Publications by authors named "Ryo Takagi"

154 Publications

Bioartificial pleura using allogenic cell sheet for closing of lung air leakage.

JTCVS Tech 2020 Dec 25;4:336-340. Epub 2020 Sep 25.

Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.

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http://dx.doi.org/10.1016/j.xjtc.2020.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307696PMC
December 2020

In vivo cooling-induced intracellular Ca elevation and tension in rat skeletal muscle.

Physiol Rep 2021 Jul;9(13):e14921

Graduate School of Informatics and Engineering, University of Electro-Communications, Tokyo, Japan.

It is an open question as to whether cooling-induced muscle contraction occurs in the in vivo environment. In this investigation, we tested the hypotheses that a rise in intracellular Ca²⁺ concentration ([Ca²⁺]i) and concomitant muscle contraction could be evoked in vivo by reducing muscle temperature and that this phenomenon would be facilitated or inhibited by specific pharmacological interventions designed to impact Ca²⁺-induced Ca²⁺-release (CICR). Progressive temperature reductions were imposed on the spinotrapezius muscle of Wistar rats under isoflurane anesthesia by means of cold fluid immersion. The magnitude, location, and temporal profile of [Ca²⁺]i were estimated using fura-2 loading. Caffeine (1.25-5.0 mM) and procaine (1.6-25.6 mM) loading were applied in separatum to evaluate response plasticity by promoting or inhibiting CICR, respectively. Lowering the temperature of the muscle surface to ~5°C produced active tension and discrete sites with elevated [Ca²⁺]i. This [Ca²⁺]i elevation differed in magnitude from fiber to fiber and also from site to site within a fiber. Caffeine at 1.25 and 5.0 mM reduced the magnitude of cooling necessary to elevate [Ca²⁺]i (i.e., from ~5°C to ~8 and ~16°C, respectively, both p < 0.05) and tension. Conversely, 25.6 mM procaine lowered the temperature at which [Ca²⁺]i elevation and tension were detected to ~2°C (p < 0.05). Herein we demonstrate the spatial and temporal relationship between cooling-induced [Ca²⁺]i elevation and muscle contractile force in vivo and the plasticity of these responses with CICR promotion and inhibition.
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http://dx.doi.org/10.14814/phy2.14921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271258PMC
July 2021

Case report of portal hepatic schwannoma: presentation of multimodality images.

BMC Gastroenterol 2021 Apr 20;21(1):183. Epub 2021 Apr 20.

Department of Radiology, Nihon University School of Medicine, Tokyo, 173-8610, Japan.

Background: Portal hepatic schwannoma is a rare benign tumor and difficult to diagnose preoperatively because of its rarity and imaging manifestations that mimic malignancy. We present a case of portal hepatic schwannoma that showed moderate contrast enhancement on computed tomography (CT), extension along the bile duct on T2-weighted imaging and magnetic resonance cholangiopancreatography (MRCP), and uptake of F-fluorodeoxyglucose (FDG) on positron emission tomography.

Case Presentation: Ultrasonography at an annual health checkup identified a hepatic mass in a 38-year-old woman. CT showed a well-defined portal hepatic tumor with mild contrast enhancement. T2-weighted imaging and MRCP showed a clavate tumor extending along the intrahepatic bile ducts but no dilatation of the ducts. The tumor exhibited increased FDG uptake, such as maximum standardized uptake values of 5.0 and 6.5 in the early and late phases, respectively. Neither dilatation of intrahepatic bile ducts nor lymphadenopathy was identified, and the multimodality imaging suggested hepatic portal lymphoma, gastrointestinal tumor, or IgG4-related disease rather than cholangiocarcinoma. A needle biopsy via endoscopic ultrasonography was performed, and immunohistology confirmed the tumor as a schwannoma.

Conclusions: The diagnosis of a portal hepatic schwannoma requires immunohistological examinations in addition to multimodality imaging studies to reflect fully the pathohistological characteristics of the tumor.
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http://dx.doi.org/10.1186/s12876-021-01767-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058999PMC
April 2021

The feasibility of a noise elimination method using continuous wave response of therapeutic ultrasound signals for ultrasonic monitoring of high-intensity focused ultrasound treatment.

J Med Ultrason (2001) 2021 Apr 1;48(2):123-135. Epub 2021 Apr 1.

Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan.

Purpose: In this study, the robustness and feasibility of a noise elimination method using continuous wave response of therapeutic ultrasound signals were investigated when tissue samples were moved to simulate the respiration-induced movements of the different organs during actual high-intensity focused ultrasound (HIFU) treatment. In addition to that, the failure conditions of the proposed algorithm were also investigated.

Methods: The proposed method was applied to cases where tissue samples were moved along both the lateral and axial directions of the HIFU transducer to simulate respiration-induced motions during HIFU treatment, and the noise reduction level was investigated. In this experiment, the speed of movement was increased from 10 to 40 mm/s to simulate the actual movement of the tissue during HIFU exposure, with the intensity and driving frequency of HIFU set to 1.0-5.0 kW/cm and 1.67 MHz, respectively. To investigate the failure conditions of the proposed algorithm, the proposed method was applied with the HIFU focus located at the boundary between the phantom and water to easily cause cavitation bubbles. The intensity of HIFU was set to 10 kW/cm.

Results: Almost all HIFU noise was constantly able to be eliminated using the proposed method when the phantom was moved along the lateral and axial directions during HIFU exposure. The noise reduction level (PRL in this study) at an intensity of 1.0, 3.0, and 5.0 kW/cm was in the range of 28-32, 38-40, and 42-45 dB, respectively. On the other hand, HIFU noise was not basically eliminated during HIFU exposure after applying the proposed method in the case of cavitation generation at the HIFU focus.

Conclusions: The proposed method can be applicable even if homogeneous tissues or organs move axially or laterally to the direction of HIFU exposure because of breathing. A condition under which the proposed algorithm failed was when instantaneous tissue changes such as cavitation bubble generation occurred in the tissue, at which time the reflected continuous wave response became less steady.
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http://dx.doi.org/10.1007/s10396-021-01083-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079307PMC
April 2021

Acute Oral Calcium Suppresses Food Intake Through Enhanced Peptide-YY Secretion Mediated by the Calcium-Sensing Receptor in Rats.

J Nutr 2021 May;151(5):1320-1328

School of Agriculture, Hokkaido University, Sapporo, Japan.

Background: Dietary calcium has been proposed to reduce appetite in human studies. Postprandial satiety is mainly controlled by gut hormones. However, the effect of calcium on appetite and the role of gut hormones remain unclear.

Objectives: We examined whether oral administration of calcium reduces food intake in rats and investigated the underlying mechanism.

Methods: Male Sprague Dawley rats (8-12 wk old) were used after an overnight fastifffng. In a series of 2 trials with 1-wk interval between challenges, food intake was measured 0.5-24 h after oral gavage of a vehicle (saline containing 1.5% carboxymethyl cellulose) as the control treatment, or the vehicle containing various calcium compounds [calcium chloride (CaCl2), calcium carbonate, calcium lactate, in a random order] at 150 mg calcium/kg dose. A conditional taste aversion test was conducted. In separate experiments, plasma calcium and gut hormone concentrations were measured 15 or 30 min after oral administration of the calcium compounds. In anesthetized rats, portal peptide-YY (PYY) concentrations were measured after intraluminal administration of a liquid meal with or without additional calcium.

Results: Oral CaCl2 reduced food intake acutely (30 min, ∼20%, P < 0.05) compared with control rats, without taste aversion. Plasma PYY concentration was higher (100%, P < 0.05) in CaCl2-preloaded rats than in control rats, 15 min after administration. In anesthetized rats, luminal meal + CaCl2 induced a 4-fold higher increase in plasma PYY than the control treatment did. Oral administration of a calcium-sensing receptor (CaSR) agonist suppressed food intake (∼30%, P < 0.05), but CaCl2 and CaSR agonist did not suppress food intake under treatment with a PYY receptor antagonist. Furthermore, the CaSR antagonist attenuated the effect of CaCl2 on food intake.

Conclusions: CaCl2 suppresses food intake partly by increasing CaSR-mediated PYY secretion in rats. Our findings could at least partially explain the satiating effect of calcium.
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http://dx.doi.org/10.1093/jn/nxab013DOI Listing
May 2021

Investigation of feasibility of noise suppression method for cavitation-enhanced high-intensity focused ultrasound treatment.

Ultrasonics 2021 Jul 25;114:106394. Epub 2021 Feb 25.

Graduate School of Engineering, Tohoku University, Sendai 980-8579, Japan.

In high-intensity focused ultrasound (HIFU) treatment, a method that monitors tissue changes while irradiating therapeutic ultrasound is needed to detect changes in the order of milliseconds due to thermal coagulation and the presence of cavitation bubbles. The new filtering method in which only the HIFU noise was reduced while the tissue signals remained intact was proposed in the conventional HIFU exposure in our preliminary study. However, HIFU was irradiated perpendicular to the direction of the imaging ultrasound in the preliminary experiment, which was believed to be impractical. This study investigated the efficacy of the proposed method a parallel setup, in which both HIFU and imaging beams have the same axis just as in a practical application. In addition, this filtering algorithm was applied to the "Trigger HIFU" sequence in which ultrasound-induced cavitation bubbles were generated in the HIFU focal region to enhance heating. In this setup and sequence, HIFU noise level was increased and the summation or difference tone induced by the interaction of HIFU waves with the imaging pulse has the potential to affect this proposed method. Ex-vivo experiments proved that the HIFU noise was selectively eliminated by the proposed filtering method in which chaotic acoustic signals were emitted by the cavitation bubbles at the HIFU focus. These results suggest that the proposed method was practically efficient for monitoring tissue changes in HIFU-induced cavitation bubbles.
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http://dx.doi.org/10.1016/j.ultras.2021.106394DOI Listing
July 2021

Crohn's Disease Activity Evaluation by Transabdominal Ultrasonography: Correlation with Double-Balloon Endoscopy.

J Ultrasound Med 2021 Feb 17. Epub 2021 Feb 17.

Department of Gastroenterology and Hepatology/Inflammatory Bowel Disease Group, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Hokkaido University Hospital, Sapporo, Japan.

Objectives: Transabdominal ultrasonography (US) has been reported as a useful tool for evaluating Crohn's disease (CD) activity. Endoscopic findings and Crohn's disease activity index (CDAI) are currently considered the gold standard for assessing CD activity. We assessed the correlation between US and double-balloon endoscopy (DBE), and CDAI for evaluating CD activity.

Methods: We analyzed patients with CD undergoing US and DBE within 10 days between the procedures. The intestine was divided into four segments and analyzed by the US scoring system (US-CD) and the simple endoscopic score for Crohn's disease (SES-CD). CDAI was compared with US-CD and SES-CD. Spearman's rank correlation coefficient was used for statistical analysis.

Results: Twenty-five patients with CD (11 women, 14 men; mean age 35.4 ± 14.9 years, range 16-65 years) were enrolled. Twenty-four patients received antitumor necrosis factor inhibitor therapy. CDAI was 128.1 (range 36-227). A significant moderate correlation was found between the US-CD and SES-CD in all segments (ρ = .64, P < .01). The US-CD showed a strong correlation with CDAI (ρ = .78, P < .01), whereas the SES-CD showed a moderate correlation (ρ = .55, P < .05).

Conclusions: US-CD and SES-CD showed a moderate correlation for assessing CD activity. US-CD showed a stronger correlation with CDAI than SES-CD, suggesting that US could more accurately evaluate the disease activity.
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http://dx.doi.org/10.1002/jum.15645DOI Listing
February 2021

Development of a nasal mucosa-removal model for evaluating cell therapy.

Regen Ther 2021 Mar 4;16:32-41. Epub 2021 Jan 4.

Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.

Introduction: Endoscopic sinus surgery is an effective surgical procedure for treating chronic sinusitis; however, extensive exposure of the bone in the nasal cavity can result in permanent disability postoperatively. Particularly, closure of the sinus drainage pathway due to bone hyperplasia associated with bone exposure can trigger the recurrence of sinusitis. It is essential to regenerate the nasal mucosa after surgery to avoid bone hyperplasia. Regenerative medicine, including cell therapy, could be one of the leading options for nasal mucosa regeneration. To date, there is a lack of effective models for evaluating treatments for prevention of bone hyperplasia that occurs after sinus surgery. The purpose of this study was to develop a model of nasal mucosal removal to evaluate cellular therapies.

Methods: The model was created in rabbits, a species with a wide nasal structure, and was generated by approaching the maxillary sinus from the nasal bone side and solely removing the maxillary sinus mucosa without destroying the structures in the nasal cavity. Adipose-derived mesenchymal stromal cell sheets prepared in temperature-responsive cell culture dishes were examined for the effect of transplantation in the animal model. Intranasal evaluation was assessed by micro-computed tomography and tissue staining.

Results: Significant bone hyperplasia in the maxillary sinus occurred on the side of mucosal removal, and no bone hyperplasia occurred in the control sham side in the same rabbits on postoperative day 28. Bone hyperplasia was observed over a short time period, with the presence of bone hyperplasia in the maxillary sinus on day 14 and calcification of the bone on day 28. The adipose-derived mesenchymal stromal cell (ADSC) sheet was transplantable in a nasal mucosa-removal model. No significant differences in bone hyperplasia were found between the transplantation side and the sham side in terms of the effect of transplantation of the ADSC sheet; however, bone hyperplasia tended to be suppressed on the transplantation side.

Conclusions: This animal model is simple, highly reproducible, and does not require special equipment or drugs. In addition, this model can be used for various therapeutic interventions, including cell therapy. The presence or absence of the nasal mucosa affects bone remodeling, which highlights the importance of regeneration of the nasal mucosa. In the nasal mucosal regeneration therapy, the ADSC sheet had an inhibitory effect on bone hyperplasia. The nasal mucosa-removal model allows observation of conditions associated with nasal mucosa removal and evaluation of the effectiveness of cell therapy.
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http://dx.doi.org/10.1016/j.reth.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797364PMC
March 2021

Association Between Vitamin A Intake and Disease Severity in Early-Onset Heterotopic Ossification of the Posterior Longitudinal Ligament of the Spine.

Global Spine J 2021 Jan 25:2192568221989300. Epub 2021 Jan 25.

Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Hokkaido, Japan.

Study Design: A sex- and age-matched case-control study and a cross-sectional study.

Objective: In our previous study, patients with early-onset (<50 years of age) ossification of the posterior longitudinal ligament (OPLL) had distinct features such as morbid obesity, a high prevalence of lifestyle-related diseases, and diffuse ossified lesions mainly affecting the thoracic spine. Our goals were to determine whether early-onset OPLL patients have unbalanced dietary habits and to identify nutritional factors associated with OPLL exacerbation.

Methods: In Study 1, the simple brief-type self-administered diet history questionnaire (BDHQ) was used to compare nutrient intake levels of early-onset OPLL patients (n = 13) with those of sex- and age-matched non-OPLL controls (n = 39) or with those of common OPLL (onset age ≥ 50 years, n = 62). In Study 2, serological validation was conducted for thoracic OPLL patients (n = 77) and non-OPLL controls (n = 101) in a nationwide multicenter study in Japan.

Results: The BDHQ showed that the early-onset OPLL patients had significantly lower intakes of vitamins A and B6 than non-OPLL controls. These results were validated by lower serum vitamins A and B6 levels in the early-onset thoracic OPLL patients. The severity of OPLL negatively correlated with serum vitamin A levels in male early-onset OPLL patients. The multiple regression analysis revealed that the severity of thoracic OPLL had an association with onset age and serum vitamin A level.

Conclusions: Vitamin A deficiency resulting from unbalanced dietary habits is associated with exacerbation of male early-onset OPLL.
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http://dx.doi.org/10.1177/2192568221989300DOI Listing
January 2021

Primary 12α-Hydroxylated Bile Acids Lower Hepatic Iron Concentration in Rats.

J Nutr 2021 03;151(3):523-530

Division of Fundamental Agriscience Research, Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan.

Background: Primary 12α-hydroxylated bile acids (12αOH BAs) enhance intestinal iron uptake due to their ability ex vivo to chelate iron. However, no information is available on their role in vivo, especially in the liver.

Objectives: To investigate the effects and mechanisms of primary 12αOH BAs on hepatic iron concentration in vivo.

Methods: Male Wistar King A Hokkaido male rats (WKAH/HkmSlc) rats aged 4-5 weeks were fed a control diet or a diet with cholic acid (CA; 0.5 g/kg diet), the primary 12αOH BA, for 2 weeks (Study 1) or 13 weeks (Study 2). In Study 3, rats fed the same diets were given drinking water either alone or containing vancomycin (200 mg/L) for 6 weeks. The variables measured included food intake (Studies 1-3), bile acid profiles (Studies 1 and 3), hepatic iron concentration (Studies 1-3), fecal iron excretion (Studies 1 and 2), iron-related liver gene expression (Studies 2 and 3), and plasma iron-related factors (Studies 2 and 3).

Results: In Study 1, CA feed reduced the hepatic iron concentration (-16%; P = 0.005) without changing food intake or fecal iron excretion. In Study 2, we found a significant increase in the aortic plasma concentration of lipocalin 2 (LCN2; +65%; P < 0.001), an iron-trafficking protein. In Study 3, we observed no effect of vancomycin treatment on the CA-induced reduction of hepatic iron concentration (-32%; P < 0.001), accompanied by increased plasma LCN2 concentration (+72%; P = 0.003), in the CA-fed rats despite a drastic reduction in the secondary 12αOH BA concentration (-94%; P < 0.001) in the aortic plasma.

Conclusions: Primary 12αOH BAs reduced the hepatic iron concentration in rats. LCN2 may be responsible for the hepatic iron-lowering effect of primary 12αOH BAs by transporting iron out of the liver.
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http://dx.doi.org/10.1093/jn/nxaa366DOI Listing
March 2021

Evaluation of human keratinocyte sheets transplanted onto porcine excised esophagus after submucosal dissection in an ex vivo model.

Regen Ther 2020 Dec 10;15:323-331. Epub 2020 Dec 10.

Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Japan.

Background: The utility of endoscopic transplantation of epithelial cell sheets to ulcer sites after endoscopic submucosal dissection (ESD) has been shown to prevent scar stenosis after ESD of early esophageal cancer. Previously, our group reported use of an endoscopic transplantation device fabricated with a 3-dimensional printer. Cell sheets are transplanted to the esophageal wound site with the following procedure: first, a cell sheet harvested from temperature-responsive culture dishes is placed on the device's deflated balloon surface and transported to the wound site with endoscopic forceps; second, by applying pressure from inflating the balloon locally at the wound site, the cell sheet is successfully transferred and adhered to the wound tissue; third, the balloon is deflated, and the device is removed. By repeating the procedure, several cell sheets can be safely transplanted to a wider ESD area. Nonetheless, possible damage to cell sheets using this procedure has not yet been assessed.

Objective: Effects of endoscopic transplantation balloon inflation on cell viability and damage of normal human epidermal keratinocyte sheets resident on the device's balloon surface were evaluated by histology after sheet placement onto lumenal surfaces in the ex vivo porcine submucosal dissection esophagus model. Endoscopic transplantation of these same cell sheets with conventional methods using a polyvinylidene fluoride (PVDF) cell sheet support membrane, balloon device transfer, and also using a novel modified balloon transfer procedure was also examined. Cell sheet transfer results obtained with these three procedures were compared.

Method: Normal human epidermal keratinocyte sheets were fabricated on temperature-responsive culture inserts. By temperature reduction to 20 °C, all cells were harvested as a single contiguous cell sheet. Freshly excised porcine esophagi purchased in a slaughter house were turned inside-out, and the exposed lumenal mucosa and submucosal layers were removed by Cooper scissors. This luminal surface was then utilized as a transplantation bed in ex vivo cell sheet experiments. Cell sheets were adhered to the endoscopic transfer device balloon, expanded by balloon inflation and resulting cell viability was evaluated by trypan blue exclusion test after cell sheet trypsinization and dispersion. Cell sheets were transferred onto the esophagus lumen ex vivo using forceps and the balloon device, and also using a modified balloon transfer method. The obtained results were compared with those without balloon expansion, and evaluated for sheet thickness and lumenal histology. Finally, TUNEL staining was performed to examine cell apoptosis.

Result: Cell sheets thinned after cell sheet balloon expansion, but no apoptosis was observed after these procedures.

Conclusion: Expanding keratinocyte cell sheets on a balloon endoscopic transfer device did not damage the cell sheets. This sheet transplantation method using the endoscopic balloon transfer device may be considered as a future standard cell sheet endoscopic transplantation procedure for repairing the esophagus.
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http://dx.doi.org/10.1016/j.reth.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770430PMC
December 2020

Reliability of an ultrasonographical scoring system for diagnosis of sinusoidal obstruction syndrome/veno-occlusive disease in patients with hematopoietic stem cell transplantation.

J Med Ultrason (2001) 2021 Jan 4;48(1):45-52. Epub 2021 Jan 4.

Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan.

Purpose: Sinusoidal obstruction syndrome (SOS)/hepatic veno-occlusive disease (VOD) is a fatal complication after hematopoietic stem cell transplantation. We previously reported the usefulness of an ultrasonographical (US) scoring system, the Hokkaido US-based scoring system consisting of ten parameters (HokUS-10): (1) hepatomegaly in the left lobe and (2) right lobe, (3) dilatation of the main portal vein (PV), (4) hepatofugal flow in the main PV, (5) decreased velocity of the PV, (6) dilatation of the para-umbilical vein (PUV), (7) appearance of blood flow signal in the PUV, (8) gallbladder (GB) wall thickening, (9) ascites, and (10) increased resistive index of the hepatic artery, for the diagnosis of SOS/VOD. However, the reliability of this system among operators remains elusive. Therefore, we prospectively evaluated the reliability of HokUS-10.

Methods: Twenty-four healthy volunteers and 40 patients with liver dysfunction were enrolled. Inter- and intra-operator reliabilities were analyzed using three sonographers.

Results: The median concordance rate of HokUS-10 among three sonographers and intra-operator in 24 volunteers was 92% (95% CI: 73-98%) and 98% (95% CI: 92-100%), respectively. In all 64 cases, in terms of the reliability between two sonographers for three representative US parameters (amount of ascites, GB wall thickening, and appearance of PUV blood flow signal), the median concordance rate was more than 98% (95% CI: 86-106%).

Conclusion: The inter- and intra-reliabilities of HokUS-10 were excellent. Thus, US might be a reliable tool for SOS/VOD diagnosis.
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http://dx.doi.org/10.1007/s10396-020-01071-1DOI Listing
January 2021

Bio-artificial pleura using autologous dermal fibroblast sheets to mitigate air leaks during thoracoscopic lung resection.

NPJ Regen Med 2021 Jan 4;6(1). Epub 2021 Jan 4.

Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.

Lung air leaks (LALs) due to visceral pleura injury during surgery are a difficult-to-avoid complication in thoracic surgery (TS). Reliable LAL closure is an important patient management issue after TS. We demonstrated both safeties of transplantation of a cultured human autologous dermal fibroblast sheet (DFS) to LALs. From May 2016 to March 2018, five patients who underwent thoracoscopic lung resection met all the inclusion criteria. Skin biopsies were acquired from each patient to source autologous dermal cells for DFS fabrication. During the primary culture, fibroblasts migrated from the dermal tissue pieces and proliferated to form cell monolayers. These fibroblasts were subcultured to confluence. Transplantable DFSs were fabricated from these subcultured fibroblasts that were trypsinized and seeded onto temperature-responsive culture dishes. After 10 days of fabrication culture, intact patient-specific DFS were harvested. DFSs were analyzed for fibroblast cell content and tissue contaminants prior to application. For closing intraoperative LAL, mean number of transplanted autologous DFS per patient was 6 ± 2 sheets. Mean chest drainage duration was 5.0 ± 4.8 days. The two patients with major LAL had a drainage duration of more than 7 days. All patients currently have no LAL recurrence after discharge. DFSs effectively maintain LAL closure via remodeling of the deposited extracellular matrix. The use of autologous DFSs to permanently close air leaks using a patient-derived source is expected to reduce surgical complications during high-risk lung resections.
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http://dx.doi.org/10.1038/s41536-020-00113-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782673PMC
January 2021

Epithelioid Hemangioma of Vertebra Mimicking Metastasis on FDG PET/CT in a Patient With Renal Cell Cancer.

Clin Nucl Med 2021 Feb;46(2):148-150

Pathology, Nihon University Hospital, Tokyo, Japan.

Abstract: Vertebral epithelioid hemangioma is a rare vascular tumor composed of the many vessels lined by distinct epithelioid endothelial cells. We present the case of a patient with renal cell cancer (RCC) and suspicious vertebral metastasis presenting with back pain, who was later found to have epithelioid hemangioma. FDG PET/CT demonstrated uptake of FDG not only in RCC, but also in the sixth thoracic vertebral body. The SUVmax of the vertebra was more than twice as high as RCC. This report indicates importance of quantitative assessment of FDG uptake, as well as combined use of MRI.
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http://dx.doi.org/10.1097/RLU.0000000000003428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774811PMC
February 2021

In vivo Ca dynamics during cooling after eccentric contractions in rat skeletal muscle.

Am J Physiol Regul Integr Comp Physiol 2021 02 18;320(2):R129-R137. Epub 2020 Nov 18.

Graduate School of Informatics and Engineering, University of Electro-Communications, Tokyo, Japan.

The effect of cooling on in vivo intracellular calcium ion concentration [Ca] after eccentric contractions (ECs) remains to be determined. We tested the hypothesis that cryotherapy following ECs promotes an increased [Ca] and induces greater muscle damage in two muscles with substantial IIb and IIx fiber populations. The thin spinotrapezius (SPINO) muscles of Wistar rats were used for in vivo [Ca] imaging, and tibialis anterior (TA) muscles provided greater fidelity and repeatability of contractile function measurements. SPINO [Ca] was estimated using fura 2-AM and the magnitude, location, and temporal profile of [Ca] determined as the temperature near the muscle surface post-ECs was decreased from 30°C (control) to 20°C or 10°C. Subsequently, in the TA, the effect of post-ECs cooling to 10°C on muscle contractile performance was determined at 1 and 2 days after ECs. TA muscle samples were examined by hematoxylin and eosin staining to assess damage. In SPINO, reducing the muscle temperature from 30°C to 10°C post-ECs resulted in a 3.7-fold increase in the spread of high [Ca] sites generated by ECs ( < 0.05). These high [Ca] sites demonstrated partial reversibility when rewarmed to 30°C. Dantrolene, a ryanodine receptor Ca release inhibitor, reduced the presence of high [Ca] sites at 10°C. In the TA, cooling exacerbated ECs-induced muscle strength deficits via enhanced muscle fiber damage ( < 0.05). By demonstrating that cooling post-ECs potentiates [Ca] derangements, this in vivo approach supports a putative mechanistic basis for how postexercise cryotherapy might augment muscle fiber damage and decrease subsequent exercise performance.
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http://dx.doi.org/10.1152/ajpregu.00253.2020DOI Listing
February 2021

Drinking Refined Deep-Sea Water Improves the Gut Ecosystem with Beneficial Effects on Intestinal Health in Humans: A Randomized Double-Blind Controlled Trial.

Nutrients 2020 Aug 31;12(9). Epub 2020 Aug 31.

Center for Regional Collaboration, Kochi University, 2-17-47 Asakurahonmachi, Kochi-City 780-8073, Kochi, Japan.

World health trends are focusing on a balanced food and beverage intake for healthy life. Refined deep-sea water (RDSW), obtained from deep-sea water collected offshore in Muroto (Japan), is mineral-rich drinking water. We previously reported that drinking RDSW improves human gut health. Here, we analyzed the effect of drinking RDSW on the gut ecosystem to understand this effect. This was a randomized double-blind controlled trial. Ninety-eight healthy adults were divided into two groups: RDSW or mineral water (control). The participants consumed 1 L of either water type daily for 12 weeks. A self-administered questionnaire and stool and urine samples were collected through the intervention. The following were determined: fecal biomarkers of secretory immunoglobulin A (sIgA), five putrefactive products, and nine short-chain-fatty-acids (SCFAs) as the primary outcomes; and three urinary isoflavones and the questionnaire as secondary outcomes. In post-intervention in the RDSW group, we found increased concentrations of five SCFAs and decreased concentrations of phenol and sIgA ( < 0.05). The multiple logistic analysis demonstrated that RDSW significantly affected two biomarkers (acetic and 3-methylbutanoic acids) of the five SCFAs mentioned above ( < 0.05). Similarly, the concentrations of urinary isoflavones tended to increase in post-intervention in the RDSW group. Constipation was significantly alleviated in the RDSW group (94%) compared with the control group (60%). Drinking RDSW improves the intestinal environment, increasing fecal SCFAs and urinary isoflavones, which leads to broad beneficial effects in human.
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http://dx.doi.org/10.3390/nu12092646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551512PMC
August 2020

Second primary malignancy after rituximab-containing immunochemotherapy for diffuse large B cell lymphoma.

Leuk Lymphoma 2020 12 27;61(14):3378-3386. Epub 2020 Aug 27.

Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Extended post-therapy long-term survival of patients with diffuse large B cell lymphoma (DLBCL) may also lead to an increase of late adverse events. We retrospectively investigated the frequency and clinical manifestation of second primary malignancy (SPM) after rituximab-containing immunochemotherapy in patients with DLBCL treated at seven institutes belonging to the Kyoto Clinical Hematology Study Group (KOTOSG) from the perspective of the existence of past or synchronous cancer history. In a median follow-up period of 899 days, 69 SPMs were observed in 58 of 809 patients. The most frequent SPM was gastric cancer, followed by lung cancer and colorectal cancer. The cumulative incidence of SPM increased steadily over time and was not significantly influenced by the presence or absence of past or synchronous cancer history. Our study suggests the need for careful attention to SPM in patients with DLBCL in daily practice.
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http://dx.doi.org/10.1080/10428194.2020.1811862DOI Listing
December 2020

Multiparametric flow analysis using four-dimensional flow magnetic resonance imaging can detect cerebral hemodynamic impairment in patients with internal carotid artery stenosis.

Neuroradiology 2020 Nov 9;62(11):1421-1431. Epub 2020 Jun 9.

Department of Radiology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.

Purpose: MRI-based risk stratification should be established to identify patients with internal carotid artery stenosis (ICS) who require further PET or SPECT evaluation. This study assessed whether multiparametric flow analysis using time-resolved 3D phase-contrast (4D flow) MRI can detect cerebral hemodynamic impairment in patients with ICS.

Methods: This retrospective study analyzed 26 consecutive patients with unilateral ICS (21 men; mean age, 71 years) who underwent 4D flow MRI and acetazolamide-stress brain perfusion SPECT. Collateral flow via the Willis ring was visually evaluated. Temporal mean flow volume rate (Net), pulsatile flow volume (ΔV), and pulsatility index (PI) at the middle cerebral artery were measured. Cerebral vascular reserve (CVR) was calculated from the SPECT dataset. Patients were assigned to the misery perfusion group if the CVR was < 10% and to the nonmisery perfusion group if the CVR was ≥ 10%. Parameters showing a significant difference in both groups were statistically evaluated.

Results: Affected side ΔV, ratio of affected to contralateral side Net (rNet), and ratio of affected to contralateral side ΔV were significantly correlated to CVR (p = 0.030, p = 0.010, p = 0.015, respectively). Absence of retrograde flow at the posterior communicating artery was observed in the misery perfusion group (p = 0.020). Combined cut-off values of the affected side ΔV (0.18 ml) and rNet (0.64) showed a sensitivity and specificity of 100% and 77.8%, respectively.

Conclusion: Multiparametric flow analysis using 4D flow MRI can detect misery perfusion by comprehensively assessing blood flow data, including blood flow volume, pulsation, and collateral flow.
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http://dx.doi.org/10.1007/s00234-020-02464-2DOI Listing
November 2020

Transplantation of autologous oral mucosal epithelial cell sheets inhibits the development of acquired external auditory canal atresia in a rabbit model.

Acta Biomater 2020 07 11;110:141-152. Epub 2020 May 11.

Department of Otorhinolaryngology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miymaeku Kanagawa, Japan. Electronic address:

Acquired external auditory canal atresia is characterized by fibrous tissue formation in the ear canal, hearing loss and chronic otorrhea. Although the disease can be treated surgically, the recurrence rate is high. This study explored whether autologous oral mucosal epithelial cell sheets could be used as a novel therapy for ear canal atresia. We succeeded in generating a rabbit model of acquired external auditory canal atresia by dissecting the skin of the ear canal. Endoscopic and histological findings in this model indicated that atresia developed over a 4-week period and was not inhibited by the placement of polyglycolic acid sheets immediately after skin dissection. By contrast, transplantation of autologous oral mucosal epithelial cell sheets, which had been fabricated by culture on temperature-responsive inserts without a feeder layer, prevented the development of atresia during the 4-week period after skin dissection. Transplantation of autologous epithelial cell sheets after surgical treatment of acquired external auditory canal atresia could be a promising new method to reduce the risk of disease recurrence. STATEMENT OF SIGNIFICANCE: Acquired external auditory canal atresia is characterized by fibrous tissue formation in the ear canal, which leads to hearing loss and chronic otorrhea. Although surgical treatments are available, the recurrence rate is high. In this study, we successfully generated a rabbit model of acquired external auditory canal atresia by dissecting the skin of the ear canal. Furthermore, we utilized this new animal model to investigate whether the transplantation of autologous oral mucosal epithelial cell sheets could be used as a novel therapy for ear canal atresia. Our results raise the possibility that the transplantation of autologous epithelial cell sheets after surgical treatment of ear canal atresia could be a promising new method to reduce the risk of disease recurrence.
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http://dx.doi.org/10.1016/j.actbio.2020.04.031DOI Listing
July 2020

Clinical Importance of Myocardial T Mapping and Texture Analysis.

Magn Reson Med Sci 2021 Jun 11;20(2):139-151. Epub 2020 May 11.

Department of Cardiology, Nihon University Hospital.

Late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) is valuable for diagnosis and assessment of the severity of various myocardial diseases owing to its potential to visualize myocardial scars. T mapping is complementary to LGE because it can quantify the degree of myocardial fibrosis or edema. As such, T-weighted imaging techniques, including LGE using an inversion recovery sequence, contribute to cardiac MRI. T-weighted imaging is widely used to characterize the tissue of many organs. T-weighted imaging is used in cardiac MRI to identify myocardial edema related to chest pain, acute myocardial diseases, or severe myocardial injuries. However, it is difficult to determine the presence and extent of myocardial edema because of the low contrast between normal and diseased myocardium and image artifacts of T-weighted images and the lack of an established method to quantify the images. T mapping quantifies myocardial T values and help identify myocardial edema. The T values are significantly related to the clinical symptoms or severity of nonischemic cardiomyopathy. Texture analysis is a postprocessing method to quantify tissue alterations that are reflected in the T-weighted images. Texture analysis provides a variety of parameters, such as skewness, entropy, and grey-scale non-uniformity, without the need for additional sequences. The abnormal signal intensity on T-weighted images or T values may correspond to not only myocardial edema but also other tissue alterations. In this review, the techniques of cardiac T mapping and texture analysis and their clinical relevance are described.
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http://dx.doi.org/10.2463/mrms.rev.2020-0007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203483PMC
June 2021

Analysis of the optimal psoas muscle mass index cut-off values, as measured by computed tomography, for the diagnosis of loss of skeletal muscle mass in Japanese people.

Hepatol Res 2020 Jun 7;50(6):715-725. Epub 2020 Apr 7.

Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

This study aimed to determine the optimal psoas muscle mass index (PMI) cut-off values for diagnosis of skeletal muscle mass loss.

Methods: We evaluated PMI in two groups of normal controls: a medical check-up group and a liver donation candidate group. We analyzed two novel PMI cut-off values, one based on the mean - two standard deviations (2SD) and one based on the lower 5%. Skeletal muscle mass index (SMI) evaluations using computed tomography (sliceOmatic; TomoVision) and bioelectrical impedance analysis and PMI evaluation were undertaken simultaneously. We analyzed the correlation between our PMI cut-off values and the Japan Society of Hepatology-defined SMI cut-off values. The prevalence of skeletal muscle mass loss in patients with liver disease was assessed using the novel PMI cut-off values.

Results: In 504 normal controls aged ≤50 years, the PMI cut-off values based on mean -2SD and the lower 5% were set at 3.30 cm /m for men and 1.69 cm /m for women and 3.74 cm /m for men and 2.29 cm /m for women, respectively. The PMI cut-off values based on the lower 5% alone showed that skeletal muscle mass loss increased with age. Furthermore, they correlated well with Japan Society of Hepatology-defined SMI (sliceOmatic) cut-off values and showed a significantly higher prevalence of skeletal muscle mass loss in patients with liver cirrhosis than those without liver cirrhosis.

Conclusions: We propose the following PMI cut-off values: 3.74 cm /m for male individuals and 2.29 cm /m for female individuals. These cut-off values can facilitate accurate diagnosis and management of sarcopenia in patients with chronic liver disease.
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http://dx.doi.org/10.1111/hepr.13499DOI Listing
June 2020

A stable protocol for the fabrication of transplantable human oral mucosal epithelial cell sheets for clinical application.

Regen Ther 2020 Jun 16;14:87-94. Epub 2020 Jan 16.

Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan.

Introduction: Cultured stratified epithelial cell sheets have been clinically utilized as transplantable grafts for the regeneration of epithelial tissues, such as the esophagus, cornea, skin, and intraoral cavity. These cell sheets are expected to gain widespread use as regenerative medicine products and save many patients. For this purpose, establishing and disseminating the stale protocol of fabricating the cell sheet is crucial. The fabrication of cultured stratified epithelial cell sheets consists of many important steps, and since the patients' epithelial cell conditions vary widely and are sometimes unstable, the qualities of the epithelial cell grafts are likewise potentially unstable. Therefore, in this paper, we report the stable protocol for fabrication of the transplantable cell sheet particularly from patient-derived oral mucosal tissues.

Methods: Serum extracted from blood and buccal mucosal tissue were collected in Nagasaki University and transported to Tokyo Women's Medical University. Oral mucosal epithelial cells were collected by minimum trypsin method, and this treatment was studied whether to be a critical procedure. After 14 days cultivation, cultured cells were examined whether to be transplantable as cell sheets.

Results: We successfully transported buccal mucosal tissue and serum without damage and contamination. Oral mucosal epithelial cells were collected with high viability by minimum trypsin method. Finally, we succeeded to stably fabricate oral mucosal epithelial cell sheets in all 10 patients.

Conclusions: We established a stable protocol for the fabrication of human oral mucosal epithelial cell sheets and their transportation in clinical settings in this study. These methodologies could also be basis for transplantation therapy using cultured cell sheets of various types other than oral mucosal epithelial cell and will contribute largely to the future development of regenerative medicine.
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http://dx.doi.org/10.1016/j.reth.2019.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970131PMC
June 2020

Comparison of the efficacy of cryotherapy and compression therapy for preventing nanoparticle albumin-bound paclitaxel-induced peripheral neuropathy: A prospective self-controlled trial.

Breast 2020 Feb 20;49:219-224. Epub 2019 Dec 20.

Departments of Outpatient Oncology Unit, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan; Departments of Endocrine and Breast Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: Recently, the efficacy of cryotherapy and compression therapy to prevent taxane-induced peripheral neuropathy has been reported. We prospectively compared the efficacy of cryotherapy using a frozen glove (FG) and compression therapy using a surgical glove (SG) to prevent nanoparticle albumin-bound paclitaxel (nab-PTX)-induced peripheral neuropathy.

Patients And Methods: Breast cancer patients who received 260 mg/m of nab-PTX were eligible to participate in this trial. Patients wore a FG on one hand (60 min) without changing and two SGs of the same size (i.e., one size smaller than the size that best fit their hand) on the other hand (90 min) during chemotherapy. Peripheral neuropathy was evaluated at each treatment cycle using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, the Patient Neurotoxicity Questionnaire (PNQ), and the Functional Assessment of Cancer Therapy-Taxane subscale. Temperatures at each fingertip in both groups were measured thermographically.

Results: Between August 2017 and March 2019, 43 patients were enrolled and 38 were evaluated. No cases showed discordance of peripheral neuropathy between each gloved group in cases of CTCAE ≥ grade 2. In cases of PNQ ≥ grade D, using the Nam equivalence test, the upper test (P = 0.0329) and lower test (P = 0.0052) both showed negative results in comparisons between each gloved group. Fingertip temperature was significantly lower in the FG group than in the SG group after treatment (P < 0.0001).

Conclusions: It seems to be no difference in incidence of nab-PTX-induced peripheral neuropathy using either cryotherapy or compression therapy.
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http://dx.doi.org/10.1016/j.breast.2019.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375545PMC
February 2020

Fabrication of tissue-engineered cell sheets by automated cell culture equipment.

J Tissue Eng Regen Med 2019 12 14;13(12):2246-2255. Epub 2019 Nov 14.

Research & Development Group|, Hitachi, Ltd., Hatoyama, Japan.

Most cells for regenerative medicine are currently cultured manually. In order to promote the widespread use of regenerative medicine, it will be necessary to develop automated culture techniques so that cells can be produced in greater quantities at lower cost and with more stable quality. In the field of regenerative medicine technology, cell sheet therapy is an effective tissue engineering technique whereby cells can be grafted by attaching them to a target site. We have developed automated cell culture equipment to promote the use of this cell sheet regenerative treatment. This equipment features a fully closed culture vessel and circuit system that avoids contamination with bacteria and the like from the external environment, and it was designed to allow 10 cell sheets to be simultaneously cultured in parallel. We used this equipment to fabricate 50 sheets of human oral mucosal epithelial cells in five automated culture tests in this trial. By analyzing these sheets, we confirmed that 49 of the 50 sheets satisfied the quality standards of clinical research. To compare the characteristics of automatically fabricated cell sheets with those of manually fabricated cell sheets, we performed histological analyses using immunostaining and transmission electron microscopy. The results confirmed that cell sheets fabricated with the automated cell culture are differentiated in the same way as cultures fabricated manually.
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http://dx.doi.org/10.1002/term.2968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972683PMC
December 2019

Sessile serrated adenoma/polyp showed rapid malignant transformation in the final 13 months.

Dig Endosc 2020 Sep 11;32(6):979-983. Epub 2019 Dec 11.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Hokkaido, Japan.

Based on the concept of the adenoma-carcinoma sequence, most colorectal cancers are considered to arise from conventional adenomas. However, recent studies suggested that a subset of colorectal cancers develop through the serrated neoplastic pathway. It has also been documented that serrated polyps can rapidly transform into invasive cancers even when they are small in size. We now describe a case of a sessile serrated adenoma/polyp which had been followed up for 4 years but eventually showed rapid transformation into an advanced cancer accompanied by a remarkable morphological change within only 13 months. Retrospective genetic and epigenetic analyses showed microsatellite instability, CpG island methylator phenotype-positive, and BRAF mutation in the lesion, suggesting the tumor had developed through the serrated neoplastic pathway. This case may provide valuable information about the natural history of sessile serrated adenoma/polyps which eventually progress to advanced cancers.
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http://dx.doi.org/10.1111/den.13572DOI Listing
September 2020

Multicenter study of carbon-ion radiation therapy for nonsquamous cell carcinomas of the oral cavity.

Cancer Med 2019 Sep 1;8(12):5482-5491. Epub 2019 Aug 1.

Hospital of the National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Sciences and Technology, Chiba, Japan.

Background: The aim of this study was to evaluate the efficacy and safety of carbon-ion radiation therapy for nonsquamous cell carcinomas of the oral cavity in a multicenter study.

Methods: Retrospective analysis of the clinicopathological features and outcomes of 76 patients with oral nonsquamous cell carcinomas with N0-1 M0 status and were treated with carbon-ion radiation therapy at four institutions in Japan between November 2003 and December 2014 was performed.

Results: Salivary gland carcinoma, mucosal melanoma, and three other carcinomas were found in 46, 27, and 3 patients, respectively. T1-3, T4a, and T4b disease was diagnosed in 27, 18, and 31 patients, respectively. Median follow-up period was 31.1 months (range, 3-118 months). Three-year local control, progression-free survival, and overall survival of all patients were 86.8%, 63.1%, and 78.4%, respectively. Multivariate analysis showed T classification (T4) to be a significant independent poor prognostic factor for local control. Acute grade 3 mucositis was observed in 38 patients. Grades 3 and 4 late morbidities were observed in 9 and 4 patients, respectively. No grade 5 late toxicity was observed.

Conclusions: Oral nonsquamous cell carcinomas could be treated effectively, with acceptable toxicity, by carbon-ion radiation therapy.
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http://dx.doi.org/10.1002/cam4.2408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745861PMC
September 2019

Influence of shortened recovery between resistance exercise sessions on muscle-hypertrophic effect in rat skeletal muscle.

Physiol Rep 2019 08;7(13):e14155

Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan.

Resistance exercise training induces muscle hypertrophy, and recovery between sessions is one of the major determinants of this effect. However, the effect of the recovery period between sessions on muscle hypertrophy following resistance exercise training remains unclear. To elucidate the effect of recovery period on hypertrophy, in the present study, we investigated changes in protein degradation systems and hypertrophic responses in rat skeletal muscle to resistance training with variable recovery periods. In the conventional recovery group (exercised every 72 h) and a shorter recovery group (exercised every 24 h), 18 bouts of resistance exercise consisting of 50 repetitions of a 3-sec maximal isometric contraction caused muscle hypertrophy and slight activation of muscle protein degradation systems. By contrast, in an excessively shorter recovery group (exercised every 8 h), 18 bouts of resistance exercise did not cause hypertrophy and markedly activated protein degradation systems, accompanied by inflammatory responses. These observations indicate that excessive shortening of recovery between sessions does not cause skeletal muscle hypertrophy, likely due to the activation of proteolysis induced by inflammatory responses to resistance exercise training.
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http://dx.doi.org/10.14814/phy2.14155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598394PMC
August 2019

Effects of dapagliflozin and/or insulin glargine on beta cell mass and hepatic steatosis in db/db mice.

Metabolism 2019 09 14;98:27-36. Epub 2019 Jun 14.

Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Objective: To explore the beneficial effects of dapagliflozin and/or insulin glargine on the pancreatic beta cell mass and hepatic steatosis in db/db mice.

Methods: Six-week-old db/db mice were assigned to one of four groups: untreated (Placebo), treated with dapagliflozin (Dapa), treated with insulin glargine (Gla), or treated with dapagliflozin and insulin glargine (Dapa+Gla). After 8 weeks of treatment, we determined glucose tolerance, beta cell mass, hepatic lipid content and gene expression.

Results: Glucose tolerance was significantly ameliorated in the three treated groups to the same degree compared with the Placebo group. Immunohistochemical analysis revealed that the pancreatic beta cell mass was significantly maintained in the Dapa and Dapa+Gla groups, but not in the Gla group, compared with the Placebo group (Placebo 2.25 ± 1.44 mg, Dapa 5.01 ± 1.63 mg, Gla 3.79 ± 0.96 mg, Dapa+Gla 5.19 ± 1.78 mg). However, the triglyceride content of the liver was markedly elevated in the Gla group compared with that in the other three groups (Placebo 24.1 ± 11.5 mg, Dapa 30.6 ± 12.9 mg, Gla 128 ± 49.7 mg, Dapa+Gla 54.4 ± 14.1 mg per gram liver). The expression levels of genes related to fatty acid synthesis and lipid storage were significantly upregulated in the Gla group.

Conclusions: Our results showed that beta cell mass was sustained and hepatic steatosis was prevented, after 8 weeks of treatment with either dapagliflozin or dapagliflozin plus insulin glargine, but not with insulin glargine alone, in db/db mice.
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http://dx.doi.org/10.1016/j.metabol.2019.06.006DOI Listing
September 2019

Glomerulocystic kidney identified in older patients by magnetic resonance imaging: Relation to renal function and renal corticomedullary differentiation.

Medicine (Baltimore) 2019 Apr;98(17):e15350

Department of Radiology, Nihon University Hospital, 1-6 Kanda-Surugadai, Chiyoda-ku, Tokyo, Japan.

Glomerulocystic kidney (GCK) is often associated with genetic disorders and identified in children or adolescents. However, there are some case reports describing sporadic adult GCK identified by magnetic resonance imaging (MRI). The purpose of this study was to evaluate relationship of GCK identified by MRI in older patients to renal function and renal corticomedullary differentiation (CMD) assessed by MRI.GCK was identified in 16 older patients (mean age, 79.2 years) by T2-weighted imaging. The cysts of GCK were numerous, homogeneously small, and located in the renal cortex on T2-weighted images. Ten of the 16 patients with GCK had renal impairment (estimated glomerular filtration rate <60 ml/min/1.73 m). Six patients who had GCK, chronic liver disease, and renal impairment showed moderate or good CMD.GCK identified by MRI may be related to renal impairment in some older patients, including those with preserved CMD as a result of chronic liver diseases.
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http://dx.doi.org/10.1097/MD.0000000000015350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831159PMC
April 2019

Consecutive bouts of electrical stimulation-induced contractions alter ribosome biogenesis in rat skeletal muscle.

J Appl Physiol (1985) 2019 06 18;126(6):1673-1680. Epub 2019 Apr 18.

Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo , Tokyo , Japan.

Ribosome biogenesis has been implicated in resistance exercise training (RET)-induced skeletal muscle hypertrophy. However, it is unclear how increasing bouts of RET affects ribosome content and biogenesis. This was investigated in the present study using simulated RET where rat skeletal muscle is subjected to increasing bouts of electrical stimulation. Sprague-Dawley rats were randomly assigned to the following seven groups: sedentary for 5 days (SED) or 6 wk (SED_6w), resistance-exercise trained with 1 bout (1B), 2 bouts (2B), 3 bouts (3B), 6 bouts (6B), and 18 bouts (18B). RET was simulated on the right gastrocnemius muscle by transcutaneous electric stimulation under isoflurane anesthesia, and a RET bout was given 3 times a week. Rats in 1B, 2B, and 3B groups showed increased 45S precursor (pre-) rRNA and 18S+28S rRNA content per muscle weight and elevated mRNA levels of c- and upstream binding factor (UBF). Increases in phosphorylated UBF and total cyclin D1 protein level were observed 48 h after RET; the former increased as a function of RET duration. In 3B, 6B, and 18B groups, the 18S+28S rRNA content per muscle weight was kept unchanged, and 45S pre-rRNA, cyclin D1, and phosphorylated UBF levels in 18B were lower than those in 3B. These results suggest that RET activates ribosome biogenesis and increases ribosome content through modulation of UBF and cyclin D1 activity at its early phase. Additional bouts of RET may not lead to a further increase in ribosome content per muscle weight through possibly the attenuation of transcription process. Ribosome biogenesis has been implicated in resistance exercise training-induced skeletal muscle hypertrophy. However, it remains unclear how this is influenced by the volume of repeated bouts of resistance exercise training. Using resistance exercise training model with rat skeletal muscle, we provide evidence that ribosome biogenesis is stimulated by the initial few bouts of resistance exercise training with no additional effect of further increase in the exercise bout.
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http://dx.doi.org/10.1152/japplphysiol.00665.2018DOI Listing
June 2019
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