Publications by authors named "Koji Watanabe"

132 Publications

Progressive Cytopenia Developing during Treatment of Cryptococcosis in a Patient with HIV Infection and Bone Marrow Cryptococcal Infection.

Intern Med 2021 Jul 30. Epub 2021 Jul 30.

AIDS Clinical Center of the National Center for Global Health and Medicine, Japan.

Cytopenia is a common complication in patients with human immunodeficiency virus (HIV) infection. Identifying the cause is demanding because of the wide range of possible diagnoses. We herein report an HIV-infected patient with disseminated cryptococcosis involving multiple organs including the blood, brain, lungs, and bone marrow, who developed progressive pancytopenia after initiation of anti-fungal treatment with liposomal amphotericin-B (L-AMB) and flucytosine (5FC). The pancytopenia persisted despite early 5FC discontinuation. A bone marrow biopsy revealed cryptococcal infiltration and the blood examination findings recovered quickly after resuming L-AMB. Thus, this HIV-infected patient's pathological findings and clinical course suggested that the primary cause of the pancytopenia was bone marrow cryptococcosis.
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http://dx.doi.org/10.2169/internalmedicine.7282-21DOI Listing
July 2021

High prevalence of circulating dual-class resistant in asymptomatic MSM in Tokyo, Japan.

JAC Antimicrob Resist 2021 Jun 30;3(2):dlab091. Epub 2021 Jun 30.

AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.

Objectives: To assess the prevalence and antibiotic resistance profile of detected from urogenital/rectal swab samples obtained from MSM in Tokyo, Japan.

Methods: We performed PCR-based screening for urogenital/rectal infection in 982 asymptomatic MSM between 1 January 2019 and 5 November 2020. Mutations in the antibiotic resistance-associated genes and and the 23S rRNA of were analysed.

Results: The prevalence of infection was 6.1%: the prevalence of rectal and urogenital infection was 4.7% and 1.4%, respectively. Among the cases, 48 were successfully analysed for 23S rRNA, 41 for mutations and 37 for mutations. Macrolide- and quinolone-resistance associated mutations (23S rRNA and mutations) were observed in 43 (89.6%) and 28 (68.3%) cases, respectively. The quinolone-resistance associated mutation-harbouring variants also harboured macrolide-resistance associated mutations. The S83I mutation in the gene was most commonly identified (24 cases, 58.5%), and its combination with M95I or D99N mutation in the gene was observed in 9 of 36 successfully analysed cases (25.0%). No significant association was observed between the presence of antibiotic resistance and antibiotic exposure for either macrolides or fluoroquinolones (0.785 and 0.402, respectively).

Conclusions: In Tokyo, there is an alarmingly high prevalence of harbouring macrolide and/or quinolone resistance-associated mutations in MSM, irrespective of antibiotic exposure. The high prevalence of strains with both and mutations limits the efficacy of sitafloxacin. Therefore, suitable alternatives are required to treat such infections.
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http://dx.doi.org/10.1093/jacamr/dlab091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242132PMC
June 2021

Decreased continuous sitting time increases heart rate variability in patients with cardiovascular risk factors.

PLoS One 2021 16;16(6):e0253399. Epub 2021 Jun 16.

Nagoya University Graduate School of Medicine, Higashi-ku, Nagoya, Japan.

Aim: The purpose of the present study was to elucidate the relationship between high-frequency heart rate variability (HF HRV) and continuous daytime sitting time in patients with cardiovascular risk factors such as mild hypertension and/or stable angina pectoris.

Background: Decreased HF HRV precedes the progression and worsening of cardiovascular diseases. Continuous sitting behavior is a major risk factor for developing metabolic syndrome and is associated with cardiovascular disease, diabetes mellitus, renal failure, sarcopenia and osteoporosis. Risk factors for cardiovascular disease can be affected by continuous daytime sitting behaviors.

Design: The present study design was a post-hoc comparison.

Methods: Patients treated at two different primary care clinics from 2014 to 2018 were enrolled in this study (n = 53). We assessed HF HRV and continuous sitting time using 24-hour Holter electrocardiography and an activity meter at baseline and 6 months. HF HRV was calculated during sleep.

Results: Sitting time had decreased in 22 patients (decreased group) and increased in 31 patients (increased group) after 6 months. The mean patient ages were 73.1 and 72.0 years in the decreased and increased sitting time groups, respectively (p = 0.503). HF HRV during sleep had increased after 6 months in the decreased sitting time group. Compared with the increased group, the decreased group showed significantly higher HF HRV during sleep after 6 months by two-way repeated-measures ANOVA after adjustment for age, sex and change in activity (p = 0.045).

Conclusion: These results suggest that a decrease in sitting time might induce parasympathetic activity during sleep. Therefore, reducing continuous sitting time during the day might contribute, in part, to improving the prognosis of patients with cardiovascular risk factors not only by avoiding muscle loss but also by providing positive influences on parasympathetic tone during sleep.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253399PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208552PMC
June 2021

Discovery of a novel series of GPR119 agonists: Design, synthesis, and biological evaluation of N-(Piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives.

Bioorg Med Chem 2021 Jul 9;41:116208. Epub 2021 May 9.

Cardiovascular & Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

We undertook an optimization effort involving propan-2-yl 4-({6-[5-(methanesulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate 1, which we had previously discovered as a novel G protein-coupled receptor 119 (GPR119) agonist. To occupy a presumed hydrophobic space between the pyrimidine and piperidine rings in interaction with GPR119, we replaced the linker oxygen with nitrogen. Subsequently, the introduction of a substituent at the bridging nitrogen atom was explored. We found that the installation of N-trifluoromethyl group 10 not only enhanced GPR119 agonist activity but also considerably improved the human ether-à-go-go-related gene (hERG) inhibition profile. These improvements were not observed for non-fluorinated substituents, such as ethyl analog 8b. The next optimization effort focused on the exploration of a new surrogate structure for the indoline ring and the isosteric replacements of the piperidine N-Boc group to improve solubility, metabolic stability, and oral bioavailability. As a result, N-{1-[3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}-6-{[1-(methanesulfonyl)piperidin-4-yl]oxy}-N-(trifluoromethyl)pyrimidin-4-amine (27) was identified as a potent and orally bioavailable GPR119 agonist. This compound augmented insulin secretion and effectively lowered plasma glucose excursion in a diabetic animal model after oral administration. In this study, we discuss the designs, syntheses, and biological activities of a novel series of N-(piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives as GPR119 agonists, and to determine the distinctive effect of the N-trifluoromethyl group on hERG inhibition, we also discuss the conformational preference of representative compounds.
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http://dx.doi.org/10.1016/j.bmc.2021.116208DOI Listing
July 2021

Efficacy of 1g ceftriaxone monotherapy compared to dual therapy with azithromycin or doxycycline for treating extragenital gonorrhea among men who have sex with men.

Clin Infect Dis 2021 May 17. Epub 2021 May 17.

AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.

Background: Evidence on efficacy of high-dose ceftriaxone monotherapy for extragenital Neisseria gonorrhoeae (NG) infection is lacking.

Methods: A cohort of men who have sex with men (MSM) were tested for NG/Chlamydia trachomatis (CT) every three months, in a single-center observational study in Tokyo, Japan. MSM aged > 19 years diagnosed with extragenital NG infection between 2017 and 2020 were included. A single dose of 1 g ceftriaxone monotherapy was provided, while dual therapy with a single oral dose of 1 g azithromycin or 100 mg doxycycline administered orally twice daily for seven days were given, for those co-infected with CT, according to infected sites. Efficacy of these treatments was calculated by the number of NG-negative subjects at test-of-cure divided by the number of subjects treated. Fisher's exact tests were used to compare the efficacy between the two groups.

Results: Of 320 cases diagnosed with extragenital NG, 208 were treated with monotherapy and 112 were treated with dual therapy. The efficacy against total, pharyngeal, and rectal infections was 98.1% (204/208, 95% Confidence Interval (CI): 95.2-99.3%), 97.8% (135/138, 95% CI: 93.8-99.4%), and 98.6% (69/70, 95% CI: 92.3-99.9%), respectively, in the monotherapy group, while the corresponding efficacy in the dual therapy was 95.5% (107/112, 95% CI: 90.0-98.1%), 96.1% (49/51, 95% CI: 86.8-99.3%) and 95.1% (58/61, 95% CI: 86.5-98.7%), respectively. No significant difference in the corresponding efficacy was observed between the two groups (p=0.29, p=0.61, p=0.34, respectively).

Conclusions: High-dose ceftriaxone monotherapy is as effective as dual therapy for extragenital NG among MSM.
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http://dx.doi.org/10.1093/cid/ciab455DOI Listing
May 2021

Successful treatment by doravirine with cobicistat-boosted darunavir for end-stage renal failure under chronic haemodialysis.

J Antimicrob Chemother 2021 04;76(5):1370-1372

Department of Pharmacy, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.

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http://dx.doi.org/10.1093/jac/dkab001DOI Listing
April 2021

Performance of an enzyme-linked immunosorbent-based serological assay for Entamoeba histolytica: Comparison with an indirect immunofluorescence assay using stored frozen samples.

J Infect Chemother 2021 May 19;27(5):736-739. Epub 2021 Jan 19.

AIDS Clinical Center, National Center of Global Health and Medicine, Tokyo, Japan; Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.

Introduction: Entamoeba histolytica infections are increasingly diagnosed as sexually transmitted infections in Japan. However, the stool ova-parasite examination (O&P) test has been the only approved diagnostic method used in Japan since production of the indirect immunofluorescence assay (IFA) serum antibody test was discontinued at the end of 2017. Herein, we assessed whether an enzyme-linked immunosorbent assay (ELISA)-based serological test could substitute for IFA.

Methods: This cross-sectional study used stored frozen serum samples from the Biobank of the National Center for Global Health and Medicine. A serological ELISA-based test was performed on these samples and their titers were compared with those previously measured by IFA based on the medical record data.

Results: Sixty seven stored frozen serum samples with differing recorded IFA antibody titers (16 samples with titers < ×100, 13 samples × 100, 16 samples × 200, 11 samples × 400, and 11 samples ≥ × 800) were analyzed. The sensitivity and specificity values for ELISA vs. IFA were 92.2% [95% confidential interval: 81.5-96.9] and 87.5% [64.0-97.8], respectively. A strong correlation between the antibody titers was confirmed by a one-way ANOVA (R square 0.83, p value < 0.0001) for the two diagnostic methods.

Conclusion: The ELISA and IFA antibody titers for E. histolytica were well correlated, and results from these methods were highly concordant. Introduction of an ELISA-based serological test for E. histolytica should be considered to improve E. histolytica infection diagnosis in Japan.
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http://dx.doi.org/10.1016/j.jiac.2020.12.026DOI Listing
May 2021

Near-chromosome level genome assembly reveals ploidy diversity and plasticity in the intestinal protozoan parasite Entamoeba histolytica.

BMC Genomics 2020 Nov 23;21(1):813. Epub 2020 Nov 23.

Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, Japan.

Background: Amoebozoa is a eukaryotic supergroup composed of unicellular and multicellular amoebic protozoa (e.g. Acanthamoeba, Dictyostelium, and Entamoeba). They are model organisms for studies in cellular and evolutionary biology and are of medical and veterinary importance. Despite their importance, Amoebozoan genome organization and genetic diversity remain poorly studied due to a lack of high-quality reference genomes. The slime mold Dictyostelium discoideum is the only Amoebozoan species whose genome is available at the chromosome-level.

Results: Here, we provide a near-chromosome-level assembly of the Entamoeba histolytica genome, the second semi-completed Amoebozoan genome. The availability of this improved genome allowed us to discover inter-strain heterogeneity in ploidy at the near-chromosome or sub-chromosome level among 11 clinical isolates and the reference strain. Furthermore, we observed ploidy-independent regulation of gene expression, contrary to what is observed in other organisms, where RNA levels are affected by ploidy.

Conclusions: Our findings offer new insights into Entamoeba chromosome organization, ploidy, transcriptional regulation, and inter-strain variation, which will help to further decipher observed spectrums of virulence, disease symptoms, and drug sensitivity of E. histolytica isolates.
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http://dx.doi.org/10.1186/s12864-020-07167-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681961PMC
November 2020

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

Effectiveness of doxycycline 100 mg twice daily for 7 days and azithromycin 1 g single dose for the treatment of rectal Chlamydia trachomatis infection among men who have sex with men.

J Antimicrob Chemother 2021 01;76(2):495-498

AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.

Objectives: To compare the effectiveness of doxycycline 100 mg twice daily for 7 days and azithromycin 1 g single dose for the treatment of rectal Chlamydia trachomatis infection among MSM in a real clinical setting.

Methods: A prospective study was performed to compare the effectiveness of doxycycline and azithromycin for the treatment of rectal C. trachomatis among MSM in Tokyo, Japan. Subjects diagnosed with rectal C. trachomatis infection were treated and test-of-cure examination (TOC) was performed at least 3 weeks after the treatment. Treatment of rectal C. trachomatis infection was decided prospectively in a time-dependent manner; in the period between January 2017 and October 2018, azithromycin was administered to all subjects, whereas from October 2018 through March 2020, doxycycline was administered to all subjects. Effectiveness of these treatments was calculated by the number of rectal C. trachomatis-negative subjects at TOC divided by the number of subjects treated.

Results: Two hundred and ninety-six MSM with rectal C. trachomatis infection were treated with azithromycin (80 patients) and doxycycline (216 patients) in a time-dependent manner. Of the 296 MSM, 274 (92.6%) were treated successfully [67 (83.7%, 95% CI = 79.6%-87.9%) in the azithromycin group versus 207 (95.8%, 95% CI = 94.5%-97.2%) in the doxycycline group, P < 0.001]. To evaluate factors associated with treatment failure, we performed logistic regression analysis. In univariate and multivariate analysis, only doxycycline treatment was inversely associated with treatment failure (OR = 0.29, 95% CI = 0.084-0.976, P = 0.046).

Conclusions: The treatment with doxycycline 100 mg twice daily for 7 days was superior to that with azithromycin 1 g single dose for rectal C. trachomatis among MSM in a real-world setting.
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http://dx.doi.org/10.1093/jac/dkaa437DOI Listing
January 2021

Adrenomedullin for steroid-resistant ulcerative colitis: a randomized, double-blind, placebo-controlled phase-2a clinical trial.

J Gastroenterol 2021 Feb 2;56(2):147-157. Epub 2020 Nov 2.

Division of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Miyazaki, Miyazaki, 889-1692, Japan.

Background: Adrenomedullin (AM) is a bioactive peptide having many pleiotropic effects, including mucosal healing and immunomodulation. AM has shown beneficial effects in rodent models and in preliminary study for patients with ulcerative colitis (UC). We performed a clinical trial to investigate the efficacy and safety of AM in patients with UC.

Methods: This was a multi-center, double-blind, placebo-controlled phase-2a trial evaluating 28 patients in Japan with steroid-resistant UC. Patients were randomly assigned to four groups and given an infusion of 5, 10, 15 ng/kg/min of AM or placebo for 8 h per day for 14 days. The primary endpoint was the change in Mayo scores at 2 weeks. Main secondary endpoints included the change in Mayo scores and the rate of clinical remission at 8 weeks, defined as a Mayo score 0.

Results: No differences in the primary or secondary endpoints were observed among the four groups at 2 weeks. Despite the insufficient tracking rate, the Mayo score at 8 weeks was only significantly decreased in the high-dose AM group (15 ng/kg/min) compared with the placebo group (- 9.3 ± 1.2 vs. - 3.0 ± 2.8, P = 0.035), with its rate of clinical remission at 8 weeks being significantly higher (3/3, 100% vs. 0/2, 0%, P = 0.025). We noted mild but no serious adverse events caused by the vasodilatory effect of AM.

Conclusions: In this double-blind randomized trial, we observed the complete remission at 8 weeks in patients with steroid-resistant UC receiving a high dose of AM.

Clinical Trial Registry: JAPIC clinical trials information; Japic CTI-205255 (200410115290). https://www.clinicaltrials.jp/cti-user/trial/Search.jsp .
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http://dx.doi.org/10.1007/s00535-020-01741-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862507PMC
February 2021

Modified self-obtained pooled sampling to screen for and infections in men who have sex with men.

Sex Transm Infect 2021 Aug 20;97(5):324-328. Epub 2020 Oct 20.

AIDS Clinical Center, National Center for Global Health and Medicine, Shinjuku-ku, Japan

Objectives: To assess whether pooled sample testing with nucleic acid amplification tests was a potential alternative to three single-site sample testing to screen for and infections in asymptomatic men who have sex with men.

Methods: We prospectively compared pooled sample testing with single-site sample testing in asymptomatic MSM. Self-obtained paired rectal samples, one gargle sample and one first-void urine sample were collected from participants to generate two sets of samples: one for pooled sample testing and the other for single-site testing. We used modified pooled sampling, which is defined as the use of gargle samples, instead of swabs, for the pooled sample to test for pharyngeal infection.

Results: This study included 513 MSM. The positive rates of and were 20.3% and 11.7%, respectively, for single-site sample testing. Compared with the sensitivity of single-site testing as the gold standard, the sensitivities of pooled sample testing for and were 94.2% (95% CI 88.0% to 97.3%) and 98.3% (95% CI 90.9% to 99.9%), respectively. The concordance rate and kappa coefficient were 98.3% (95% CI 96.7% to 99.2%) and 0.945 (95% CI 0.859 to 1.000), respectively, for and 98.8% (95% CI 90.1% to 100%) and 0.943 (95% CI 0.857 to 1.000), respectively, for .

Conclusions: The modified pooled sampling had a comparably high consistency with single-site sample testing. The results strongly suggest that the gargle sample is suitable as a part of pooled sample for STI screening of and .
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http://dx.doi.org/10.1136/sextrans-2020-054666DOI Listing
August 2021

Design and Identification of a GPR40 Full Agonist () Possessing a 2-Carbamoylphenyl Piperidine Moiety.

J Med Chem 2020 09 9;63(18):10352-10379. Epub 2020 Sep 9.

Research Division, SCOHIA PHARMA Inc., Shonan Health Innovation Park, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.

GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic β-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative , we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)phenyl piperidine , which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with -alkyl--aryl benzamides to lower the lipophilicity and restrict the -alkyl moieties to the presumed lipophilic pocket using the intramolecular π-π stacking of cis-preferential -alkyl--aryl benzamide. Among these, orally available (3)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid () effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00843DOI Listing
September 2020

Utility of the Rapid Antigen Detection Test E. histolytica Quik Chek for the Diagnosis of Entamoeba histolytica Infection in Nonendemic Situations.

J Clin Microbiol 2020 10 21;58(11). Epub 2020 Oct 21.

Department of Parasitology, National Institutes of Infectious Diseases, Tokyo, Japan.

infection is an increasingly common sexually transmitted infection in Japan. Currently, stool ova and parasite examination (O&P) is the only approved diagnostic method. Here, we assessed the utility of the commercially available rapid antigen detection test (Quik Chek) for A multicenter cross-sectional study was conducted. Stool samples that had been submitted for O&P were included. The samples were subjected to both Quik Chek and PCR, and the Quik Chek results were assessed in comparison with PCR as the reference standard. infection was confirmed in 5.8% (38/657) of the samples and comprised 20 diarrheal and 18 nondiarrheal cases. The overall sensitivity and specificity of Quik Chek were 44.7% (95% confidence interval, 30.1 to 60.3) and 99.8% (99.1 to 100), respectively. The sensitivity of Quik Chek was higher for diarrheal cases (60.0%) than for nondiarrheal cases (27.8%). Furthermore, the combined use of Quik Chek with O&P increased the sensitivity (78.9%), especially for diarrheal cases (up to 90%). The burden assessed by quantitative PCR was similar between Quik Chek-positive and -negative samples. The Quik Chek assay sensitivity was lower for cyst-containing stools than for trophozoite-containing stools, although it was shown that cultured clinical strains from Quik Chek-negative cyst-containing stools exhibited antigenicity The present study confirmed the high specificity of Quik Chek for infection. Combined use with O&P increased the sensitivity of detection, facilitating the use of Quik Chek in point-of-care settings in nonendemic situations.
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http://dx.doi.org/10.1128/JCM.01991-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587111PMC
October 2020

A New Classification for Ankle Arthrodesis When Using an External Fixator.

Strategies Trauma Limb Reconstr 2019 Sep-Dec;14(3):148-154

Department of Orthopaedic Surgery, Kanazawa University, Takaramachi, Kanazawa, Japan.

Background: We have classified ankle arthrodesis when using an external fixator into four types based on the deformity and defect. Each of the four types of technique have been evaluated retrospectively.

Materials And Methods: Thirty-three lower limb segments in 30 patients (average age 49 years) were treated by ankle arthrodesis using an external fixator in our institution. We classified the pre-treatment problems into four types and adjusted the surgical treatment accordingly: type I-no bone defect, no or mild deformity; type II-no bone defect, severe deformity; type III-bone defect with the possibility to shorten acutely after resection of the pathological focus; and type IV-bone defect but without the ability to shorten acutely after resection of the pathological focus. Type I problems were treated with curettage of ankle cartilage and bone graft with external fixation. Type II problems were treated with mobilisation using an external fixation after performing a type I ankle arthrodesis. Type III problems were treated with ankle arthrodesis using acute shortening and distraction. Type IV problems were treated with ankle arthrodesis using bone transport.

Results: All patients had secure ankle fusion and were able to bear total weight in walking on completion of treatment. The mean external fixation period was 96 days in type I, 181 days in type II, 231 days with lengthening in type III and IV. The complications included re-fracture in three cases, deformity at the lengthening site in one, delayed union in one, and infection at fusion site in one.

Conclusion: We have strategized ankle arthrodesis procedures using an external fixator into four groups in order to align the surgical technique with the pre-treatment problem. Our classification can help decide the appropriate operative method when using an external fixator, especially for difficult cases.

How To Cite This Article: Matsubara H, Watanabe K, Takata M, A New Classification for Ankle Arthrodesis When Using an External Fixator. Strategies Trauma Limb Reconstr 2019;14(3):148-154.
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http://dx.doi.org/10.5005/jp-journals-10080-1436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368357PMC
August 2020

Clinical features and gut microbiome of asymptomatic Entamoeba histolytica infection.

Clin Infect Dis 2020 Jun 21. Epub 2020 Jun 21.

AIDS Clinical Center, National Center of Global Health and Medicine, Tokyo, Japan.

Background: Entamoeba histolytica infection is a sexually transmitted disease in some developed countries. Asymptomatic infection often occurs and can be a source of transmission; however, limited data are available regarding the pathogenesis of E. histolytica.

Methods: This is a single center cross-sectional study. Specimens were prospectively collected from patients with clinically suspected cases. "E. histolytica infection" was defined as a case in which the identification of E. histolytica was confirmed by PCR of a clinical specimen. Data from asymptomatic cases were compared with those from symptomatic invasive cases.

Results: Sixty-four E. histolytica-infected cases, including 13 asymptomatic cases, were identified during the study period. Microbiological diagnosis was made by endoscopic sampling in 26.6% of these cases (17/64). Endoscopy identified macroscopically visible lesions in all cases; however, the sensitivity of histopathology on biopsy samples was low (45.5%) compared with PCR (94.7%). In asymptomatic cases, infection sites were limited around the proximal colon; moreover, trophozoites were frequently identified at infection sites whereas cystic forms were commonly detected in stools. Gut microbiome analyses showed more uniform composition in asymptomatic cases than in symptomatic invasive cases, which were represented by a relatively high abundance of Ruminococcaceae, Coriobacteriaceae, and Clostridiaceae, and a low abundance of Streptococcaceae.

Conclusion: These results indicate that the encystation and attenuation of E. histolytica are highly affected by the intestinal contents, including the gut microbiome.
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http://dx.doi.org/10.1093/cid/ciaa820DOI Listing
June 2020

Gut microbiome communication with bone marrow regulates susceptibility to amebiasis.

J Clin Invest 2020 08;130(8):4019-4024

Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

The microbiome provides resistance to infection. However, the underlying mechanisms are poorly understood. We demonstrate that colonization with the intestinal bacterium Clostridium scindens protects from Entamoeba histolytica colitis via innate immunity. Introduction of C. scindens into the gut microbiota epigenetically altered and expanded bone marrow granulocyte-monocyte progenitors (GMPs) and resulted in increased intestinal neutrophils with subsequent challenge with E. histolytica. Introduction of C. scindens alone was sufficient to expand GMPs in gnotobiotic mice. Adoptive transfer of bone marrow from C. scindens-colonized mice into naive mice protected against amebic colitis and increased intestinal neutrophils. Children without E. histolytica diarrhea also had a higher abundance of Lachnoclostridia. Lachnoclostridia C. scindens can metabolize the bile salt cholate, so we measured deoxycholate and discovered that it was increased in the sera of C. scindens-colonized specific pathogen-free and gnotobiotic mice, as well as in children protected from amebiasis. Administration of deoxycholate alone increased GMPs and provided protection from amebiasis. We elucidated a mechanism by which C. scindens and the microbially metabolized bile salt deoxycholic acid alter hematopoietic precursors and provide innate protection from later infection with E. histolytica.
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http://dx.doi.org/10.1172/JCI133605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410058PMC
August 2020

Two cases of endoscopically diagnosed amebic colitis treated with paromomycin monotherapy.

PLoS Negl Trop Dis 2020 03 19;14(3):e0008013. Epub 2020 Mar 19.

AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1371/journal.pntd.0008013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081979PMC
March 2020

Seroprevalence of at a voluntary counselling and testing centre in Tokyo: a cross-sectional study.

BMJ Open 2020 02 25;10(2):e031605. Epub 2020 Feb 25.

AIDS Clinical Center, National Center for Global Health and Medicine Hospital, Shinjuku-ku, Japan

Background: Amebiasis, which is caused by , is a re-emerging public health issue owing to sexually transmitted infection (STI) in Japan. However, epidemiological data are quite limited.

Methods: To reveal the relative prevalence of sexually transmitted infection to other STIs, we conducted a cross-sectional study at a voluntary counselling and testing (VCT) centre in Tokyo. Seroprevalence of was assessed according to positivity with an ELISA for -specific IgG in serum samples collected from anonymous VCT clients.

Results: Among 2083 samples, seropositive rate for was 2.64%, which was higher than that for HIV-1 (0.34%, p<0.001) and comparable to that for syphilis (rapid plasma reagin (RPR) 2.11%, p=0.31). Positivity for in urine by transcription-mediated amplification (TMA) was 4.59%. Seropositivity for was high among RPR/ hemagglutination (TPHA)-positive individuals and it was not different between clients with and without other STIs. Both seropositivity of and RPR were high among male clients. The seropositive rate for anti- antibody was positively correlated with age. TMA positivity for urine was high among female clients and negatively correlated with age. Regression analysis identified that male sex, older age and TPHA-positive results are independent risk factors of seropositivity.

Conclusions: Seroprevalence of was 7.9 times higher than that of HIV-1 at a VCT centre in Tokyo, with a tendency to be higher among people at risk for syphilis infection. There is a need for education and specific interventions against this parasite, as a potentially re-emerging pathogen.
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http://dx.doi.org/10.1136/bmjopen-2019-031605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044870PMC
February 2020

CD74 Signaling Links Inflammation to Intestinal Epithelial Cell Regeneration and Promotes Mucosal Healing.

Cell Mol Gastroenterol Hepatol 2020 28;10(1):101-112. Epub 2020 Jan 28.

Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia. Electronic address:

Background & Aims: The inflammatory response to intestinal damage promotes healing through mechanisms that are incompletely understood. Gene expression of cluster of differentiation 74 (CD74), the receptor for cytokine macrophage migration inhibitory factor, is increased in patients with inflammatory bowel disease (IBD), however, the role of CD74 signaling in intestinal inflammation remains poorly understood. The aim of this study was to determine the functional role of CD74 signaling in intestinal inflammation.

Methods: We studied the characteristics of CD74 protein expression in human IBD and experimental colitis. The functional role of CD74 signaling in the intestine was investigated using cellular models; wild-type, CD74, and bone marrow chimera mice; neutralizing anti-CD74 antibodies; flow cytometry; immunohistochemistry; immunofluorescence; immunoblotting; and clustered regularly interspaced short palindromic repeats and associated protein 9 technology.

Results: In IBD patients and experimental colitis, CD74-receptor protein expression was increased in inflamed intestinal tissue, prominently in the crypt epithelial cells. By using distinct but complementary chemical and non-chemically induced mouse models of colitis with genetic and antibody neutralization approaches, we found that CD74 signaling was necessary for gut repair. Mechanistically, we found that the macrophage migration inhibitory factor cytokine, which also is increased in colitis, stimulated the CD74 receptor, enhancing intestinal epithelial cell proliferation through activation of the protein kinase B and the extracellular signal-regulated kinase pathways. Our data also suggest that CD74 signaling in immune cells was not essential for mucosal healing.

Conclusions: CD74 signaling is strongly activated during intestinal inflammation and protects the host by promoting epithelial cell regeneration, healing, and maintaining mucosal barrier integrity. Enhancing the CD74 pathway may represent a unique therapeutic strategy for promoting healing in IBD.
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http://dx.doi.org/10.1016/j.jcmgh.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215244PMC
May 2021

A historical case of primary triglyceride deposit cardiomyovasculopathy.

Pathol Int 2020 Jan 18;70(1):58-61. Epub 2019 Dec 18.

Laboratory of Cardiovascular Disease, Novel, Non-invasive, and Nutritional Therapeutics (CNT) and Triglyceride Research Center (TGRC), Graduate School of Medicine, Osaka University, Osaka, Japan.

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http://dx.doi.org/10.1111/pin.12884DOI Listing
January 2020

High prevalence and incidence of rectal Chlamydia infection among men who have sex with men in Japan.

PLoS One 2019 10;14(12):e0220072. Epub 2019 Dec 10.

AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.

Background: Rectal Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections have been neglected and epidemiological data are unavailable in Japan. Thus, we evaluated the prevalence and incidence of rectal CT/NG in a cohort of HIV-negative men who have sex with men (MSM), which was established at the National Center for Global Health and Medicine (NCGM), in Tokyo, Japan, in January 2017.

Methods: HIV-negative MSM aged ≥16 years old were included. The prevalence of rectal CT/NG among HIV-negative MSM was compared with that among an existing HIV-positive MSM cohort at NCGM. The HIV-negative MSM cohort was examined for rectal and pharyngeal CT/NG every 3 months. Urethral CT/NG was evaluated at the physician's discretion. The incidences of CT/NG were evaluated in December 2018.

Results: Of 502 MSM initially included in this study, 13 men were diagnosed with HIV infection at enrollment and were subsequently excluded from the analysis. We evaluated 561 HIV-positive MSM for rectal CT/NG. The mean ages of the two cohorts were 33.6 and 46.2 years old, respectively (p<0.001). The prevalences of rectal CT were 16.4% and 15.9% (p = 0.707) and the prevalences of rectal NG were 4.1% and 2.3% (p = 0.101), for the HIV-negative and HIV-positive MSM cohorts, respectively. Of 489 HIV-negative MSM, 328 were followed at least twice, with 261.1 person-years during the study period. The incidences of rectal CT/NG were 17.2 and 3.8/100 person-years and the incidences of pharyngeal CT/NG were 2.0 and 11.0/100 person-years for the two cohorts, respectively. Approximately 37.9% of incident cases were attributed to recurrent infection.

Conclusions: The prevalence and incidence of rectal CT/NG were high among MSM in Tokyo, Japan, suggesting that urgent countermeasures for early diagnosis and treatment are necessary.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220072PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903740PMC
March 2020

Purification of Antibodies Against Entamoeba histolytica MIF and Their Use in Analyzing Human and Mouse Samples.

Methods Mol Biol 2020 ;2080:237-247

Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.

Macrophage migration inhibitory factor (MIF) is a proinflammatory and proproliferative cytokine expressed in humans. MIF homologs also exist in many pathogenic protozoans, including Entamoeba, Plasmodium, Toxoplasma, and Leishmania. Production of antibodies against parasite proteins allows for the generation of assays to measure and visualize parasite infection within hosts. In this chapter, we describe how to specifically purify antibodies against Entamoeba histolytica MIF (EhMIF), and subsequently use anti-EhMIF antibodies for ELISA on mouse and human samples and for immunohistochemistry on human tissue. These methods can be applied to any protein for high-quality antibody purification.
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http://dx.doi.org/10.1007/978-1-4939-9936-1_21DOI Listing
December 2020

Significance of amebiasis: 10 reasons why neglecting amebiasis might come back to bite us in the gut.

PLoS Negl Trop Dis 2019 11 14;13(11):e0007744. Epub 2019 Nov 14.

Department of Medicine, University of Virginia School of Medicine Charlottesville, Virginia, United States of America.

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http://dx.doi.org/10.1371/journal.pntd.0007744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855409PMC
November 2019

Case Report: Acute Amebic Colitis Triggered by Colonoscopy: Exacerbation of Asymptomatic Chronic Infection with Accompanied by Dysbiosis.

Am J Trop Med Hyg 2019 12;101(6):1384-1387

AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.

Recent data show that the gut microbiome plays a role in determining the clinical outcome of infection. We report the case of a patient who developed recurrent acute amebic colitis (second episode of acute colitis) after colonoscopy. Genotyping of revealed that she developed a second episode of acute amebic colitis with the same genotype as that of the first episode, indicating chronic infection had persisted asymptomatically for > 10 months between the first and second episodes. Analysis of the gut microbiome, in addition to the clinical findings, suggested that dysbiosis at colonoscopy induced the change in the clinical form of infection from asymptomatic chronic infection to symptomatic colitis.
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http://dx.doi.org/10.4269/ajtmh.19-0396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896890PMC
December 2019

Case report of two pregnancies and deliveries by a woman with Buerger disease.

J Obstet Gynaecol Res 2019 Oct 31;45(10):2100-2104. Epub 2019 Jul 31.

Department of Anesthesiology and Pain Medicine, Juntendo University Urayasu Hospital, Urayasu-shi, Chiba, Japan.

Buerger disease is a chronic inflammatory disease that involves blood clot formation in the medium and small arteries, resulting in thrombophlebitis. It is usually observed in middle-aged men who smoke and is very rare in young women. Previous reports have indicated that Buerger disease worsens during pregnancy due to hypercoagulability associated with pregnancy, and newborns' birth weights were often lower than normal. This report describes a young woman with Buerger disease who experienced two pregnancies and deliveries. During the 1st pregnancy, d-dimer and soluble fibrin levels slightly increased, but no treatment was needed. However, during the 2nd pregnancy, d-dimer and soluble fibrin levels abruptly increased at 20 weeks of pregnancy, and heparin was administered subcutaneously. Four days after heparin administration, d-dimer and soluble fibrin levels decreased to normal pregnancy levels. d-dimer and soluble fibrin measurements were useful for evaluating the coagulation tendencies of this pregnant woman with Buerger disease.
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http://dx.doi.org/10.1111/jog.14087DOI Listing
October 2019

Increased Activity in Patients with Cardiovascular Risk Factors Increases Heart Rate Variability.

West J Nurs Res 2020 06 22;42(6):431-436. Epub 2019 Jul 22.

Department of Nursing, Sugiyama Jogakuen University, Nagoya, Aichi, Japan.

This study evaluated the effect of increased physical activity on high-frequency (HF) heart rate variability (HRV) during the first hour after sleep onset in patients with hypertension and/or stable angina pectoris. Physical activity and HF were measured using activity monitors and 24-hour Holter monitors at baseline and 6 months later. The physical activity increased in 28 patients (increase group) and decreased in 20 patients (decrease group) after 6 months. In this study, after 6 months, compared to the decreased physical activity group, the increased physical activity group showed a significant increase in the HF index during the first hour after sleep onset. Therefore, the increase in the HF index may have been due to the increase in physical activity. An increase in physical activity suggests that the quality of sleep early in the sleep cycle may be improved, which may affect the patient's prognosis.
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http://dx.doi.org/10.1177/0193945919864700DOI Listing
June 2020

Bif-1/Endophilin B1/SH3GLB1 regulates bone homeostasis.

J Cell Biochem 2019 11 26;120(11):18793-18804. Epub 2019 Jun 26.

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

Skeletal tissue homeostasis is maintained via the balance of osteoclastic bone resorption and osteoblastic bone formation. Autophagy and apoptosis are essential for the maintenance of homeostasis and normal development in cells and tissues. We found that Bax-interacting factor 1 (Bif-1/Endophillin B1/SH3GLB1), involving in autophagy and apoptosis, was upregulated during osteoclastogenesis. Furthermore, mature osteoclasts expressed Bif-1 in the cytosol, particularly the perinuclear regions and podosome, suggesting that Bif-1 regulates osteoclastic bone resorption. Bif-1-deficient (Bif-1 ) mice showed increased trabecular bone volume and trabecular number. Histological analyses indicated that the osteoclast numbers increased in Bif-1 mice. Consistent with the in vivo results, osteoclastogenesis induced by receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) was accelerated in Bif-1 mice without affecting RANKL-induced activation of RANK downstream signals, such as NF-κB and mitogen-activated protein kinases (MAPKs), CD115/RANK expression in osteoclast precursors, osteoclastic bone-resorbing activity and the survival rate. Unexpectedly, both the bone formation rate and osteoblast surface substantially increased in Bif-1 mice. Treatment with β-glycerophosphate (β-GP) and ascorbic acid (A.A) enhanced osteoblastic differentiation and mineralization in Bif-1 mice. Finally, bone marrow cells from Bif-1 mice showed a significantly higher colony-forming efficacy by the treatment with or without β-GP and A.A than cells from wild-type (WT) mice, suggesting that cells from Bif-1 mice had higher clonogenicity and self-renewal activity than those from WT mice. In summary, Bif-1 might regulate bone homeostasis by controlling the differentiation and function of both osteoclasts and osteoblasts (235 words).
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http://dx.doi.org/10.1002/jcb.29193DOI Listing
November 2019

Case report: new development of fibrosing interstitial lung disease triggered by HIV-related pneumocystis pneumonia.

BMC Pulm Med 2019 Mar 18;19(1):65. Epub 2019 Mar 18.

AIDS Clinical Center, National Center of Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.

Background: Fibrosing interstitial lung disease is the poor prognostic non-infectious lung disease by unknown etiology. Here, we present one case developing interstitial pneumonia with fibrosis after treatment of pneumocystis pneumonia (PCP) in newly diagnosed HIV-1 infected case.

Case Presentation: A previously healthy 63-year old male was referred to our institute because of protracted dyspnea on effort in 2 weeks after pneumocystis pneumonia treatment. At referral, arterial blood oxygen pressure was within normal range (93.5 mmHg) at rest, but decreased rapidly 30 s after a slow walk (44.5 mmHg). Respiratory function tests showed severe restrictive ventilator impairment (vital capacity = 36.5%; forced expiratory volume in 1 s = 107.4%). Chest computed tomography showed severe fibrotic changes at bilateral basal parts and diffuse fibrotic changes in which PCP lesions were seen initially in previous images although β-D glucan was not elevated and P. jirovecii was not detected in saliva at referral. Other etiologies of fibrotic IP including infectious and/or autoimmune diseases were excluded by serology. Fibrotic lesion did not expand thereafter although it had not responded to the high-dose corticosteroid therapy.

Conclusion: We report the first case of fibrosing interstitial lung disease triggered by HIV-related PCP.
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http://dx.doi.org/10.1186/s12890-019-0831-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423812PMC
March 2019
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