 33 patients were tumor-free, and their 3-year overall survival rate was surprisingly 86%. On the other hand, 3-year overall survival rate in the remaining 19 patients was significantly low. To select good response cases for ICT was important. In such cases, TPF should be applied repeatedly, which achieved a 61% response rate even in AHNC. A long-term TS-1 oral medication suppressed cancer regrowth and contributed to long-term survival.
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http://dx.doi.org/10.3950/jibiinkoka.119.734DOI Listing
May 2016

Relationship between tumor-associated macrophage subsets and CD47 expression in squamous cell carcinoma of the head and neck in the tumor microenvironment.

Lab Invest 2016 09 20;96(9):994-1003. Epub 2016 Jun 20.

Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, Gunma, Japan.

Tumor-associated macrophages (TAM) have been classified into an immunostimulatory M1 subset against microbes and malignancies, and an immunoregulatory M2 subset that secretes immunosuppressive cytokines in order to repair tissues damaged by malignancies. The infiltration of M2 in the tumor microenvironment is known to facilitate immunosuppression and tumor-promoting properties. In the present study, we investigated the phagocytic potential of these macrophage subsets in oral squamous cell carcinoma (OSCC) in relation to the expression of CD47, the 'don't eat me' signal against macrophages. The macrophage subsets M1 (induced by GM-CSF and IFN-γ) and M2 (induced by M-CSF and IL-10) were derived from the CD14(+) cells of healthy donors. Phagocytosis of the CFSE-labeled CD47(+) cell line HSC-3 by M1/M2 was assessed using flow cytometry and suppressed by an anti-CD47 neutralizing antibody or CD47 siRNA. Furthermore, CD68(+) and CD163(+) macrophage subset counts infiltrating tumor tissue and the expression of CD47 on cancer cells were examined immunohistochemically in 74 cases of OSCC, and their relationships with clinicopathological parameters or prognoses were determined. The phagocytic potential of M1 was similar to that of M2 in vitro. Phagocytosis by M1 increased in a CD47-dependent manner by the neutralizing antibody and siRNA, but did not in M2. An immunohistochemical (IHC) analysis revealed that the expression of CD47 did not correlate with macrophage subsets in peritumoral tissue or with any clinicopathological parameters; however, the stronger expression of CD47 by cancer cells and larger number of total macrophages/M2 were independently related to shorter survivals. Our results suggest that the expression of CD47 by cancer cells is related to evasion from phagocytosis, particularly that by M1 in vitro. IHC results indicate that various mechanisms are involved in the engulfing potential of TAM subsets in vivo.
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http://dx.doi.org/10.1038/labinvest.2016.70DOI Listing
September 2016

Mutational spectrum and clinical features of patients with ACTG1 mutations identified by massively parallel DNA sequencing.

Ann Otol Rhinol Laryngol 2015 May 19;124 Suppl 1:84S-93S. Epub 2015 Mar 19.

Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan

Objectives: ACTG1 has been reported to be a causative gene for autosomal dominant sensorineural hearing loss, DFNA20/26. In this study we sought to clarify the detailed mutational spectrum, clinical features, and genotype-phenotype correlations.

Methods: Massively parallel DNA sequencing (MPS) of 63 target candidate genes was used to screen 1120 Japanese hearing loss patients.

Results: MPS screening successfully identified 4 ACTG1 mutations in 5 families. The majority of patients showed high frequency-involved progressive hearing loss, with the age of onset mostly in the first or second decade. One patient received electric acoustic stimulation (EAS), which showed a good outcome.

Conclusions: Target exon-sequencing using MPS was proven to be a powerful new clinical diagnostic tool for the identification of rare causative genes such as ACTG1. The present clinical findings not only confirmed those previous reports but also provided important new clinical information.
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http://dx.doi.org/10.1177/0003489415575057DOI Listing
May 2015

Alteration of cancer stem cell-like phenotype by histone deacetylase inhibitors in squamous cell carcinoma of the head and neck.

Cancer Sci 2013 Nov 1;104(11):1468-75. Epub 2013 Oct 1.

Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan.

Recent progression in the understanding of stem cell biology has greatly facilitated the identification and characterization of cancer stem cells (CSCs). Moreover, evidence has accumulated indicating that conventional cancer treatments are potentially ineffective against CSCs. Histone deacetylase inhibitors (HDACi) have multiple biologic effects consequent to alterations in the patterns of acetylation of histones and are a promising new group of anticancer agents. In this study, we investigated the effects of two HDACi, suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), on two CD44+ cancer stem-like cell lines from squamous cell carcinoma of the head and neck (SCCHN) cultured in serum-free medium containing epidermal growth factor and basic fibroblast growth factor. Histone deacetylase inhibitors inhibited the growth of SCCHN cell lines in a dose-dependent manner as measured by MTS assays. Moreover, HDACi induced cell cycle arrest and apoptosis in these SCCHN cell lines. Interestingly, the expression of cancer stem cell markers, CD44 and ABCG2, on SCCHN cell lines was decreased by HDACi treatment. In addition, HDACi decreased mRNA expression levels of stemness-related genes and suppressed the epithelial-mesencymal transition phenotype of CSCs. As expected, the combination of HDACi and chemotherapeutic agents, including cisplatin and docetaxel, had a synergistic effect on SCCHN cell lines. Taken together, our data indicate that HDACi not only inhibit the growth of SCCHN cell lines by inducing apoptosis and cell cycle arrest, but also alter the cancer stem cell phenotype in SCCHN, raising the possibility that HDACi may have therapeutic potential for cancer stem cells of SCCHN.
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http://dx.doi.org/10.1111/cas.12271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654248PMC
November 2013

Subglottic Schwannoma: a report of a rare case that was treated with medial thyrotomy.

Am J Otolaryngol 2013 Sep-Oct;34(5):569-73. Epub 2013 May 21.

Department of Otolaryngology, Gunma University Graduate School of Medicine, Gunma, Japan.

We present a rare case of primary subglottic schwannoma in a 51-year-old man. He presented with subacute dyspnea and progressively worsening stridor. Videoendoscopy revealed the presence of a submucosal mass in the subglottic area, which measured 2 cm in diameter and had occluded approximately 80% of the lumen. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a tumor arising from the left posterior wall of the subglottis and extending from the level of the cricoid cartilage to the first tracheal ring. After tracheostomy for airway management, subglottic schwannoma was diagnosed via fiberscopy-assisted punch biopsy. We removed the tumor via a medial thyrotomy (laryngofissure), and the post-excisional raw surface of the cricoid and tracheal cartilage was covered with a free buccal mucosal flap, which was attached using absorbable sutures and fibrin glue. No complications including recurrent nerve palsy developed after the procedure, and early postoperative ambulation was successfully performed. The patient is currently well, and the subglottic wound is clear. Although long-term follow-up is required, medial thyrotomy and coverage of the exposed cartilage with a free buccal mucosal flap is more effective for large subglottic schwannomas than laryngeal or tracheal resection with permanent tracheal tunnel formation from the viewpoint of phonation disability and the risk of complications.
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http://dx.doi.org/10.1016/j.amjoto.2013.04.009DOI Listing
April 2014

Improvement of tracheal flap method for laryngotracheal separation.

Laryngoscope 2013 Feb 15;123(2):440-5. Epub 2012 Oct 15.

Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Objectives/hypothesis: Recurrent pneumonia due to intractable aspiration is a life-threatening disease. A tracheal flap method for children without previous tracheostomy has been previously reported. This study reports that improvements of this method and its three subtypes are widely applicable to patients with various conditions.

Study Design: Surgical technique study.

Methods: The tracheal flap method does not involve transection of the trachea but achieves laryngotracheal separation using the tracheal, mucoperichondrial, and sternohyoid muscle, along with anterior cervical skin flaps. This method can be divided into three subtypes as follows: A-type, utilizing the tracheal flap (for patients without previous tracheostomy); B-type, utilizing the mucoperichondrial and sternohyoid muscle flaps (for patients lacking an anterior tracheal wall); and C-type, utilizing the esophageal flap (for patients with severe hypersalivation). In all three subtypes, the anterior cervical skin flap is employed.

Results: The tracheal flap method was performed in 30 patients (24 children and six adults) at risk of developing intractable aspiration pneumonia. In all 30 cases, aspiration pneumonia was prevented without severe complications. No fistula formation was observed.

Conclusions: All three subtypes (A-, B-, and C-type) of the tracheal flap method are effective in preventing the recurrence of aspiration pneumonia. This method is applicable to diverse patient backgrounds regardless of age or previous tracheostomy. It is less invasive than Lindeman procedure. Furthermore, this method is acceptable to patients' families and improves the QOL of both patients and caregivers.
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http://dx.doi.org/10.1002/lary.23632DOI Listing
February 2013

A new and less invasive procedure for arytenoid adduction surgery: endoscopic-assisted arytenoid adduction surgery.

Laryngoscope 2011 Jun 6;121(6):1274-80. Epub 2011 May 6.

Department of Otolaryngology, Gunma University Graduate School of Medicine, Gunma, Japan.

Objectives/hypothesis: Arytenoid adduction (AA) is the most effective procedure for improving voice function in patients affected by unilateral vocal fold paralysis (UVFP), but it is often associated with severe complications following airway obstruction. The aim of this study is to describe a new and less invasive AA surgical procedure termed endoscopic-assisted AA surgery (EAAS) and to evaluate its voice outcomes.

Study Design: We demonstrated this method using extirpated larynges from three laryngeal cancer patients. Ten patients with severe UVFP underwent EAAS alone or combined with type I thyroplasty or lipoinjection laryngoplasty.

Methods: EAAS involves the placement of permanent adducting sutures around the muscular process (MP) of the arytenoid cartilage using two needles, a penetration needle and a loop needle, under endoscopic guidance. To define the anatomic position of the MP for safer needle insertion, the location of the MP was measured relative to three landmarks on computed tomography/X-ray images of the larynges and in resected larynges. For all patients with UVFP, the maximum phonation time, mean airflow rate, and three acoustic analysis parameters were measured before and after EAAS.

Results: The values of the three variables were similar in all cases. Most patients achieved a maximum phonation time of more than 10 seconds and a mean airflow rate of less than 200 mL/second. All three acoustic analysis parameters were significantly improved after surgery.

Conclusions: EAAS is a simple and effective arytenoid rotation procedure.
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http://dx.doi.org/10.1002/lary.21762DOI Listing
June 2011

Angiotensin II receptor blocker-induced angioedema in the oral floor and epiglottis.

Am J Otolaryngol 2011 Nov-Dec;32(6):624-6. Epub 2011 Feb 15.

Department of Otolaryngology-Head & Neck Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan.

We report the rare case of angioedema (also known as Quincke edema), which was induced by valsartan, an angiotensin II receptor blocker (ARB). ARBs are a new class of antihypertensive agent that is developed to exclude the adverse effects of angiotensin-converting enzyme inhibitors. In theory, ARBs do not contribute to the occurrence of angioedema because they do not increase the serum level of bradykinin, the responsible substance for angioedema. However, some reports of ARB-induced angioedema have recently been published. In this study, we present the forth case and the first Asian case of angioedema due to valsartan, which is one of the ARBs. Otolaryngologist should be wary of the prescribing ARB and discontinue ARBs treatment soon, if angioedema is recognized.
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http://dx.doi.org/10.1016/j.amjoto.2010.11.014DOI Listing
March 2012

Stress-evoked tyrosine phosphorylation of signal regulatory protein α regulates behavioral immobility in the forced swim test.

J Neurosci 2010 Aug;30(31):10472-83

Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.

Severe stress induces changes in neuronal function that are implicated in stress-related disorders such as depression. The molecular mechanisms underlying the response of the brain to stress remain primarily unknown, however. Signal regulatory protein alpha (SIRPalpha) is an Ig-superfamily protein that undergoes tyrosine phosphorylation and binds the protein tyrosine phosphatase Shp2. Here we show that mice expressing a form of SIRPalpha that lacks most of the cytoplasmic region manifest prolonged immobility (depression-like behavior) in the forced swim (FS) test. FS stress induced marked tyrosine phosphorylation of SIRPalpha in the brain of wild-type mice through activation of Src family kinases. The SIRPalpha ligand CD47 was important for such SIRPalpha phosphorylation, and CD47-deficient mice also manifested prolonged immobility in the FS test. Moreover, FS stress-induced tyrosine phosphorylation of both the NR2B subunit of the NMDA subtype of glutamate receptor and the K+-channel subunit Kvbeta2 was regulated by SIRPalpha. Thus, tyrosine phosphorylation of SIRPalpha is important for regulation of depression-like behavior in the response of the brain to stress.
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http://dx.doi.org/10.1523/JNEUROSCI.0257-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634652PMC
August 2010

Production of short-chain-length/medium-chain-length polyhydroxyalkanoate (PHA) copolymer in the plastid of Arabidopsis thaliana using an engineered 3-ketoacyl-acyl carrier protein synthase III.

Biomacromolecules 2009 Apr;10(4):686-90

Division of Biotechnology and Macromolecular Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan.

Short-chain-length/medium-chain-length (SCL/MCL) polyhydroxyalkanoate (PHA) was produced in the plastids of Arabidopsis thaliana. Phe87Thr (F87T) mutated 3-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) from Escherichia coli , and Ser325Thr/Gln481Lys (ST/QK) mutated polyhydroxyalkanoate (PHA) synthase (PhaC1) from Pseudomonas sp. 61-3, along with the beta-ketothiolase (PhaA) and acetoacetyl-CoA reductase (PhaB) from Ralstonia eutropha (Cupriavidus necator) genes were introduced into Arabidopsis. The transgenic Arabidopsis produced PHA copolymers composed of monomers consisting of 4-14 carbons. The introduction of the engineered PHA synthase resulted in a 10-fold increase in PHA content compared to plants expressing the wild-type PHA synthase. In addition, expression of the engineered fabH gene in the plastid led to an increase in the amount of the SCL monomer, 3-hydroxybutyrate, incorporated into PHA, and contributed to supply of MCL monomers for PHA production.
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http://dx.doi.org/10.1021/bm8013878DOI Listing
April 2009

Trans-endocytosis of CD47 and SHPS-1 and its role in regulation of the CD47-SHPS-1 system.

J Cell Sci 2008 Apr 18;121(Pt 8):1213-23. Epub 2008 Mar 18.

Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.

CD47 and SHPS-1 are transmembrane proteins that interact with each other through their extracellular regions and constitute a bidirectional cell-cell communication system (the CD47-SHPS-1 system). We have now shown that the trans-interaction of CD47 and SHPS-1 that occurred on contact of CD47-expressing CHO cells and SHPS-1-expressing CHO cells resulted in endocytosis of the ligand-receptor complex into either cell type. Such trans-endocytosis of CD47 by SHPS-1-expressing cells was found to be mediated by clathrin and dynamin. A juxtamembrane region of SHPS-1 was indispensable for efficient trans-endocytosis of CD47, which was also regulated by Rac and Cdc42, probably through reorganization of the actin cytoskeleton. Inhibition of trans-endocytosis of CD47 promoted the aggregation of CD47-expressing cells with the cells expressing SHPS-1. Moreover, CD47 expressed on the surface of cultured mouse hippocampal neurons was shown to undergo trans-endocytosis by neighboring astrocytes expressing endogenous SHPS-1. These results suggest that trans-endocytosis of CD47 is responsible for removal of the CD47-SHPS-1 complex from the cell surface and hence regulates the function of the CD47-SHPS-1 system, at least in neurons and glial cells.
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http://dx.doi.org/10.1242/jcs.025015DOI Listing
April 2008

CD47 promotes neuronal development through Src- and FRG/Vav2-mediated activation of Rac and Cdc42.

J Neurosci 2006 Nov;26(48):12397-407

Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.

The development of axons and dendrites is controlled by small GTP-binding proteins of the Rho family, but the upstream signaling mechanisms responsible for such regulation remain unclear. We have now investigated the role of the transmembrane protein cluster of differentiation 47 (CD47) in this process with hippocampal neurons. CD47-deficient neurons manifested markedly impaired development of dendrites and axons, whereas overexpression of CD47 promoted such development. Interaction of SH2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1) with CD47 also induced the formation of dendritic filopodia and spines. These effects of CD47 were prevented by inhibition of either cell division cycle 42 (Cdc42) or Rac. In CD47-deficient neurons, autophosphorylation of Src was markedly reduced. In addition, overexpression of CD47 promoted the autophosphorylation of Src. Inhibition of Src family kinases indeed prevented CD47-promoted dendritic development. Inhibition of either FGD1-related Cdc42-guanine nucleotide exchange factor (GEF) (FRG) or Vav2, which is a GEF for Cdc42 and Rac and is activated by Src, also prevented the effects of CD47 on dendritic development. These results indicate that CD47 promotes development of dendrites and axons in hippocampal neurons in a manner dependent, at least in part, on activation of Cdc42 and Rac mediated by Src as well as by FRG and Vav2.
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http://dx.doi.org/10.1523/JNEUROSCI.3981-06.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6674889PMC
November 2006

Enhancement of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) production in the transgenic Arabidopsis thaliana by the in vitro evolved highly active mutants of polyhydroxyalkanoate (PHA) synthase from Aeromonas caviae.

Biomacromolecules 2005 Jul-Aug;6(4):2126-30

Polymer Chemistry Laboratory, RIKEN Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.

In this study, the enhancement of photosynthetic PHA production was achieved using the highly active mutants of PHA synthase created by the in vitro evolutionally techniques. The wild-type and mutated PHA synthase genes from Aeromonas caviae were introduced into Arabidopsis thaliana together with the NADPH-dependent acetoacetyl-CoA reductase gene from Ralstonia eutropha. Expression of the highly active mutated PHA synthase genes, N149S and D171G, led to an 8-10-fold increase in PHA content in the T1 transgenic Arabidopsis, compared to plants harboring the wild-type PHA synthase gene. In homozygous T2 progenies, PHA content was further increased up to 6.1 mg/g cell dry weight. GC/MS analysis of the purified PHA from the transformants revealed that these PHAs were poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [P(3HB-co-3HV)] copolymers consisting of 0.2-0.8 mol % 3HV. The monomer composition of the P(3HB-co-3HV) copolymers synthesized by the wild-type and mutated PHA synthases reflected the substrate specificities observed in Escherichia coli. These results indicate that in vitro evolved PHA synthases can enhance the productivity of PHA and regulate the monomer composition in transgenic plants.
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http://dx.doi.org/10.1021/bm050113gDOI Listing
November 2005
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