Publications by authors named "Shota Nakamura"

257 Publications

Characterization of salivary microbiota in elderly patients with type 2 diabetes mellitus: a matched case-control study.

Clin Oral Investig 2021 Jun 18. Epub 2021 Jun 18.

Department of Dentistry and Oral Surgery, Osaka Medical College, 2-7 Daigaku-machi. Takatsuki City, Osaka, 569-8686, Japan.

Objective: The importance of oral health in type 2 diabetes mellitus (T2DM) is widely recognized; however, oral microbiota characteristics associated with T2DM in the elderly population are not well-understood. This study was conducted to evaluate the characteristics of the salivary microbiota in elderly Japanese patients with T2DM.

Methods: Saliva samples were collected from 42 elderly Japanese patients with T2DM and 42 age- and sex-matched subjects without T2DM (control). 16S ribosomal RNA metagenomic analysis and comparative analysis of both groups were performed. Random forest classification by machine learning was performed to discriminate between the salivary microbiota in the two groups.

Results: There were significant differences in the overall salivary microbiota structure between the T2DM and control groups (beta diversity; unweighted UniFrac distances, p = 0.001; weighted UniFrac distances, p = 0.001). The phylum Firmicutes was abundant in patients with T2DM, whereas the phylum Bacteroidetes was abundant in controls. The T2DM prediction model by random forest based on salivary microbiota data was verified with a high predictive potential in five cross-validation tests (area under the curve (AUC) = 0.938 (95% CI, 0.824-1.000)).

Conclusion: Characterization revealed that the salivary microbiota profile of the elderly patients with T2DM is significantly distinct from that of the controls.

Clinical Relevance: These data indicate the necessity of oral health management based on the characteristics of the salivary microbiota in elderly patients with T2DM. Our findings will contribute to future research on the development of new diagnostic and therapeutic methods for this purpose.
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http://dx.doi.org/10.1007/s00784-021-04027-yDOI Listing
June 2021

Rapid and simultaneous identification of three mutations by the Novaplex™ SARS-CoV-2 variants I assay kit.

J Clin Virol 2021 May 29;141:104877. Epub 2021 May 29.

Department of Infectious, Respiratory and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus. 207 Uehara, Nishihara, Okinawa 903-0215, Japan.

Background: . The emergence of SARS-CoV-2 variants has caused an unexpected rebound globally. The World Health Organization has listed three variants (B.1.1.7, B.1.351, and P.1) as variants of concern. To understand the epidemiology and thereby plan appropriate safety measures, differential identification of the variants is indeed critical.

Objectives: . Although whole-genome sequencing is the gold standard for variant identification, it is time-consuming and relatively expensive. Therefore, a rapid, easy, and cost-effective platform targeting multiple regions of the genome is required. Here, we assessed the usefulness of the Novaplex™ SARS-CoV-2 Variants I Assay kit in identifying mutations in the variants.

Study Design: . We retrospectively examined 30 stored nasal swabs from COVID-19-positive patients tested between November 2020 and March 2021. RNA extracted from these swabs was subjected to the commercial kit and real-time reverse transcription-PCR was performed. To determine the genome sequences of SARS-CoV-2 in the collected samples and deduce the consensus sequences among the identified variants, genome sequencing libraries were prepared and mapped to the reference genome.

Results: . Four of the tested samples were determined as variants. Of them, two harbored both H69/V70 deletion and N501Y substitution, whereas two harbored E484K substitution alone.

Conclusions: . The variant with E484K substitution alone ("R.1") has been now categorized as a variant of interest in Japan. Additionally, the kit-based assay was found to be feasible, convenient, and user-friendly in identifying the abovementioned mutations with a turnaround time of only 2 h.
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http://dx.doi.org/10.1016/j.jcv.2021.104877DOI Listing
May 2021

The gut microbiota associated with high-Gleason prostate cancer.

Cancer Sci 2021 May 29. Epub 2021 May 29.

Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan.

We have found that intestinal bacteria and their metabolites, short-chain fatty acids (SCFAs), promote cancer growth in prostate cancer (PCa) mouse models. To clarify the association between gut microbiota and PCa in humans, we analysed the gut microbiota profiles of men with suspected PCa. 152 Japanese men undergoing prostate biopsies (96 with cancer and 56 without cancer) were included in the study and randomly divided into two cohorts: discovery cohort (114 samples) and test cohort (38 samples). The gut microbiota was compared between two groups, a high-risk group (men with Grade group 2 or higher PCa) and a negative + low-risk group (men with negative biopsy or Grade group 1 PCa) using 16S rRNA gene sequencing. The relative abundances of Rikenellaceae, Alistipes, and Lachnospira, all SCFAs-producing bacteria, were significantly increased in high-risk group. In receiver operating characteristic curve analysis, the index calculated from the abundance of 18 bacterial genera which were selected by least absolute shrinkage and selection operator regression, detected high-risk PCa in the discovery cohort with higher accuracy than the prostate specific antigen test (area under the curve (AUC) = 0.85 vs. 0.74). Validation of the index in the test cohort showed similar results (AUC = 0.81 vs. 0.67). The specific bacterial taxa were associated with high-risk PCa. The gut microbiota profile could be a novel useful marker for the detection of high-risk PCa and could contribute the carcinogenesis of PCa. Supporting Information Document S1: Mathematical structure of the FMPI.
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http://dx.doi.org/10.1111/cas.14998DOI Listing
May 2021

Gut microbiota-derived short-chain fatty acids promote prostate cancer growth via IGF-1 signaling.

Cancer Res 2021 May 26. Epub 2021 May 26.

Department of Urology, Graduate School of Medicine, Osaka University.

Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer (PCa). Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific Pten knockout mice as a PCa model to investigate whether there is a gut microbiota-mediated connection between animal fat intake and PCa. Oral administration of an antibiotic mixture (Abx) in PCa-bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including Rikenellaceae and Clostridiales, inhibited PCa cell proliferation, and reduced prostate Igf1 expression and circulating IGF-1 levels. In PCa tissue, MAPK and PI3K activities, both downstream of the IGF-1 receptor, were suppressed by Abx administration. IGF-1 directly promoted the proliferation of PCa cell lines DU145 and 22Rv1 in vitro. Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF-1 levels. In humans, IGF-1 was found to be highly expressed in PCa tissue from obese patients. In conclusion, IGF-1 production stimulated by SCFAs from gut microbes influences the growth of PCa via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF-1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in PCa prevention and treatment.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-4090DOI Listing
May 2021

Analysis of appendectomy samples identified dysbiosis in acute appendicitis.

Biosci Microbiota Food Health 2021 14;40(2):92-97. Epub 2020 Nov 14.

Department of Microbiome Research, School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.

Appendicitis is the most common cause of sudden-onset abdominal pain requiring surgery. Culture-independent techniques have revealed that the complex intestinal bacterial ecology is associated with various diseases. To evaluate differences in patient characteristics and gut microbiota distribution in patients with appendicitis, we enrolled 12 patients who underwent appendectomy for appendicitis (appendicitis group) and 13 patients who underwent ileocecal resection or right hemicolectomy for colon cancer (control group). Microbiota were analyzed using next-generation sequencing of surgical specimens from appendix swab samples collected postoperatively. Overall differences in the structure of the gut microbiota were evaluated using the α- and β-diversity indices, which were calculated using the weighted or unweighted UniFrac distance. Changes in the gut microbial distribution were taxonomically evaluated at the phylum and genus levels. The α-diversity of observed species was significantly different between patients with and without inflammation of the appendix. The appendiceal microbiome of patients with appendicitis exhibited the highest unweighted UniFrac distances. There were no significant differences at the phylum level. (p=0.02) and f_erysipelotrichaceae_g_clostridium (p=0.005) were increased in the control group compared with the appendicitis group. This pilot study provides the first report of the correlation of the gut microbiota with the pathogenesis of appendicitis evaluated using mucus-origin sampling.
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http://dx.doi.org/10.12938/bmfh.2020-051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099629PMC
November 2020

Gut Dysbiosis Associated with Antibiotics and Disease Severity and Its Relation to Mortality in Critically Ill Patients.

Dig Dis Sci 2021 May 3. Epub 2021 May 3.

Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.

Background: The gut microbiota are reported to be altered in critical illness. The pattern and impact of dysbiosis on prognosis has not been thoroughly investigated in the ICU setting.

Aims: We aimed to evaluate changes in the gut microbiota of ICU patients via 16S rRNA gene deep sequencing, assess the association of the changes with antibiotics use or disease severity, and explore the association of gut microbiota changes with ICU patient prognosis.

Methods: Seventy-one mechanically ventilated patients were included. Fecal samples were collected serially on days 1-2, 3-4, 5-7, 8-14, and thereafter when suitable. Microorganisms of the fecal samples were profiled by 16S rRNA gene deep sequencing.

Results: Proportions of the five major phyla in the feces were diverse in each patient at admission. Those of Bacteroidetes and Firmicutes especially converged and stabilized within the first week from admission with a reduction in α-diversity (p < 0.001). Significant differences occurred in the proportional change of Actinobacteria between the carbapenem and non-carbapenem groups (p = 0.030) and that of Actinobacteria according to initial SOFA score and changes in the SOFA score (p < 0.001). An imbalance in the ratio of Bacteroidetes to Firmicutes within seven days from admission was associated with higher mortality when the ratio was > 8 or < 1/8 (odds ratio: 5.54, 95% CI: 1.39-22.18, p = 0.015).

Conclusions: Broad-spectrum antibiotics and disease severity may be associated with gut dysbiosis in the ICU. A progression of dysbiosis occurring in the gut of ICU patients might be associated with mortality.
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http://dx.doi.org/10.1007/s10620-021-07000-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090918PMC
May 2021

Alleviation of colonic inflammation by Lypd8 in a mouse model of inflammatory bowel disease.

Int Immunol 2021 Jun;33(7):359-372

Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

Dysfunction of the intestinal mucosal barrier causes inflammatory bowel diseases (IBDs). Indeed, mucosal barrier impairment in the gut of IBD patients results from decreased expression of barrier molecules. Ly6/Plaur domain containing 8 (Lypd8) segregates microbiota from the colonic epithelial layer. In this study, we found that Lypd8-/- mice, in which flagellated bacteria invaded the mucosal surface of the colon, developed spontaneous colitis when dysbiosis was induced by a high-fat diet (HFD). On the basis of this finding, we assessed whether the application of human LYPD8 (hLYPD8) protein exhibiting the glycan-dependent inhibition of bacterial motility is effective in a colitis model. Oral and anal treatments with hLYPD8 protein ameliorate dextran sulfate sodium-induced colitis and HFD-induced colitis in Lypd8-/- mice. These results indicate a therapeutic potential of hLYPD8 protein supplementation for IBD.
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http://dx.doi.org/10.1093/intimm/dxab012DOI Listing
June 2021

Importance of lymph node immune responses in MSI-H/dMMR colorectal cancer.

JCI Insight 2021 May 10;6(9). Epub 2021 May 10.

Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo/Chiba, Japan.

Patients with colorectal cancers (CRCs) generally exhibit improved survival through intensive lymph node (LN) dissection. However, recent progress in cancer immunotherapy revisits the potential importance of regional LNs, where T cells are primed to attack tumor cells. To elucidate the role of regional LN, we investigated the immunological status of nonmetastatic regional LN lymphocytes (LNLs) in comparison with those of the tumor microenvironment (tumor-infiltrating lymphocytes; TILs) using flow cytometry and next-generation sequencing. LNLs comprised an intermediate level of the effector T cell population between peripheral blood lymphocytes (PBLs) and TILs. Significant overlap of the T cell receptor (TCR) repertoire was observed in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) CRCs with high tumor mutation burden (TMB), although limited TCRs were shared between nonmetastatic LNs and primary tumors in microsatellite stable/MMR proficient (MSS/pMMR) CRC patients with low TMB. In line with the overlap of the TCR repertoire, an excessive LN dissection did not provide a positive impact on long-term prognosis in our MSI-H/dMMR CRC cohort (n = 130). We propose that regional LNs play an important role in antitumor immunity, particularly in MSI-H/dMMR CRCs with high TMB, requiring care to be taken regarding excessive nonmetastatic LN dissection in MSI-H/dMMR CRC patients.
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http://dx.doi.org/10.1172/jci.insight.137365DOI Listing
May 2021

Differential impacts of postoperative complications on patients' survival in completely resected non-small-cell lung cancer.

Gen Thorac Cardiovasc Surg 2021 Mar 9. Epub 2021 Mar 9.

Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objective: The aim of this study was to investigate the effects of inflammatory respiratory complications on long-term survival in patients with resected non-small cell lung cancer. We defined inflammatory respiratory complications to include the following six conditions: pneumonia, empyema, bronchial fistula, respiratory dysfunction, acute interstitial pneumonia, and atelectasis.

Methods: Part of the National Clinical Database was linked to our prospective database from 2014 to 2017. Linkage was achieved for 866 patients. The Kaplan-Meier method was used to evaluate the overall, relapse-free, and cancer-related survival. The Cox proportional hazard model was used to analyze the impact of each complication.

Results: Of the 736 patients included in the study, 149 had complications. The 5-year overall and cancer-specific survival rates were significantly lower in patients with inflammatory respiratory complications. The Cox proportional hazard model showed that the inflammatory respiratory complications had a significant impact on overall survival (hazard ratio 2.48, 95% confidence interval 1.41-4.38) but not air leak (hazard ratio 1.38, 95% confidence interval 0.70-2.70).

Conclusions: Our study shows the differential impact of each complication on the survival of patients with non-small cell lung cancer. The presence of inflammatory respiratory complications was the only predictor of poor overall survival.
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http://dx.doi.org/10.1007/s11748-021-01619-zDOI Listing
March 2021

Left brachiocephalic vein aneurysm: a case report.

Surg Case Rep 2021 Mar 9;7(1):66. Epub 2021 Mar 9.

Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: Aneurysm of the left brachiocephalic vein is a very rare clinical disease and only 40 cases have been reported so far.

Case Presentation: The patient was a 61-year-old woman with no related medical history. She underwent CT to investigate the cause of a cough and a mass was noted in the anterior mediastinum. Dynamic computed tomography with contrast medium injected into the left basilic vein demonstrated the venous aneurysm with blood flow to the left brachiocephalic vein. The patient had no symptoms, but because of the risk of pulmonary infarction and aneurysm rupture, the aneurysm was surgically resected. A median sternotomy was a reasonable approach because of the fragility of the venous aneurysm wall with little working space in the anterior mediastinum.

Conclusions: We diagnosed an aneurysm of the left brachiocephalic vein on preoperative imaging and excised it through a median sternotomy. The venous wall was thin and fragile in some areas and so this approach was appropriate in view of the possibility of intraoperative injury.
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http://dx.doi.org/10.1186/s40792-021-01148-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943670PMC
March 2021

Preoperative paraspinous muscle sarcopenia and physical performance as prognostic indicators in non-small-cell lung cancer.

J Cachexia Sarcopenia Muscle 2021 Jun 4;12(3):646-656. Epub 2021 Mar 4.

Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Despite the associations of both preoperative sarcopenia and physical performance with post-operative mortality in non-small-cell lung cancer (NSCLC), there have been no comprehensive studies of the impact of physical status on prognosis. This study was performed to investigate the prognostic significance of preoperative sarcopenia and physical performance in NSCLC.

Methods: This retrospective cohort study was performed in NSCLS patients undergoing curative lung resection at a university hospital between January 2014 and December 2017. The patients were divided into four groups according to the skeletal muscle index [sarcopenia (lowest sex-specific tertile) and non-sarcopenia] and 6 min walking distance (6MWD) [short distance (<400 m) and long distance (≥400 m)]. Sarcopenia was assessed by preoperative cross-sectional areas of right and left paraspinous muscles at the level of the 12th thoracic vertebra from computed tomography images, and physical performance was determined by preoperative 6MWD. The primary and secondary endpoints were post-operative overall survival (OS) and disease-free survival (DFS).

Results: The 587 patients [mean age: 68.5 ± 8.8 years, 399 men (68%)] included in the study were divided into the non-sarcopenia/long-distance group (58%), sarcopenia/long-distance group (26%), non-sarcopenia/short-distance group (9%), and sarcopenia/short-distance group (7%). A total of 109 (18.6%) deaths and 209 (35.6%) combined endpoints were observed over a mean follow-up of 3.1 ± 1.3 years. After adjusting for other covariates, the sarcopenia/short-distance group showed significant associations with shorter OS (hazard ratio, 3.38; 95% confidence interval, 1.79-6.37; P < 0.001) and DFS (hazard ratio, 2.11; 95% confidence, 1.27-3.51; P = 0.004) compared with the non-sarcopenia/long-distance group on multivariate analyses. Although not significant, adding skeletal muscle index and 6MWD to the pre-existing risk model increased the area under the curve on time-dependent receiver operating characteristic curve analysis for OS and DFS, except within 2 years of surgery.

Conclusions: The presence of both preoperative paraspinous muscle sarcopenia and short distance in 6MWD had an adverse effect on post-operative prognosis in patients with NSCLC, suggesting that preoperative assessment of thoracic sarcopenia and physical performance may be useful for risk stratification of surgical candidates with potential for targeted interventions.
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http://dx.doi.org/10.1002/jcsm.12691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200441PMC
June 2021

Characterization of Salivary Microbiota in Patients with Atherosclerotic Cardiovascular Disease: A Case-Control Study.

J Atheroscler Thromb 2021 Feb 19. Epub 2021 Feb 19.

Department of Cardiology, Osaka Medical College.

Aims: Oral bacteria have been reported to be associated with the pathogenesis of atherosclerosis; however, the relationship between the oral microbiota and atherosclerosis remains unclear. The present study aimed to investigate whether or not salivary microbiota of patients with atherosclerotic cardiovascular disease (ACVD) differs from that of subjects without ACVD, and to characterize the salivary microbiota of patients with ACVD.

Methods: This study included 43 patients with ACVD and 86 age- and sex-matched non-ACVD individuals. 16S rRNA metagenomic analysis were performed using DNA isolated from the saliva samples of the participants. To select unique operational taxonomic unit (OTU) sets of ACVD, we conducted the random forest algorithm in machine learning, followed by confirmation via 10-fold cross-validation Results: There was no difference in richness or evenness between the ACVD and non-ACVD groups (alpha diversity; observed OTU index, p=0.503; Shannon's index, p=0.478). However, significant differences were found in the overall salivary microbiota structure (beta diversity; unweighted UniFrac distances, p=0.001; weighted UniFrac distances, p=0.001). The Actinobacteria phylum was highly abundant in patients with ACVD, while the Bacteroidetes phylum was less abundant. The random forest classifier identified 43 OTUs as an optimal marker set of ACVD. In a 10-fold cross validation using the validation data, an area under the curve (AUC) of 0.933 (95% CI, 0.855-1.000) was obtained.

Conclusions: The salivary microbiota in patients with ACVD was distinct from that of non-ACVD individuals, indicating that the salivary microbiota may be related to ACVD.
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http://dx.doi.org/10.5551/jat.60608DOI Listing
February 2021

Whole-genome analyses of extended-spectrum or AmpC β-lactamase-producing Escherichia coli isolates from companion dogs in Japan.

PLoS One 2021 5;16(2):e0246482. Epub 2021 Feb 5.

Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Osaka, Japan.

The emergence and global spread of extended-spectrum or AmpC β-lactamase (ESBL/AmpC)-producing Enterobacteriaceae in companion animals have led to the hypothesis that companion animals might be reservoirs for cross-species transmission because of their close contact with humans. However, current knowledge in this field is limited; therefore, the role of companion animals in cross-species transmission remains to be elucidated. Herein, we studied ESBL/AmpC-producing Enterobacteriaceae, Escherichia coli in particular, isolated from extraintestinal sites and feces of companion dogs. Whole-genome sequencing analysis revealed that (i) extraintestinal E. coli isolates were most closely related to those isolated from feces from the same dog, (ii) chromosomal sequences in the ST131/C1-M27 clade isolated from companion dogs were highly similar to those in the ST131/C1-M27 clade of human origin, (iii) certain plasmids, such as IncFII/pMLST F1:A2:B20/blaCTX-M-27, IncI1/pMLST16/blaCTX-M-15, or IncI1/blaCMY-2 from dog-derived E. coli isolates, shared high homology with those from several human-derived Enterobacteriaceae, (iv) chromosomal blaCTX-M-14 was identified in the ST38 isolate from a companion dog, and (v) eight out of 14 tested ESBL/AmpC-producing E. coli isolates (i.e., ST131, ST68, ST405, and ST998) belonged to the human extraintestinal pathogenic E. coli (ExPEC) group. All of the bla-coding plasmids that were sequenced genome-wide were capable of horizontal transfer. These results suggest that companion dogs can spread ESBL/AmpC-producing ExPEC via their feces. Furthermore, at least some ESBL/AmpC-producing ExPECs and bla-coding plasmids can be transmitted between humans and companion dogs. Thus, companion dogs can act as an important reservoir for ESBL/AmpC-producing E. coli in the community.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246482PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864471PMC
February 2021

Impacts of sleep on the characteristics of dental biofilm.

Sci Rep 2021 01 8;11(1):138. Epub 2021 Jan 8.

Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Dental biofilm present on the tooth surface is associated with oral diseases, such as dental caries and periodontal disease. Because bacterial numbers rapidly increase in saliva during sleep, oral care before sleeping is recommended for the prevention of chronic oral diseases. However, temporal circadian changes in the quantity and quality of dental biofilms are poorly understood. This study aimed to investigate the impacts of sleeping on dental biofilm amounts and compositions by using an in situ model. The use of this in situ model enabled us to investigate dental biofilm formed in the oral cavity and to perform a quantitative analysis. Subjects began wearing oral splints in the morning or before sleeping, and biofilm samples were collected at 8, 16, and 24 h after the subjects began wearing oral splints; these samples were then used in various experiments. No significant changes in the numbers of biofilm-forming bacteria were caused by sleep. However, the relative abundances of genera related to periodontitis (i.e., Fusobacterium and Prevotella) increased after awakening. In conclusion, the numbers of biofilm-forming bacteria were not affected by sleep, and the abundances of obligate anaerobes increased after sleep. This research may aid in defining efficacious preventive oral care.
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http://dx.doi.org/10.1038/s41598-020-80541-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794455PMC
January 2021

Iodine-related attenuation in contrast-enhanced dual-energy computed tomography in small-sized solid-type lung cancers is associated with the postoperative prognosis.

Cancer Imaging 2021 Jan 7;21(1). Epub 2021 Jan 7.

Department of Radiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: To investigate the correlation between iodine-related attenuation in contrast-enhanced dual-energy computed tomography (DE-CT) and the postoperative prognosis of surgically resected solid-type small-sized lung cancers.

Methods: We retrospectively reviewed the DE-CT findings and postoperative course of solid-type lung cancers ≤3 cm in diameter. After injection of iodinated contrast media, arterial phases were scanned using 140-kVp and 80-kVp tube voltages. Three-dimensional iodine-related attenuation (3D-IRA) of primary tumors at the arterial phase was computed using the "lung nodule" application software. The corrected 3D-IRA normalized to the patient's body weight and contrast medium concentration was then calculated.

Results: A total of 120 resected solid-type lung cancers ≤3 cm in diameter were selected for analysis (82 males and 38 females; mean age, 67 years). During the observation period (median, 47 months), 32 patients showed postoperative recurrence. Recurrent tumors had significantly lower 3D-IRA and corrected 3D-IRA at early phase compared to non-recurrent tumors (p = 0.046 and p = 0.027, respectively). The area under the receiver operating characteristic curve for postoperative recurrence was 0.624 for the corrected 3D-IRA at early phase (p = 0.025), and the cutoff value was 5.88. Kaplan-Meier curves for disease-free survival indicated that patients showing tumors with 3D-IRA > 5.88 had a significantly better prognosis than those with tumors showing 3D-IRA < 5.88 (p = 0.017).

Conclusions: The 3D-IRA of small-sized solid-type lung cancers on contrast-enhanced DE-CT was significantly associated with postoperative prognosis, and low 3D-IRA tumors showed a higher TNM stage and a significantly poorer prognosis.
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http://dx.doi.org/10.1186/s40644-020-00368-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791656PMC
January 2021

Genomic characterization of clinical Enterobacter roggenkampii co-harbouring bla- and bla-encoding IncP6 and mcr-9-encoding IncHI2 plasmids isolated in Japan.

J Glob Antimicrob Resist 2021 Mar 29;24:220-227. Epub 2020 Dec 29.

Division of Microbiology, Osaka Institute of Public Health, 8-34 Tojo-cho, Tennoji-ku, Osaka, Japan.

Objectives: The spread of carbapenemase-producing Enterobacterales (CPE) with colistin resistance is a critical public health issue. We genetically characterized the clinical isolate Enterobacter roggenkampii OIPH-N260, which harboured carbapenemase genes bla and bla with multiple resistance genes, including mcr-9 and bla.

Methods: This isolate was characterized by whole-genome sequencing, comparative analysis of resistance plasmids, susceptibility tests, bacterial conjugation, S1-nuclease digested pulsed-field-gel electrophoresis, and Southern blot hybridization.

Results: The OIPH-N260 isolate exhibited resistance to most β-lactams and colistin. It co-harboured two resistance plasmids, the bla- and bla-encoding IncP6 plasmid pN260-3 and mcr-9- and bla-encoding IncHI2 plasmid pN260-1. The comparative analysis of pN260-3 indicated that a unique bla-surrounding region was inserted into the bla-encoding plasmid with the mobile element IS26, which plays an important role in the spread of resistance genes. pN260-1 did not possess the mcr-9 expression regulative gene qseBC. Both plasmids were transferable into other bacterial species via conjugation.

Conclusions: This is the first study to report not only a bla and bla co-encoding plasmid, but also the co-harbouring of another plasmid carrying mcr-9 and bla in Enterobacter cloacae complex. The development of advanced resistance via IS26-mediated insertion and the co-harbouring of resistance plasmids highlights the need to monitor for resistance genes in CPE.
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http://dx.doi.org/10.1016/j.jgar.2020.11.028DOI Listing
March 2021

A Metagenome-Wide Association Study of Gut Microbiome in Patients With Multiple Sclerosis Revealed Novel Disease Pathology.

Front Cell Infect Microbiol 2020 11;10:585973. Epub 2020 Dec 11.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.

While microbiome plays key roles in the etiology of multiple sclerosis (MS), its mechanism remains elusive. Here, we conducted a comprehensive metagenome-wide association study (MWAS) of the relapsing-remitting MS gut microbiome ( = 26, = 77) in the Japanese population, by using whole-genome shotgun sequencing. Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis, and pathway analysis). Phylogenetic case-control association tests showed discrepancies of eight clades, most of which were related to the immune system (false discovery rate [FDR] < 0.10; e.g., . and ). Gene association tests found an increased abundance of one putative dehydrogenase gene (Clo1100_2356) and one ABC transporter related gene (Mahau_1952) in the MS metagenome compared with controls (FDR < 0.1). Molecular pathway analysis of the microbiome gene case-control comparisons identified enrichment of multiple Gene Ontology terms, with the most significant enrichment on cell outer membrane ( = 1.5 × 10). Interaction between the metagenome and host genome was identified by comparing biological pathway enrichment between the MS MWAS and the MS genome-wide association study (GWAS) results (i.e., MWAS-GWAS interaction). No apparent discrepancies in alpha or beta diversities of metagenome were found between MS cases and controls. Our shotgun sequencing-based MWAS highlights novel characteristics of the MS gut microbiome and its interaction with host genome, which contributes to our understanding of the microbiome's role in MS pathophysiology.
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http://dx.doi.org/10.3389/fcimb.2020.585973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759502PMC
June 2021

Solitary fibrous tumor/hemangiopericytoma treated with temozolomide plus bevacizumab: a report of four cases and literature review.

Nagoya J Med Sci 2020 Nov;82(4):631-644

Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.

Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a rare tumor derived from mesenchymal tissue. Although standard chemotherapy for SHT/HPC has not been established, temozolomide plus bevacizumab (TMZ+Bev) therapy for SFT/HPC has been reported. The effectiveness and safety of TMZ+Bev (temozolomide 150 mg/m orally on days 1-7 and days 15-21 and bevacizumab 5 mg/kg intravenously on day 8 and day 22 on a 28-day cycle), which was administered from December 2013 until April 2019 to four patients with SFT/HPC, were retrospectively analyzed. Four patients with SFT/HPC received TMZ+Bev. The age of the patients ranged from 41 to 75 years. Two were male, and the primary tumor sites were the meninges in three patients and the pleura in one. One achieved partial response; the others, stable disease (SD). The progression-free survival time ranged from 9.4 to 29.6 months according to RECIST v1.1. One patient died 59 months after using TMZ+Bev, and the others survived for 17 to 64 months. All patients experienced Grade 3 or higher lymphopenia, and three had Grade 3 or higher leukopenia and neutropenia. One patient subsequently received doxorubicin; another, pazopanib. TMZ+Bev therapy for SFT/HPC is safe and effective for maintaining long-term SD.
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http://dx.doi.org/10.18999/nagjms.82.4.631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719452PMC
November 2020

Oral intake of silica nanoparticles exacerbates intestinal inflammation.

Biochem Biophys Res Commun 2021 01 22;534:540-546. Epub 2020 Nov 22.

Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan; WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan; Institute for Open and Transdisciplinary Research Initiative, Osaka University, Suita, Osaka, 565-0871, Japan. Electronic address:

Nanoparticles, i.e., particles with a diameter of ≤100 nm regardless of their composing material, are added to various foods as moisturizers, coloring agents, and preservatives. Silicon dioxide (SiO, silica) nanoparticles in particular are widely used as food additives. However, the influence of SiO nanoparticle oral consumption on intestinal homeostasis remains unclear. The daily intake of 10-nm-sized SiO nanoparticles exacerbates dextran sulfate sodium (DSS)-induced colitis, whereas the daily intake of 30-nm-sized SiO nanoparticles has no influence on intestinal inflammation. The exacerbation of colitis induced by consuming 10-nm-sized SiO nanoparticles was abolished in mice deficient in apoptosis-associated speck-like protein containing a CARD (ASC). Our study indicates that the oral intake of small SiO nanoparticles poses a risk for worsening intestinal inflammation through activation of the ASC inflammasome.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.047DOI Listing
January 2021

Pulmonary disease caused by a newly identified mycobacterium: Mycolicibacterium toneyamachuris: a case report.

BMC Infect Dis 2020 Nov 25;20(1):888. Epub 2020 Nov 25.

Department of Respiratory Medicine, National Hospital Organization Osaka Toneyama Medical Center, 5-1-1 Toneyama Toyonaka, Osaka, Japan.

Background: Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is becoming a significant health burden. Recent advances in analysis techniques have allowed the accurate identification of previously unknown NTM species. Here, we report a case of NTM-PD caused by a newly identified mycobacteria in an immunocompetent patient.

Case Presentation: A 44-year-old woman was referred to our hospital due to the frequent aggravation of her chronic respiratory symptoms, with NTM-PD-compatible computed tomography findings. Unidentified mycobacterium was repeatedly isolated from respiratory specimens and we diagnosed her as NTM-PD of unidentified mycobacterium. Subsequent whole-genome analysis revealed that the unidentified mycobacterium was a novel mycobacterium genetically close to Mycolicibacterium mucogenicum. We started combination therapy with clarithromycin, moxifloxacin, amikacin, and imipenem/cilastatin, referring to drug sensitivity test results and observed its effect on M. mucogenicum infection. Her symptoms and radiological findings improved significantly.

Conclusion: We report a case of NTM-PD caused by a newly identified mycobacteria, Mycolicibacterium toneyamachuris, genetically close to M. mucogenicum. This pathogenic mycobacterium showed different characteristics from M. mucogenicum about clinical presentation and drug sensitivity. The clinical application of genomic sequencing will advance the identification and classification of pathogenic NTM species, and enhance our understanding of mycobacterial diseases.
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http://dx.doi.org/10.1186/s12879-020-05626-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690136PMC
November 2020

Comparative evaluation of microbial profiles of oral samples obtained at different collection time points and using different methods.

Clin Oral Investig 2021 May 25;25(5):2779-2789. Epub 2020 Sep 25.

Department of Dentistry and Oral Surgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka, 569-8686, Japan.

Objectives: Recently, the oral microbiome has been found to be associated with oral and general health status. Although various oral sample collection protocols are available, the potential differences between the results yielded by these protocols remain unclear. In this study, we aimed to determine the effects of different time points and methods of oral sample collection on the outcomes of microbiome analysis.

Materials And Methods: Oral samples were collected from eight healthy individuals at four different time points: 2 h after eating, immediately after teeth brushing, immediately after waking up, and 2 h after eating on the subsequent day. Four methods of saliva collection were evaluated: spitting, gum chewing, cotton swab, and oral rinse. Oral microbiomes of these samples were compared by analyzing the bacterial 16S rRNA gene sequence data.

Results: The oral microbial composition at the genus level was similar among all sample collection time points and methods. Alpha diversity was not significantly different among the groups, whereas beta diversity was different between the spitting and cotton swab methods. Compared with the between-subject variations, the weighted UniFrac distances between the groups were not minor.

Conclusions: Although the oral microbiome profiles obtained at different collection time points and using different methods were similar, some differences were detected.

Clinical Relevance: The results of the present study suggest that although all the described protocols are useful, comparisons among microbiomes of samples collected by different methods are not appropriate. Researchers must be aware of the issues regarding the impact of saliva collection methods.
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http://dx.doi.org/10.1007/s00784-020-03592-yDOI Listing
May 2021

SH3P2 suppresses osteoclast differentiation through restricting membrane localization of myosin 1E.

Genes Cells 2020 Nov 7;25(11):707-717. Epub 2020 Oct 7.

Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Osteoclasts are multinucleated cells responsible for bone resorption. Src homology 3 (SH3) domain-containing protein-2 (SH3P2)/osteoclast-stimulating factor-1 regulates osteoclast differentiation, but its exact role remains elusive. Here, we show that SH3P2 suppresses osteoclast differentiation. SH3P2 knockout (KO) mice displayed decreased femoral trabecular bone mass and enhanced localization of osteoclasts on the tibial trabecular bone surface, suggesting that SH3P2 suppresses bone resorption by osteoclasts. Osteoclast differentiation based on cellular multinuclearity induced by macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL) was enhanced in bone marrow-derived macrophages lacking SH3P2. RANKL induced SH3P2 dephosphorylation, which increased the association of actin-dependent motor protein myosin 1E (Myo1E) with SH3P2 and thereby prevented Myo1E localization to the plasma membrane. Consistent with this, Myo1E in the membrane fraction increased in SH3P2-KO cells. Together with the attenuated osteoclast differentiation in Myo1E knocked down cells, SH3P2 may suppress osteoclast differentiation by preventing their cell-to-cell fusion depending on Myo1E membrane localization.
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http://dx.doi.org/10.1111/gtc.12806DOI Listing
November 2020

Thymic lipofibroadenoma accompanied with largish calcifications.

Gen Thorac Cardiovasc Surg 2021 Feb 4;69(2):394-397. Epub 2020 Sep 4.

Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Thymic lipofibroadenomas are extremely rare; their radiological features have never been reported. We report the first case of a lipofibroadenoma with some largish calcifications mimicking a teratoma. A 28-year-old man had an anterior mediastinal tumor with some calcifications on preoperative computed tomography, which was suspected to be a mature teratoma and resected through robot-assisted thoracic surgery. This tumor had strands of epithelial cells separated by abundant fibrous stroma containing fat cells and was thus diagnosed as a lipofibroadenoma. He was well without any recurrence 6 months postoperatively. Largish calcifications on preoperative computed tomography make distinguishing between teratomas and lipfibroadenomas difficult.
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http://dx.doi.org/10.1007/s11748-020-01475-3DOI Listing
February 2021

Total Synthesis of the Proposed Structure for Protoaculeine B, a Polycationic Marine Sponge Metabolite, with a Homogeneous Long-Chain Polyamine.

J Nat Prod 2020 09 1;83(9):2769-2775. Epub 2020 Sep 1.

Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan.

By establishing the procedures for sequential deprotections, reaction monitoring, purification, and handling, for the first time, we achieved the total synthesis of the proposed structure for protoaculeine B (), which is a highly hydrophilic and polycationic amino acid. The NMR and mass spectra and chemical reactivity of the synthetic sample differed from those of natural protoaculeine B, which indicates the necessity for revision of the originally reported structure.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00761DOI Listing
September 2020

Detection of Genetic Elements Carrying in Vancomycin-Resistant VE80 Isolated from Retail Chicken Meat.

Foodborne Pathog Dis 2020 12 14;17(12):772-774. Epub 2020 Aug 14.

Division of Bacteriology, Osaka Institute of Public Health, Osaka, Japan.

In this study, we aimed to detect genetic elements carrying in VE80 isolated from retail chicken in Vietnam. The structures of vancomycin-resistance determinants and the location of vancomycin-resistance genes were detected by sequencing the gene cluster, Southern hybridization analyses, and whole-genome sequence analyses. The Tn-related elements harboring clusters, which exhibited a characteristic structure with five point mutations compared with the prototype Tn, were located on the 76-kb plasmid pVE80-1 of VE80. The sequence of VE80 harboring three point mutations was 100% identical to those of vancomycin-resistant enterococci isolated from poultry in Taiwan and Japan, indicating that the element may be prevalent in poultry production farms in Asia.
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http://dx.doi.org/10.1089/fpd.2020.2827DOI Listing
December 2020

Factors associated with changes in the 12-m stair-climbing time after lung lobectomy.

Gen Thorac Cardiovasc Surg 2021 Feb 6;69(2):282-289. Epub 2020 Aug 6.

Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Objective: Postoperative loss-of-exercise capacity is one of the main concerns for patients undergoing lung cancer surgery. This study was designed to identify the factors associated with loss-of-exercise capacity after lobectomy, using an easy surrogate measure: the 12-m stair-climbing time (SCt).

Methods: Ninety-eight patients undergoing lobectomy for suspected stage I lung cancer were prospectively enrolled. SCt and pulmonary function test were evaluated preoperatively as baseline and at 6 months postoperatively. At 6 months postoperatively, 20 patients dropped out. Loss-of-exercise capacity was defined as at least a 3.3% decline (lower quartile) in the estimated maximal oxygen uptake (VOt: 43.06 - 0.4 × SCt). Factors associated with loss-of-exercise capacity were analyzed.

Results: Median (interquartile range) baseline SCt was 31.5 (28.2-36.7) s. Baseline SCt was not significantly associated with complications. At 6 months postoperatively, SCt increased by + 4.4 (+ 3.2, + 6.8) s in patients with loss-of-exercise capacity. Sex, smoking status, lobe, procedure, and forced expiratory volume in 1 s showed no significant association with loss-of-exercise capacity. In the multivariable logistic regression, older age (≥ 73 years) (odds ratio: 5.25, 95% confidence interval: 1.50-18.43, p = 0.010) and lower baseline diffusing capacity of the lung for carbon monoxide (< 75%) (odds ratio: 9.23, 95% confidence interval: 1.94-43.93, p = 0.005) were significantly associated with loss-of-exercise capacity.

Conclusion: Age and the baseline diffusing capacity of the lung for carbon monoxide were identified as significant variables associated with variation of exercise capacity after lung cancer surgery, using pre- and postoperative SCt.
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http://dx.doi.org/10.1007/s11748-020-01458-4DOI Listing
February 2021

Emergence and diversification of a host-parasite RNA ecosystem through Darwinian evolution.

Elife 2020 07 21;9. Epub 2020 Jul 21.

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

In prebiotic evolution, molecular self-replicators are considered to develop into diverse, complex living organisms. The appearance of parasitic replicators is believed inevitable in this process. However, the role of parasitic replicators in prebiotic evolution remains elusive. Here, we demonstrated experimental coevolution of RNA self-replicators (host RNAs) and emerging parasitic replicators (parasitic RNAs) using an RNA-protein replication system we developed. During a long-term replication experiment, a clonal population of the host RNA turned into an evolving host-parasite ecosystem through the continuous emergence of new types of host and parasitic RNAs produced by replication errors. The host and parasitic RNAs diversified into at least two and three different lineages, respectively, and they exhibited evolutionary arms-race dynamics. The parasitic RNA accumulated unique mutations, thus adding a new genetic variation to the whole replicator ensemble. These results provide the first experimental evidence that the coevolutionary interplay between host-parasite molecules plays a key role in generating diversity and complexity in prebiotic molecular evolution.
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http://dx.doi.org/10.7554/eLife.56038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378860PMC
July 2020

Prognostic factors of stage I thymic epithelial tumors.

Gen Thorac Cardiovasc Surg 2021 Jan 3;69(1):59-66. Epub 2020 Jul 3.

Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Objective: According to the tumor-node-metastasis classification for thymic malignancies, the proportion of patients diagnosed with stage I is expected to increase significantly. However, whether those patients have homogenous clinicopathological features and survival has not been fully evaluated.

Methods: We reviewed 153 consecutive patients with stage I thymic epithelial tumors (133 thymomas, 15 thymic carcinomas, and 5 neuroendocrine tumors) who underwent complete resection at our institution between 2001 and 2016 and evaluated the prognostic significance of their clinicopathological factors.

Results: The stage I patients accounted for 78% of all thymic epithelial tumors. The 5-year overall survival and recurrence-free survival rates of the 153 patients were 94% and 80%, respectively. The patients with the histology of thymic carcinoma or neuroendocrine tumor and with a tumor larger than 5.0 cm showed significantly worse recurrence-free survival in multivariate analysis (p = 0.027 and 0.038, respectively). Only the tumor size was revealed as a significant prognostic factor for recurrence-free survival when limited in the 133 cases of thymoma (p = 0.048).

Conclusions: Patients with large tumors showed significantly worse recurrence-free survival than those with small tumors both in stage I thymic epithelial tumors and thymomas.
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http://dx.doi.org/10.1007/s11748-020-01427-xDOI Listing
January 2021

Fecal Gram staining of phagocytosed bacteria to differentiate methicillin-resistant Staphylococcus aureus: A case report.

J Infect Chemother 2020 Oct 29;26(10):1078-1081. Epub 2020 Jun 29.

Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan. Electronic address:

Antibiotic-associated diarrhea is a relatively common problem, and the main bacterial cause is Clostridioides difficile followed by Staphylococcus aureus and other pathogens. The diagnostic procedure for methicillin-resistant S. aureus enteritis is not well established. Phagocytosis is a key antimicrobial process involved in host defense. Phagocytosed bacteria identified by Gram staining are one marker to identify causative microorganisms and select subsequent treatment strategies. However, there are few reports on fecal Gram staining using phagocytosed bacteria as a target for diarrhea treatment. We report the successful use of fecal Gram staining to diagnose and treat methicillin-resistant S. aureus enteritis.
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http://dx.doi.org/10.1016/j.jiac.2020.05.021DOI Listing
October 2020