Publications by authors named "Takashi Ando"

219 Publications

Double J stent migration as renal penetration.

Urol Case Rep 2021 Nov 22;39:101759. Epub 2021 Jun 22.

Division of Molecular Oncology, Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi-dori 1-757, Chuo-ku, Niigata, 951-8510, Japan.

Transurethral double J (DJ) stent placement is a standard method for drainage during ureteral obstruction caused by a ureteral stone and for the management of complications after transurethral ureterolithotripsy (TUL). This is a safe and minimally invasive technique; however, severe cases of DJ stent migration have been reported, although rarely. Herein, we report the CASE of a 48-year-old man with DJ stent migration as renal penetration, which arose as a complication after an unsuccessful TUL. As transurethral DJ stent placement is one of the basic techniques performed by urologists, possible rare complications of the placement should be taken into consideration.
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http://dx.doi.org/10.1016/j.eucr.2021.101759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253939PMC
November 2021

Multiple system atrophy variant with severe hippocampal pathology.

Brain Pathol 2021 Jul 13:e13002. Epub 2021 Jul 13.

Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan.

The striatonigral and olivopontocerebellar systems are known to be vulnerable in multiple system atrophy (MSA), showing neuronal loss, astrogliosis, and alpha-synuclein-immunoreactive inclusions. MSA patients who displayed abundant neuronal cytoplasmic inclusions (NCIs) in the regions other than the striatonigral or olivopontocerebellar system have occasionally been diagnosed with variants of MSA. In this study, we report clinical and pathologic findings of MSA patients characterized by prominent pathologic involvement of the hippocampus. We assessed 146 consecutively autopsied MSA patients. Semi-quantitative analysis of anti-alpha-synuclein immunohistochemistry revealed that 12 of 146 patients (8.2%) had severe NCIs in two or more of the following areas: the hippocampal granule cells, cornu ammonis areas, parahippocampal gyrus, and amygdala. In contrast, the remaining 134 patients did not show severe NCIs in any of these regions. Patients with severe hippocampal involvement showed a higher representation of women (nine women/three men; Fisher's exact test, p = 0.0324), longer disease duration (13.1 ± 5.9 years; Mann-Whitney U-test, p = 0.000157), higher prevalence of cognitive impairment (four patients; Fisher's exact test, p = 0.0222), and lower brain weight (1070.3 ± 168.6 g; Mann-Whitney U-test, p = 0.00911) than other patients. The hippocampal granule cells and cornu ammonis area 1/subiculum almost always showed severe NCIs. The NCIs appeared to be ring-shaped or neurofibrillary tangle-like, fibrous configurations. Three of 12 patients also had dense, round-shaped NCIs that were morphologically similar to pick bodies. The patients with Pick body-like inclusions showed more severe atrophy of the medial temporal lobes and broader spreading of NCIs than those without. Immunohistochemistry for hyperphosphorylated tau and phosphorylated TDP-43 revealed minimal aggregations in the hippocampus of the hippocampal MSA patients. Our observations suggest a pathological variant of MSA that is characterized by severe involvement of hippocampal neurons. This phenotype may reinforce the importance of neuronal alpha-synucleinopathy in the pathogenesis of MSA.
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http://dx.doi.org/10.1111/bpa.13002DOI Listing
July 2021

Combined Anticancer Effect of Plasma-Activated Infusion and Salinomycin by Targeting Autophagy and Mitochondrial Morphology.

Front Oncol 2021 4;11:593127. Epub 2021 Jun 4.

Department of Research and Development, Plasma ChemiBio Laboratory, Plasma ChemiBio Laboratory, Nasushiobara, Tochigi, Japan.

Non-thermal atmospheric pressure plasma (NTAPP)-activated liquids have emerged as new promising anticancer agents because they preferentially injure malignant cells. Here, we report plasma-activated infusion (PAI) as a novel NTAPP-based anti-neoplastic agent. PAI was prepared by irradiating helium NTAP to form a clinically approved infusion fluid. PAI dose-dependently killed malignant melanoma and osteosarcoma cell lines while showing much lower cytotoxic effects on dermal and lung fibroblasts. We found that PAI and salinomycin (Sal), an emerging anticancer stem cell agent, mutually operated as adjuvants. The combined administration of PAI and Sal was much more effective than single-agent application in reducing the growth and lung metastasis of osteosarcoma allografts with minimal adverse effects. Mechanistically, PAI explicitly induced necroptosis and increased the phosphorylation of receptor-interacting protein 1/3 rapidly and transiently. PAI also suppressed the ambient autophagic flux by activating the mammalian target of the rapamycin pathway. PAI increased the phosphorylation of Raptor, Rictor, and p70-S6 kinase, along with decreased LC3-I/II expression. In contrast, Sal promoted autophagy. Moreover, Sal exacerbated the mitochondrial network collapse caused by PAI, resulting in aberrant clustering of fragmented mitochondrial in a tumor-specific manner. Our findings suggest that combined administration of PAI and Sal is a promising approach for treating these apoptosis-resistant cancers.
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http://dx.doi.org/10.3389/fonc.2021.593127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212785PMC
June 2021

Exogenous parathyroid hormone attenuates ovariectomy-induced skeletal muscle weakness in vivo.

Bone 2021 10 7;151:116029. Epub 2021 Jun 7.

Department of Orthopaedic Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.

Osteoporosis commonly affects the elderly and is associated with significant morbidity and mortality. Loss of bone mineral density induces muscle atrophy and increases fracture risk. However, muscle lipid content and droplet size are increased by aging and mobility impairments, inversely correlated with muscle function, and a cause of reduced motor function. Teriparatide, the synthetic form of human parathyroid hormone (PTH) 1-34, has been widely used to treat osteoporosis. Although PTH positively affects muscle differentiation in vitro, the precise function and mechanisms of muscle mass and power preservation are still poorly understood, especially in vivo. In this study, we investigated the effect of PTH on skeletal muscle atrophy and dysfunction using an ovariectomized murine model. Eight-week-old female C57BL/6J mice were ovariectomized or sham-operated. Within each surgical group, the mice were divided into PTH injection or control subgroups. Motor function was evaluated based on grip strength, treadmill running, and lactic acid concentration. PTH receptor was expressed in skeletal muscle cells and myoblasts. PTH inhibited ovariectomy-induced bone loss but not uterine atrophy or increased body weight; PTH not only abolished ovariectomy-induced reduction in grip strength and maximum running speed, but also significantly reduced the ovariectomy-induced increase in lactic acid concentration (compared with that observed in the vehicle control). PTH also abrogated the ovariectomy-induced reduction in the oxidative capacity of muscle fibers, their cross-sectional area, and intramyocellular lipid content, and induced cell proliferation, cell migration, and muscle differentiation, while reducing lipid secretion by C2C12 myoblasts via the Wnt/β-catenin pathway. PTH significantly ameliorated muscle weakness and attenuated exercise-induced lactate levels in ovariectomized mice. Our in vitro study demonstrated that PTH/Wnt signaling regulated the proliferation, migration, and differentiation of myoblasts and also reduced lipid secretion in myoblasts. Thus, PTH could regulate several aspects of muscle function and physiology, and may represent a novel therapeutic strategy for patients with osteoporosis.
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http://dx.doi.org/10.1016/j.bone.2021.116029DOI Listing
October 2021

Nested Case-Control Study Utilizing MID-NET® on Thrombocytopenia Associated With Pegfilgrastim in Patients Treated With Antineoplastic Agents.

Clin Pharmacol Ther 2021 Apr 18. Epub 2021 Apr 18.

Office of Medical Informatics and Epidemiology, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.

Although several spontaneous case reports on the occurrence of thrombocytopenia in patients treated with human granulocyte colony-stimulating factor (G-CSF) preparations have been accumulated, its actual causality is still unclear. To investigate the association between G-CSF preparations (filgrastim, nartograstim, lenograstim, and pegfilgrastim) available in Japan and thrombocytopenia in patients treated with antineoplastic agents, a nested case-control study was conducted using the Medical Information Database NETwork (MID-NET®) with the cohort of the Japanese population taking antineoplastic agents between 2009 and 2018. A case of thrombocytopenia was defined as a patient who had decreased platelet counts (< 50,000/mm ). We identified a maximum of 10 controls for each case matched on the index date. Adjusted odds ratios (aORs) and their 95% confidence intervals (CIs) of thrombocytopenia for the use of G-CSF preparations compared with nonuse were estimated using conditional logistic regression. From the cohort in which 33,124 patients were included, 733 cases and 5,592 controls were identified. Compared with the nonuse of G-CSF preparations, the use of any G-CSF preparations increased the risk of thrombocytopenia (aOR: 5.7, 95% CI: 4.3-7.5). More detailed analysis showed that a distinctive increased risk was observed when pegfilgrastim was prescribed at 2-7 days before the index date (aOR: 7.4 95% CI: 2.0-28.1). Associations of the other G-CSF preparations with thrombocytopenia were unclear due to the inconsistent results among different analyses. A significantly increased risk of thrombocytopenia associated with pegfilgrastim was identified, leading to a revision of precautions in the package inserts of pegfilgrastim as a regulatory safety action.
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http://dx.doi.org/10.1002/cpt.2263DOI Listing
April 2021

All-case Japanese post-marketing surveillance of the real-world safety and efficacy of rituximab treatment in patients with refractory nephrotic syndrome.

Clin Exp Nephrol 2021 Aug 1;25(8):854-864. Epub 2021 Apr 1.

Pharmacovigilance and Quality Assurance Department, Zenyaku Kogyo Co., Ltd, 6-15, Otsuka 5-Chome, Bunkyo-ku, Tokyo, 112-8650, Japan.

Background: Rituximab is conditionally approved in Japan for use in patients with refractory nephrotic syndrome. To meet the conditions of approval, an all-case post-marketing surveillance study was conducted to confirm the real-world safety and efficacy of rituximab in patients of all ages with refractory nephrotic syndrome.

Methods: All patients scheduled to receive rituximab treatment for refractory nephrotic syndrome were eligible to register (registration: August 29, 2014 through April 15, 2016); the planned observation period was 2 years from the initiation of rituximab treatment (intravenous infusion, 375 mg/m once weekly for four doses). The study was conducted at 227 hospitals throughout Japan. Adverse drug reactions (ADRs) were collected for safety outcomes. The efficacy outcomes were relapse-free period and the degree of growth in pediatric (< 15 years) patients.

Results: In total, 997 (447 pediatric) patients were registered; 981 (445) were included in the safety analysis set; 852 (402) completed the 2-year observation period; and 810 (429) were included in the efficacy analysis set. Refractory nephrotic syndrome had developed in childhood for 85.0% of patients, and 54.6% were aged ≥15 years. ADRs were observed in 527 (53.7%) patients, treatment-related infection/infestation in 235 (24.0%) patients, and infusion reactions in 313 (31.9%) patients. The relapse-free period was 580 days (95% confidence interval, 511-664). There was a significant change in height standard deviation score (pediatric patients; mean change, 0.093; standard deviation, 0.637; P = 0.009).

Conclusion: The safety and efficacy of rituximab treatment in patients with refractory nephrotic syndrome were confirmed in the real-world setting.

Clinical Trial Registration: UMIN000014997.
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http://dx.doi.org/10.1007/s10157-021-02035-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260412PMC
August 2021

EHF suppresses cancer progression by inhibiting ETS1-mediated ZEB expression.

Oncogenesis 2021 Mar 12;10(3):26. Epub 2021 Mar 12.

Department of Biochemistry, Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.

ETS homologous factor (EHF) belongs to the epithelium-specific subfamily of the E26 transformation-specific (ETS) transcription factor family. Currently, little is known about EHF's function in cancer. We previously reported that ETS1 induces expression of the ZEB family proteins ZEB1/δEF1 and ZEB2/SIP1, which are key regulators of the epithelial-mesenchymal transition (EMT), by activating the ZEB1 promoters. We have found that EHF gene produces two transcript variants, namely a long form variant that includes exon 1 (EHF-LF) and a short form variant that excludes exon 1 (EHF-SF). Only EHF-SF abrogates ETS1-mediated activation of the ZEB1 promoter by promoting degradation of ETS1 proteins, thereby inhibiting the EMT phenotypes of cancer cells. Most importantly, we identified a novel point mutation within the conserved ETS domain of EHF, and found that EHF mutations abolish its original function while causing the EHF protein to act as a potential dominant negative, thereby enhancing metastasis in vivo. Therefore, we suggest that EHF acts as an anti-EMT factor by inhibiting the expression of ZEBs, and that EHF mutations exacerbate cancer progression.
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http://dx.doi.org/10.1038/s41389-021-00313-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955083PMC
March 2021

Seeded assembly in vitro does not replicate the structures of α-synuclein filaments from multiple system atrophy.

FEBS Open Bio 2021 Apr 24;11(4):999-1013. Epub 2021 Feb 24.

MRC Laboratory of Molecular Biology, Cambridge, UK.

The propagation of conformational strains by templated seeding is central to the prion concept. Seeded assembly of α-synuclein into filaments is believed to underlie the prion-like spreading of protein inclusions in a number of human neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We previously determined the atomic structures of α-synuclein filaments from the putamen of five individuals with MSA. Here, we used filament preparations from three of these brains for the in vitro seeded assembly of recombinant human α-synuclein. We find that the structures of the seeded assemblies differ from those of the seeds, suggesting that additional, as yet unknown, factors play a role in the propagation of the seeds. Identification of these factors will be essential for understanding the prion-like spreading of α-synuclein proteinopathies.
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http://dx.doi.org/10.1002/2211-5463.13110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016116PMC
April 2021

Effect of Hepatitis C Drugs on Blood Coagulability in Patients on Warfarin Using the Medical Information Database Network (MID-NET) in Japan.

Ther Innov Regul Sci 2021 05 3;55(3):539-544. Epub 2021 Jan 3.

Office of Medical Informatics and Epidemiology, Pharmaceuticals and Medical Devices Agency, Shin-Kasumigaseki Building, 3-3-2 Kasumigaseki, Chiyodaku, Tokyo, 100-0013, Japan.

Background: Previous studies suggested that direct-acting antivirals (DAAs) against hepatitis C increased the blood coagulability of patients on warfarin. This study aims to descriptively investigate the effects of DAAs on the blood coagulability and liver function of patients on warfarin in Japan.

Methods: The Medical Information Database Network (MID-NET) was used as data source. Fluctuations of blood coagulability and liver function were examined before and after DAA treatment in patients who were prescribed both DAAs and warfarin at least once during the study period from January 1, 2010, to December 31, 2017.

Results: For the 16 eligible patients, the mean values of both PT-INR and WSI (warfarin sensitivity index) defined as the value obtained by dividing the PT-INR by the warfarin daily dose slightly decreased at the date of completion of the DAA treatment in comparison with those at the date of initiation and subsequently increased at 12 weeks after treatment completion. In contrast, the warfarin daily dose increased at the date of completion of the DAA treatment, followed by a decrease at 12 weeks after its completion. Several laboratory tests related to the liver function also revealed a similar decrease at the end of the DAA treatment.

Conclusion: The analysis of MID-NET data provides useful information on drug safety assessment of real-world patients. The results of this study imply that fluctuation of the liver function test results may relate to the fluctuation of blood coagulability in patients on both DAA and warfarin. This study contributes to a deeper understanding of the usefulness and limitations of real-world data in MID-NET for regulatory purposes.
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http://dx.doi.org/10.1007/s43441-020-00247-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021533PMC
May 2021

A case of signet ring cell carcinoma and mucosa-associated lymphoid tissue lymphoma of the stomach diagnosed simultaneously via magnifying endoscopy with narrow-band imaging.

Clin J Gastroenterol 2021 Apr 3;14(2):453-459. Epub 2021 Jan 3.

Department of Pathology, Japanese Red Cross Shizuoka Hospital, 8-2 Outemachi, Aoi-ku, Shizuoka-City , Shizuoka, 420-0853, Japan.

We present the case of a 57-year-old woman who experienced 3 weeks of intermittent tarry stools and epigastric pain. She had a 25-year history of smoking and a 12-year history of heavy alcohol consumption but had discontinued both 12 years prior. Laboratory investigations revealed elevated anti-H. Pylori IgG antibody levels. Conventional upper gastrointestinal endoscopy revealed two lesions. Magnifying endoscopy with narrow-band imaging showed the characteristic appearance of a diffuse-type gastric cancer 0-IIc lesion with a demarcation line and abnormal vessels ("wavy micro-vessels" and a "cork-screw pattern"). There was also "ballooning" of the crypts and a "tree-like vessel appearance" in an "unstructured area" characteristic of gastric mucosa-associated lymphoid tissue lymphoma with ulceration. Accurate target biopsies were obtained. We performed a laparoscopic total gastrectomy with D1 lymphadenectomy. Pathological examination revealed poorly differentiated stage I adenocarcinoma of the stomach with features of signet ring cell carcinoma as well as stage I mucosa-associated lymphoid tissue lymphoma. In conclusion, we encountered a case of co-existing diffuse-type gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. Magnifying endoscopy with narrow-band imaging was effective for diagnosing these two co-existing tumors and resulted in the collection of adequate biopsy specimens allowing for an accurate pathological diagnosis and optimal treatment.
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http://dx.doi.org/10.1007/s12328-020-01325-yDOI Listing
April 2021

The wide-ranging clinical and genetic features in Japanese families with valosin-containing protein proteinopathy.

Neurobiol Aging 2021 04 14;100:120.e1-120.e6. Epub 2020 Nov 14.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. Electronic address:

Mutations in the valosin-containing protein (VCP) gene are known to cause various neurodegenerative disorders. Here, we report 8 Japanese patients [6 men, 2 women; median age at onset: 49.5 (range, 35-58) years] from 5 unrelated families with VCP missense mutations. Although 7 of 8 patients were diagnosed with either inclusion body myopathy or amyotrophic lateral sclerosis, 1 patient showed demyelinating polyneuropathy, which was confirmed by longitudinal nerve conduction studies. Sural nerve biopsy of the patient revealed intranuclear ubiquitin staining in Schwann cells. Three known pathogenic VCP mutations (p.Arg191Gln, p.Arg155Cys, and p.Ile126Phe) were detected. A novel mutation, c.293 A>T (p.Asp98Val), was also identified in a patient with amyotrophic lateral sclerosis and frontotemporal dementia. This mutation was predicted to be "deleterious" or "disease causing" using in silico mutation analyses. In conclusion, demyelinating polyneuropathy may be a novel phenotype caused by VCP mutations. The p.Asp98Val mutation was found to be a novel pathogenic mutation of VCP proteinopathy. We believe our cases represent a wide clinical spectrum of VCP mutations.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.028DOI Listing
April 2021

Gemcitabine and Rapamycin Exhibit Additive Effect against Osteosarcoma by Targeting Autophagy and Apoptosis.

Cancers (Basel) 2020 Oct 23;12(11). Epub 2020 Oct 23.

Department of Orthopeadic Surgery, Yamanashi University School of Medicine, Yamanashi 409-3898, Japan.

The overall prognosis for sarcoma-based cancer patients has remained largely unchanged over the past 10 years. Because there is no effective anticancer drug for patients with chemoresistant osteosarcoma (OS), novel approaches are needed to improve the prognosis. Here, we investigated whether rapamycin (Rapa) could enhance the anti-tumor effects of gemcitabine (Gem) in OS. Gem dose-dependently killed the OS cells, but exhibited much lower cytotoxicity on osteoblasts. Treatment with a combination Gem and Rapa was much more effective than that of either single agent with respect to reducing cell viability, cell invasion, cell migration and vascular endothelial growth factor production in vitro. Moreover, the combination of these agents suppressed tumor growth, angiogenesis, and lung metastasis in allograft and xenograft murine models of OS with minimal adverse effects. Overall, the combination therapy prolonged the overall survival of tumor-bearing mice. Mechanistically, Gem induced apoptosis and increased the levels of cleaved caspases, while Rapa induced autophagy and microtubule-associated protein light chain 3 (LC3)-I/LC3-II expression both in vitro and in vivo. Our findings suggest that chemotherapy using Gem combined with Rapa may be a novel and promising therapeutic approach for the treatment of OS.
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http://dx.doi.org/10.3390/cancers12113097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690839PMC
October 2020

Influenza virus vaccination in children with nephrotic syndrome: insignificant risk of relapse.

Clin Exp Nephrol 2020 Nov 27;24(11):1069-1076. Epub 2020 Jul 27.

Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan.

Background: Immunization with various vaccines is considered desirable for children with idiopathic nephrotic syndrome (NS) because of their high risk of severe infections. Vaccinations may precipitate relapses of NS, but there is no available data regarding inactivated influenza (flu) virus vaccines.

Methods: We retrospectively reviewed the medical records of children with NS who had received flu vaccines between 2002 and 2015. The day of flu vaccination was defined as day 0, and the period between the pre-vaccination and the post-vaccination days was defined as - X to + Y. The risk ratios and their 95% confidence intervals for NS relapse rate were estimated by generalized estimating equation (GEE) Poisson regression.

Results: A total of 104 pediatric patients received 208 flu vaccines. The mean age at onset of NS was at 4.85 ± 3.87 years old. There were 261 NS relapses between days - 180 and + 180. Compared with the relapse rate in the - 180 to 0 interval (1.19 times/person-year), those in 0 to + 30 (1.23), + 31 to + 60 (1.58), + 61 to + 90 (1.41), + 91 to + 120 (1.41), and + 121 to + 180 (1.32) days groups were slightly increased, but without significance. Multivariate analysis using GEE Poisson regression also showed no significant increase in relapse rate in each day group compared with days - 180 to 0. Risk ratios for NS relapse were significantly higher in children who were treated with steroids at the first vaccination.

Conclusions: Our results suggest that flu vaccines should not be avoided in children with NS based on the potential for NS relapses.
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http://dx.doi.org/10.1007/s10157-020-01930-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383070PMC
November 2020

Aspirin Induces Mitochondrial Ca Remodeling in Tumor Cells via ROS‒Depolarization‒Voltage-Gated Ca Entry.

Int J Mol Sci 2020 Jul 5;21(13). Epub 2020 Jul 5.

Plasma ChemiBio Laboratory, Nasushiobara, Tochigi 329-2813, Japan.

Aspirin (acetylsalicylic acid) and its metabolite salicylate, have an anti-melanoma effect by evoking mitochondrial dysfunction through poorly understood mechanisms. Depolarization of the plasma membrane potential leads to voltage-gated Ca entry (VGCE) and caspase-3 activation. In the present study, we investigated the role of depolarization and VGCE in aspirin's anti-melanoma effect. Aspirin and to a lesser extent, salicylate (≥2.5 mM) induced a rapid (within seconds) depolarization, while they caused comparable levels of depolarization with a lag of 2~4 h. Reactive oxygen species (ROS) generation also occurred in the two-time points, and antioxidants abolished the early ROS generation and depolarization. At the same concentrations, the two drugs induced apoptotic and necrotic cell death in a caspase-independent manner, and antioxidants and Ca channel blockers prevented cell death. Besides ROS generation, reduced mitochondrial Ca (Ca) and mitochondrial membrane potential preceded cell death. Moreover, the cells expressed the Ca1.2 isoform of l-type Ca channel, and knockdown of Ca1.2 abolished the decrease in Ca. Our findings suggest that aspirin and salicylate induce Ca remodeling, mitochondrial dysfunction, and cell death via ROS-dependent depolarization and VGCE activation.
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http://dx.doi.org/10.3390/ijms21134771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370041PMC
July 2020

Later-Onset Multiple System Atrophy: A Multicenter Asian Study.

Mov Disord 2020 09 4;35(9):1692-1693. Epub 2020 Jul 4.

Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.

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http://dx.doi.org/10.1002/mds.28177DOI Listing
September 2020

Role of Platelet C-Type Lectin-Like Receptor 2 in Promoting Lung Metastasis in Osteosarcoma.

J Bone Miner Res 2020 09 1;35(9):1738-1750. Epub 2020 Jun 1.

Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi, Japan.

The overall prognosis of patients with sarcoma-based cancers has changed little in the last 20 years. There is an urgent need to investigate the metastatic potential of these tumors and to develop anti-metastatic drugs. It is becoming increasingly clear that platelets play an important role in the establishment of metastasis of carcinoma cells and could be a useful therapeutic target for patients with carcinoma. However, little is known about the role of platelets in sarcoma progression. Here, we investigated how osteosarcoma progression relates to platelet function to explore the possibility of anti-platelet therapy. We found that, similar to carcinoma cells, podoplanin (also known as Aggrus)-positive osteosarcoma cells induce platelet aggregation and activation. Administration of anti-glycoprotein Ibα (GPIbα, also known as CD42b) antibody reduced the lung metastasis of osteosarcoma. The supernatant from platelets cocultured with osteosarcoma cells contained several growth factors and promoted proliferation, invasiveness, and sphere formation of osteosarcoma cells in vitro. In addition, the development of lung metastasis was highly dependent on direct interaction between osteosarcoma cells and platelets. To explore the therapeutic target, we focused on the interactions between podoplanin on osteosarcoma and C-type lectin-like receptor (CLEC)-2 on platelets. The administration of a depleting antibody against CLEC-2 efficiently suppressed osteosarcoma metastasis into the lung. We also analyzed clinical data from patient samples at primary and metastatic sites. Although GPIbα expression was similar between the two sites, there was a significant increase in podoplanin at the metastatic site compared to that in the primary site, and the level of podoplanin expression in the primary site correlated with patient prognosis. These findings suggest that blockade of interactions between platelets CLEC-2 and osteosarcoma podoplanin represent the most promising therapeutic strategy for preventing the lung metastasis of osteosarcoma. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4045DOI Listing
September 2020

Structures of α-synuclein filaments from multiple system atrophy.

Nature 2020 09 27;585(7825):464-469. Epub 2020 May 27.

MRC Laboratory of Molecular Biology, Cambridge, UK.

Synucleinopathies, which include multiple system atrophy (MSA), Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases. Existing treatments are at best symptomatic. These diseases are characterized by the presence of, and believed to be caused by the formation of, filamentous inclusions of α-synuclein in brain cells. However, the structures of α-synuclein filaments from the human brain are unknown. Here, using cryo-electron microscopy, we show that α-synuclein inclusions from the brains of individuals with MSA are made of two types of filament, each of which consists of two different protofilaments. In each type of filament, non-proteinaceous molecules are present at the interface of the two protofilaments. Using two-dimensional class averaging, we show that α-synuclein filaments from the brains of individuals with MSA differ from those of individuals with DLB, which suggests that distinct conformers or strains characterize specific synucleinopathies. As is the case with tau assemblies, the structures of α-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, which has implications for understanding the mechanisms of aggregate propagation and neurodegeneration in the human brain. These findings have diagnostic and potential therapeutic relevance, especially because of the unmet clinical need to be able to image filamentous α-synuclein inclusions in the human brain.
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http://dx.doi.org/10.1038/s41586-020-2317-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116528PMC
September 2020

The prevalence and antimicrobial susceptibility of Streptococcus pneumoniae isolated from patients at Jikei University Hospitals after the implementation of the pneumococcal vaccination program in Japan.

J Infect Chemother 2020 Jul 14;26(7):769-774. Epub 2020 May 14.

Department of Laboratory Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan; Department of Clinical Laboratory, The Jikei University Hospital, 3-19-18 Nishi-shimbashi, Minato-ku, Tokyo, 105-8471, Japan.

Studies have shown that pneumococcal vaccination reduces the incidence of Streptococcus pneumoniae infections but does not change the prevalence of S. pneumoniae nasopharyngeal colonization. To comprehensively and longitudinally assess the epidemiology of S. pneumoniae after the introduction of pneumococcal vaccination, we monitored the prevalence and antimicrobial susceptibility of S. pneumoniae, irrespective of its serotypes or pathogenicity, by analyzing specimens collected from a large number of patients at Jikei University Hospitals from 2009 to 2017. A total of 5763 S. pneumoniae isolates were identified out of 375,435 specimens from various sources of patients in different age groups. The prevalence of S. pneumoniae isolated only from patients <5 years old was significantly reduced with the widespread use of pneumococcal vaccines, although this reduction differed by areas where patients resided. The incidence of pneumococcal infections, including bacteremia and otitis media, clearly decreased among patients <5 years old after the introduction of pneumococcal vaccination, while the prevalence of S. pneumoniae isolated from blood specimens of patients 15-64 years old increased, suggesting the involvement of non-vaccine serotypes in the incidence of invasive pneumococcal infections. The antimicrobial susceptibility of S. pneumoniae improved after the introduction of pneumococcal vaccination. Our results show that pneumococcal vaccination has a suppressive effect on the prevalence of S. pneumoniae and the incidence of pneumococcal infections, at least for children <5 years old, in association with an improvement in the antimicrobial susceptibility of S. pneumoniae. However, further measures will be needed to control invasive pneumococcal infections caused by non-vaccine serotypes.
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http://dx.doi.org/10.1016/j.jiac.2020.04.018DOI Listing
July 2020

Helicobacter pylori eradication therapy outcome according to clarithromycin susceptibility testing in Japan.

Helicobacter 2020 Aug 5;25(4):e12698. Epub 2020 May 5.

Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: Helicobacter pylori (Hp) infection increases the risk of gastric cancer. Therefore, eradication is a global goal, which requires continuous monitoring of therapeutic regimens and effectiveness. Clarithromycin resistance is an important contributor to eradication failure, and metronidazole is recommended as second-line treatment in such cases. Here, we retrospectively evaluated the clarithromycin and metronidazole resistance rates and treatment effectiveness in patients with Hp using tailored therapies according to clarithromycin susceptibility testing.

Methods: Data on drug susceptibility were obtained for 5249 Japanese Hp patients between July 2005 and August 2018. Clarithromycin/metronidazole resistance rates were analyzed according to year, gender, and age with Fisher's exact test. The relationship between clarithromycin resistance and Hp therapy outcomes was assessed for 1300 patients. Treatment regimens included a clarithromycin- or metronidazole-containing 7-day triple therapy with one of several proton pump inhibitors and vonoprazan.

Results: Clarithromycin resistance increased annually and was higher in women and younger patients (<30 years). Rates of metronidazole resistance were stable but decreased with age. Hp treatment regimens using PPIs had eradication rates of 88% and 45% among clarithromycin-sensitive and clarithromycin-resistant cases, respectively, while regimens including vonoprazan had eradication rates of around 90% regardless of clarithromycin susceptibility. In particular, triple therapy with vonoprazan, amoxicillin, and metronidazole achieved 98% eradication.

Conclusion: Clarithromycin-containing triple therapy even using vonoprazan did not achieve satisfactory eradication rates even in the clarithromycin-sensitive group. To avoid antibiotic misuse in population with low metronidazole resistance, 7-day vonoprazan, amoxicillin, and metronidazole triple therapy might be a strong candidate as a first-line eradication therapy.
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http://dx.doi.org/10.1111/hel.12698DOI Listing
August 2020

Pancreatic metastasis from locally recurrent neuroendocrine differentiated prostate cancer after radical prostatectomy.

Urol Case Rep 2020 Jul 2;31:101155. Epub 2020 Apr 2.

Department of Urology, Niigata Prefectural Central Hospital, Shinnancho 205, Jouetsushi, Niigata, 943-0192, Japan.

Pancreatic metastasis from prostate cancer (PC) is quite rare. Herein, we report the case of a 67-year-old man with pancreatic metastasis from a neuroendocrine differentiated PC (NEDPC), a local recurrence after radical prostatectomy and androgen deprivation therapy for 6 years. Chemoradiotherapy was initiated for the locally recurrent NEDPC, and it had almost disappeared after the therapy. However, rapidly enlarged pancreatic metastasis from the NEDPC was detected 6 months after therapy. There is no standard treatment available for pancreatic metastasis from NEDPC owing to its rarity; hence, further knowledge and clinical experience regarding it are crucial.
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http://dx.doi.org/10.1016/j.eucr.2020.101155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139108PMC
July 2020

Report of a rare case of periaortitis at the aortic arch and successful therapeutic strategy with prednisolone.

J Cardiol Cases 2019 Nov 22;20(5):174-179. Epub 2019 Aug 22.

Department of Internal Medicine, Fukaya Japan Red Cross Hospital, Saitama, Japan.

Periaortitis is one of the less common manifestations of the aorta pathology. Periaortitis mostly arises from the outer layers of the abdominal aorta and iliac arteries. However, other large arteries may also be involved, but rarely the thoracic aorta. Here we present a successful conservative treatment using prednisolone therapy for periaortitis of the aortic arch which shows various clinical symptoms. < Periaortitis is one of the less common manifestations of the aorta pathology. Periaortitis rarely has an impact on the thoracic aorta. The treatment strategy for this complication, especially the dose of prednisolone, is not well established. This case report supports documenting periaortitis in the aortic arch. Not only did we begin initial prednisolone treatment at 45 mg/day, but also performed a downward titration after only half a year.>.
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http://dx.doi.org/10.1016/j.jccase.2019.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834946PMC
November 2019

Duodenal and rectal obstructions due to urothelial cancer infiltration from recurrent renal pelvic cancer in the bladder wall: An autopsy case.

Urol Case Rep 2019 Nov 7;27:100903. Epub 2019 May 7.

Department of Urology, Niigata Prefectural Central Hospital, Shinnancho 205, Jouetsushi, Niigata, 943-0192, Japan.

Duodenal and rectal obstructions due to urological malignancies are relatively uncommon. We report an autopsy case of an 83-year-old man with a history of renal pelvic cancer who presented these obstructions. Autopsy revealed that urothelial cancer infiltrated the bladder wall, duodenal wall, rectal wall, and prostate and widely spread in the retroperitoneal lymphatic vessel. We concluded that renal pelvic cancer recurred in the bladder wall and then infiltrated into each organ because of lymphatic dissemination. The gastrointestinal obstructions due to urinary tract cancer were lethal. Further knowledge and clinical experience regarding these types of obstructions are crucial.
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http://dx.doi.org/10.1016/j.eucr.2019.100903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819769PMC
November 2019

Prognosis and acute complications at the first onset of idiopathic nephrotic syndrome in children: a nationwide survey in Japan (JP-SHINE study).

Nephrol Dial Transplant 2021 02;36(3):475-481

Department of Nephrology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

Background: Information on the epidemiology of idiopathic nephrotic syndrome (INS) in children, complications of INS and the side effects of steroid therapy is scarce.

Methods: The Japanese Pediatric Survey Holding Information of Nephrotic Syndrome, a nationwide cohort study, was conducted by the Japanese Study Group of Renal Disease in Children and enrolled 2099 children with newly diagnosed INS between 1 January 2010 and 31 December 2012. We conducted a follow-up study of the complications during the first onset and the patients' prognosis in this cohort.

Results: We obtained follow-up data on 999 children (672 males) with a median age at onset of 4.5 years [interquartile range (IQR) 2.8-9.4] and a median follow-up period of 4.1 years (IQR 2.5-5.1). At the first onset, 24% of patients experienced severe acute kidney injury (AKI), defined as a serum creatinine increase to a level two or more times the baseline. On logistic regression analysis, age, hematuria, severe hypoalbuminemia (serum albumin <1.0 g/dL) and severe bacterial infection were not independent factors, but female sex {hazard ratio [HR] 1.5 [95% confidence interval (CI) 1.1-1.7]} and hypertension [HR 4.0 (95% CI 2.6-6.0)] were significantly related to AKI. During the observation period, ocular hypertension requiring treatment occurred in 17.4% of patients, among which 0.4% received surgical treatment. Progression to frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome in 3 years was seen in 44.2% of the patients and was shown by the Cox regression analysis to be significantly related to younger age and days until remission at the first episode, but not to sex, hematuria, the minimum serum albumin level or AKI. Two patients died during the observation period. One patient showed progression to end-stage kidney disease.

Conclusion: Based on the results of a multicenter questionnaire survey, the overall survival and renal survival rates were found to be excellent. However, proper management of complications, particularly in AKI and ocular hypertension, is mandatory.
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http://dx.doi.org/10.1093/ndt/gfz185DOI Listing
February 2021

Degenerative inferior olivary nucleus and medullary tegmentum produced the characteristic magnetic resonance imaging signs in Alexander disease: A case report.

J Neurol Sci 2019 Aug 2;403:159-161. Epub 2019 Jul 2.

Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan 1-1 Yazakokarimata, Nagakute, Aichi 4801195, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2019.06.032DOI Listing
August 2019

[Unicuspid Aortic Valve Replacement;Report of a Case].

Kyobu Geka 2019 Jun;72(6):463-465

Department of Cardiovascular Surgery, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Yokohama, Japan.

A 45-year-old female was admitted to our hospital due to severe aortic stenosis. Transthoracic and transesophageal echocardiography indicated the aortic valve was bicuspid, but we confirmed that the aortic valve was unicuspid by intraoperative finding. There was 1 open commissure between the left coronary cusp and the noncoronary cusp position. Aortic valve replacement was performed with a mechanical valve, and the postoperative course was uneventful. We report a very rare case of unicuspid aortic valve replacement.
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June 2019

Trousseau's syndrome manifesting as multiple cerebral infarctions caused by bladder cancer.

Urol Case Rep 2019 May 27;24:100884. Epub 2019 Mar 27.

Department of Urology, Niigata Prefectural Central Hospital, Shinnancho 205, Jouetsushi, Niigata, 943-0192, Japan.

Cerebral infarction in patients with cancer is often called Trousseau's syndrome, which is a cancer-associated hypercoagulative state that causes thrombosis; however, the syndrome is rarely caused by bladder cancer. We report a case of Trousseau's syndrome manifesting as multiple cerebral infarctions caused by advanced bladder cancer in a 46-year-old male patient. The patient died due to the infarctions in the hospital. The prognosis of patients with Trousseau's syndrome caused by advanced cancer is poor. According to changing urological clinical settings, considering the risk of Trousseau's syndrome has become crucial for urologists treating patients with advanced cancer.
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http://dx.doi.org/10.1016/j.eucr.2019.100884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562831PMC
May 2019

Increased prevalence of granulovacuolar degeneration in C9orf72 mutation.

Acta Neuropathol 2019 11 29;138(5):783-793. Epub 2019 May 29.

Raymond Escourolle Neuropathology Department, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, AP-HP, 75651 Cedex 13, Paris, France.

Granulovacuolar degeneration (GVD) is usually found in Alzheimer's disease (AD) cases or in elderly individuals. Its severity correlates positively with the density of neurofibrillary tangles (NFTs). Mechanisms underlying GVD formation are unknown. We assessed the prevalence and distribution of GVD in cases with TDP-43-related frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS-TDP). Consecutively autopsied cases with FTLD/ALS-TDP and C9orf72 mutations (FTLD/ALS-C9; N = 29), cases with FTLD/ALS-TDP without C9orf72 mutations (FTLD/ALS-nonC9; N = 46), and age-matched healthy controls (N = 40) were studied. The prevalence of GVD was significantly higher in the FTLD/ALS-C9 cases (26/29 cases) than in the FTLD/ALS-nonC9 cases (15/46 cases; Fisher exact test; p < 2×10) or in the control group (12/40 individuals; p < 1×10). Average Braak stages and ages of death were not significantly different among the groups. The CA2 sector was most frequently affected in the FTLD/ALS-C9 group, whereas the CA1/subiculum was the most vulnerable area in the other groups. Extension of GVD correlated with the clinical duration of the disease in the FTLD/ALS-C9 cases but not in the FTLD/ALS-nonC9 cases. The GVD-containing neurons frequently had dipeptide repeat (DPR) protein inclusions. GVD granules labeled with antibodies directed against charged multivesicular body protein 2B or casein kinase 1δ were attached to DPR inclusions within GVD. Our results suggest that development of GVD and DPR inclusions is related to common pathogenic mechanisms and that GVD is not only associated with NFTs seen in AD cases or aging individuals.
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http://dx.doi.org/10.1007/s00401-019-02028-6DOI Listing
November 2019

Hereditary Angioedema Type 1 with Recurrent Dizziness.

Intern Med 2019 Jul 28;58(13):1961-1963. Epub 2019 Mar 28.

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

A 41-year-old woman presented with recurrent dizziness. After an attack of dizziness, she felt edematous sensations in her hands. However, according to photographs taken during the attack, the edema on the back of the patient's hands and fingers appeared mild. Laboratory examinations revealed a low C4 and C1 inhibitor (INH) activity. A direct sequencing analysis of C1INH revealed a pathogenic gene mutation. Based on these results, she was diagnosed with hereditary angioedema (HAE) type 1. These findings indicate that HAE can cause recurrent dizziness, and it should therefore be included in the differential diagnosis in patients with recurrent neurologic symptoms, even in the absence of severe edema.
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http://dx.doi.org/10.2169/internalmedicine.2015-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663529PMC
July 2019

Vasculitic neuropathy with anti-phosphatidylserine/prothrombin complex antibody.

Muscle Nerve 2019 06 14;59(6):E44-E46. Epub 2019 Mar 14.

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

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http://dx.doi.org/10.1002/mus.26458DOI Listing
June 2019