Publications by authors named "Eiji Kawamoto"

44 Publications

Endothelial connexin-integrin crosstalk in vascular inflammation.

Biochim Biophys Acta Mol Basis Dis 2021 May 13;1867(9):166168. Epub 2021 May 13.

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

Cardiovascular diseases including blood vessel disorders represent a major cause of death globally. The essential roles played by local and systemic vascular inflammation in the pathogenesis of cardiovascular diseases have been increasingly recognized. Vascular inflammation triggers the aberrant activation of endothelial cells, which leads to the functional and structural abnormalities in vascular vessels. In addition to humoral mediators such as pro-inflammatory cytokines and prostaglandins, the alteration of physical and mechanical microenvironment - including vascular stiffness and shear stress - modify the gene expression profiles and metabolic profiles of endothelial cells via mechano-transduction pathways, thereby contributing to the pathogenesis of vessel disorders. Notably, connexins and integrins crosstalk each other in response to the mechanical stress, and, thereby, play an important role in regulating the mechano-transduction of endothelial cells. Here, we provide an overview on how the inter-play between connexins and integrins in endothelial cells unfold during the mechano-transduction in vascular inflammation.
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http://dx.doi.org/10.1016/j.bbadis.2021.166168DOI Listing
May 2021

The Spike Glycoprotein of SARS-CoV-2 Binds to β1 Integrins Expressed on the Surface of Lung Epithelial Cells.

Viruses 2021 04 9;13(4). Epub 2021 Apr 9.

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

The spike glycoprotein attached to the envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to and exploits angiotensin-converting enzyme 2 (ACE2) as an entry receptor to infect pulmonary epithelial cells. A subset of integrins that recognize the arginyl-glycyl-aspartic acid (RGD) sequence in the cognate ligands has been predicted in silico to bind the spike glycoprotein and, thereby, to be exploited for viral infection. Here, we show experimental evidence that the β1 integrins predominantly expressed on human pulmonary epithelial cell lines and primary mouse alveolar epithelial cells bind to this spike protein. The cellular β1 integrins support adhesive interactions with the spike protein independently of ACE2, suggesting the possibility that the β1 integrins may function as an alternative receptor for SARS-CoV-2, which could be targeted for the prevention of viral infections.
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http://dx.doi.org/10.3390/v13040645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069079PMC
April 2021

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

Brain 2021 Apr;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

Irisin supports integrin-mediated cell adhesion of lymphocytes.

Biochem Biophys Rep 2021 Jul 8;26:100977. Epub 2021 Mar 8.

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

Irisin, a myokine released from skeletal muscle, has recently been found to act as a ligand for the integrins αVβ5, αVβ1, and α5β1 expressed on mesenchymal cells, thereby playing an important role in the metabolic remodeling of the bone, skeletal muscle and adipose tissues. Although the immune-modulatory effects of irisin in chronic inflammation have been documented, its interactions with lymphocytic integrins have yet to be elucidated. Here, we show that irisin supports the cell adhesion of human and mouse lymphocytes. Cell adhesion assays using a panel of inhibitory antibodies to integrins have shown that irisin-mediated lymphocyte adhesion involves multiple integrins including not only α4β1 and α5β1, but also leukocyte-specific αLβ2 and α4β7. Importantly, mouse lymphocytic TK-1 cells that lack the expression of β1 integrins have exhibited αLβ2- and α4β7-mediated cell adhesion to irisin. Irisin has also been demonstrated to bind to purified recombinant integrin αLβ2 and α4β7 proteins. Thus, irisin represents a novel ligand for integrin αLβ2 and α4β7, capable of supporting lymphocyte cell adhesion independently of β1 integrins. These results suggest that irisin may play an important role in regulating lymphocyte adhesion and migration in the inflamed vasculature.
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http://dx.doi.org/10.1016/j.bbrep.2021.100977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944048PMC
July 2021

Remodeling of Bone Marrow Niches and Roles of Exosomes in Leukemia.

Int J Mol Sci 2021 Feb 13;22(4). Epub 2021 Feb 13.

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

Leukemia is a hematological malignancy that originates from hematopoietic stem cells in the bone marrow. Significant progress has made in understanding its pathogensis and in establishing chemotherapy and hematopoietic stem cell transplantation therapy (HSCT). However, while the successive development of new therapies, such as molecular-targeted therapy and immunotherapy, have resulted in remarkable advances, the fact remains that some patients still cannot be saved, and resistance to treatment and relapse are still problems that need to be solved in leukemia patients. The bone marrow (BM) niche is a microenvironment that includes hematopoietic stem cells and their supporting cells. Leukemia cells interact with bone marrow niches and modulate them, not only inducing molecular and functional changes but also switching to niches favored by leukemia cells. The latter are closely associated with leukemia progression, suppression of normal hematopoiesis, and chemotherapy resistance, which is precisely the area of ongoing study. Exosomes play an important role in cell-to-cell communication, not only with cells in close proximity but also with those more distant due to the nature of exosomal circulation via body fluids. In leukemia, exosomes play important roles in leukemogenesis, disease progression, and organ invasion, and their usefulness in the diagnosis and treatment of leukemia has recently been reported. The interaction between leukemia cell-derived exosomes and the BM microenvironment has received particular attention. Their interaction is believed to play a very important role; in addition to their diagnostic value, exosomes could serve as a marker for monitoring treatment efficacy and as an aid in overcoming drug resistance, among the many problems in leukemia patients that have yet to be overcome. In this paper, we will review bone marrow niches in leukemia, findings on leukemia-derived exosomes, and exosome-induced changes in bone marrow niches.
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http://dx.doi.org/10.3390/ijms22041881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918833PMC
February 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

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

Potential Roles of Muscle-Derived Extracellular Vesicles in Remodeling Cellular Microenvironment: Proposed Implications of the Exercise-Induced Myokine, Irisin.

Front Cell Dev Biol 2021 5;9:634853. Epub 2021 Feb 5.

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

Extracellular vesicles (EVs) have emerged as key players of intercellular communication and mediate crosstalk between tissues. Metastatic tumors release tumorigenic EVs, capable of pre-conditioning distal sites for organotropic metastasis. Growing evidence identifies muscle cell-derived EVs and myokines as potent mediators of cellular differentiation, proliferation, and metabolism. Muscle-derived EVs cargo myokines and other biological modulators like microRNAs, cytokines, chemokines, and prostaglandins hence, are likely to modulate the remodeling of niches in vital sites, such as liver and adipose tissues. Despite the scarcity of evidence to support a direct relationship between muscle-EVs and cancer metastasis, their indirect attribution to the regulation of niche remodeling and the establishment of pre-metastatic homing niches can be put forward. This hypothesis is supported by the role of muscle-derived EVs in findings gathered from other pathologies like inflammation and metabolic disorders. In this review, we present and discuss studies that evidently support the potential roles of muscle-derived EVs in the events of niche pre-conditioning and remodeling of metastatic tumor microenvironment. We highlight the potential contributions of the integrin-mediated interactions with an emerging myokine, irisin, to the regulation of EV-driven microenvironment remodeling in tumor metastasis. Further research into muscle-derived EVs and myokines in cancer progression is imperative and may hold promising contributions to advance our knowledge in the pathophysiology, progression and therapeutic management of metastatic cancers.
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http://dx.doi.org/10.3389/fcell.2021.634853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892973PMC
February 2021

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

Ligand-competent fractalkine receptor is expressed on exosomes.

Biochem Biophys Rep 2021 Jul 2;26:100932. Epub 2021 Feb 2.

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

Expression of chemokine receptor CX3CR1 is reportedly restricted to several cell types including natural killer cells, cytotoxic T cells, monocytes, and macrophages. However, its expression and function on exosomes, which are nanosized extracellular vesicles known to act as mediators of intercellular communications, remain unclear. Here, we investigated CX3CR1 expression on exosomes isolated from various cell types. Although we found that all the exosomes tested in our study highly expressed CX3CR1, this chemokine receptor was expressed only inside, but barely on, their source cells. Moreover, exosomal CX3CR1 was capable of binding soluble CX3CL1. Therefore, our study suggests that CX3CR1 is a novel and ligand-competent exosome receptor.
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http://dx.doi.org/10.1016/j.bbrep.2021.100932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859287PMC
July 2021

The characteristics, types of intervention, and outcomes of postoperative patients who required rapid response system intervention: a nationwide database analysis.

J Anesth 2021 04 1;35(2):222-231. Epub 2021 Feb 1.

Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.

Purpose: Improving the safety of general wards is a key to reducing serious adverse events in the postoperative period. We investigated the characteristics, treatment, and outcomes of postoperative patients managed by a rapid response system (RRS) in Japan to improve postoperative management.

Methods: This retrospective study analyzed cases requiring RRS intervention that were included in the In-Hospital Emergency Registry in Japan. We analyzed data reported by 34 Japanese hospitals between January 2014 and March 2018, mainly focusing on postoperative patients for whom the RRS was activated within 7 days of surgery. Non-postoperative patients, for whom the RRS was activated in all other settings, were used for comparison as necessary.

Results: There were 609 (12.7%) postoperative patients among the total patients in the registry. The major criteria were staff concerns (30.2%) and low oxygen saturation (29.7%). Hypotension, tachycardia, and inability to contact physicians were observed as triggers significantly more frequently in postoperative patients when compared with non-postoperative patients. Among RRS activations within 7 days of surgery, 68.9% of activations occurred within postoperative day 3. The ordering of tests (46.8%) and fluid bolus (34.6%) were major interventions that were performed significantly more frequently in postoperative patients when compared with non-postoperative patients. The rate of RRS activations resulting in ICU care was 32.8%. The mortality rate at 1 month was 16.2%.

Conclusion: Approximately, 70% of the RRS activations occurred within postoperative day 3. Circulatory problems were a more frequent cause of RRS activation in the postoperative group than in the non-postoperative group.
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http://dx.doi.org/10.1007/s00540-021-02900-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969491PMC
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

Methods to Study Integrin Functions on Exosomes.

Methods Mol Biol 2021 ;2217:265-281

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

Exosomes represent an important group of extracellular vesicles. They are formed in endosomal compartments and are actively secreted to extracellular spaces. Several membrane proteins, including integrins, are present on the surface of exosomes. As exosomal integrins are competent for binding to ligand, they can play important roles in directing the tissue distribution of exosomes. Integrin-directed exosomal trafficking in vivo is involved in regulating the remodeling of cell homing niches for metastatic cancers and migrating lymphocytes. This chapter describes the methods used to study integrin functions on exosomes including: isolation and biophysical characterization of exosomes, exosomal integrin-ligand binding assays, and in vivo competitive exosome homing assays.
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http://dx.doi.org/10.1007/978-1-0716-0962-0_15DOI Listing
March 2021

Integrin-Ligand Interactions in Inflammation, Cancer, and Metabolic Disease: Insights Into the Multifaceted Roles of an Emerging Ligand Irisin.

Front Cell Dev Biol 2020 26;8:588066. Epub 2020 Oct 26.

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

Integrins are transmembrane proteins that mediate cellular adhesion and migration to neighboring cells or the extracellular matrix, which is essential for cells to undertake diverse physiological and pathological pathways. For integrin activation and ligand binding, bidirectional signaling across the cell membrane is needed. Integrins aberrantly activated under pathologic conditions facilitate cellular infiltration into tissues, thereby causing inflammatory or tumorigenic progressions. Thus, integrins have emerged to the forefront as promising targets for developing therapeutics to treat autoimmune and cancer diseases. In contrast, it remains a fact that integrin-ligand interactions are beneficial for improving the health status of different tissues. Among these ligands, irisin, a myokine produced mainly by skeletal muscles in an exercise-dependent manner, has been shown to bind to integrin αVβ5, alleviating symptoms under unfavorable conditions. These findings may provide insights into some of the underlying mechanisms by which exercise improves quality of life. This review will discuss the current understanding of integrin-ligand interactions in both health and disease. Likewise, we not only explain how diverse ligands play different roles in mediating cellular functions under both conditions via their interactions with integrins, but also specifically highlight the potential roles of the emerging ligand irisin in inflammation, cancer, and metabolic disease.
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http://dx.doi.org/10.3389/fcell.2020.588066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649757PMC
October 2020

Intestinal Epithelium-Derived Luminally Released Extracellular Vesicles in Sepsis Exhibit the Ability to Suppress TNF-a and IL-17A Expression in Mucosal Inflammation.

Int J Mol Sci 2020 Nov 10;21(22). Epub 2020 Nov 10.

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

Sepsis is a systemic inflammatory disorder induced by a dysregulated immune response to infection resulting in dysfunction of multiple critical organs, including the intestines. Previous studies have reported contrasting results regarding the abilities of exosomes circulating in the blood of sepsis mice and patients to either promote or suppress inflammation. Little is known about how the gut epithelial cell-derived exosomes released in the intestinal luminal space during sepsis affect mucosal inflammation. To study this question, we isolated extracellular vesicles (EVs) from intestinal lavage of septic mice. The EVs expressed typical exosomal (CD63 and CD9) and epithelial (EpCAM) markers, which were further increased by sepsis. Moreover, septic-EV injection into inflamed gut induced a significant reduction in the messaging of pro-inflammatory cytokines TNF-a and IL-17A. MicroRNA (miRNA) profiling and reverse transcription and quantitative polymerase chain reaction (RT-qPCR) revealed a sepsis-induced exosomal increase in multiple miRNAs, which putatively target and . These results imply that intestinal epithelial cell (IEC)-derived luminal EVs carry miRNAs that mitigate pro-inflammatory responses. Taken together, our study proposes a novel mechanism by which IEC EVs released during sepsis transfer regulatory miRNAs to cells, possibly contributing to the amelioration of gut inflammation.
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http://dx.doi.org/10.3390/ijms21228445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696152PMC
November 2020

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

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

Shock 2021 Mar;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

Recombinant Human Soluble Thrombomodulin Suppresses Monocyte Adhesion by Reducing Lipopolysaccharide-Induced Endothelial Cellular Stiffening.

Cells 2020 07 30;9(8). Epub 2020 Jul 30.

Department of Pharmacology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo-city, Shimane 693-8501, Japan.

Endothelial cellular stiffening has been observed not only in inflamed cultured endothelial cells but also in the endothelium of atherosclerotic regions, which is an underlying cause of monocyte adhesion and accumulation. Although recombinant soluble thrombomodulin (rsTM) has been reported to suppress the inflammatory response of endothelial cells, its role in regulating endothelial cellular stiffness remains unclear. The purpose of this study was to investigate the impact of anticoagulant rsTM on lipopolysaccharide (LPS)-induced endothelial cellular stiffening. We show that LPS increases endothelial cellular stiffness by using atomic force microscopy and that rsTM reduces LPS-induced cellular stiffening not only through the attenuation of actin fiber and focal adhesion formation but also via the improvement of gap junction functionality. Moreover, post-administration of rsTM, after LPS stimulation, attenuated LPS-induced cellular stiffening. We also found that endothelial cells regulate leukocyte adhesion in a substrate- and cellular stiffness-dependent manner. Our result show that LPS-induced cellular stiffening enhances monocytic THP-1 cell line adhesion, whereas rsTM suppresses THP-1 cell adhesion to inflamed endothelial cells by reducing cellular stiffness. Endothelial cells increase cellular stiffness in reaction to inflammation, thereby promoting monocyte adhesion. Treatment of rsTM reduced LPS-induced cellular stiffening and suppressed monocyte adhesion in a cellular stiffness-dependent manner.
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http://dx.doi.org/10.3390/cells9081811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463703PMC
July 2020

Targeted remodeling of breast cancer and immune cell homing niches by exosomal integrins.

Diagn Pathol 2020 Apr 18;15(1):38. Epub 2020 Apr 18.

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

Exosomes represent an important subset of extracellular vesicles involved in inter-cellular communications in health and diseases. Exosomes secreted from cancer and immune cells travel to the specific tissues containing homing niches. The exosomes reaching the niches dynamically modify the gene expression and molecular architectures of the homing niche micro-environments. Cell adhesion molecule integrins regulate the tissue-specific homing patterns of not only cancer and immune cells, but also of the exosomes secreted from those cells. The exosome-mediated remodeling of the homing niches would affect immune lymphocyte migration and host defense, as well as cancer metastasis, thereby representing a potential therapeutic target.
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http://dx.doi.org/10.1186/s13000-020-00959-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165434PMC
April 2020

Virtual reality as a non-pharmacologic analgesic for fasciotomy wound infections in acute compartment syndrome: a case report.

J Med Case Rep 2020 Apr 14;14(1):46. Epub 2020 Apr 14.

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

Background: Fasciotomy is a life-saving procedure to treat acute compartment syndrome, a surgical emergency. As fasciotomy dramatically improves wound pain, it should be performed as soon as possible. Moreover, delays in the use of fasciotomy can increase the rate of wound infections. Once the fasciotomy wound is infected, pain control is achieved via the long-term use of opioids or anti-inflammatory analgesics. However, the administration of high doses of opioids may cause complications, such as respiratory depression, over-sedation, and constipation. Therefore, treatment methods other than narcotic administration should be established to better manage the pain caused by fasciotomy wound infections. Virtual reality has recently been introduced in analgesic therapy as a replacement, or complement, to conventional pharmacological treatments. Its use has been extensively studied in the pain management of patients with burns. An increasing number of painful conditions are being successfully treated with virtual reality. Here, we report a case of acute compartment syndrome complicated by fasciotomy wound infection.

Case Presentation: A 40-year-old Japanese man suffering from acute compartment syndrome of his leg due to a car accident trauma was treated with a fasciotomy to decompress intra-compartmental pressure and restore tissue perfusion, and admitted to an intensive care unit. Unfortunately, as the open fasciotomy wound was complicated by infection, he complained of hyperalgesia and severe pain during wound debridement. He was therefore given acetaminophen and high-dose intravenous patient-controlled analgesic fentanyl (35 μg/kg per day) to reduce the pain. Despite these efforts, the pain was poorly controlled and opioid-induced side effects such as respiratory depression were observed. An immersive virtual reality analgesic therapy aimed at distraction and relaxation was used and effectively alleviated the pain. Three sessions of virtual reality analgesic therapy over 2 days produced sustainable analgesic effects, which led to a 25-75% dose reduction in fentanyl administration and the concomitant alleviation of respiratory depression.

Conclusions: This case suggests the feasibility of virtual reality analgesic therapy for pain management of fasciotomy wound complications in acute compartment syndromes. Virtual reality represents a treatment option that would reduce analgesic consumption and eliminate opioid-induced respiratory depression to treat fasciotomy wound infection.
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http://dx.doi.org/10.1186/s13256-020-02370-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158090PMC
April 2020

Acquired factor XIII deficiency in two patients with bleeding events during veno-venous extracorporeal membrane oxygenation treatment.

J Artif Organs 2020 Sep 13;23(3):283-287. Epub 2019 Dec 13.

Mie University Hospital, Tsu, Japan.

We report two cases of acquired factor XIII deficiency with bleeding events during veno-venous extracorporeal membrane oxygenation (ECMO). Case 1: A 76-year-old man diagnosed with aspiration pneumonia after near-drowning was started on ECMO. Later, the patient presented with hemoptysis and anemia. Blood tests showed a decreased factor XIII activity of 29%. Although the patient recovered after receiving 1200 International Units of factor XIII concentrate, the patient had another episode of decreased factor XIII activity and bloody stool and was treated again with factor XIII concentrate. Case 2: A 48-year-old female diagnosed with pneumonia was started on ECMO. Soon after, she presented with hemoptysis and anemia. Blood tests showed a decreased factor XIII activity of 39%. The patient was treated with 720 IU of factor XIII concentrate with good recovery. Acquired factor XIII deficiency cannot be detected by routine coagulation tests, therefore it may be under-diagnosed in the ICU. Detection of acquired factor XIII deficiency is essential when treating a bleeding ECMO patient.
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http://dx.doi.org/10.1007/s10047-019-01148-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458886PMC
September 2020

Exosomes in Sepsis and Inflammatory Tissue Injury.

Curr Pharm Des 2019 ;25(42):4486-4495

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

Sepsis is the leading cause of death in medical intensive care units, and thus represents a serious healthcare problem worldwide. Sepsis is often caused by the aberrant host responses to infection, which induce dysregulated inflammation that leads to life-threatening multiple organ failures. Mediators such as proinflammatory cytokines that drive the sepsis pathogenesis have been extensively studied. Exosomes, biological lipid bilayer nanoparticles secreted via the endosomal pathway of cells, have recently emerged as important cargos that carry multiple mediators critical for the pathogenesis of sepsis-associated organ dysfunctions. Here we will review current knowledge on the exosomes in sepsis and relevant inflammatory tissue injuries.
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http://dx.doi.org/10.2174/1381612825666191116125525DOI Listing
June 2020

Differential Roles of Dendritic Cells in Expanding CD4 T Cells in Sepsis.

Biomedicines 2019 Jul 18;7(3). Epub 2019 Jul 18.

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

Sepsis is a systemically dysregulated inflammatory syndrome, in which dendritic cells (DCs) play a critical role in coordinating aberrant immunity. The aim of this study is to shed light on the differential roles played by systemic versus mucosal DCs in regulating immune responses in sepsis. We identified a differential impact of the systemic and mucosal DCs on proliferating allogenic CD4 T cells in a mouse model of sepsis. Despite the fact that the frequency of CD4 T cells was reduced in septic mice, septic mesenteric lymph node (MLN) DCs proved superior to septic spleen (SP) DCs in expanding allogeneic CD4 T cells. Moreover, septic MLN DCs markedly augmented the surface expression of MHC class II and CD40, as well as the messaging of interleukin-1β (IL-1β). Interestingly, IL-1β-treated CD4 T cells expanded in a dose-dependent manner, suggesting that this cytokine acts as a key mediator of MLN DCs in promoting septic inflammation. Thus, mucosal and systemic DCs were found to be functionally different in the way CD4 T cells respond during sepsis. Our study provides a molecular basis for DC activity, which can be differential in nature depending on location, whereby it induces septic inflammation or immune-paralysis.
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http://dx.doi.org/10.3390/biomedicines7030052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783955PMC
July 2019

Talin-2 regulates integrin functions in exosomes.

Biochem Biophys Res Commun 2019 05 14;512(3):429-434. Epub 2019 Mar 14.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Mie, 514-8507, Japan. Electronic address:

Integrins on exosomes have been shown to mediate binding to recipient cells, potentially playing important roles in controlling exosomal internalization and organ distributions. Although the ability of cellular integrins to mediate cell adhesion is known to be regulated by the cytoplasmic adaptor protein talin, whether the activity of exosomal integrins is similarly regulated by talin remains to be elucidated. Here we have studied this question in T-cell exosomes that surface express the integrins αLβ2 and α4β7. T-cells and T-cell exosomes engineered to lack talin-2 showed reduced binding to the integrin ligand ICAM-1 and MAdCAM-1 compared with control T-cells and exosomes, despite the fact that those T cells and exosomes express intact levels of the other isoform talin-1. In addition, talin-2-deficient T-cell exosomes were less efficiently internalized by endothelial cells, compared with control exosomes. These results suggest that the mechanisms of talin-mediated integrin regulation operate similarly in cells and exosomes.
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http://dx.doi.org/10.1016/j.bbrc.2019.03.027DOI Listing
May 2019

Anti-adhesive effects of human soluble thrombomodulin and its domains.

Biochem Biophys Res Commun 2019 04 15;511(2):312-317. Epub 2019 Feb 15.

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

We reported previously that leukocyte β2 integrins (LFA-1 and Mac-1) bind to the serine/threonine-rich domain of thrombomodulin (TM) expressed on vascular endothelial cells (VECs). Recombinant human soluble TM (rhsTM, TMD123) has been approved as a therapeutic drug for septic disseminated intravascular coagulation. However, the roles of TMD123 on the adhesion of leukocyte integrins to VECs remain unclear. In the current study, we have revealed that an integrin-dependent binding between human peripheral blood mononuclear cells (PBMCs) and VECs was inhibited by TMD123. Next, using mutant proteins composed of isolated TM extracellular domains, we examined the structural characteristics responsible for the anti-adhesion properties of TMD123. Namely, we investigated whether the effects of the binding of TM and leukocytes was inhibited by the administration of TMD123. In fact, we confirmed that TMD123, TMD1, and TMD3 inhibited the binding of PBMCs to the immobilized recombinant proteins TMD123 and TMD3. These results indicate that TMD123 inhibited the adhesion of leukocytes to endothelial cells via β2 integrins and endothelial TM. Moreover, since TMD1 might bind to leukocytes via other adhesion receptors than integrins, TMD1 and TMD3 appear to inhibit leukocyte binding to TM on VECs via different mechanisms. In summary, TMD123 (rhsTM), TMD1 or TMD3 is a promising treatment option for sepsis that attenuates integrin-dependent binding of leukocytes to VECs, and may inhibit the undesirable adhesion and migration of leukocytes to VECs in sepsis.
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http://dx.doi.org/10.1016/j.bbrc.2019.02.041DOI Listing
April 2019

Connexins and Integrins in Exosomes.

Cancers (Basel) 2019 Jan 17;11(1). Epub 2019 Jan 17.

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

Connexins and integrins, the two structurally and functionally distinct families of transmembrane proteins, have been shown to be inter-connected by various modes of cross-talk in cells, such as direct physical coupling via lateral contact, indirect physical coupling via actin and actin-binding proteins, and functional coupling via signaling cascades. This connexin-integrin cross-talk exemplifies a biologically important collaboration between channels and adhesion receptors in cells. Exosomes are biological lipid-bilayer nanoparticles secreted from virtually all cells via endosomal pathways into the extracellular space, thereby mediating intercellular communications across a broad range of health and diseases, including cancer progression and metastasis, infection and inflammation, and metabolic deregulation. Connexins and integrins are embedded in the exosomal membranes and have emerged as critical regulators of intercellular communication. This concise review article will explain and discuss recent progress in better understanding the roles of connexins, integrins, and their cross-talk in cells and exosomes.
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http://dx.doi.org/10.3390/cancers11010106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356207PMC
January 2019

Exosomal regulation of lymphocyte homing to the gut.

Blood Adv 2019 01;3(1):1-11

Department of Molecular Pathobiology and Cell Adhesion Biology.

Exosomes secreted from T cells have been shown to affect dendritic cells, cancer cells, and other T cells. However, little is known about how T-cell exosomes (T exosomes) modulate endothelial cell functions in the context of tissue-specific homing. Here, we study the roles of T exosomes in the regulation of gut-specific T-cell homing. The gut-tropic T cells induced by retinoic acid secrete the exosomes that upregulate integrin α4β7 binding to the MAdCAM-1 expressed on high endothelial venules in the gut. T exosomes were preferentially distributed to the villi of the small intestine in an α4β7-dependent manner. Exosomes from gut-tropic T cells suppressed the expression of MAdCAM-1 in the small intestine, thereby inhibiting T-cell homing to the gut. Moreover, microRNA (miRNA) profiling analysis has shown that exosomes from gut-tropic T cells were enriched with miRNAs targeting NKX2.3, a transcription factor critical to MAdCAM-1 expression. Taken together, our study proposes that α4β7-expressing T exosomes distribute themselves to the small intestine and modify the expression of microenvironmental tissues such that any subsequent lymphocyte homing is precluded. This may represent a novel mechanism by which excessive lymphocyte homing to the intestinal tissues is downsized.
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http://dx.doi.org/10.1182/bloodadvances.2018024877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325302PMC
January 2019

Biomechanical profiles of tracheal intubation: a mannequin-based study to make an objective assessment of clinical skills by expert anesthesiologists and novice residents.

BMC Med Educ 2018 Dec 4;18(1):293. Epub 2018 Dec 4.

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

Background: Tracheal intubation (TI) is a key medical skill used by anesthesiologists and critical care physicians in airway management in operating rooms and critical care units. An objective assessment of dexterity in TI procedures would greatly enhance the quality of medical training. This study aims to investigate whether any biomechanical parameters obtained by 3D-motion analysis of body movements during TI procedures can objectively distinguish expert anesthesiologists from novice residents.

Methods: Thirteen expert anesthesiologists and thirteen residents attempted TI procedures on an airway mannequin using a Macintosh laryngoscope. Motion capturing technology was utilized to digitally record movements during TI procedures. The skill with which experts and novices measured biomechanical parameters of body motions were comparatively examined.

Results: The two groups showed similar outcomes (success rates and mean time needed to complete the TI procedures) as well as similar mean absolute velocity values in all 21 body parts examined. However, the experts exhibited significantly lower mean absolute acceleration values at the head and the left hand than the residents. In addition, the mean-absolute-jerk measurement revealed that the experts commanded potentially smoother motions at the head and the left hand. The Receiver Operating Characteristic (ROC) curves analysis demonstrated that mean-absolute-acceleration and -jerk measurements provide excellent measures for discriminating between experts and novices.

Conclusions: Biomechanical parameter measurements could be used as a means to objectively assess dexterity in TI procedures. Compared with novice residents, expert anesthesiologists possess a better ability to control their body movements during TI procedures, displaying smoother motions at the selected body parts.
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http://dx.doi.org/10.1186/s12909-018-1410-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280424PMC
December 2018