Publications by authors named "Seiji Watanabe"

121 Publications

Osteocalcin promotes proliferation, differentiation, and survival of PC12 cells.

Biochem Biophys Res Commun 2021 Jun 15;557:174-179. Epub 2021 Apr 15.

Division of Applied Pharmacology, Department of Health Promotion, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580, Japan. Electronic address:

Involvement of the bone matrix protein osteocalcin (OC) in the development of learning and memory, and the prevention of anxiety-like behaviors in mice. However, the direct effects of OC on neurons are still unknown comparing to the mechanism how OC affects systemic energy expenditure and glucose homeostasis. In this study, we investigated the effect of OC on proliferation, differentiation, and survival of neurons using the rat pheochromocytoma cell line PC12. RT-PCR analysis for OC receptor candidates revealed that Gpr158, but not Gprc6a, mRNA was expressed in PC12 cells. The growth of PC12 cells cultured in the presence of 5-50 ng/mL of either uncarboxylated (GluOC) or carboxylated (GlaOC) OC was increased compared to cells cultured in the absence of OC. In addition, NGF-induced neurite outgrowth was enhanced by OC, and HO-induced cell death was suppressed by pretreatment with OC. All of these results were observed for both GluOC and GlaOC at comparable levels, suggesting that OC may directly affect cell proliferation, differentiation, and survival by binding to its candidate receptor, GPR158.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.146DOI Listing
June 2021

Widespread anorectal lymphovascular networks and tissue drainage: analyses from submucosal India ink injection and indocyanine green fluorescence imaging.

Colorectal Dis 2021 Feb 11. Epub 2021 Feb 11.

Department of Gastroenterological Surgery, Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori, Japan.

Aim: Abdominoperineal resection is associated with poor prognosis in patients with advanced lower rectal cancer. This study aimed to analyse the functional lymphovascular network and tissue drainage in the anorectal region.

Methods: In this descriptive study, we performed microanatomical evaluations and intra-operative imaging analysis in a cadaver and patients with rectal cancer. Specimens with India ink injection were collected from a cadaver and from six patients who underwent abdominoperineal resection. Intra-operative indocyanine green fluorescence imaging was performed on four patients who underwent surgery for lower rectal cancer. India ink was injected into the submucosa at the dentate line of specimens. Tissue sections were examined by immunohistochemistry for D2-40 and CD31. Intra-operative indocyanine green was injected into the submucosa at the dentate line. Lymph flow was traced using a near-infrared camera system.

Results: Fascia branching from the rectal longitudinal muscle layer extended to the posterior hiatal ligament and lateral endopelvic fascia connective tissue lamina on the surface of the levator ani muscle. The fascia contained veins labelled with ink in their lumina and initial lymphatics. Intra-operative indocyanine green fluorescence imaging revealed extensive lymph flow from the muscle layer of the anal canal to the hiatal ligament and endopelvic fascia along the longitudinal muscle layer fibres.

Conclusions: The anorectal region contained widespread venous and lymphatic networks in proportion to its specific connective tissue framework around the longitudinal-muscle-layer-extending muscle bundles, which provides extensive networks for tissue fluid and cells.
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http://dx.doi.org/10.1111/codi.15582DOI Listing
February 2021

Previously unreported permanent tattoo-associated angiolymphoid hyperplasia with eosinophilia/epithelioid hemangioma.

Pathol Int 2021 Mar 27;71(3):219-221. Epub 2021 Jan 27.

Department of Anatomic Pathology, Kurashiki Central Hospital, Okayama, Japan.

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http://dx.doi.org/10.1111/pin.13063DOI Listing
March 2021

Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease.

Acta Neuropathol Commun 2021 01 5;9(1). Epub 2021 Jan 5.

Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Aichi, 464-8601, Japan.

Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, App with amyloid pathology, rTg4510 with tauopathy, and SOD1 with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1 microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.
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http://dx.doi.org/10.1186/s40478-020-01099-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786928PMC
January 2021

A Nasal High-Flow System Prevents Upper Airway Obstruction and Hypoxia in Pediatric Dental Patients Under Intravenous Sedation.

J Oral Maxillofac Surg 2021 Mar 16;79(3):539-545. Epub 2020 Oct 16.

Professor, Division of Dental Anesthesiology, Department of Science of Physical Functions, Kyushu Dental University, Fukuoka, Japan.

Purpose: Upper airway obstruction (UAO) and oxygen desaturation are risk factors for major complications of intravenous sedation (IVS) in pediatric dental patients. This study aimed to investigate the use of a nasal high-flow (NHF) system for the prevention of UAO and oxygen desaturation in pediatric dental patients under IVS.

Methods: The authors implemented a prospective randomized design. Thirty pediatric patients (aged 3 to 12), scheduled for dental treatment under IVS, were enrolled in this study. The subjects were randomly assigned to 1 of 2 groups: patients who received oxygen at 5 L/minute through a nasal cannula (NC group) and patients who received oxygen at 2 kg/L/minute, up to a maximum of 30 L/minute, through the NHF system (NHF group). The predictor variable was flow rate. The primary outcome variable was the need for intervention during treatment, and the secondary outcome variable was the lowest peripheral capillary oxygen saturation values during the procedure. Additional study variables measured included patient age, gender, weight, height, and surgical duration. The Mann-Whitney U test and Fisher exact test were used for statistical analysis, with P < .05 considered as significant.

Results: Both the NC (n = 15; mean age, 6.2 ± 2.3) and NHF (n = 15; mean age, 5.9 ± 2.5) groups had a male:female ratio of 2:1. The use of the NHF system significantly improved the lowest peripheral capillary oxygen saturation values during treatment (P < .05). Jaw lifting, to relieve UAO and facilitate spontaneous breathing, was required in both the NC (n = 10) and NHF (n = 3) groups (P < .05). The need for interventions during treatment was significantly lower in the NHF group (P < .05).

Conclusions: The results of this study suggest that the use of the NHF system can prevent UAO and improve the respiratory condition of pediatric dental patients under IVS.
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http://dx.doi.org/10.1016/j.joms.2020.10.018DOI Listing
March 2021

Aggresome formation and liquid-liquid phase separation independently induce cytoplasmic aggregation of TAR DNA-binding protein 43.

Cell Death Dis 2020 10 23;11(10):909. Epub 2020 Oct 23.

Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan.

Cytoplasmic inclusion of TAR DNA-binding protein 43 (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and a subtype of frontotemporal lobar degeneration (FTLD). Recent studies have suggested that the formation of cytoplasmic TDP-43 aggregates is dependent on a liquid-liquid phase separation (LLPS) mechanism. However, it is unclear whether TDP-43 pathology is induced through a single intracellular mechanism such as LLPS. To identify intracellular mechanisms responsible for TDP-43 aggregation, we established a TDP-43 aggregation screening system using a cultured neuronal cell line stably expressing EGFP-fused TDP-43 and a mammalian expression library of the inherited ALS/FTLD causative genes, and performed a screening. We found that microtubule-related proteins (MRPs) and RNA-binding proteins (RBPs) co-aggregated with TDP-43. MRPs and RBPs sequestered TDP-43 into the cytoplasmic aggregates through distinct mechanisms, such as microtubules and LLPS, respectively. The MRPs-induced TDP-43 aggregates were co-localized with aggresomal markers and dependent on histone deacetylase 6 (HDAC6), suggesting that aggresome formation induced the co-aggregation. However, the MRPs-induced aggregates were not affected by 1,6-hexanediol, an LLPS inhibitor. On the other hand, the RBPs-induced TDP-43 aggregates were sensitive to 1,6-hexanediol, but not dependent on microtubules or HDAC6. In sporadic ALS patients, approximately half of skein-like TDP-43 inclusions were co-localized with HDAC6, but round and granular type inclusion were not. Moreover, HDAC6-positive and HDAC6-negative inclusions were found in the same ALS patient, suggesting that the two distinct pathways are both involved in TDP-43 pathology. Our findings suggest that at least two distinct pathways (i.e., aggresome formation and LLPS) are involved in inducing the TDP-43 pathologies.
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http://dx.doi.org/10.1038/s41419-020-03116-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585435PMC
October 2020

Novel Selenium-based compounds with therapeutic potential for SOD1-linked amyotrophic lateral sclerosis.

EBioMedicine 2020 Sep 30;59:102980. Epub 2020 Aug 30.

Molecular Biophysics Group, Department of Biochemistry and System Biology, Institute of System, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, L69 7ZB, United Kingdom.

Background: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease as well as Lou Gehrig's disease, is a progressive neurological disorder selectively affecting motor neurons with no currently known cure. Around 20% of the familial ALS cases arise from dominant mutations in the sod1 gene encoding superoxide dismutase1 (SOD1) enzyme. Aggregation of mutant SOD1 in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits.

Methods: We have utilised the ebselen template to develop novel compounds that redeem stability of mutant SOD1 dimer and prevent aggregation. Binding modes of compounds have been visualised by crystallography. In vitro neuroprotection and toxicity of lead compounds have been performed in mouse neuronal cells and disease onset delay of ebselen has been demonstrated in transgenic ALS mice model.

Finding: We have developed a number of ebselen-based compounds with improvements in A4V SOD1 stabilisation and in vitro therapeutic effects with significantly better potency than edaravone. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1. We also show clear disease onset delay of ebselen in transgenic ALS mice model holding encouraging promise for potential therapeutic compounds.

Interpretation: Our finding established the new generation of organo-selenium compounds with better in vitro neuroprotective activity than edaravone. The potential of this class of compounds may offer an alternative therapeutic agent for ALS treatment. The ability of these compounds to target cysteine 111 in SOD may have wider therapeutic applications targeting cysteines of enzymes involved in pathogenic and viral diseases including main protease of SARS-Cov-2 (COVID-19).

Funding: Project funding was supported by the ALS Association grant (WA1128) and Fostering Joint International Research (19KK0214) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.
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http://dx.doi.org/10.1016/j.ebiom.2020.102980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456458PMC
September 2020

Expression of , a kidney-specific gene, parallels the function and maturation of proximal tubular cells.

Am J Physiol Renal Physiol 2020 10 24;319(4):F603-F611. Epub 2020 Aug 24.

Department of Pediatrics, Child Health Research Center, University of Virginia School of Medicine, Charlottesville, Virginia.

The acyl-CoA synthetase medium-chain family member 2 () gene was first identified and cloned by our group as a kidney-specific "" gene. However, its expression pattern and function remain to be clarified. In the present study, we found that the gene was expressed specifically and at a high level in normal adult kidneys. Expression of in kidneys followed a maturational pattern: it was low in newborn mice and increased with kidney development and maturation. In situ hybridization and immunohistochemistry revealed that was expressed specifically in proximal tubular cells of adult kidneys. Data from the Encyclopedia of DNA Elements database revealed that the gene locus in the mouse has specific histone modifications related to the active transcription of the gene exclusively in kidney cells. Following acute kidney injury, partial unilateral ureteral obstruction, and chronic kidney diseases, expression of in the proximal tubules was significantly decreased. In human samples, the expression pattern of , a homolog of mouse , was similar to that in mice, and its expression decreased with several types of renal injuries. These results indicate that the expression of parallels the structural and functional maturation of proximal tubular cells. Downregulation of its expression in several models of kidney disease suggests that may serve as a novel marker of proximal tubular injury and/or dysfunction.
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http://dx.doi.org/10.1152/ajprenal.00348.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642889PMC
October 2020

[Qualitative analysis of provided information and advice from occupational physicians to attending clinical physicians in supporting an employee's work-treatment balance].

Sangyo Eiseigaku Zasshi 2021 Jan 9;63(1):6-20. Epub 2020 Jul 9.

Department of Occupational Health Practice and Management, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health.

Objectives: In Japan, the population is aging and there is a declining birth rate. It is an important occupational health issue to support the balance between illness treatment (including nursing care, childcare, etc.) and work. Many patients require mental and financial support to help them with their work-treatment balance. In 2016, the Ministry of Health, Labor and Welfare provided guidelines for supporting employee's work-treatment balance, and in 2018, "Consulting Fee" was approved as an insured medical treatment when clinic doctors supported their patients for continuing to work. The request for the consulting fee requires that the clinician and the occupational physician exchange information on the support necessary for the patient to continue working. Generally, occupational physicians obtain medical information from clinicians to give advice on a worker's employment considerations. However, we do not know what kind of workplace information clinicians hope to know when treating their patients. Therefore, we conducted this survey to clarify how occupational physicians could provide useful information to clinicians.

Methods: We asked approximately 1,500 occupational physicians from the Occupational Health Subcommittee of the Japan Society for Occupational Health to provide us with a letter sent to their clinician to assist workers. From the collected letters, the structural parts of the letters (titles, greetings, acknowledgments, etc.) were removed. We defined a section as a contextual unit that does not impair the meaning. The prepared sections underwent qualitative inductive analysis using the content analysis method of "Berelson, B."

Results: A total of 103 cases and 178 documents from 42 people were included in the analysis. Extracting descriptions that could be interpreted as providing information, including descriptions related to treatment, employment, and living environment, and opinions and suggestions from occupational physicians resulted in 596 sections. As a result of the qualitative and inductive classification, the information was classified into three large categories that consisted of information provision, opinions of occupational physicians, and information handling, five middle and eighteen small classifications. In addition, some good practices that were considered significant to clinicians were illustrated.

Conclusions: We analyzed and categorized the information present in the letters sent by occupational physicians to clinicians. The letter does not need to contain all the information in the category table. However, it is important that it should have the necessary and sufficient information considering the case in question. We believe that this category table will aid occupational physicians in writing letters to clinicians.
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http://dx.doi.org/10.1539/sangyoeisei.2020-012-EDOI Listing
January 2021

Impact of Subglottic Saline Irrigation on Reducing Bacterial Contamination for Oral Surgery Patients.

Anesth Prog 2020 06;67(2):79-85

Professor and Chairperson, Division of Dental Anesthesiology, Department of Science of Physical Functions, Kyushu Dental University, Fukuoka, Japan.

This study investigated the effectiveness of subglottic irrigation (SI) with 100 mL of saline on reducing bacterial contamination in the subglottic space during oral surgery procedures without the use of throat packs. Subglottic lavage and irrigation were performed through the suction lumen located on specialized endotracheal tubes (ETTs) with capabilities of permitting evacuation from the subglottic space. Fifty-three patients who were scheduled for oral surgery procedures under general anesthesia while intubated with specialized ETTs at Kyushu Dental University Hospital were enrolled in this study. Subglottic irrigation was performed, and the sample fluid was collected through the ETT suction lumen for smear and culture bacterial examinations after 3 points in time: immediately after intubation, after completing the surgical procedure, and again after SI. Oral surgery without a throat pack significantly increased bacterial contamination in the subglottic lavage (p < .001), and SI decreased bacterial contamination (p < .001) similarly to levels found after tracheal intubation. Subglottic irrigation with 100 mL of saline was effective in reducing bacterial load in the subglottic space to levels similarly noted immediately after intubation for patients undergoing intraoral surgical procedures without the use of a throat pack.
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http://dx.doi.org/10.2344/anpr-66-04-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342813PMC
June 2020

Modified permeable cryoprotectant-free vitrification method for three or fewer ejaculated spermatozoa from cryptozoospermic men and 7-year follow-up study of 14 children born from this method.

Hum Reprod 2020 05;35(5):1019-1028

Department of Obstetrics and Gynecology, Juntendo University School of Medicine, Tokyo, Japan.

Study Question: What technique can be used to successfully cryopreserve three or fewer ejaculated spermatozoa from cryptozoospermic men and is the physical and cognitive development of children born after this technique normal?

Summary Answer: The modified cryopreservation method for three or fewer human spermatozoa from cryptozoospermic men showed a recovery rate above 95% and a survival rate just under 90%, and the physical and cognitive abilities of the children born after ICSI were comparable to those born after natural conception.

What Is Known Already: Clinical outcomes of ICSI using cryptozoospermic men's ejaculated spermatozoa are considered to be inferior to that using testicular spermatozoa from microsurgical testicular sperm extraction (Micro-TESE), possibly because the DNA fragmentation rate is higher in ejaculated spermatozoa than in testicular spermatozoa from Micro-TESE.

Study Design, Size, Duration: Evaluation of the efficiency of cryopreservation of three or fewer spermatozoa was conducted retrospectively at St. Mother Clinic. The physical and cognitive development of children born after this method was studied between 2011 and 2018.

Participants/materials, Setting, Methods: This study included 28 cryptozoospermic men who had three or fewer morphologically normal and motile spermatozoa in their ejaculate after centrifugation and who preferred using cryopreserved spermatozoa to Micro-TESE. Control subjects were 31 cryptozoospermic patients using fresh spermatozoa from their ejaculates and 20 non-obstructive azoospermic patients with fewer than 10 spermatozoa obtained by TESE and vitrified. Clinical outcomes among three groups, vitrified spermatozoa from the ejaculate, fresh spermatozoa from the ejaculate and vitrified spermatozoa from the testis, were statistically analysed. For the 7-year follow up study of the 14 children born after ICSI using the ejaculated vitrified spermatozoa, the Japanese government-issued Boshi Kenko Techo (Mother-Child Handbook) and Kinder Infant Development Scale (KIDS scale) were used to determine whether their physical and cognitive development was comparable to that of naturally conceived children.

Main Results And The Role Of Chance: Recovery and survival rates were 97.8% (510/521) and 87.1% (444/510) for vitrified spermatozoa from the ejaculate and 92.7% (152/164) and 60.5% (92/152) for vitrified spermatozoa from the testis. Clinical pregnancies (%), miscarriages (%) and live birth rates (%), respectively, among the three groups were as follows: vitrified spermatozoa from the ejaculate: 15(25.0), 2(13.3), 13(21.7); fresh spermatozoa from the ejaculate: 26(24.3), 5(19.2), 20(18.7); and vitrified spermatozoa from the testis: 3(16.7), 0(0.0), 3(16.7). Among the groups, there were no statistically significant differences except for the sperm survival rate and the oocyte fertilisation rate, which were lower for vitrified spermatozoa from the testis compared with vitrified spermatozoa from the ejaculate. The 7-year follow-up study showed that the physical and cognitive development of 14 children born after ICSI using vitrified ejaculated spermatozoa from the ejaculate was comparable to that of naturally conceived children.

Limitations, Reasons For Cautions: The maximum number of spermatozoa to which this method can be applied successfully is about 10. When the number of aspirated spermatozoa is over 10, some of them change direction after colliding with each other inside the aspiration pipette and reach the mineral oil, and once this happens, they cannot be expelled out of the pipette. Even though we did not find evidence of DNA fragmentation, further studies with larger participant numbers and longer time periods are necessary.

Wider Implications Of The Findings: This technique is very useful for the cryopreservation of very small numbers of testicular spermatozoa (fewer than 10) in order to avoid or reduce Micro-TESE interventions.

Study Funding/competing Interest(s): No external funding was received to undertake this study. There are no competing interests.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa072DOI Listing
May 2020

A detailed pathway and termination of thoracic duct in a Japanese female cadaver with situs inversus totalis.

Anat Sci Int 2020 Jun 19;95(3):425-428. Epub 2020 Feb 19.

Department of Anatomical Science, Hirosaki University Graduate School of Medicine, 5 Zaifucho, Hirosaki, Aomori, 036-8562, Japan.

Although the thoracic duct (TD) requires special attention during thoracic surgery, to our knowledge, its detailed course in the situs inversus totalis (SIT) case has not been reported. We encountered an 86-year-old Japanese female cadaver with SIT during a student anatomical practice and examine the TD. The TD originated from the cisterna chyli at the level of the 2nd lumbar vertebra, ascended along with the left side of aorta and then passed behind the aortic arch on the right side of the esophagus. The TD turned right at the first thoracic vertebra and finally emptied into the basal portion of the right external jugular vein without branching. The present running pathway of the TD was approximately in the inverted position of the normal, but its connection site to the vein and manner was very rare and has not been reported to date. Therefore, this junctional anomaly may occur during the developmental period in SIT. Further anatomical and embryological studies are required, but this report provides useful morphogenetic information of the TD and lymphovenous junction in SIT.
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http://dx.doi.org/10.1007/s12565-020-00532-4DOI Listing
June 2020

Modification of TRPV4 activity by acetaminophen.

Heliyon 2020 Jan 31;6(1):e03301. Epub 2020 Jan 31.

Division of Applied Pharmacology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, 803-8580, Japan.

-Acetyl-p-aminophenol (APAP/acetaminophen) is a widely used analgesic/antipyretic with weaker inhibitory effects on cyclooxygenase compared to those of non-steroidal anti-inflammatory drugs. The effect of APAP is mediated by its metabolites, -arachidonoyl-phenolamine and -acetyl--benzoquinone imine, which activate transient receptor potential (TRP) channels, including TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) or cannabinoid receptor type 1. However, the exact molecular mechanism underlying the cellular actions of APAP remains unclear. Recently, we observed that APAP promotes cell migration through TRPV4; in this study, we examined the effect of APAP on Ca-channel activity of TRPV4. In the rat cell line PC12 expressing TRPV4, GSK1016790A (GSK), a TRPV4 agonist, stimulated an increase in [Ca]; these effects were abrogated by HC-067047 treatment. This GSK-induced Ca entry through TRPV4 was inhibited by APAP in a dose-dependent manner, whereas APAP alone did not affect [Ca]. The specificity of the effect of APAP on TRPV4 was further confirmed using HeLa cells, which lack endogenous TRPV4 but stably express exogenous TRPV4 (HeLa-mTRPV4). GSK-induced [Ca] elevation was only observed in HeLa-mTRPV4 cells compared to that in the control HeLa cells, indicating the specific action of GSK on TRPV4. APAP dose-dependently suppressed this GSK-induced Ca entry in HeLa-mTRPV4. However, it is unlikely that the metabolites of APAP were involved in these effects as the reaction in this study was rapid. The results suggest that APAP suppresses the newly identified target TRPV4 without being metabolized and exerts antipyretic/analgesic and/or other effects on TRPV4-related phenomena in the body. The effect of APAP on TRPV4 was opposite to that on TRPV1 or TRPA1, as the latter is activated by APAP.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002858PMC
January 2020

ALS-linked TDP-43 knock-in mice exhibit splicing deregulation without neurodegeneration.

Mol Brain 2020 01 20;13(1). Epub 2020 Jan 20.

Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan.

Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43), a DNA/RNA binding protein, is a pathological signature of amyotrophic lateral sclerosis (ALS). Missense mutations in the TARDBP gene are also found in inherited and sporadic ALS, indicating that dysfunction in TDP-43 is causative for ALS. To model TDP-43-linked ALS in rodents, we generated TDP-43 knock-in mice with inherited ALS patient-derived TDP-43 mutation. Homozygous TDP-43 mice developed normally without exhibiting detectable motor dysfunction and neurodegeneration. However, splicing of mRNAs regulated by TDP-43 was deregulated in the spinal cords of TDP-43 mice. Together with the recently reported TDP-43 knock-in mice with ALS-linked mutations, our finding indicates that ALS patient-derived mutations in the TARDBP gene at a carboxyl-terminal domain of TDP-43 may cause a gain of splicing function by TDP-43, however, were insufficient to induce robust neurodegeneration in mice.
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http://dx.doi.org/10.1186/s13041-020-0550-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971932PMC
January 2020

A de novo TOP2B variant associated with global developmental delay and autism spectrum disorder.

Mol Genet Genomic Med 2020 03 17;8(3):e1145. Epub 2020 Jan 17.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Background: TOP2B encodes type II topoisomerase beta, which controls topological changes during DNA transcription. TOP2B is expressed in the developing nervous system and is involved in brain development and neural differentiation. Recently, a de novo missense TOP2B variant (c.187C>T) has been identified in an individual with neurodevelopmental disorder (NDD). However, the association between TOP2B variants and NDDs remains uncertain.

Methods: Trio-based whole-exome sequencing was performed on a 7-year-old girl, presenting muscle hypotonia, stereotypic hand movements, epilepsy, global developmental delay, and autism spectrum disorder. Brain magnetic resonance images were normal. She was unable to walk independently and spoke no meaningful words.

Results: We found a de novo variant in TOP2B (NM_001330700.1:c.187C>T, p.(His63Tyr)), which is identical to the previous case. The clinical features of the two individuals with the c.187C>T variant overlapped.

Conclusion: Our study supports the finding that TOP2B variants may cause NDDs.
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http://dx.doi.org/10.1002/mgg3.1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057084PMC
March 2020

POLR3A variants in striatal involvement without diffuse hypomyelination.

Brain Dev 2020 Apr 10;42(4):363-368. Epub 2020 Jan 10.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address:

Background: Biallelic variants in POLR3A encoding the largest subunit of RNA polymerase III cause POLR3-related (or 4H) leukodystrophy characterized by neurologic dysfunction, abnormal dentition, endocrine abnormalities and ocular abnormality. Recently, whole-exome sequencing enabled the discovery of POLR3A variants in cases lacking diffuse hypomyelination, the principal MRI phenotype of POLR3-related leukodystrophy. Homozygous c.1771-6C > G variants in POLR3A were recently suggested to cause striatal and red nucleus involvement without white matter involvement.

Case Report: Here, we report three cases in two families with biallelic POLR3A variants. We identified two sets of compound heterozygous variants in POLR3A, c.1771-6C > G and c.791C > T, p.(Pro264Leu) for family 1 and c.1771-6C > G and c.2671C > T, p.(Arg891*) for family 2. Both families had the c.1771-6C > G variant, which led to aberrant mRNA splicing. Neuropsychiatric regression and severe intellectual disability were identified in three patients. Two cases showed dystonia and oligodontia. Notably, characteristic bilateral symmetric atrophy and abnormal signal of the striatum without diffuse white matter signal change were observed in brain MRI of all three individuals.

Conclusions: Striatum abnormalities may be another distinctive MRI finding associated with POLR3A variants, especially in cases including c.1771-6C > G variants and our cases can expand the phenotypic spectrum of POLR3A-related disorders.
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http://dx.doi.org/10.1016/j.braindev.2019.12.012DOI Listing
April 2020

All-Inside Double-Bundle Anterior Cruciate Ligament Reconstruction via the Transtibial Approach With a Laser-Tip Guide System for Drilling.

Arthrosc Tech 2019 Jul 17;8(7):e755-e762. Epub 2019 Jul 17.

Department of Orthopaedic Surgery, Ehime University Graduate School of Medicine, Toon, Japan.

Anterior cruciate ligament reconstruction using an all-inside method to reduce bone damage caused by drill hole preparation and enhance the stability of the reconstructed ligament in the drill hole has been reported in recent years. We made a custom-designed drill guide pin and reamer, which are assembled in the joint, to create drill holes in the femur and tibia. For the transtibial method, our femoral drill hole-positioning technique, which uses a laser, is extremely convenient for accurate positioning of the drill holes. Therefore, a combination of these methods facilitates implementation of the all-inside double-bundle anterior cruciate ligament reconstruction technique.
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http://dx.doi.org/10.1016/j.eats.2019.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715831PMC
July 2019

Mice deficient in the C-terminal domain of TAR DNA-binding protein 43 develop age-dependent motor dysfunction associated with impaired Notch1-Akt signaling pathway.

Acta Neuropathol Commun 2019 07 25;7(1):118. Epub 2019 Jul 25.

Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Chikusa-ku, Nagoya, Aichi, 464-8601, Japan.

Intracellular mislocalization of TAR DNA-binding protein 43 (TDP-43), a nuclear DNA/RNA-binding protein involved in RNA metabolism, is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Although the aggregation-prone, TDP-43 C-terminal domain is widely considered as a key component of TDP-43 pathology in ALS, recent studies including ours suggest that TDP-43 N-terminal fragments (TDP-∆C) may also contribute to the motor dysfunction in ALS. However, the specific pathological functions of TDP-43 N-terminal fragments in mice have not been elucidated. Here, we established TDP-∆C knock-in mice missing a part of exon 6 of murine Tardbp gene, which encodes the C-terminal region of TDP-43. Homozygous TDP-∆C mice showed embryonic lethality, indicating that the N-terminal domain of TDP-43 alone is not sufficient for normal development. In contrast, heterozygous TDP-∆C mice developed normally but exhibited age-dependent mild motor dysfunction with a loss of C-boutons, large cholinergic synaptic terminals on spinal α-motor neurons. TDP-∆C protein broadly perturbed gene expression in the spinal cords of aged heterozygous TDP-∆C mice, including downregulation of Notch1 mRNA. Moreover, the level of Notch1 mRNA was suppressed both by TDP-43 depletion and TDP-∆C expression in Neuro2a cells. Decreased Notch1 mRNA expression in aged TDP-∆C mice was associated with the age-dependent motor dysfunction and loss of Akt surviving signal. Our findings indicate that the N-terminal region of TDP-43 derived from TDP-∆C induces the age-dependent motor dysfunction associated with impaired Notch1-Akt axis in mice.
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http://dx.doi.org/10.1186/s40478-019-0776-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657153PMC
July 2019

Association between sensory processing and dental fear among female undergraduates in Japan.

Acta Odontol Scand 2019 Oct 13;77(7):525-533. Epub 2019 Jun 13.

Division of Dental Anesthesiology, Kyushu Dental University , Fukuoka , Japan.

The aim of cross-sectional study was to investigate the association between sensory processing patterns and dental fear among female undergraduates. Three hundred and ten female university students were included in the present study. Dental fear and sensory processing patterns were measured using the Dental Fear Survey and Adolescent/Adult Sensory Profile with other possible confounders, respectively. Sensory processing patterns were categorized into sensory sensitivity, sensory avoidance, low registration and sensation seeking. We conducted structural equation modelling based on the hypothesis that sensory processing directly affects dental fear, including the confounding role of negative experiences with dentistry, autistic traits and the mediating role of trait anxiety. Based on our proposed model, sensory processing patterns, excluding sensation seeking and negative experiences significantly contributed to dental fear (β = 0.33,  < .001 and β = 0.32,  < .001, respectively) and autistic traits and trait anxiety did not significantly contribute to dental fear. : Extreme sensory processing patterns seem to be associated with a high level of dental fear; thus, the difference in sensory processing might play an important role in the aetiology of dental fear.
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http://dx.doi.org/10.1080/00016357.2019.1610190DOI Listing
October 2019

Can cytoplasmic donation rescue aged oocytes?

Reprod Med Biol 2019 Apr 28;18(2):128-139. Epub 2018 Oct 28.

Department of Anatomical Science Hirosaki University Graduate School of Medicine Aomori Japan.

Background: The pregnancy and delivery rates following assisted reproductive technology (ART) start to decrease and that the miscarriage rate increases rapidly from 35 years old. The miscarriage rate exceeds 50% at 43 years old. The number of aneuploid fetuses in miscarriages increases according to female age, reaching more than 90% when women are over 40 years old.

Methods: Different cytoplasmic donation technologies used to rescue aged oocytes with high percentage of aneuploidy were analyzed, and their efficacy compared.

Main Findings Results: Germinal vesicle transfer (GVT) might be superior to spindle chromosome transfer (ST) theoretically from the point of higher capability of rescuing the disjunction at meiosis I which cannot be helped by ST. However, actually, in vitro maturation (IVM) of oocyte after GVT has not yet been totally completed. ST among other nuclear donations showed the higher possibility to rescue them, due to the fact it does not require in vitro maturation and it has an ethical advantage over pronuclear transfer (PNT) which requires the destruction of an embryo.

Conclusion: Spindle chromosome transfer has the potential to rescue aged oocytes to some extent, but we have to continue the basic study further to establish the clinical application of cytoplasmic donation to rescue aged oocytes.
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http://dx.doi.org/10.1002/rmb2.12252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452014PMC
April 2019

Coexistence of a CAV3 mutation and a DMD deletion in a family with complex muscular diseases.

Brain Dev 2019 May 2;41(5):474-479. Epub 2019 Feb 2.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Whole-exome sequencing (WES) can comprehensively detect both pathogenic single nucleotide variants and copy number variants, enabling identification of a coexistence of two or more genetic etiologies. Here we report a family consisting of individuals with Becker muscular dystrophy and rippling muscle disease. The proband, a 12-year-old boy, was diagnosed with Becker muscular dystrophy with exon 45-55 DMD deletions at age 4. He had myalgia and muscle stiffness. Interestingly, percussion-induced muscle mounding (PIMM), which is a characteristic of rippling muscle disease, was also observed. The father also showed muscle stiffness, myalgia, fatigability, muscle rippling and PIMM. WES revealed a missense CAV3 mutation (NM_033337.2:c.80G>A) in the proband, the father, the oldest sister and the grandmother, who had an elevated serum creatine kinase (CK) level. The c.80G>A mutation was considered pathogenic according to ACMG guidelines. The second older sister, the mother and the paternal grandfather did not have the CAV3 mutation and had normal CK. Using two programs for copy number analysis with WES data, we successfully identified the DMD deletion in the proband, the older sister and the mother. We revealed the coexistence of the CAV3 mutation and the DMD deletion in a family with complex muscular diseases and confirmed the usefulness of WES for elucidating such etiology.
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http://dx.doi.org/10.1016/j.braindev.2019.01.005DOI Listing
May 2019

Transducin-like enhancer of split 3 regulates proliferation of melanoma cells via histone deacetylase activity.

Oncotarget 2019 Jan 8;10(3):404-414. Epub 2019 Jan 8.

Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan.

Melanoma, one of the most aggressive neoplasms, is characterized by rapid cell proliferation. Transducin-like Enhancer of Split (TLE) is an important regulator of cell proliferation via Histone deacetylase (HDAC) recruitment. Given that HDAC activity is associated with melanoma progression, we examined the relationship between TLE3, a TLE family member, and melanoma. TLE3 expression was increased during the progression of human patient melanoma (p < 0.05). Overexpression of Tle3 in B16 murine melanoma cells led to an increase in cell proliferation (p < 0.01) as well as the number of cyclinD1-positive cells. injection of mice with B16 cells overexpressing Tle3 resulted in larger tumor formation than in mice injected with control cells (p < 0.05). In contrast, siRNA-mediated knockdown of Tle3 in B16 cells or TLE3 in HMV-II human melanoma cells decreased proliferation (p < 0.01). Treatment of B16 cells with trichostatin A (2.5 μM), a class I and II HDAC inhibitor, prevented the effect s of Tle3 on proliferation. In conclusion, these data indicate that Tle3 is required, at least in part, for proliferation in the B16 mouse melanoma model.
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http://dx.doi.org/10.18632/oncotarget.26552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349449PMC
January 2019

Ninety babies born after round spermatid injection into oocytes: survey of their development from fertilization to 2 years of age.

Fertil Steril 2018 08;110(3):443-451

University of Hawaii Medical School, Honolulu, Hawaii.

Objective: To compare physical and cognitive development of babies born after round spermatid injection (ROSI) with those born after natural conception.

Design: Comparison of efficiencies of ROSI and ICSI using testicular spermatozoa, performed in the St. Mother Clinic. Physical and cognitive development of ROSI babies recorded by parents in the government-issued Mother-Child Handbook was checked and verified by attending pediatricians. Data included baby's weight gain and response to parents' voice/gesture.

Setting: Assisted reproduction technology practice.

Patient(s): A total of 721 men participated in ROSI; 90 ROSI babies were followed for 2 years for their physical and cognitive development. Control subjects were 1,818 naturally born babies.

Intervention(s): Surgical retrieval of spermatogenic cells from testes; selection and injection of round spermatids into oocytes; oocyte activation, in vitro culture of fertilized eggs, and embryo transfer to mothers.

Main Outcome Measure(s): Physical and cognitive development of ROSI babies (e.g., body weight increase, response to parents, and understanding and speaking simple language) compared with naturally born babies.

Result(s): Of 90 ROSI babies, three had congenital aberrations at birth, which corrected spontaneously (ventricular septa) or after surgery (cleft lip and omphalocele). Physical and cognitive development of ROSI babies was similar to those of naturally born babies.

Conclusion(s): There were no significant differences between ROSI and naturally conceived babies in either physical or cognitive development during the first 2 years after birth.

Clinical Trial Registration Number: UMIN Clinical Trials Registry UMIN000006117.
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http://dx.doi.org/10.1016/j.fertnstert.2018.04.033DOI Listing
August 2018

Sedation With a Combination of Dexmedetomidine and Midazolam for Pediatric Dental Surgery.

Anesth Prog 2018 ;65(2):124-126

Department of Science of Physical Functions, Division of Dental Anesthesiology, Kyushu Dental University, Kokurakita, Kitakyushu, Japan.

Intravenous sedation (IVS) is commonly used to complete dental treatment for uncooperative pediatric patients. Propofol (PRO) is widely used for IVS because of its short context sensitive half-time and amnestic effect. However, administering PRO to patients who have a history of egg anaphylaxis is still somewhat controversial. The evidence that supports the potential risks for allergic reactions following PRO use in patients with egg allergies is limited with some anesthesiologists recommending against its use in these patients. Alternative drug regimens for procedural sedation in this population are therefore desirable. Dexmedetomidine (DEX), a selective α-2 agonist, has antianxiety and sedative properties and has been widely used not only for procedural sedation with mild inhibitory effects on respiration but also during minor surgeries for its analgesic effect. In this paper, we describe the successful administration of a combination of DEX and low-dose midazolam (MDZ) for sedation in an uncooperative pediatric patient. Both DEX and MDZ have been reported as safe and useful sedatives for dental treatment, and their combination may provide a helpful option for IVS of pediatric patients for whom PRO is not preferred.
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http://dx.doi.org/10.2344/anpr-65-03-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022792PMC
October 2019

[Factors Associated with Stress Check Attendance: Possible Effect of Timing of Annual Health Examination].

Nihon Eiseigaku Zasshi 2018 ;73(2):235-240

Department of Occupational Health Practice and Management, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan.

Objectives: The stress check program has been part of annual employees' health screening since 2015. Employees are recommended, but not obliged, to undergo the stress check offered. This study was designed to examine the factors associated with stress check attendance.

Methods: A total of 31,156 Japanese employees who underwent an annual health examination and a stress check service at an Occupational Health Service Center in 2016 participated in this study. Data from the annual health examination and stress check service included stress check attendance, date of attendance (if implemented), gender, age, workplace industry, number of employees at the workplace, and tobacco and alcohol consumption. Data were analyzed using multiple logistic regression.

Results: The mean rate of stress check attendance was 90.8%. A higher rate of stress check attendance was associated with a lower duration from the annual health examination, age ≥30 years, construction and transport industry, and 50-999 employees at the workplace. A lower rate of stress check attendance was associated with medical and welfare industry and ≥1,000 employees at the workplace.

Conclusions: These findings provide insights into developing strategies for improving the rate of stress check attendance. In particular, stress check attendance may improve if the stress check service and annual health examination are conducted simultaneously.
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http://dx.doi.org/10.1265/jjh.73.235DOI Listing
August 2018

Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes.

Cell Death Differ 2018 12 22;25(12):2130-2146. Epub 2018 Mar 22.

Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.

There is compelling evidence that glial-immune interactions contribute to the progression of neurodegenerative diseases. The adaptive immune response has been implicated in disease processes of amyotrophic lateral sclerosis (ALS), but it remains unknown if innate immune signaling also contributes to ALS progression. Here we report that deficiency of the innate immune adaptor TIR domain-containing adaptor inducing interferon-β (TRIF), which is essential for certain Toll-like receptor (TLR) signaling cascades, significantly shortens survival time and accelerates disease progression of ALS mice. While myeloid differentiation factor 88 (MyD88) is also a crucial adaptor for most TLR signaling pathways, MyD88 deficiency had only a marginal impact on disease course. Moreover, TRIF deficiency reduced the number of natural killer (NK), NK-T-lymphocytes, and CD8-T cells infiltrating into the spinal cord of ALS mice, but experimental modulation of these populations did not substantially influence survival time. Instead, we found that aberrantly activated astrocytes expressing Mac2, p62, and apoptotic markers were accumulated in the lesions of TRIF-deficient ALS mice, and that the number of aberrantly activated astrocytes was negatively correlated with survival time. These findings suggest that TRIF pathway plays an important role in protecting a microenvironment surrounding motor neurons by eliminating aberrantly activated astrocytes.
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http://dx.doi.org/10.1038/s41418-018-0098-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261996PMC
December 2018

A copper-deficient form of mutant Cu/Zn-superoxide dismutase as an early pathological species in amyotrophic lateral sclerosis.

Biochim Biophys Acta Mol Basis Dis 2018 06 16;1864(6 Pt A):2119-2130. Epub 2018 Mar 16.

Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University, Yokohama 223-8522, Japan. Electronic address:

Dominant mutations in the gene encoding copper and zinc-binding superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS). Abnormal accumulation of misfolded SOD1 proteins in spinal motoneurons is a major pathological hallmark in SOD1-related ALS. Dissociation of copper and/or zinc ions from SOD1 has been shown to trigger the protein aggregation/oligomerization in vitro, but the pathological contribution of such metal dissociation to the SOD1 misfolding still remains obscure. Here, we tested the relevance of the metal-deficient SOD1 in the misfolding in vivo by developing a novel antibody (anti-apoSOD), which exclusively recognized mutant SOD1 deficient in metal ions at its copper-binding site. Notably, anti-apoSOD-reactive species were detected specifically in the spinal cords of the ALS model mice only at their early pre-symptomatic stages but not at the end stage of the disease. The cerebrospinal fluid as well as the spinal cord homogenate of one SOD1-ALS patient also contained the anti-apoSOD-reactive species. Our results thus suggest that metal-deficiency in mutant SOD1 at its copper-binding site is one of the earliest pathological features in SOD1-ALS.
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http://dx.doi.org/10.1016/j.bbadis.2018.03.015DOI Listing
June 2018

Factors associated with the prevalence of back pain and work absence in shipyard workers.

BMC Musculoskelet Disord 2018 01 11;19(1):12. Epub 2018 Jan 11.

Department of Orthopaedic Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan.

Background: We conducted a questionnaire survey of shipyard workers to identify difficulties experienced due to orthopedic or musculoskeletal disorders.

Methods: The subjects were 375 workers (male, 361; female, 14) who worked for a single shipbuilding company. Questionnaire items covered the working environment, including work environment, working posture, and the weight of objects that the subject dealt with, as well as physical and lifestyle characteristics, namely smoking habits, drinking habits, sleeping hours, medications, exercise habits, and any weight gain of 20 kg or more since the age of 20. Subjects were also asked to indicate if they regularly experienced any of 17 listed difficulties in their daily lives, and to use an illustration of the human body to mark any body parts that were painful or hard to move.

Results: The mean age was 41.8 years (19-73 years). The lower and/or upper back was the most frequent site of pain (46.5%), followed by the shoulders (11.4%), knees (9.6%), and neck (5.3%). Maintaining a half-sitting posture was the most problematic activity of daily living. Back pain was less frequent in subjects who exercised regularly, and more common in those who worked with heavy loads or in narrow spaces. A multinomial logistic regression analysis showed that absence from work was more common in subjects with back pain who had gained weight since their youth, who smoked, who used fire while welding metal, or who worked in a lying posture. While 35.4% of subjects had experienced absence from work due to musculoskeletal pain, only 5.1% were permitted by their employer to alter their work content or reduce their workload.

Conclusions: These results indicate that a large number of shipyard workers have difficulties in their work and daily life activities due to back pain. To prevent worsening of pain and to reduce work absence, it is important to provide appropriate training to minimize the risk factors for back pain that were identified in this study.
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http://dx.doi.org/10.1186/s12891-018-1931-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765670PMC
January 2018

Effect of acetaminophen on osteoblastic differentiation and migration of MC3T3-E1 cells.

Pharmacol Rep 2018 Feb 15;70(1):29-36. Epub 2017 Jul 15.

Division of Applied Pharmacology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Japan. Electronic address:

Background: N-acetyl-p-aminophenol (APAP, acetaminophen, paracetamol) is a widely used analgesic/antipyretic with weak inhibitory effects on cyclooxygenase (COX) compared to non-steroidal anti-inflammatory drugs (NSAIDs). The mechanism of action of APAP is mediated by its metabolite that activates transient receptor potential channels, including transient receptor potential vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) or the cannabinoid receptor type 1 (CB1). However, the exact molecular mechanism and target underlying the cellular actions of APAP remain unclear. Therefore, we investigated the effect of APAP on osteoblastic differentiation and cell migration, with a particular focus on TRP channels and CB1.

Methods: Effects of APAP on osteoblastic differentiation and cell migration of MC3T3-E1, a mouse pre-osteoblast cell line, were assessed by the increase in alkaline phosphatase (ALP) activity, and both wound-healing and transwell-migration assays, respectively.

Results: APAP dose-dependently inhibited osteoblastic differentiation, which was well correlated with the effects on COX activity compared with other NSAIDs. In contrast, cell migration was promoted by APAP, and this effect was not correlated with COX inhibition. None of the agonists or antagonists of TRP channels and the CB receptor affected the APAP-induced cell migration, while the effect of APAP on cell migration was abolished by down-regulating TRPV4 gene expression.

Conclusion: APAP inhibited osteoblastic differentiation via COX inactivation while it promoted cell migration independently of previously known targets such as COX, TRPV1, TRPA1 channels, and CB receptors, but through the mechanism involving TRPV4. APAP may have still unidentified molecular targets that modify cellular functions.
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http://dx.doi.org/10.1016/j.pharep.2017.07.006DOI Listing
February 2018

Intracerebroventricular administration of Cystatin C ameliorates disease in SOD1-linked amyotrophic lateral sclerosis mice.

J Neurochem 2018 04 7;145(1):80-89. Epub 2018 Feb 7.

Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Chikusa-ku, Aichi, Japan.

Cystatin C (CysC) is a major protein component of Bunina bodies, which are a pathological hallmark observed in the remaining motor neurons of patients with amyotrophic lateral sclerosis (ALS). Dominant mutations in the SOD1 gene, encoding Cu/Zn superoxide dismutase (SOD1), are causative for a subset of inherited ALS cases. Our previous study showed that CysC exerts a neuroprotective effect against mutant SOD1-mediated toxicity in vitro; however, in vivo evidence of the beneficial effects mediated by CysC remains obscure. Here we examined the therapeutic potential of recombinant human CysC in vivo using a mouse model of ALS in which the ALS-linked mutated SOD1 gene is expressed (SOD1 mice). Intracerebroventricular administration of CysC during the early symptomatic SOD1 mice extended their survival times. Administered CysC was predominantly distributed in ventral horn neurons including motor neurons, and induced autophagy through AMP-activated kinase activation to reduce the amount of insoluble mutant SOD1 species. Moreover, PGC-1α, a disease modifier of ALS, was restored by CysC through AMP-activated kinase activation. Finally, the administration of CysC also promoted aggregation of CysC in motor neurons, which is similar to Bunina bodies. Taken together, our findings suggest that CysC represents a promising therapeutic candidate for ALS.
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http://dx.doi.org/10.1111/jnc.14285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947136PMC
April 2018