Publications by authors named "Hiroshi Imai"

248 Publications

Anticoagulant-free venovenous extracorporeal membrane oxygenation for diffuse alveolar hemorrhage with bowel bleeding caused by antineutrophil cytoplasmic antibody-associated vasculitis: A case report.

Respir Med Case Rep 2021 11;34:101513. Epub 2021 Sep 11.

Emergency and Critical Care Center, Mie University Hospital, Japan.

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is sometimes complicated by diffuse alveolar hemorrhage (DAH), which may cause respiratory failure. Venovenous extracorporeal membrane oxygenation (VV-ECMO) without an anticoagulant because of hemorrhagic status, showed the effectiveness for severe respiratory failure by DAH with AAV. A 44-year-old woman developed DAH with bowel bleeding following the onset of AAV, with positive anti-proteinase-3 (PR3) antibodies. Although ventilator management could not support her respiratory status, VV-ECMO was performed. The patient was given immunosuppressive therapy comprising a steroid pulse, plasma exchange, and cyclophosphamide. After about 10 days of VV-ECMO and immunosuppressive therapy, VV-ECMO was withdrawn, and on day 12, ventilator support was stopped. Although a thrombus developed within the inferior vena cava (IVC), which required IVC filtration, the patient was discharged on day 51. VV-ECMO support was effective for treating DAH in this patient with new-onset AAV, which takes some time to achieve remission with immunosuppressive therapy.
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http://dx.doi.org/10.1016/j.rmcr.2021.101513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441063PMC
September 2021

Impact of Helicopter Transport on Reperfusion Times and Long-Term Outcomes in Acute Myocardial Infarction Patients in Rural Areas: A Report From the Mie Acute Coronary Syndrome Registry.

Air Med J 2021 Sep-Oct;40(5):337-343. Epub 2021 May 30.

Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

Objective: Helicopter emergency medical services (HEMS) are effective for time-sensitive conditions, such as stroke and trauma. However, prognostic data on helicopter transport for acute myocardial infarction (AMI) patients are insufficient.

Methods: We registered 2,681 AMI patients in the Mie Acute Coronary Syndrome Registry and enrolled 163 patients from rural areas to HEMS base hospitals with HEMS or ground emergency medical services (GEMS). They were categorized into 4 groups according to the transportation method for interhospital transfer (direct HEMS: n = 52, direct GEMS: n = 54, interhospital HEMS: n = 32, and interhospital GEMS: n = 25). The primary end point was the emergency medical services (EMS) call-to-balloon time. The secondary end point was 2-year major adverse cardiac and cerebrovascular events.

Results: The direct HEMS group was younger than the direct GEMS group (P = .029). The EMS call-to-balloon time was shorter in the direct HEMS and interhospital HEMS groups than in each GEMS group (P = .015 and P = .046). The incidence of 2-year major adverse cardiac and cerebrovascular events tended to be lower in both HEMS groups than in each GEMS group.

Conclusion: Direct HEMS for AMI in rural areas shortens the time from the EMS call to reperfusion when the transport distance is expected to exceed 30 km, which may result in a better patient prognosis. In addition, prehospital diagnostic modalities, such as 12-lead electrocardiography and echocardiography, may shorten the duration from the EMS call to reperfusion.
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http://dx.doi.org/10.1016/j.amj.2021.05.001DOI Listing
May 2021

Identification of a small pericardial effusion on contrast-enhanced computed tomography indicating cardiac perforation and pericardial injury following blunt trauma: A case report.

Trauma Case Rep 2021 Oct 3;35:100515. Epub 2021 Aug 3.

Emergency and Critical Care Center, Mie University Hospital, Japan.

Blunt trauma may cause cardiac perforation requiring emergency surgical repair. Cardiac perforations are usually diagnosed by the presence of a pericardial effusion on echocardiography. However, cardiac perforations and pericardial effusions are sometimes too small to detect, resulting in underdiagnosis. In this case report, we describe a 22-year-old man who was involved in a traffic accident, admitted in a state of shock, and was initially treated for tension pneumothorax and liver and spleen injuries. His initial computed tomography scans revealed a small region of enhancement, corresponding to a small pericardial effusion, indicative of a cardiac perforation. Thus, an emergency median sternotomy was performed. He was diagnosed with perforation of the left atrial ear and right atrium, which were repaired surgically. His liver and spleen injuries were also treated, and the patient was discharged 44 days after admission. The detection of a small pericardial effusion on enhanced computed tomography enabled rapid diagnosis of a cardiac perforation and ensured emergency surgical repair could be performed as soon as possible.

Learning Objectives: •To acknowledge the difficulty of diagnosing cardiac perforation in patients with pericardial injury, based on conventional signs of blunt cardiac injury, such as sternal fracture, serum cardiac enzymes, and hemothorax.•To recognize that a small pericardial effusion on enhanced computed tomography scans is an important finding that should raise suspicion of cardiac perforation and pericardial injury.
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http://dx.doi.org/10.1016/j.tcr.2021.100515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353503PMC
October 2021

Consistency of Pituitary Adenoma: Prediction by Pharmacokinetic Dynamic Contrast-Enhanced MRI and Comparison with Histologic Collagen Content.

Cancers (Basel) 2021 Aug 3;13(15). Epub 2021 Aug 3.

Department of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.

Prediction of tumor consistency is valuable for planning transsphenoidal surgery for pituitary adenoma. A prospective study was conducted involving 49 participants with pituitary adenoma to determine whether quantitative pharmacokinetic analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is useful for predicting consistency of adenomas. Pharmacokinetic parameters in the adenomas including volume of extravascular extracellular space (EES) per unit volume of tissue (v), blood plasma volume per unit volume of tissue (v), volume transfer constant between blood plasma and EES (K), and rate constant between EES and blood plasma (k) were obtained. The pharmacokinetic parameters and the histologic percentage of collagen content (PCC) were compared between soft and hard adenomas using Mann-Whitney test. Pearson's correlation coefficient was used to correlate pharmacokinetic parameters with PCC. Hard adenomas showed significantly higher PCC (44.08 ± 15.14% vs. 6.62 ± 3.47%, < 0.01), v (0.332 ± 0.124% vs. 0.221 ± 0.104%, < 0.01), and K (0.775 ± 0.401/min vs. 0.601 ± 0.612/min, = 0.02) than soft adenomas. Moreover, a significant positive correlation was found between v and PCC (r = 0.601, < 0.01). The v derived using DCE-MRI may have predictive value for consistency of pituitary adenoma.
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http://dx.doi.org/10.3390/cancers13153914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345382PMC
August 2021

Sociometric wearable devices for studying human behavior in corporate and healthcare workplaces.

Biotechniques 2021 Jul 24;71(1):392-399. Epub 2021 Jun 24.

Department of Molecular Pathobiology & Cell Adhesion Biology, Mie University Graduate School of Medicine, Mie, 5148507, Japan.

Wearable sensor technology enables objective data collection of direct human interactions. The authors review sociometric wearable devices (SWD) and their application in healthcare. Human interactions captured by wearable sensors have been shown to correlate with social constructs such as teamwork and productivity in the office. Application of SWD in the field of healthcare requires special considerations: validation studies have shown technological disadvantages in acute medical settings. Application of SWD in healthcare should be considered based on the strengths and weaknesses of the methodology. SWD can also play an important role in investigation of human interaction and epidemic spread. When study designs and methodologies are carefully considered, incorporation of SWD in healthcare research has promising potential for new insights.
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http://dx.doi.org/10.2144/btn-2020-0160DOI Listing
July 2021

Treatment of osteochondritis dissecans of the humeral capitellum with a fragment fixation method using absorbable pins.

JSES Int 2021 May 8;5(3):564-570. Epub 2021 Mar 8.

Department of Bone and Joint Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon-City, Ehime, 791-0295 JAPAN.

Hypothesis: This study aimed to investigate the results, indications, and limitations of absorbable pin fixation for osteochondritis dissecans of the humeral capitellum in the separation stage.

Methods: This study included 35 patients (mean age, 14.0 years). Patients were divided into two groups: Group A included those who obtained complete union within 6 months and Group B included those who did not observe complete union within 6 months. The clinical findings were compared between the groups.

Results: There were 26 and 6 patients in Groups A and B, respectively. Two patients did not obtain complete union. Clinical outcomes improved after the procedure. In univariate analysis, delayed union was associated with larger major diameter ( = .0004) and more depth ( = .03) of the osteochondral fragment measured by computed tomography, the presence of osteosclerosis in the subchondral bed on X-ray imaging ( = .003), and the presence of comminution of subchondral bone on ultrasound imaging ( = .01). In multivariate analysis, there was a significant difference only in the major diameter of the osteochondral fragment ( = .03). Receiver operating characteristic curves analysis shows that if the major diameter of the osteochondral fragment is 11 mm or less, 85% of patients achieve complete union of the osteochondral fragments within 6 months.

Conclusion: Absorbable pin fixation may be considered for the osteochondral fragments with major diameter of 11 mm or less and should not be considered for patients who demonstrate osteosclerosis in the subchondral bed or comminution of subchondral bone.
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http://dx.doi.org/10.1016/j.jseint.2020.12.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178622PMC
May 2021

Use and effectiveness of a two-level initiation strategy for fixed-dose prothrombin complex concentrate according to the initial international normalized ratio in an emergency department in Japan.

Acute Med Surg 2021 Jan-Dec;8(1):e669. Epub 2021 Jun 2.

Emergency and Critical Care Center Mie University Hospital Mie Japan.

Aim: Prothrombin complex concentrate (PCC) was recently approved for patients on warfarin therapy with international normalized ratios (INRs) exceeding 2 in Japan. However, rapid normalization of INR is necessary even in patients who do not meet the aforementioned criteria. We previously found that a fixed PCC dose of 500 IU is insufficient in some patients with INR elevation but is effective in patients with INR less than 2.5. On the basis of the results, we revised the protocol to administer a PCC dose of 500 IU to patients with INR less than 2.5 or 1,000 IU to patients with higher INRs. This study aimed to validate this revised protocol at an emergency department (ED) in Japan.

Methods: We retrospectively collected data for all patients who received PCC in accordance with the revised protocol at our ED between October 2014 and December 2017 (period B) and compared the findings with those in the previous period (January 2013 to September 2014, period A).

Results: In total, 15 and 11 patients received PCC without complications during periods A and B, respectively. All but one patient obeyed the protocol during period B. The average INRs at baseline and within 120 min after PCC infusion were 2.58 and 1.39, respectively, in period A ( = 9), versus 2.54 and 1.28, respectively, in period B ( = 8). Significantly more patients exhibited optimal responses (INR < 1.35) during period B (7/8) than during period A (3/9,  = 0.049).

Conclusion: Our revised protocol effectively normalized INR.
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http://dx.doi.org/10.1002/ams2.669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172621PMC
June 2021

Effects of The Prone Position on Regional Neutrophilic Lung Inflammation According To 18F-FDG PET In An Experimental Ventilator-Induced Lung Injury Model.

Shock 2021 Jun 8. Epub 2021 Jun 8.

Department of Emergency and Critical Care Center, Mie University Hospital, Tsu, Japan Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan Department of Molecular Imaging, Institute for Medical Photonics Research, Hamamatsu University School of Medicine, Hamamatsu, Japan Department of Surgery, National Defense Medical College, Tokorozawa, Japan Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan Division of Anesthesia and Perioperative Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan Department of Acute and Critical Care Medicine, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan.

Abstract: Ventilator-induced lung injury (VILI) can be life-threatening and it is important to prevent the development of VILI. It remains unclear whether the prone position affects neutrophilic inflammation in the lung regions in vivo, which plays a crucial role in the pathogenesis of VILI. This study aimed to assess the relationship between the use of the prone position and the development of VILI-associated regional neutrophilic lung inflammation. Regional neutrophilic lung inflammation and lung aeration during low tidal volume mechanical ventilation were assessed using in vivo 2-deoxy-2-[(18)F] fluoro-D-glucose (18F-FDG) positron emission tomography and computed tomography in acutely experimentally injured rabbit lungs (lung injury induced by lung lavage and excessive ventilation). Direct comparisons were made among three groups: control, supine, and prone position. After approximately 7 hours, tissue-normalized 18F-FDG uptake differed significantly between the supine and prone positions (SUP: 0.038 ± 0.014 vs. PP: 0.029 ± 0.008, P = 0.038), especially in the ventral region (SUP: 0.052 ± 0.013 vs. PP: 0.026 ± 0.007, P = 0.003). The use of the prone position reduced lung inhomogeneities, which was demonstrated by the correction of the disproportionate rate of voxel gas over the given lung region. The progression of neutrophilic inflammation was affected by the interaction between the total strain (for aeration) and the inhomogeneity. The prone position is effective in slowing down the progression of VILI-associated neutrophilic inflammation. Under low-tidal-volume ventilation, the main drivers of the its effect may be homogenization of lung tissue and that of mechanical forces.
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http://dx.doi.org/10.1097/SHK.0000000000001818DOI Listing
June 2021

Acute Megakaryoblastic Leukemia Harboring a Subclone Expressing BCR-ABL1 Fusion Gene Product.

Intern Med 2021 May 29. Epub 2021 May 29.

Department of Hematology, Suzuka Kaisei Hospital, Japan.

Acute myeloid leukemia (AML) with BCR-ABL1, also termed Philadelphia chromosome-positive AML (Ph+ AML), is a rare leukemia subtype classified by the World Health Organization in 2016. The characteristics of Ph+ AML have not been fully identified yet. We herein report a patient with Ph+ AML who phenotypically exhibited megakaryoblastic characteristics, FAB:M7 and harbored a subclone expressing BCR-ABL1 gene fusion products. This case suggests that BCR-ABL1 was acquired as a subclone due to a secondary event that might have occurred late during leukemia evolution. Our findings may aid in deciphering the mechanism underlying Ph+ AML development in future studies.
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http://dx.doi.org/10.2169/internalmedicine.7335-21DOI Listing
May 2021

Randomized trial of granulocyte colony-stimulating factor for spinal cord injury.

Brain 2021 04;144(3):789-799

G-SPIRIT Study Group, Chiba, Japan.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.
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http://dx.doi.org/10.1093/brain/awaa466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041047PMC
April 2021

Reduced Field-of-View Diffusion-Weighted Magnetic Resonance Imaging of the Pancreas With Tilted Excitation Plane: A Preliminary Study.

J Magn Reson Imaging 2021 09 11;54(3):715-720. Epub 2021 Mar 11.

Department of Radiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.

Background: Reduced field-of-view diffusion-weighted imaging (rDWI) with tilted two-dimensional radiofrequency (RF) excitation planes has not yet been applied to the imaging of the pancreas although the utility of this technique which allows the acquisition of high-quality images without aliasing artifacts in the phase-encoding direction has been evaluated for brain and spinal cord imaging.

Purpose: To evaluate the visual image quality of the pancreas by tilting the excitation plane (tilted rDWI) in comparison to conventional DWI (cDWI) and rDWI without using the tilted excitation plane.

Study Type: Retrospective.

Population: Thirty-two patients evaluated for suspected pancreatobiliary diseases.

Field Strength/sequence: Echo-planar imaging DWI (cDWI, rDWI, and tilted rDWI) acquired at 3 T.

Assessment: Images from each DWI sequence were analyzed by five radiologists to compare image quality (conspicuity of pancreatic edges, interslice signal homogeneity, overall image quality, and conspicuity of focal pancreatic lesions) and artifacts (presence of blurring or ghosting artifacts, susceptibility artifacts, and aliasing artifact).

Statistical Tests: Shapiro-Wilk test was performed to assess whether data were normally distributed. Friedman test followed by Bonferroni-adjusted Wilcoxon signed-rank test for post hoc analysis was performed to compare image quality and artifact scores.

Results: The mean scores for conspicuity of pancreatic edges (3.36 vs. 2.37), interslice signal homogeneity (3.14 vs. 2.81), presence of ghosting artifacts (3.32 vs. 2.66), susceptibility artifacts (3.06 vs. 2.30), and aliasing artifacts (3.90 vs. 2.34), and overall image quality (3.49 vs. 2.36) were significantly higher in the tilted rDWI than in the rDWI (P < 0.017 for all parameters). The conspicuity score for focal pancreatic lesions tended to be higher in tilted rDWI than in rDWI (2.44 vs. 2.00, P = 0.07).

Data Conclusion: Tilted rDWI had better image quality and reduced artifacts relative to cDWI and rDWI techniques in the pancreas.

Level Of Evidence: 4 TECHNICAL EFFICACY: Stage 2.
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http://dx.doi.org/10.1002/jmri.27590DOI Listing
September 2021

Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.

Medicine (Baltimore) 2021 Mar;100(9):e24980

Emergency and Critical Care Center, Mie University Hospital, 2-174 Edobashi, Tsu city, Mie 514-8507, Japan.

Rationale: Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.

Patient Concerns: A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.

Diagnosis: After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.

Interventions: We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.

Outcomes: Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.

Lessons: First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
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http://dx.doi.org/10.1097/MD.0000000000024980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939188PMC
March 2021

A Scoring System for Anterior Longitudinal Ligament Ossification of the Lumbar Spine in Diffuse Idiopathic Skeletal Hyperostosis: Relationship Between the Extent of Ligament Ossification and the Range of Motion.

Global Spine J 2021 Mar 3:2192568221996681. Epub 2021 Mar 3.

Department of Orthopedic Surgery, Ehime University School of Medicine, Shitsukawa, Tohon City, Ehime, Japan.

Study Design: Retrospective observational study.

Objective: To investigate the relationship between the extent of ligament ossification and the range of motion (ROM) of the lumbar spine and develop a new scoring system.

Methods: Forty-three patients (30 men and 13 women) with lumbar spinal canal stenosis who underwent decompression from January to December 2018. Ligament ossification at L1/2 to L5/S was assessed on plain X-ray (Xp) and computed tomography (CT) using a modified Mata scoring system (0 point: no ossification, 1 point: ossification of less than half of the intervertebral disc height, 2 points: ossification of half or more of the intervertebral disc height, 3 points: complete bridging), and the intra-rater and inter-rater reliability of the scoring was assessed. The relationship of the scores with postoperative lumbar ROM was investigated.

Result: Intra-rater reliability was high (Cronbach's α was 0.74 for L5/S on Xp but 0.8 or above for other sections), as was inter-rater reliability (Cronbach's α was 0.8 or above for all the segments). ROM significantly decreased as the score increased (scores 1 to 2, and 2 to 3). A significant moderate negative correlation was found between the sum of the scores at L1/2-L5/S and the ROM at L1-S (ρ = - 0.4493, = 0.025).

Conclusion: Our scoring system reflects lumbar mobility and is reproducible. It is effective for assessing DISH in fractures and spinal conditions, and monitoring effects on treatment outcomes and changes over time.
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http://dx.doi.org/10.1177/2192568221996681DOI Listing
March 2021

Early central nervous system relapse of monomorphic epitheliotropic intestinal T-cell lymphoma after cord blood transplantation.

Int J Hematol 2021 Jul 1;114(1):129-135. Epub 2021 Mar 1.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare subtype of intestinal T-cell lymphoma that occurs mostly in Asia. CHOP-like therapy is usually selected, but the prognosis is very poor. This report concerns a 43-year-old woman with newly diagnosed stage IVA MEITL. The patient obtained a partial response after 4 cycles of GDP (gemcitabine, dexamethasone, cisplatin) and achieved a complete response (CR) after cord blood transplantation (CBT) conditioned with total body irradiation, cyclophosphamide, and cytarabine. Seven months after transplantation, the patient experienced cognitive impairment. Magnetic resonance imaging of the brain showed a high-intensity lesion in the right cerebral peduncle and internal capsule. A cerebrospinal fluid examination confirmed central nervous system (CNS) relapse of MEITL. After 3 cycles of MPV (methotrexate, procarbazine, vincristine) followed by whole-brain radiotherapy, her cognitive impairment improved. Due to disease progression, she died 6 months after CNS relapse. Given the CNS relapse after achieving a CR with GDP and CBT in this patient, CNS prophylaxis during first-line therapy may be beneficial in the treatment of MEITL.
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http://dx.doi.org/10.1007/s12185-021-03107-9DOI Listing
July 2021

A dynein-associated photoreceptor protein prevents ciliary acclimation to blue light.

Sci Adv 2021 Feb 26;7(9). Epub 2021 Feb 26.

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan.

Light-responsive regulation of ciliary motility is known to be conducted through modulation of dyneins, but the mechanism is not fully understood. Here, we report a novel subunit of the two-headed f/I1 inner arm dynein, named DYBLUP, in animal spermatozoa and a unicellular green alga. This subunit contains a BLUF (sensors of blue light using FAD) domain that appears to directly modulate dynein activity in response to light. DYBLUP (dynein-associated BLUF protein) mediates the connection between the f/I1 motor domain and the tether complex that links the motor to the doublet microtubule. lacking the DYBLUP ortholog shows both positive and negative phototaxis but becomes acclimated and attracted to high-intensity blue light. These results suggest a mechanism to avoid toxic strong light via direct photoregulation of dyneins.
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http://dx.doi.org/10.1126/sciadv.abf3621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909887PMC
February 2021

Thoracic spondylotic myelopathy presumably caused by diffuse idiopathic skeletal hyperostosis in a patient who underwent decompression and percutaneous pedicle screw fixation.

SAGE Open Med Case Rep 2021 21;9:2050313X20987796. Epub 2021 Jan 21.

Department of Orthopedic Surgery, Ehime University School of Medicine, Tohon, Japan.

A 74-year-old man developed bilateral lower limb spastic paresis. He was diagnosed with thoracic spondylotic myelopathy presumably caused by mechanical stress that was generated in the intervertebral space (T1-T2) between a vertebral bone bridge (C5-T1) due to diffuse idiopathic skeletal hyperostosis after anterior fixation of the lower cervical spine and a vertebral bone bridge (T2-T7) due to diffuse idiopathic skeletal hyperostosis in the upper thoracic spine. Treatment included posterior decompression (T1-T2 laminectomy) and percutaneous pedicle screw fixation at the C7-T4 level. Six months after surgery, the patient could walk with a cane, and the vertebral bodies T1-T2 were bridged without bone grafting. For thoracic spondylotic myelopathy associated with diffuse idiopathic skeletal hyperostosis, decompression and percutaneous pedicle screw fixation are effective therapies.
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http://dx.doi.org/10.1177/2050313X20987796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829458PMC
January 2021

Internet-Based Individualized Cognitive Behavioral Therapy for Shift Work Sleep Disorder Empowered by Well-Being Prediction: Protocol for a Pilot Study.

JMIR Res Protoc 2021 Mar 18;10(3):e24799. Epub 2021 Mar 18.

Departments of Molecular and Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu City, Mie, Japan.

Background: Shift work sleep disorders (SWSDs) are associated with the high turnover rates of nurses, and are considered a major medical safety issue. However, initial management can be hampered by insufficient awareness. In recent years, it has become possible to visualize, collect, and analyze the work-life balance of health care workers with irregular sleeping and working habits using wearable sensors that can continuously monitor biometric data under real-life settings. In addition, internet-based cognitive behavioral therapy for psychiatric disorders has been shown to be effective. Application of wearable sensors and machine learning may potentially enhance the beneficial effects of internet-based cognitive behavioral therapy.

Objective: In this study, we aim to develop and evaluate the effect of a new internet-based cognitive behavioral therapy for SWSD (iCBTS). This system includes current methods such as medical sleep advice, as well as machine learning well-being prediction to improve the sleep durations of shift workers and prevent declines in their well-being.

Methods: This study consists of two phases: (1) preliminary data collection and machine learning for well-being prediction; (2) intervention and evaluation of iCBTS for SWSD. Shift workers in the intensive care unit at Mie University Hospital will wear a wearable sensor that collects biometric data and answer daily questionnaires regarding their well-being. They will subsequently be provided with an iCBTS app for 4 weeks. Sleep and well-being measurements between baseline and the intervention period will be compared.

Results: Recruitment for phase 1 ended in October 2019. Recruitment for phase 2 has started in October 2020. Preliminary results are expected to be available by summer 2021.

Conclusions: iCBTS empowered with well-being prediction is expected to improve the sleep durations of shift workers, thereby enhancing their overall well-being. Findings of this study will reveal the potential of this system for improving sleep disorders among shift workers.

Trial Registration: UMIN Clinical Trials Registry UMIN000036122 (phase 1), UMIN000040547 (phase 2); https://tinyurl.com/dkfmmmje, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046284.

International Registered Report Identifier (irrid): DERR1-10.2196/24799.
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http://dx.doi.org/10.2196/24799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088862PMC
March 2021

Hand tumors: A review of 186 patients at a single institute.

J Orthop Surg (Hong Kong) 2021 Jan-Apr;29(1):2309499021993994

Department of Bone and Joint Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan.

Purpose: The spectrum of diagnoses and clinical features of hand tumors differ from those of tumors in other body parts. However, only a few reports have comprehensively referenced the diagnosis and clinical features of hand tumors. This study aimed to elucidate the diagnostic distribution and the clinical features of hand tumors undergone surgery in our institute.

Patients And Methods: A total of 235 lesions in 186 patients diagnosed with hand tumors between 1978 and 2020 were reviewed. Age at surgery, gender, chief complaint, tumor location, and pathological diagnosis were analyzed.

Results: There were 121 benign bone tumors, 98 benign soft tissue tumors, and 16 malignant tumors. Chondroma and tenosynovial giant cell tumor were common benign bone and soft tissue tumors at the proximal phalanx of the ring finger and the palm, respectively. Meanwhile, chondrosarcoma and synovial sarcoma were common malignant tumors at the dorsal part of the hand. Local pain and painless mass were the chief complaints in patients with benign bone and soft tissue tumors, respectively. Most patients with malignant tumors were referred after unplanned resection. When patients were classified into two categories by tumor size according to maximal diameter, tumors larger than 19 mm had a significantly higher risk of malignant ( = 0.031) despite being smaller than other tumors in different body parts.

Conclusion: When a tumor malignancy is suspected, the patient should be referred to a specialist to avoid unplanned resection or delayed diagnosis due to misdiagnosis. Knowing the distribution and clinical features should help in diagnosing hand tumors.
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http://dx.doi.org/10.1177/2309499021993994DOI Listing
June 2021

A Simple Method for Positioning the Traction Table during Fixation Surgery for a Displaced Femoral Trochanteric Fracture in a Patient Following Ipsilateral Above-the-knee Amputation: A Case Report.

J Orthop Case Rep 2020 Oct;10(7):76-79

Department of Emergency Medicine and Critical Care, Ehime University, Shitsukawa, Toon, Ehime 791-0295. Japan.

Introduction: It is difficult to use a traction table during surgery for an ipsilateral displaced femoral trochanteric fracture following above-the-knee amputation. However, there are few reports regarding such cases. We describe the simple method we used for positioning the traction table and reducing fracture site during fixation surgery for a displaced femoral trochanteric fracture in this patient following above-the-knee amputation.

Case Report: An 80-year-old man was injured in a head-on collision with an oncoming vehicle. We diagnosed him with traumatic gastric perforation, multiple right lower leg fractures, and right lower leg severe crush wound. We performed right above-the-knee amputation and laparoscopic gastrorrhaphy for lifesaving purposes. Thereafter we performed internal fixation for the right femoral trochanteric fracture on the 5th day after the injury. In that operation, we first inserted a 2.4 mm Kirschner wire under fluoroscopic guidance 3 cm proximal to the femoral cut end and attached a horseshoe and traction rope to it. Then, we tightened the rope to the foot piece of the traction table and secured it. Although shortening of the bone fracture was reduced by traction, rotation control was impossible; therefore, the horseshoe was manually controlled through clean sheets during surgery to reduce rotational displacement. We performed internal fixation surgery using a trochanteric femoral nail in the usual manner.

Conclusion: In the osteosynthesis surgery of displaced femoral trochanteric fractures following above-the-knee amputation, the method of inserting the Kirschner wire at the distal end of the patient's femur and pulling it through the rope enables surgeons to reduce fracture shortening. Reduction of rotational displacement was possible by controlling the horseshoe by hand. In this way, intramedullary nail fixation could be performed without trouble under fluoroscopic guidance.
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http://dx.doi.org/10.13107/jocr.2020.v10.i07.1926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857662PMC
October 2020

The Lectin-Like Domain of Thrombomodulin Inhibits β1 Integrin-Dependent Binding of Human Breast Cancer-Derived Cell Lines to Fibronectin.

Biomedicines 2021 Feb 7;9(2). Epub 2021 Feb 7.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie 514-8507, Japan.

Thrombomodulin is a molecule with anti-coagulant and anti-inflammatory properties. Recently, thrombomodulin was reported to be able to bind extracellular matrix proteins, such as fibronectin and collagen; however, whether thrombomodulin regulates the binding of human breast cancer-derived cell lines to the extracellular matrix remains unknown. To investigate this, we created an extracellular domain of thrombomodulin, TMD123-Fc, or domain deletion TM-Fc proteins (TM domain 12-Fc, TM domain 23-Fc) and examined their bindings to fibronectin in vitro by ELISA. The lectin-like domain of thrombomodulin was found to be essential for the binding of the extracellular domain of thrombomodulin to fibronectin. Using a V-well cell adhesion assay or flow cytometry analysis with fluorescent beads, we found that both TMD123-Fc and TMD12-Fc inhibited the binding between β1 integrin of human breast cancer-derived cell lines and fibronectin. Furthermore, TMD123-Fc and TMD12-Fc inhibited the binding of activated integrins to fibronectin under shear stress in the presence of Ca and Mg but not under strong integrin-activation conditions in the presence of Mg without Ca. This suggests that thrombomodulin Fc fusion protein administered exogenously at a relatively early stage of inflammation may be applied to the development of new therapies that inhibit the binding of β1 integrin of breast cancer cell lines to fibronectin.
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http://dx.doi.org/10.3390/biomedicines9020162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914543PMC
February 2021

GTP-dependent formation of straight tubulin oligomers leads to microtubule nucleation.

J Cell Biol 2021 04;220(4)

Laboratory for Molecular Biophysics, RIKEN Center for Brain Science, Saitama, Japan.

Nucleation of microtubules (MTs) is essential for cellular activities, but its mechanism is unknown because of the difficulty involved in capturing rare stochastic events in the early stage of polymerization. Here, combining rapid flush negative stain electron microscopy (EM) and kinetic analysis, we demonstrate that the formation of straight oligomers of critical size is essential for nucleation. Both GDP and GTP tubulin form single-stranded oligomers with a broad range of curvatures, but upon nucleation, the curvature distribution of GTP oligomers is shifted to produce a minor population of straight oligomers. With tubulin having the Y222F mutation in the β subunit, the proportion of straight oligomers increases and nucleation accelerates. Our results support a model in which GTP binding generates a minor population of straight oligomers compatible with lateral association and further growth to MTs. This study suggests that cellular factors involved in nucleation promote it via stabilization of straight oligomers.
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http://dx.doi.org/10.1083/jcb.202007033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871348PMC
April 2021

How ICU Patient Severity Affects Communicative Interactions Between Healthcare Professionals: A Study Utilizing Wearable Sociometric Badges.

Front Med (Lausanne) 2020 3;7:606987. Epub 2020 Dec 3.

Departments of Molecular and Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.

Numerous factors affecting the interactions between healthcare professionals in the workplace demand a comprehensive understanding if the quality of patient healthcare is to be improved. Our previous cross-sectional analysis showed that patient severity scores [i.e., Acute Physiology and Chronic Health Evaluation (APACHE) II] in the 24 h following admission positively correlated with the length of the face-to-face interactions among ICU healthcare professionals. The present study aims to address how the relationships between patient severity and interaction lengths can change over a period of time during both admission and treatment in the ICU. We retrospectively analyzed data prospectively collected between 19 February to 17 March 2016 from an open ICU in a University Hospital in Japan. We used wearable sensors to collect a spatiotemporal distribution dataset documenting the face-to-face interactions between ICU healthcare professionals, which involved 76 ICU staff members, each of whom worked for 160 h, on average, during the 4-week period of data collection. We studied the longitudinal relationships among these interactions, which occurred at the patient bedside, vis-à-vis the severity of the patient's condition [i.e., the Sequential Organ Failure Assessment (SOFA) score] assessed every 24 h. On Day 1, during which a total of 117 patients stayed in the ICU, we found statistically significant positive associations between the interaction lengths and their SOFA scores, as shown by the Spearman's correlation coefficient value (R) of 0.447 ( < 0.01). During the course of our observation from Day 1 to Day 10, the number of patients () who stayed in the ICU gradually decreased ( = 117, Day1; = 10, Day 10), as they either were discharged or died. The statistically significant positive associations of the interaction lengths with the SOFA scores disappeared from Days 2 to 6, but re-emerged on Day 7 ( = 0.620, < 0.05) and Day 8 ( = 0.625, < 0.05), then disappearing again on Days 9 and 10. Whereas all 6 SOFA sub-scores correlated well with the interaction lengths on Day 1, only a few of the sub-scores (coagulation, cardiovascular, and central nervous system scores) did so; specifically, those on Days 7 and 8. The results suggest that patient severity may play an important role in affecting the interactions between ICU healthcare professionals in a time-related manner on ICU Day 1 and on Days 7/8.
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http://dx.doi.org/10.3389/fmed.2020.606987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744931PMC
December 2020

Social Network Analysis of Intensive Care Unit Health Care Professionals Measured by Wearable Sociometric Badges: Longitudinal Observational Study.

J Med Internet Res 2020 12 31;22(12):e23184. Epub 2020 Dec 31.

Department of Molecular Pathobiology and Cell Adhesion Biology, Graduate School of Medicine, Mie University, Tsu-City, Japan.

Background: Use of wearable sensor technology for studying human teamwork behavior is expected to generate a better understanding of the interprofessional interactions between health care professionals.

Objective: We used wearable sociometric sensor badges to study how intensive care unit (ICU) health care professionals interact and are socially connected.

Methods: We studied the face-to-face interaction data of 76 healthcare professionals in the ICU at Mie University Hospital collected over 4 weeks via wearable sensors.

Results: We detail the spatiotemporal distributions of staff members' inter- and intraprofessional active face-to-face interactions, thereby generating a comprehensive visualization of who met whom, when, where, and for how long in the ICU. Social network analysis of these active interactions, concomitant with centrality measurements, revealed that nurses constitute the core members of the network, while doctors remain in the periphery.

Conclusions: Our social network analysis using the comprehensive ICU interaction data obtained by wearable sensors has revealed the leading roles played by nurses within the professional communication network.
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http://dx.doi.org/10.2196/23184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808885PMC
December 2020

Oncocytic intraductal carcinoma of salivary glands: a distinct variant with TRIM33-RET fusions and BRAF V600E mutations.

Histopathology 2021 Sep 31;79(3):338-346. Epub 2021 Mar 31.

Department of Anatomical Pathology, Tokyo Medical University, Tokyo, Japan.

Aims: Salivary gland intraductal carcinoma (IDC) is a complex ductal neoplasm surrounded by a layer of myoepithelial cells. Recent insights have shown that there are three different types: intercalated duct-like, with frequent NCOA4-RET fusions; apocrine, with salivary duct carcinoma-like mutations; and mixed intercalated duct-like/apocrine, with RET fusions, including TRIM27-RET. In addition, an oncocytic IDC has been described, but it remains unclear whether it represents a fourth variant or simply oncocytic metaplasia of another IDC type. Our aim was to more completely characterize oncocytic IDC.

Methods And Results: Six IDCs with oncocytic changes were retrieved from the authors' archives, from three men and three women ranging in age from 45 to 75 years (mean, 63 years). Five arose in the parotid gland, with one in an accessory parotid gland. Four patients with follow-up were free of disease after 1-23 months. Several immunostains (S100, mammaglobin, androgen receptor, and p63/p40) and molecular tools (RNA sequencing, RET fluorescence in-situ hybridisation, BRAF V600E VE1 immunohistochemistry, and Sanger sequencing) were applied. Histologically, the tumours were variably cystic with solid intracystic nodules often difficult to recognise as intraductal. In all, tumour ducts were positive for S100 and mammaglobin, negative for androgen receptor, and completely surrounded by myoepithelial cells positive for p63/p40. Molecular analysis revealed TRIM33-RET in two of six cases, NCOA4-RET in one of six cases, and BRAF V600E in two of six cases. One case had no identifiable alterations.

Conclusions: Oncocytic IDC shares similarities with intercalated duct-like IDC. Although additional verification is needed, the oncocytic variant appears to be sufficiently unique to be now regarded as the fourth distinct subtype of IDC. Because of its indolent nature, oncocytic IDC should be distinguished from histological mimics.
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http://dx.doi.org/10.1111/his.14296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315294PMC
September 2021

The Role of Innate Lymphoid Cells in the Regulation of Immune Homeostasis in Sepsis-Mediated Lung Inflammation.

Diagnostics (Basel) 2020 Oct 12;10(10). Epub 2020 Oct 12.

Department of Molecular Pathobiology and Cell Adhesion Biology, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu City, Mie 514-8507, Japan.

Septic shock/severe sepsis is a deregulated host immune system response to infection that leads to life-threatening organ dysfunction. Lung inflammation as a form of acute lung injury (ALI) is often induced in septic shock. Whereas macrophages and neutrophils have been implicated as the principal immune cells regulating lung inflammation, group two innate lymphoid cells (ILC2s) have recently been identified as a new player regulating immune homeostasis. ILC2 is one of the three major ILC subsets (ILC1s, ILC2s, and ILC3s) comprised of newly identified innate immune cells. These cells are characterized by their ability to rapidly produce type 2 cytokines. ILC2s are predominant resident ILCs and, thereby, have the ability to respond to signals from damaged tissues. ILC2s regulate the immune response, and ILC2-derived type 2 cytokines may exert protective roles against sepsis-induced lung injury. This focused review not only provides readers with new insights into the signaling mechanisms by which ILC2s modulate sepsis-induced lung inflammation, but also proposes ILC2 as a novel therapeutic target for sepsis-induced ALI.
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http://dx.doi.org/10.3390/diagnostics10100808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600279PMC
October 2020

SOX11-induced decrease in vimentin and an increase in prostate cancer cell migration attributed to cofilin activity.

Exp Mol Pathol 2020 12 21;117:104542. Epub 2020 Sep 21.

Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.

SOX11 is a transcription factor in the SOX family of genes that regulate multiple cellular events by influencing the expression of key genes in developmental, physiological, and tumorigenic cells. To elucidate the role of SOX11 in prostate cancer cells, PC-3 prostate cancer cells were cloned (S6 and S9 cells) to highly express SOX11. We demonstrated that both S6 and S9 lose vimentin expression, acquiring epithelial marker proteins, which indicates the Epithelial state phenotype. S6 and S9 cells have cancer-promoting characteristics that include higher migratory properties compared with control cells. The mechanisms that are responsible for the enhanced migration are cofilin activity and keratin 18 expression. TCGA (The Cancer Genome Atlas) dataset analysis revealed that metastatic prostate cancer tumors tend to have more SOX11 gene amplification compared with primary tumors. These results suggest the tumor promotive role and epithelial protein induction of SOX11 in prostate cancer cell.
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http://dx.doi.org/10.1016/j.yexmp.2020.104542DOI Listing
December 2020

Immune cell infiltration landscapes in pediatric acute myocarditis analyzed by CIBERSORT.

J Cardiol 2021 02 3;77(2):174-178. Epub 2020 Sep 3.

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

Background: Myocarditis is an inflammatory disease of the myocardium, which leads to cardiac dysfunction and heart failure. Previous studies have suggested that complex cross-talk between innate and adaptive immune responses is involved in the pathogenesis of acute myocarditis. Immunohistochemistry is the current standard method for the evaluation of infiltrating immune cells, however, it is difficult to investigate and quantify many immune cell populations using this technique.

Methods: Endomyocardial biopsy samples of five pediatric patients with myocarditis were analyzed by cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT), a computational method for quantifying cell fractions from tissue gene expression profiles. CIBERSORT results were then compared with immunohistochemistry analyses.

Results: Significant results of immune infiltrate deconvolution were obtained in four patients with fulminant myocarditis by CIBERSORT analysis. Among 22 immune cell types, 19 cell types were detected in one or more patients. Activated NK cells were the most prevalent population in two patients, whereas activated memory CD4 T cells and M2 macrophages were the most prevalent population in one patient each. Overall CIBERSORT results were consistent with those of immunohistochemistry, although some discrepancies were observed.

Conclusions: Infiltrating immune cell subsets detected by CIBERSORT analysis can reflect the time course of innate and adaptive immune responses in acute myocarditis. CIBERSORT may have the potential to characterize the detail of infiltrating immune cells in myocardial tissues and provide novel insights into the pathogenesis of acute myocarditis.
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http://dx.doi.org/10.1016/j.jjcc.2020.08.004DOI Listing
February 2021

Cancer-related gene mutations and intratumoral genetic heterogeneity in human epidermal growth factor receptor 2 heterogeneous gastric cancer.

Pathol Int 2020 Nov 1;70(11):865-870. Epub 2020 Sep 1.

Department of Oncologic Pathology, Mie University Graduate School of Medicine, Mie, Japan.

Human epidermal growth factor receptor 2 (HER2) protein overexpression is associated with HER2 gene amplification, a critical driver oncogenetic change in gastric cancer. HER2 heterogeneity in advanced gastric cancer is associated with a poor prognosis and affects the clinical efficacy of trastuzumab. However, the mechanisms of HER2 heterogeneity are not fully understood. Here, we examined whether HER2 heterogeneous gastric cancer exhibited intratumoral genetic heterogeneity in other cancer-related genes. Two cases of advanced gastric cancer with HER2 heterogeneity were selected, and samples of HER2-positive and HER2-negative areas in each case were analyzed using a cancer-associated multiple gene panel. In both cases, TP53 mutations were observed in both HER2-positive and HER2-negative areas, whereas many of the potential driver and passenger mutations differed between HER2-positive and HER2-negative areas. Overall, our findings demonstrated that HER2 heterogeneous gastric cancer exhibited intratumoral genetic heterogeneity in other cancer-related genes and that the molecular mechanisms could differ between HER2-positive and -negative areas.
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http://dx.doi.org/10.1111/pin.13004DOI Listing
November 2020

Sepsis Induces Deregulation of IL-13 Production and PD-1 Expression in Lung Group 2 Innate Lymphoid Cells.

Shock 2021 03;55(3):357-370

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu City, Mie, Japan.

Abstract: Deregulation of the immune system in sepsis plays the central role in the pathogenesis of multiple organ failure including septic lung injury. Group 2 innate lymphoid cells (ILC2s) have emerged as a new player in regulating immune homeostasis in the lung; however, the role of ILC2s in lung injury in sepsis remains poorly understood. Here, we investigated temporal changes in stimulatory and inhibitory receptor expression and intracellular type 2 cytokine expression of ILC2s in the lung using a cecal ligation and puncture mouse sepsis model. We found that IL-13 production by ILC2s, which were predominately composed of the resident natural ILC2 subset rather than the migratory inflammatory ILC2 subset, was reduced in the lungs of sepsis mice on day 1 and gradually restored through day 7. Although the expression levels of ST2 and inducible T-cell costimulator (stimulatory receptors) were high, IL-13 production by ILC2s was reduced while showing high programmed cell death 1 (PD-1) (inhibitory receptor) expression. Furthermore, using IL-33 knockout mice, we have shown that IL-33 regulates the capacity of ILC2s to produce IL-13, possibly through the modulation of ST2 and PD-1 expression and signaling in the septic lung. To the best of our knowledge, this is the first report showing differential costimulatory/inhibitory receptor expression on ILC2s in a septic lung in the context of an IL-33/IL-13 pathway-mediated type 2 immune response in the progression and resolution of inflammation. Our present findings contribute to a better understanding of the underlying immunological mechanism of ILC2s and may fill the critical knowledge gap regarding immune homeostasis in the lung that hampers the development of new therapeutic strategies for sepsis-induced acute lung injury.
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http://dx.doi.org/10.1097/SHK.0000000000001647DOI Listing
March 2021

Refractory Ileal Perforations in a Cytomegalovirus-Infected Premature Neonate Resolved After Ganciclovir Therapy.

Front Pediatr 2020 14;8:352. Epub 2020 Jul 14.

Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan.

Severe neonatal gastrointestinal diseases such as necrotizing enterocolitis or spontaneous intestinal perforation are potentially lethal conditions which predominantly occur in preterm infants. Cytomegalovirus (CMV), which is known to cause congenital and acquired infections in the newborns, has also been implicated in such severe gastrointestinal diseases in premature infants. However, the pathogenic role of CMV and effect of antiviral therapy in severe gastrointestinal disease in premature neonates is currently unclear. We present an infant, born at 26-weeks' gestation, presented with progressive dyspepsia and abdominal distention after the closure of the symptomatic patent ductus arteriosus at the day of life (DOL) 4, requiring the emergent surgery for ileal perforation at the DOL8. After the surgery, abdominal symptoms persisted and the second emergent surgery was performed for the recurrent ileal perforation at DOL17. Even then the abdominal symptoms prolonged and pathological examination in the affected intestine at the second surgery showed CMV inclusion body. Immunoreactivity for CMV antigen was detected in the specimen at the first surgery on DOL8. Blood and urinary CMV-DNA were detected at DOL28. CMV-DNA was also detected in the dried umbilical cord which was obtained within a week from birth. A 6-week course of intravenous ganciclovir (12 mg/kg/day) was started at DOL34 and then symptoms resolved along with decreasing blood CMV-DNA. Pathological findings characteristic of CMV were not detected in the resection specimen at the ileostomy closure at DOL94. These observations indicate that anti-CMV therapy may be beneficial for some premature infants with severe CMV-associated gastrointestinal diseases and warrants further studies focusing on pathogenic role, diagnosis, treatment and prevention of this underrecognized etiology of severe gastrointestinal diseases particularly in premature neonates.
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http://dx.doi.org/10.3389/fped.2020.00352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372912PMC
July 2020
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