Publications by authors named "Shinichi Miyazaki"

50 Publications

Visualization of intracellular lipid metabolism in brown adipocytes by time-lapse ultra-multiplex CARS microspectroscopy with an onstage incubator.

J Chem Phys 2021 Sep;155(12):125102

Department of Applied Physics, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8573, Japan.

We visualized a dynamic process of fatty acid uptake of brown adipocytes using a time-lapse ultra-broadband multiplex coherent anti-Stokes Raman scattering (CARS) spectroscopic imaging system with an onstage incubator. Combined with the deuterium labeling technique, the intracellular uptake of saturated fatty acids was traced up to 9 h, a substantial advance over the initial multiplex CARS system, with an analysis time of 80 min. Characteristic metabolic activities of brown adipocytes, such as resistance to lipid saturation, were elucidated, supporting the utility of the newly developed system.
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http://dx.doi.org/10.1063/5.0063250DOI Listing
September 2021

Neurogenic pulmonary edema secondary to epileptic seizure.

Clin Case Rep 2020 Dec 4;8(12):3559-3560. Epub 2020 Aug 4.

Department of Respiratory Medicine Yokkaichi Municipal Hospital Yokkaichi-shi Japan.

Neurogenic pulmonary edema (NPE) is a non-cardiogenic pulmonary edema that is caused by an acute central nervous system injury and usually develops rapidly after an injury. Although several episodes of NPE resolve spontaneously, the condition may cause unexpected death among patients with epilepsy.
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http://dx.doi.org/10.1002/ccr3.3196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752324PMC
December 2020

Prevalence and genotype/subtype distribution of hepatitis E virus (HEV) among wild boars in Japan: Identification of a genotype 5 HEV strain.

Virus Res 2020 10 7;287:198106. Epub 2020 Aug 7.

Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi-Ken 329-0498, Japan.

To further investigate the prevalence of hepatitis E virus (HEV) infection and characterize HEV genomes among Japanese wild boars (Sus scrofa leucomystax), 1880 boars captured in 17 prefectures in Japan from 2013 to 2019 were studied. Overall, anti-HEV IgG was detected in 8.9 % and HEV RNA was detected in 3.9 % of boars, which was comparable with our previous studies during 2003-2013 (10.3 % and 3.5 %, respectively). Among 74 boar HEV strains obtained from infected boars in the present study, 50 (68 %) were classified into genotype 3 (3a and 3b), 23 (31 %) were classified into genotype 4 (4i), and the remaining strain (wbJGF_19-1) was classified into genotype 5. The wbGF_19-1 strain shared 92.7 % identity over the entire genome with the prototype genotype 5 strain (JBOAR135-Shiz09). The identification of the second genotype 5 HEV strain in a place that is located only 100 km from the site at which JBOAR135-Shiz09 was identified, suggests that genotype 5 HEV circulates within a relatively close range in Japan. Genetically similar HEV strains forming a clade were identified from wild boars living in each area during the observation period of 11-13 years, although the nucleotide sequence changed gradually, accounting for up to 3.4-3.6 % within the 412-nucleotide ORF2 sequence. Eight groups of boars with a cluster of HEV infections were observed, consisting of two, three or four infected offspring, presumably born to the same mother or offspring with their mother. These results suggest that wild boars continue to be important reservoirs for HEV infection in humans in Japan.
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http://dx.doi.org/10.1016/j.virusres.2020.198106DOI Listing
October 2020

An EGFR T790M-mutated lung adenocarcinoma undergoing large-cell neuroendocrine carcinoma transformation after osimertinib therapy: a case report.

J Med Case Rep 2020 Aug 7;14(1):122. Epub 2020 Aug 7.

Department of Respiratory Medicine, Yokkaichi Municipal Hospital, 2-2-37, Shibata, Yokkaichi-shi, Mie, 510-0822, Japan.

Background: Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is selective for both epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. Almost all patients who initially respond to an epidermal growth factor receptor tyrosine kinase inhibitor subsequently report disease progression. Epidermal growth factor receptor-dependent resistance mechanisms, bypass pathway activation, and histological transformation have been reported with osimertinib therapy.

Case Presentation: We report a case of a 64-year-old Asian man with epidermal growth factor receptor T790M-positive adenocarcinoma that transformed to epidermal growth factor receptor T790M-negative large-cell neuroendocrine carcinoma after osimertinib therapy. A prompt rebiopsy revealed a rare mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitor, and subsequently treatment with carboplatin and etoposide was effective.

Conclusions: Despite the promising emergence of circulating tumoral DNA testing, this case report emphasizes the importance of rebiopsy of a progressive epidermal growth factor receptor-mutant tumor.
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http://dx.doi.org/10.1186/s13256-020-02447-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412784PMC
August 2020

Coinfection with SARS-CoV-2 and influenza A virus.

BMJ Case Rep 2020 Jul 1;13(7). Epub 2020 Jul 1.

Department of Respiratory Medicine, Yokkaichi Municipal Hospital, Yokkaichi, Mie, Japan.

Since December 2019, coronavirus disease 2019 (COVID-19) has been an international public health emergency. The possibility of COVID-19 should be considered primarily in patients with new-onset fever or respiratory tract symptoms. However, these symptoms can occur with other viral respiratory illnesses. We reported a case of severe acute respiratory syndrome coronavirus 2 and influenza A virus coinfection. During the epidemic, the possibility of COVID-19 should be considered regardless of positive findings for other pathogens.
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http://dx.doi.org/10.1136/bcr-2020-236812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358105PMC
July 2020

Pulmonary mucosa-associated lymphoid tissue lymphoma mimicking lung cancer.

Clin Case Rep 2019 Aug 19;7(8):1615-1616. Epub 2019 Jun 19.

Department of Respiratory Medicine Yokkaichi Municipal Hospital Yokkaichi-shi Japan.

Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is the most frequent subset of primary pulmonary lymphoma. MALT lymphoma may manifest as a solid mass, mimicking lung cancer.
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http://dx.doi.org/10.1002/ccr3.2276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692979PMC
August 2019

Repressive role of stabilized hypoxia inducible factor 1α expression on transforming growth factor β-induced extracellular matrix production in lung cancer cells.

Cancer Sci 2019 Jun 13;110(6):1959-1973. Epub 2019 May 13.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Activation of transforming growth factor β (TGF-β) combined with persistent hypoxia often affects the tumor microenvironment. Disruption of cadherin/catenin complexes induced by these stimulations yields aberrant extracellular matrix (ECM) production, characteristics of epithelial-mesenchymal transition (EMT). Hypoxia-inducible factors (HIF), the hallmark of the response to hypoxia, play differential roles during development of diseases. Recent studies show that localization of cadherin/catenin complexes at the cell membrane might be tightly regulated by protein phosphatase activity. We aimed to investigate the role of stabilized HIF-1α expression by protein phosphatase activity on dissociation of the E-cadherin/β-catenin complex and aberrant ECM expression in lung cancer cells under stimulation by TGF-β. By using lung cancer cells treated with HIF-1α stabilizers or carrying doxycycline-dependent HIF-1α deletion or point mutants, we investigated the role of stabilized HIF-1α expression on TGF-β-induced EMT in lung cancer cells. Furthermore, the underlying mechanisms were determined by inhibition of protein phosphatase activity. Persistent stimulation by TGF-β and hypoxia induced EMT phenotypes in H358 cells in which stabilized HIF-1α expression was inhibited. Stabilized HIF-1α protein expression inhibited the TGF-β-stimulated appearance of EMT phenotypes across cell types and species, independent of de novo vascular endothelial growth factor A (VEGFA) expression. Inhibition of protein phosphatase 2A activity abrogated the HIF-1α-induced repression of the TGF-β-stimulated appearance of EMT phenotypes. This is the first study to show a direct role of stabilized HIF-1α expression on inhibition of TGF-β-induced EMT phenotypes in lung cancer cells, in part, through protein phosphatase activity.
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http://dx.doi.org/10.1111/cas.14027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549927PMC
June 2019

Transudative chylothorax associated with alcoholic cirrhosis.

Oxf Med Case Reports 2019 Mar 29;2019(3):omz019. Epub 2019 Mar 29.

Department of Respiratory Medicine, Yokkaichi Municipal Hospital, Sibata2-2-37, Shibata, Yokkaichi-shi, Mie, Japan.

We present the case of a 53-year-old man with decompensated alcoholic cirrhosis who was referred for right pleural effusion. After investigation, the patient was ultimately diagnosed with cirrhotic chylothorax. Chylothorax is a rare manifestation of cirrhosis, which results from the trans-diaphragmatic passage of chylous ascites. While chylothorax generally results in an exudative pleural effusion, cirrhotic chylothorax is always a transudative effusion. Biochemical characteristics are useful for diagnosis, avoiding potentially harmful diagnostic and therapeutic procedures.
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http://dx.doi.org/10.1093/omcr/omz019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440272PMC
March 2019

Birt-Hogg-Dubé syndrome in the elderly.

J Gen Fam Med 2019 Mar 21;20(2):72-73. Epub 2018 Dec 21.

Department of Pulmonary Medicine Yokkaichi Municipal Hospital Yokkaichi-shi, Mie Japan.

We present the case of a 73-year-old woman who developed pneumothorax for the first time that was a clinical clue to the diagnosis of Birt-Hogg-Dubé (BHD) syndrome. Although younger onset of pneumothorax is more common in BHD syndrome, the characteristic chest CT findings may contribute to the diagnosis of this disorder in spontaneous pneumothorax of the elderly.
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http://dx.doi.org/10.1002/jgf2.227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399594PMC
March 2019

IgA nephropathy with diffuse alveolar haemorrhage.

BMJ Case Rep 2018 Dec 22;11(1). Epub 2018 Dec 22.

Department of Pulmonary Medicine, Yokkaichi Municipal Hospital, Yokkaichi, Japan.

Immunoglobulin (Ig)A nephropathy is the most common cause of primary glomerulonephritis worldwide. While IgA nephropathy has been associated with a variety of other diseases, pulmonary complications are extremely rare. A 58-year-old man presented with a 2-week history of fever and exertional dyspnoea. A chest imaging revealed bilateral consolidation predominantly in upper lungs. Laboratory findings showed elevated serum creatinine with proteinuria and haematuria. Flexible bronchoscopy revealed diffuse alveolar haemorrhage, and IgA nephropathy was confirmed on a renal biopsy. He received prednisone with good effect. This case highlights the need to consider IgA nephropathy in the differential diagnosis of pulmonary renal syndrome.
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http://dx.doi.org/10.1136/bcr-2018-227382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350714PMC
December 2018

Oral ulcer due to dabigatran capsule.

BMJ Case Rep 2018 Oct 3;2018. Epub 2018 Oct 3.

Department of Pulmonary Medicine, Yokkaichi Municipal Hospital, Yokkaichi, Mie, Japan.

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http://dx.doi.org/10.1136/bcr-2018-227401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194431PMC
October 2018

Airway foreign body manifested as a coin lesion.

Clin Case Rep 2018 Sep 8;6(9):1913-1914. Epub 2018 Aug 8.

Department of Respiratory Medicine Yokkaichi Municipal Hospital Yokkaichi-shi Japan.

Foreign body aspiration is a potentially life-threatening event. The nature of the inhaled objects is highly variable, ranging from organic to inorganic material. Although most pills are radiolucent, lanthanum carbonate is radiopaque and may be identified on chest X-rays.
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http://dx.doi.org/10.1002/ccr3.1754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132148PMC
September 2018

Pulmonary metastasis from endometrial carcinoma.

BMJ Case Rep 2018 Mar 7;2018. Epub 2018 Mar 7.

Shiritsu Yokkaichi Byoin, Yokkaichi, Japan.

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http://dx.doi.org/10.1136/bcr-2017-223916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847939PMC
March 2018

Negative-pressure pulmonary oedema following choking on a rice ball.

BMJ Case Rep 2018 Jan 3;2018. Epub 2018 Jan 3.

Department of Respiratory Medicine, Shiritsu Yokkaichi Byoin, Yokkaichi, Japan.

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http://dx.doi.org/10.1136/bcr-2017-222520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775784PMC
January 2018

Pulmonary tumor thrombotic microangiopathy successfully treated with corticosteroids: a case report.

J Med Case Rep 2017 Dec 23;11(1):356. Epub 2017 Dec 23.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan.

Background: Pulmonary tumor thrombotic microangiopathy is a special type of tumor thromboembolism. We report the case of a patient who developed pulmonary tumor thrombotic microangiopathy with alveolar hemorrhage. Almost all patients with pulmonary tumor thrombotic microangiopathy die within 1 week of the onset of dyspnea; however, the prognosis in this case was better, with 10 weeks of survival from presentation.

Case Presentation: A 62-year-old Japanese man was referred to our hospital with a 4-week history of dyspnea on exertion and severe pulmonary hypertension. Five years previously, he had undergone distal gastrectomy for gastric cancer. He was afebrile, normotensive, and hypoxemic. A physical examination was unremarkable except for purpura on his upper extremities and trunk. Blood tests showed anemia and disseminated intravascular coagulation. Chest computed tomography revealed diffuse ground-glass opacities with emphysema in his upper lungs, moderate pleural effusions, mediastinal lymphadenopathy, and enlargement of the right ventricle and main pulmonary artery. A computed tomography pulmonary angiogram showed no evidence of pulmonary embolism. Lung perfusion scintigraphy showed multiple segmental defects. Although recurrence of gastric cancer was confirmed from the results of bone marrow biopsy, bronchoscopy was not performed due to bleeding diathesis. He was treated with corticosteroids, antibiotics, and platelet transfusion, following which resolution of the abnormal lung shadows and right ventricular pressure overload along with partial alleviation of respiratory failure was observed. Because of his poor performance status, he was eventually transited to palliative care and died 6 weeks after admission. Necropsy of the lung confirmed the diagnosis of pulmonary tumor thrombotic microangiopathy with alveolar hemorrhage.

Conclusions: Pulmonary tumor thrombotic microangiopathy should be considered in the differential diagnosis of patients with cancer who present with severe pulmonary hypertension. In pulmonary tumor thrombotic microangiopathy, local inflammation in pulmonary microvasculature may contribute to pulmonary hypertension, and regulation of inflammation using corticosteroids may help improve the prognosis.
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http://dx.doi.org/10.1186/s13256-017-1524-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741930PMC
December 2017

Impact of mild to moderate COPD on feasibility and prognosis in non-small cell lung cancer patients who received chemotherapy.

Int J Chron Obstruct Pulmon Dis 2017 11;12:3541-3547. Epub 2017 Dec 11.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Non-small cell lung cancer (NSCLC) is the predominant cause of death in patients with COPD, and the severity of COPD in NSCLC patients is classified mainly as mild to moderate. Most advanced NSCLC patients with mild to moderate COPD are treated with chemotherapy; however, the feasibility for and prognosis after chemotherapy of these patients are not well understood. The aim of this study was to elucidate the impact of mild to moderate COPD on the feasibility for and prognosis after chemotherapy in NSCLC patients.

Patients And Methods: A retrospective review was performed on 268 NSCLC patients who received first-line chemotherapy from 2009 to 2014 in our institution. Finally, 85 evaluable patients were included in this study. The clinical characteristics, toxicity profile, objective response rate, and prognosis were analyzed and compared between patients with mild to moderate COPD and those without COPD (non-COPD).

Results: Forty-three patients were classified as COPD (27 cases mild and 16 cases moderate) and 42 patients as non-COPD. The COPD group were older and had fewer never-smokers than the non-COPD group. The objective response rate did not differ between groups (=0.14). There was no significant difference in overall survival between COPD and non-COPD groups (15.0 and 17.0 months, log-rank test =0.57). In the multivariate Cox's proportional hazard model, the adjusted hazard ratio (HRadj) was statistically significant for male sex (HRadj =5.382, 95% CI: 1.496-19.359; =0.010), pathological diagnosis of adenocarcinoma (HRadj =0.460, 95% CI: 0.223-0.948; =0.035), and epithelial growth factor receptor negative mutation (HRadj =6.040, 95% CI: 1.158-31.497; =0.033), but not for the presence of COPD (HRadj =0.661, 95% CI: 0.330-1.325; =0.24). Toxicity profile in COPD group was favorable, as in the non-COPD group.

Conclusion: Mild to moderate COPD did not have a significant deleterious impact on toxicity and prognosis in NSCLC patients.
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http://dx.doi.org/10.2147/COPD.S149456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729822PMC
September 2018

Sleep in vertebrate and invertebrate animals, and insights into the function and evolution of sleep.

Neurosci Res 2017 May 10;118:3-12. Epub 2017 May 10.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Japan. Electronic address:

Many mammalian species, including humans, spend a substantial fraction of their life sleeping. Sleep deprivation in rats ultimately leads to death, indicating the essential role of sleep. Exactly why sleep is so essential, however, remains largely unknown. From an evolutionary point of view, almost all animal species that have been investigated exhibit sleep or sleep-like states, suggesting that sleep may benefit survival. In certain mammalian and avian species, sleep can be further divided into at least two stages, rapid eye movement (REM) sleep and non-REM sleep. In addition to a widely conserved role for sleep, these individual sleep stages may have roles unique to these animals. The recent use of state-of-the-art techniques, including optogenetics and chemogenetics, has greatly broadened our understanding of the neural mechanisms of sleep regulation, allowing us to address the function of sleep. Studies focusing on non-mammalian animals species have also provided novel insights into the evolution of sleep. This review provides a comprehensive overview regarding the current knowledge of the function and evolution of sleep.
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http://dx.doi.org/10.1016/j.neures.2017.04.017DOI Listing
May 2017

Exogenous induction of unphosphorylated PTEN reduces TGFβ-induced extracellular matrix expressions in lung fibroblasts.

Wound Repair Regen 2017 01 25;25(1):86-97. Epub 2017 Jan 25.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Transforming growth factor β (TGFβ) plays an important role in regulating aberrant extracellular matrix (ECM) production from alveolar/epithelial cells (AECs) and fibroblasts in pulmonary fibrosis. Although the tumor suppressor gene phosphatase and tensin homologue deleted from chromosome 10 (PTEN) can negatively control many TGFβ-activated signaling pathways via the phosphatase activity, hyperactivation of the TGFβ-related signaling pathways is often observed in fibrosis. Loss of PTEN expression might cause TGFβ-induced ECM production. In addition, TGFβ was recently shown to induce loss of PTEN enzymatic activity by phosphorylating the PTEN C-terminus. Therefore, we hypothesized that exogenous transfer of unphosphorylated PTEN (PTEN4A) might lead to reduce TGFβ-induced ECM expression in not only epithelial cells but also fibroblasts. Adenovirus-based exogenous PTEN4A induction successfully reduced TGFβ-induced fibronectin expression and retained β-catenin at the cell membrane in human epithelial cells. Exogenous unphosphorylated PTEN also attenuated TGFβ-induced ECM production and inhibited TGFβ-induced β-catenin translocation in a human fibroblast cell line and in mouse primary isolated lung fibroblasts. Conversely, TGFβ-induced α-smooth muscle actin expression did not seem to be inhibited in these fibroblasts. Our data suggest that exogenous administration of unphosphorylated PTEN might be a promising strategy to restore TGFβ-induced loss of PTEN activity and reduce aberrant TGFβ-induced ECM production from epithelial cells and fibroblasts in lung fibrosis as compared with wild-type PTEN induction.
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http://dx.doi.org/10.1111/wrr.12506DOI Listing
January 2017

Factors associated with symptomatic pseudotumors following metal-on-metal total hip arthroplasty.

BMC Musculoskelet Disord 2016 11 7;17(1):456. Epub 2016 Nov 7.

Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan.

Background: Pseudotumors associated with metal-on-metal hips can be symptomatic or asymptomatic. The purpose of this study was to identify the characteristics of pseudotumors associated with pain.

Methods: A total of 239 large-diameter, metal-on-metal total hip arthroplasties (THAs) were performed in 222 patients. Screening for pseudotumors was performed using magnetic resonance imaging (MRI) in all patients who underwent metal-on-metal THA, and 57 patients with 62 affected hips showed pseudotumors. There were 45 women with 49 hips and 12 men with 13 hips affected, with a mean age of 64 years and a mean body mass index (BMI) of 23.9 kg/m. Sixteen hips had symptomatic pseudotumors with pain, and 46 hips were asymptomatic. Pseudotumor size was determined. The anatomical position of pseudotumors was divided into anterior position and posterolateral position. Types of pseudotumors were divided into two types: cystic type; and mixed solid cystic and solid type without a cystic component. The follow-up study of pseudotumors was determined using MRI in 33 patients. The serum cobalt and chromium ion levels were measured in 38 patients after unilateral THA. Univariate and multivariate analyses were performed comparing symptomatic and asymptomatic patients to identify the characteristics of symptomatic pseudotumors.

Results: The mean BMI was 25.4 kg/m in symptomatic patients and 23.4 kg/m in asymptomatic patients; a higher BMI was associated with symptoms (P = 0.036). Symptomatic pseudotumors were significantly larger (three-fold) than asymptomatic pseudotumors (1812 mm vs 642 mm, P = 0.003). Pseudotumors located in the anterior position were associated with symptoms (P = 0.032), and mixed solid cystic and solid type pseudotumors were associated with symptoms (P = 0.007). A multivariate analysis showed significant differences only in size (R  = 0.298, P = 0.031). No asymptomatic patients with pseudotumors became symptomatic during the follow-up period of MRI evaluation.

Conclusion: Larger size was a significant factor for pain on multivariate analysis.
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http://dx.doi.org/10.1186/s12891-016-1317-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100170PMC
November 2016

Forward-genetics analysis of sleep in randomly mutagenized mice.

Nature 2016 11 2;539(7629):378-383. Epub 2016 Nov 2.

Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.

Sleep is conserved from invertebrates to vertebrates, and is tightly regulated in a homeostatic manner. The molecular and cellular mechanisms that determine the amount of rapid eye movement sleep (REMS) and non-REMS (NREMS) remain unknown. Here we identify two dominant mutations that affect sleep and wakefulness by using an electroencephalogram/electromyogram-based screen of randomly mutagenized mice. A splicing mutation in the Sik3 protein kinase gene causes a profound decrease in total wake time, owing to an increase in inherent sleep need. Sleep deprivation affects phosphorylation of regulatory sites on the kinase, suggesting a role for SIK3 in the homeostatic regulation of sleep amount. Sik3 orthologues also regulate sleep in fruitflies and roundworms. A missense, gain-of-function mutation in the sodium leak channel NALCN reduces the total amount and episode duration of REMS, apparently by increasing the excitability of REMS-inhibiting neurons. Our results substantiate the use of a forward-genetics approach for studying sleep behaviours in mice, and demonstrate the role of SIK3 and NALCN in regulating the amount of NREMS and REMS, respectively.
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http://dx.doi.org/10.1038/nature20142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076225PMC
November 2016

Comparison of Midterm Outcomes of Minimally Invasive Computer-Assisted vs Minimally Invasive Jig-Based Total Knee Arthroplasty.

J Arthroplasty 2017 01 15;32(1):43-46. Epub 2016 Jul 15.

Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

Background: Minimally invasive surgery (MIS) has perceived advantages in the early postoperative stage for total knee arthroplasty (TKA). It is not clear whether the improved radiographic alignment achieved by computer-assisted navigation surgery (CAS) improves midterm clinical outcomes. The aim of this study was to compare patient outcomes of MIS TKA performed with and without CAS after a minimum follow-up of 7 years.

Methods: Between 2007 and 2009, 50 patients underwent CAS and MIS TKA, and 50 patients underwent jig-based MIS TKA in this prospective study. Ninety-six patients were evaluated after a mean follow-up of 7.7 years, and clinical and radiological evaluations were performed.

Results: Midterm results demonstrated that the Knee Society knee score, function score, and range of motion were comparable in the 2 groups. The percentage of patients with the mechanical axis within ±3° of neutral was significantly higher in the CAS group than in the jig-based group (94% vs 79%, respectively; P = .038). No knees had loosening after TKA. However, 1 patient in the CAS group demonstrated late infection 4 years postoperatively.

Conclusion: CAS did not improve midterm outcomes after MIS TKA compared with jig-based surgery, although CAS reduced outliers in coronal alignment.
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http://dx.doi.org/10.1016/j.arth.2016.07.005DOI Listing
January 2017

Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers.

Cancer Cell Int 2016 18;16:33. Epub 2016 Apr 18.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-Ku, Nagoya 466-8550 Japan.

Background: Persistent hypoxia stimulation, one of the most critical microenvironmental factors, accelerates the acquisition of epithelial-mesenchymal transition (EMT) phenotypes in lung cancer cells. Loss of phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression might accelerate the development of lung cancer in vivo. Recent studies suggest that tumor microenvironmental factors might modulate the PTEN activity though a decrease in total PTEN expression and an increase in phosphorylation of the PTEN C-terminus (p-PTEN), resulting in the acquisition of the EMT phenotypes. Nevertheless, it is not known whether persistent hypoxia can modulate PTEN phosphatase activity or whether hypoxia-induced EMT phenotypes are negatively regulated by the PTEN phosphatase activity. We aimed to investigate hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers.

Methods: Western blotting was performed in five lung cancer cell lines to evaluate total PTEN expression levels and the PTEN activation. In a xenograft model of lung cancer cells with endogenous PTEN expression, the PTEN expression was evaluated by immunohistochemistry. To examine the effect of hypoxia on phenotypic alterations in lung cancer cells in vitro, the cells were cultured under hypoxia. The effect of unphosphorylated PTEN (PTEN4A) induction on hypoxia-induced EMT phenotypes was evaluated, by using a Dox-dependent gene expression system.

Results: Lung cancer cells involving the EMT phenotypes showed a decrease in total PTEN expression and an increase in p-PTEN. In a xenograft model, loss of PTEN expression was observed in the tumor lesions showing tissue hypoxia. Persistent hypoxia yielded an approximately eight-fold increase in the p-PTEN/PTEN ratio in vitro. PTEN4A did not affect stabilization of hypoxia-inducible factor 1α. PTEN4A blunted hypoxia-induced EMT via inhibition of β-catenin translocation into the cytoplasm and nucleus.

Conclusion: Our study strengthens the therapeutic possibility that compensatory induction of unphosphorylated PTEN may inhibit the acquisition of EMT phenotypes in lung cancer cells under persistent hypoxia.
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http://dx.doi.org/10.1186/s12935-016-0308-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836157PMC
April 2016

Comparison of three different anti-Xa assays in major orthopedic surgery patients treated with fondaparinux.

Int J Hematol 2016 May 27;103(5):554-9. Epub 2016 Feb 27.

Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, Japan.

Anti-Xa assays are useful for monitoring the effects of selective anti-Xa drugs, such as fondaparinux, in the prophylaxis of deep vein thrombosis. In the present study, anti-Xa activity was measured using three different assays, Testzym(®) Heparin S, STA(®)-Liquid Anti-Xa and HemosIL(®) Liquid Heparin. Anti-Xa activity in each assay gradually increased from day one after administration to day eight, and still remained on day 15. Although there were significant differences in anti-Xa activity among the three assays, the activity showed significant correlation across assays. There were no significant differences in the anti-Xa activity between patients with and without DVT or between patients with and without massive bleeding on day one before and after administration, day four, day eight and day 15. Anti-Xa activity in each assay was weakly correlated with antithrombin (AT) activity. The AT activity in patients were significantly higher on days four, eight and 15 compared with day one before and after administration, suggesting that AT activity increases following the administration of fondaparinux. The three anti-Xa assay kits tested are useful for monitoring fondaparinux treatment in orthopedic surgery patients.
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http://dx.doi.org/10.1007/s12185-016-1963-9DOI Listing
May 2016

Fibrin-related markers for diagnosing acute-, subclinical-, and pre-venous thromboembolism in patients with major orthopedic surgery.

Int J Hematol 2016 May 12;103(5):560-6. Epub 2016 Feb 12.

Departments of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, Japan.

Venous thromboembolism (VTE) is a common complication in patients who have undergone major orthopedic surgery, but there are few predictors of VTE after major orthopedic surgery treated with an anticoagulant. We measured levels of fibrin-related markers (FRMs), such as D-dimer, soluble fibrin (SF), and fibrinogen and fibrin degradation products (FDPs) in 66 patients with acute-phase VTE, and 367 patients undergoing major orthopedic surgery. Plasma FDP, D-dimer, and SF levels were significantly higher in patients with acute VTE, but only FDP and D-dimer levels were significantly higher in subclinical VTE. Adequate cut-off levels of D-dimer were 2.2 μg/ml for diagnosing acute VTE and 1.5 μg/ml for diagnosing subclinical VTE. D-dimer of less than 1.9 or 0.7 μg/ml ruled out acute VTE or subclinical VTE. D-dimer of more than 1.3 μg/ml preoperatively showed a moderate risk for postoperative VTE. Measurement of FRMs is useful for evaluating the risk of subclinical or postoperative VTE in patients with major orthopedic surgery. In particular, FDP is the most valuable marker for diagnosing acute VTE, whereas D-dimer is the most valuable for diagnosing subclinical VTE or predicting VTE.
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http://dx.doi.org/10.1007/s12185-016-1954-xDOI Listing
May 2016

The Evaluation of Fibrin-Related Markers for Diagnosing or Predicting Acute or Subclinical Venous Thromboembolism in Patients Undergoing Major Orthopedic Surgery.

Clin Appl Thromb Hemost 2018 Jan 21;24(1):107-114. Epub 2016 Oct 21.

1 Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, Japan.

Objective: The cutoff values of fibrin-related markers (FRMs) diagnosing or predicting the occurrence of a venous thromboembolism (VTE) were evaluated.

Materials And Methods: Fibrin-related markers such as fibrin monomer complex (FMC), D-dimer, and fibrinogen and fibrin degradation products (FDPs) before surgery were measured in 326 patients undergoing orthopedic surgery to diagnose subclinical VTE or predict postoperative VTE.

Results: Although the FMC, D-dimer, and FDP levels were all useful for the diagnosis of acute VTE, the FDP level was not useful for diagnosing subclinical VTE or predicting postoperative VTE. The results of several D-dimer assays closely correlated with other D-dimer assays. There were various cutoff ranges for diagnosing or predicting VTE. Some D-dimer assays were useful for diagnosing low levels of D-dimer and others were useful for diagnosing moderate to high D-dimer levels. Increased D-dimer levels were useful for diagnosing acute (cutoff values: 2.0-5.9 μg/mL) or about 10% of subclinical VTE (cutoff values: 3.4-5.3 μg/mL), for predicting about 10% of postoperative VTE (cutoff values: 3.4-5.3 μg/mL), and for excluding VTE.

Conclusion: Although increased D-dimer levels were useful for diagnosing subclinical VTE and predicting the risk of VTE, there were various cutoff values for the diagnosis or prediction of VTE.
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http://dx.doi.org/10.1177/1076029616674824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714636PMC
January 2018

Direct regulation of transforming growth factor β-induced epithelial-mesenchymal transition by the protein phosphatase activity of unphosphorylated PTEN in lung cancer cells.

Cancer Sci 2015 Dec 6;106(12):1693-704. Epub 2015 Nov 6.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Transforming growth factor β (TGFβ) causes the acquisition of epithelial-mesenchymal transition (EMT). Although the tumor suppressor gene PTEN (phosphatase and tensin homologue deleted from chromosome 10) can negatively regulate many signaling pathways activated by TGFβ, hyperactivation of these signaling pathways is observed in lung cancer cells. We recently showed that PTEN might be subject to TGFβ-induced phosphorylation of its C-terminus, resulting in a loss of its enzyme activities; PTEN with an unphosphorylated C-terminus (PTEN4A), but not PTEN wild, inhibits TGFβ-induced EMT. Nevertheless, whether or not the blockade of TGFβ-induced EMT by the PTEN phosphatase activity might be attributed to the unphosphorylated PTEN C-terminus itself has not been fully determined. Furthermore, the lipid phosphatase activity of PTEN is well characterized, whereas the protein phosphatase activity has not been determined. By using lung cancer cells carrying PTEN domain deletions or point mutants, we investigated the role of PTEN protein phosphatase activities on TGFβ-induced EMT in lung cancer cells. The unphosphorylated PTEN C-terminus might not directly retain the phosphatase activities and repress TGFβ-induced EMT; the modification that keeps the PTEN C-terminus not phosphorylated might enable PTEN to retain the phosphatase activity. PTEN4A with G129E mutation, which lacks lipid phosphatase activity but retains protein phosphatase activity, repressed TGFβ-induced EMT. Furthermore, the protein phosphatase activity of PTEN4A depended on an essential association between the C2 and phosphatase domains. These data suggest that the protein phosphatase activity of PTEN with an unphosphorylated C-terminus might be a therapeutic target to negatively regulate TGFβ-induced EMT in lung cancer cells.
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http://dx.doi.org/10.1111/cas.12831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714667PMC
December 2015

Longitudinal magnetic resonance imaging of pseudotumors following metal-on-metal total hip arthroplasty.

J Arthroplasty 2014 Dec 15;29(12):2236-8. Epub 2014 May 15.

Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu City, Mie, Japan.

The purpose of the study was to determine the natural history of pseudotumors following metal-on-metal total hip arthroplasty (THA) using magnetic resonance imaging (MRI). Initial MRI was conducted at a mean of 36months postoperatively. Follow-up MRI was performed at a mean of 20months after the detection of 24 asymptomatic pseudotumors. Pseudotumor size was determined on MRI. The mean pseudotumor size changed from 729mm(2) to 877mm(2). Pseudotumors increased in size in eight and decreased in six. Ten hips showed no changes. The bigger the pseudotumor size, the more likely the size would increase. In conclusion, pseudotumors frequently change in size. A single MRI study in the clinical decision-making process should be avoided and a longitudinal study should be performed.
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http://dx.doi.org/10.1016/j.arth.2014.05.006DOI Listing
December 2014

Gonococcal endocarditis in a 47-year-old Japanese man.

Intern Med 2014 ;53(5):505-9

Department of Respiratory Medicine, Chubu Rosai Hospital, Japan.

A 47-year-old sexually active Japanese man was admitted with a persistent fever and weight loss. A physical examination revealed a cardiac murmur. A transthoracic echocardiogram was nondiagnostic, although blood cultures grew Neisseria gonorrhoeae. Gonococcal endocarditis was diagnosed based on the modified Duke criteria. The administration of antimicrobial therapy resulted in an adequate initial resolution; however, two months after completing the therapy, the patient developed cardiac failure. Severe aortic regurgitation was identified, and the patient underwent emergent aortic valve replacement. Despite the rarity of gonococcal endocarditis, this disease should nevertheless be considered in patients presenting with a fever, cardiac murmur and a consistent sexual history.
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http://dx.doi.org/10.2169/internalmedicine.53.1301DOI Listing
May 2015

Postoperative recurrence of an IPMN of the pancreas with a fistula to the stomach.

World J Gastrointest Endosc 2010 Oct;2(10):349-51

Masaya Uesato, Yoshihiro Nabeya, Takashi Akai, Kiyohiko Shuto, Hisahiro Matsubara, Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8677, Japan.

We report on a case of a 74 year old man who was diagnosed with a recurrence of non-invasive carcinoma of intraductal papillary mucinous neoplasm (non-invasive IPMN) by postoperative gastroscopy (GS). A pylorus preserving pancreatico duodenectomy for IPMN in the pancreatic head was performed. A histopathological study revealed non-invasive adenocarcinoma. At first, the local recurrence of the tumor around the superior mesenteric artery circumference was diagnosed and disappeared with gemcitabine. Later, the GS showed the elevated lesion with mucin hypersecretion in the remnant stomach. The lesion had a central dip and a fistula common to the pancreas was confirmed on fisterography. We diagnosed a recurrence of IPMN and administered chemotherapy again. However, he died of his original illness. There are no reports of postoperative recurrence of IPMN checked by GS. It should be remembered that the elevated lesion of the remnant stomach is considered as one of the recurrent patterns of IPMN.
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http://dx.doi.org/10.4253/wjge.v2.i10.349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999103PMC
October 2010
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