Publications by authors named "Takahiro Sawada"

101 Publications

Dark crescent sign: high-risk calcified coronary plaque detected by electrocardiogram-gated non-contrast computed tomography.

Eur Heart J Case Rep 2022 Jan 16;6(1):ytab519. Epub 2021 Dec 16.

Division of Cardiovascular Medicine, Hyogo Brain and Heart Center, Saisho-Kou-520, Himeji 670-0981, Japan.

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http://dx.doi.org/10.1093/ehjcr/ytab519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755483PMC
January 2022

Transcriptional Regulation of 25-Hydroxyvitamin D-24-Hydroxylase (CYP24A1) by Calcemic Factors in Keratinocytes.

J Nutr Sci Vitaminol (Tokyo) 2021 ;67(6):424-428

Research Institute of Innovative Medicine, Tokiwa Foundation.

CYP24A1 regulates serum vitamin D (VD) levels by inactivating 25(OH)D, which is the precursor of the active form of VD [1α,25(OH)D], and CYP24A1 expression is controlled by multiple calcemic factors such as 1α,25(OH)D, calcium, and phosphate. A major phosphaturic factor, FGF23, has also been identified as a regulator of serum VD levels by affecting renal CYP24A1 gene expression; however, its effect on CYP24A1 in extrarenal cells remains largely unstudied. Therefore, the direct effect of FGF23 on CYP24A1 was examined in a human keratinocyte cell line (HaCaT). In this cell line, significant induction of CYP24A1 gene expression by 1α,25(OH)D was seen within 4 h by qRT-PCR, and this was mediated by the VD receptor, as shown in a mutant cell line genetically deficient in this receptor. However, FGF23 treatment up to 12 h did not induce CYP24A1 expression, although the expected activation of the downstream MAPK signaling pathway was seen. High calcium and phosphate treatments were also ineffective in inducing CYP24A1 gene expression. Furthermore, a luciferase assay showed no activation of a VD-sensitive proximal CYP24A1 promoter in response to the calcium and phosphate treatments, suggesting that the effect of FGF23 on dermal CYP24A1 gene expression is indirect. From these findings, we speculate that CYP24A1 gene regulation by FGF23 occurs mainly in renal cells, but not in extrarenal cells, at least not in keratinocytes.
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http://dx.doi.org/10.3177/jnsv.67.424DOI Listing
January 2022

Profiling of Androgen-Dependent Enhancer RNAs Expression in Human Prostate Tumors: Search for Malignancy Transition Markers.

Res Rep Urol 2021 14;13:705-713. Epub 2021 Sep 14.

Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki, Japan.

Introduction: Although the ability of androgens to promote prostate cancer development has been known for decades, the molecular mechanisms of androgen receptor (AR) signaling in the tumorigenesis remain unclear. Enhancer RNAs (eRNAs) transcribed from strong enhancers, or super-enhancers (SEs), have recently emerged as a novel class of regulatory non-coding RNAs (ncRNAs) that facilitate transcription, including that of androgen target genes, through chromatin looping to position enhancers proximate to the promoters. The aim of this study was to assess androgen-dependent transcription in prostate tumors of eRNAs (designated as KLK3eRNAs) from the SE of the gene encoding the prostate-specific antigen (PSA) protein, a clinical marker of prostate carcinogenesis.

Materials And Methods: The androgen-induced KLK3eRNAs were identified in the LNCaP human prostate cancer cell line. The expressions of these KLK3eRNAs together with KLK3 and AR mRNA transcripts were assessed by qRT-PCR in prostate tumor samples from five prostate cancer patients.

Results: Androgen-induced KLK3eRNAs have been identified in the LNCaP cells, and their expression was further analyzed in tumors of prostate cancer patients. Transcripts of the tested KLK3eRNAs have been detected in all clinical samples, but their expression patterns differed between individual tumor specimens. We found a statistically significant correlation between the levels of the KLK3 and AR mRNAs with those of the previously reported KLK3eRNAs, while such correlation was not observed for novel KLK3eRNAs described in our recent report.

Conclusion: Presented data suggest that prostate tumor development may associate with epigenetic reorganization in the KLK3 genomic regulatory elements reflected by changes of the KLK3eRNA expression. Our findings support a potential of eRNAs profiling to be used as diagnostic marker.
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http://dx.doi.org/10.2147/RRU.S328661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449685PMC
September 2021

Additional ablation effect of low-speed rotational atherectomy following high-speed rotational atherectomy on early calcified in-stent restenosis: A case report.

Clin Case Rep 2021 Jul 21;9(7):e04550. Epub 2021 Jul 21.

Division of Cardiovascular Medicine Hyogo Brain and Heart Center Himeji Japan.

Optical frequency domain imaging-guided additional low-speed rotational atherectomy following sufficient high-speed rotational atherectomy for early calcified in-stent restenosis might be a safe and useful option for achieving additional large lumen gains and stent expansion.
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http://dx.doi.org/10.1002/ccr3.4550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294135PMC
July 2021

Androgen-dependent and DNA-binding-independent association of androgen receptor with chromatic regions coding androgen-induced noncoding RNAs.

Biosci Biotechnol Biochem 2021 Sep;85(10):2121-2130

Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki, Fukushima, Japan.

Androgen induces the binding of its receptor (AR) to androgen-responsive elements (AREs), while genome-wide studies showed that most androgen-induced AR binding sites on chromatin were unrelated to AREs. Enhancer RNAs (eRNAs), a class of noncoding RNAs (ncRNAs), are transcribed from superenhancers (SEs) and trigger the formation of large ribonucleoprotein condensates of transcription factors. By in silico search, an SE is found to be located on the locus of KLK3 that encodes prostate specific antigen. On the KLK3 SE, androgen-induced expression of ncRNAs was detected and designated as KLK3eRNAs in LNCaP cells, and androgen-induced association of AR and FOXA1 on the KLK3eRNA coding regions was detected. Such androgen-induced association of an AR mutant lacking DNA binding activity on the KLK3eRNA coding regions was undetectable on an exogenous ARE. Thus, the present findings suggest a molecular basis of androgen-induced association of AR with chromatin on ARE-unrelated sequences.
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http://dx.doi.org/10.1093/bbb/zbab135DOI Listing
September 2021

Novel strategy for ostial left anterior descending artery acute myocardial infarction: Combined treatment with directional coronary atherectomy followed by drug-coated balloon angioplasty.

Clin Case Rep 2021 Mar 12;9(3):1095-1100. Epub 2021 Jan 12.

Division of Cardiovascular Medicine Department of Internal Medicine Hyogo Brain and Heart Center Himeji Japan.

A 69-year-old female diagnosed with ostial left anterior descending artery acute myocardial infarction underwent percutaneous coronary intervention using combined directional coronary atherectomy followed by drug-coated balloon angioplasty. This report highlights a novel management strategy with no permanent scaffold left in the coronary artery.
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http://dx.doi.org/10.1002/ccr3.3659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981620PMC
March 2021

Comparison of the 9-Month Intrastent Condition and 30-Month Clinical Outcomes After Resolute Zotarolimus-Eluting Stent Implantation Between Standard-Duration and 1-Month Dual Antiplatelet Therapy Followed by Prasugrel Monotherapy.

Circ Rep 2020 Dec 23;3(1):55-65. Epub 2020 Dec 23.

Division of Cardiovascular Medicine, Hyogo Prefectural Himeji Cardiovascular Center Himeji Japan.

In this study we investigated the efficacy and safety of very short duration (1-month) dual antiplatelet therapy (DAPT) followed by prasugrel monotherapy. In particular, we compared intrastent conditions using optical coherence tomography (OCT) after second-generation drug-eluting stent implantation between standard-duration and 1-month DAPT followed by prasugrel monotherapy. Between May 2015 and February 2018, 120 consecutive patients who underwent elective Resolute zotarolimus-eluting stent implantation were enrolled and divided into those receiving standard-duration or 1-month (1M) DAPT followed by prasugrel monotherapy; 47 patients (n=55 stents) and 46 patients (n=54 stents) in the standard and 1M groups, respectively, completed the protocol. The primary endpoint was the prevalence of abnormal intrastent tissue at the 9-month examination, as observed by OCT. The secondary endpoint was the presence of composite adverse events, including all-cause death, myocardial infarction, stent thrombosis, target lesion and vessel revascularization, and major and minor bleeding. The prevalence of abnormal intrastent tissue was similar between the standard and 1M groups (1.6% vs. 1.5%, respectively; non-inferiority P<0.01). There was a tendency for fewer composite events in the 1M than standard group at the 30-month follow-up examination (28.3% vs. 44.7%, respectively; P=0.41). In conclusion, 1M DAPT followed by prasugrel monotherapy after second-generation drug-eluting stent implantation was not inferior to standard-duration DAPT in terms of intrastent thrombus formation and composite adverse events.
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http://dx.doi.org/10.1253/circrep.CR-20-0126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939786PMC
December 2020

The impact of vildagliptin on the daily glucose profile and coronary plaque stability in impaired glucose tolerance patients with coronary artery disease: VOGUE-A multicenter randomized controlled trial.

BMC Cardiovasc Disord 2021 02 15;21(1):92. Epub 2021 Feb 15.

Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

Background: The impact of reduction in glycemic excursion on coronary plaques remains unknown. This study aimed to elucidate whether a dipeptidyl peptidase 4 inhibitor could reduce the glycemic excursion and stabilize the coronary plaques compared with conventional management in coronary artery disease (CAD) patients with impaired glucose tolerance (IGT).

Methods: This was a multicenter, randomized controlled trial including CAD patients with IGT under lipid-lowering therapy receiving either vildagliptin (50 mg once a day) or no medication (control group) regarding glycemic treatment. The primary endpoint was changes in the minimum fibrous cap thickness and lipid arc in non-significant native coronary plaques detected by optical coherence tomography at 6 months after intervention. Glycemic variability expressed as the mean amplitude of glycemic excursion (MAGE) measured with a continuous glucose monitoring system was evaluated before and 6 months after intervention.

Results: A total of 20 participants with 47 lesions were allocated to either the vildagliptin group (10 participants, 22 lesions) or the control group (10 participants, 25 lesions). The adjusted difference of mean changes between the groups was - 18.8 mg/dl (95% confidence interval, - 30.8 to - 6.8) (p = 0.0064) for the MAGE (vildagliptin, - 20.1 ± 18.0 mg/dl vs. control, 2.6 ± 12.7 mg/dl), - 22.8° (- 40.6° to - 5.1°) (p = 0.0012) for the mean lipid arc (vildagliptin, - 9.0° ± 25.5° vs. control, 15.8° ± 16.8°), and 42.7 μm (15.3 to 70.1 μm) (p = 0.0022) for the minimum fibrous cap thickness (vildagliptin, 35.7 ± 50.8 μm vs. control, - 15.1 ± 25.2 μm).

Conclusions: Vildagliptin could reduce the MAGE at 6 months and may be associated with the decreased lipid arc and increased minimum FCT of the coronary plaques in CAD patients with IGT as compared with the control group. These findings may represent its potential stabilization effect on coronary plaques, which are characteristic in this patient subset. Trial registration Registered in the UMIN clinical trial registry (UMIN000008620), Name of the registry: VOGUE trial, Date of registration: Aug 6, 2012, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000010058.
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http://dx.doi.org/10.1186/s12872-021-01902-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885219PMC
February 2021

Early detection of drug-resistant Streptococcus pneumoniae and Haemophilus influenzae by quantitative flow cytometry.

Sci Rep 2021 02 3;11(1):2873. Epub 2021 Feb 3.

Fundamental Research Laboratory, Research and Development Division, Eiken Chemical Co., Ltd., 143 Nogi, Nogimachi, Shimotsuga-gun, Tochigi, 329-0114, Japan.

Early detection of drug resistance contributes to combating drug-resistant bacteria and improving patient outcomes. Microbial testing in the laboratory is essential for treating infectious diseases because it can provide critical information related to identifying pathogenic bacteria and their resistance profiles. Despite these clinical requirements, conventional phenotypic testing is time-consuming. Additionally, recent rapid drug resistance tests are not compatible with fastidious bacteria such as Streptococcus and Haemophilus species. In this study, we validated the feasibility of direct bacteria counting using highly sensitive quantitative flow cytometry. Furthermore, by combining flow cytometry and a nucleic acid intercalator, we constructed a highly sensitive method for counting viable fastidious bacteria. These are inherently difficult to measure due to interfering substances from nutrients contained in the medium. Based on the conventional broth microdilution method, our method acquired a few microliter samples in a time series from the same microplate well to exclude the growth curve inconsistency between the samples. Fluorescent staining and flow cytometry measurements were completed within 10 min. Therefore, this approach enabled us to determine antimicrobial resistance for these bacteria within a few hours. Highly sensitive quantitative flow cytometry presents a novel avenue for conducting rapid antimicrobial susceptibility tests.
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http://dx.doi.org/10.1038/s41598-021-82186-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859230PMC
February 2021

Vascular Response Occurring at 3 Months After Everolimus-Eluting Cobalt-Chromium Stent Implantation in Patients With ST-Segment Elevation Myocardial Infarction vs. Stable Coronary Artery Disease.

Circ J 2020 10 2;84(11):1941-1948. Epub 2020 Oct 2.

Iwate Medical University.

Background: Second-generation drug-eluting stents (DES) reduce the incidence of stent thrombosis, even in patients with ST-segment elevated myocardial infarction (STEMI). However, the early local vascular healing after DES implantation in STEMI lesions, which mainly concerns stent thrombosis, is still unclear.Methods and Results:We attempted to determine early local vascular healing 3 months after cobalt-chromium everolimus-eluting stent (CoCr-EES) implantation in STEMI lesions relative to stable coronary artery disease (CAD) lesions. This prospective, multicenter study analyzed 96 total lesions (STEMI=49, stable CAD=51) by frequency domain-optical coherence tomography (FD-OCT) performed post-procedure and at the 3-month follow-up. Although CoCr-EES implanted in STEMI were almost entirely covered at 3 months, they had a relatively high incidence of uncovered struts compared with stable CAD (5.5% vs. 1.6%, P<0.001). Intrastent thrombus in the 2 groups was primarily resolved at the 3-month follow-up (STEMI: 91.7%→26.5%, stable CAD: 74.5%→11.8%). Regarding irregular protrusion, complete resolution was observed in stable CAD (21.6%→0%), while a few stents remained in STEMI (79.2%→8.2%). Although there were almost no changes for the serial change of average lumen area in STEMI, there were slight but significant decreases in stable CAD [STEMI 0.08 (-0.44, 0.55) mm, stable CAD -0.35 (-0.55, 0.11) mm; P=0.009].

Conclusions: Although strut coverage after CoCr-EES implantation for STEMI lesions was slightly delayed, the healing process appeared to be acceptable in both STEMI and stable CAD.
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http://dx.doi.org/10.1253/circj.CJ-20-0264DOI Listing
October 2020

A case report of a perigraft inflammatory reaction to a Viabahn stent-graft: diagnosis with MRI and treatment with steroids.

CVIR Endovasc 2020 Sep 20;3(1):49. Epub 2020 Sep 20.

Division of Cardiovascular Medicine, Department of Internal Medicine, Hyogo Prefectural Himeji Cardiovascular Center, 520, Saisho-Kou, Himeji, Hyogo, 670-0981, Japan.

Background: Perigraft inflammatory reactions to prosthetic graft materials in vascular surgery have been reported; however, to our knowledge, this is the first report of a perigraft inflammatory reaction to a Viabahn stent-graft used in a superficial femoral artery occlusion lesion.

Case Presentation: A 76-year-old man with right leg claudication was diagnosed with a right superficial femoral artery occlusion via contrast-enhanced computed tomography. Endovascular treatment included intravascular ultrasound for passing through the true lumen. A 25-cm Viabahn stent-graft (diameter 5 mm) was implanted. The patient developed pain and local swelling of the right thigh 5 days after endovascular treatment. Blood analysis revealed elevated inflammatory marker levels. Magnetic resonance imaging revealed extensive soft-tissue edema and a high perivascular T2 signal around the right superficial femoral artery. Clinical symptoms resolved within 7 days after initiating steroid therapy, which was gradually decreased and halted after 3 weeks. Follow-up magnetic resonance imaging demonstrated substantially reduced inflammation over the following months.

Conclusions: Perigraft inflammatory reaction to a Viabahn stent-graft implant can be immediately diagnosed via magnetic resonance imaging and treated with steroids to reduce the possibility of stent-graft occlusion.
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http://dx.doi.org/10.1186/s42155-020-00140-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474048PMC
September 2020

Possible mechanism of late lumen enlargement after treatment for de novo coronary lesions with drug-coated balloon.

Int J Cardiol 2020 Dec 22;321:30-37. Epub 2020 Jul 22.

Hyogo Prefectural Himeji Cardiovascular Center, Division of Cardiovascular Medicine, 520, Saisho-Kou, Himeji, Hyogo 670-0981, Japan.

Background: Drug-coated balloon (DCB) treatment for de novo coronary artery disease has demonstrated late lumen enlargement (LLE) in mid-term follow-up and it was considered as clinical benefit; however, its mechanism and the predictive factor remains unclear.

Methods: This study enrolled 46 consecutive patients (54 lesions) treated with DCB, using intravascular ultrasound (IVUS) at the index procedure and at the 9-month follow-up. We measured IVUS parameters at 1-mm intervals and calculated the mean volume of the external elastic membrane (EEM), lumen, and plaque. We calculated the dissection index (DI) defined as summation of the following points, 2: dissection over EEM, 1: intra-EEM dissection, 0: no dissection at every 1-mm interval, and divided by lesion length.

Results: IVUS showed that there was no flow limiting dissection just after DCB treatment, the mean EEM and lumen volume (LV) had significantly increased while mean plaque volume had significantly decreased at 9 months, and 74.1% lesions exhibited LLE. We divided the patients into three groups according to delta mean LV. Mean EEM volume significantly increased and mean plaque volume significantly decreased in the larger and smaller LLE groups, but not in the non-LLE group. The DI was higher in a descending order in the three groups. The multiple regression analysis demonstrated that the DI was the strongest predictor of the change in mean LV.

Conclusions: LLE after DCB treatment may be caused by vessel enlargement and plaque regression. The non-flow limiting larger dissection just after DCB treatment may strongly associate with the intending LLE.
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http://dx.doi.org/10.1016/j.ijcard.2020.07.028DOI Listing
December 2020

[Pneumopericardium 4 Years after Surgery of Thymic Cancer].

Kyobu Geka 2020 Feb;73(2):124-126

Department of Thoracic Surgery, Kouhoukai Takagi Hospital, Okawa, Japan.

A 67-year-old man had undergone thymectomy with partial resection of the left upper lobe and pericardium for thymic cancer. Four years later, he visited our hospital due to chest pain. Chest computed tomography revealed pneumopericardium. Nine months later, surgical treatment was performed due to the development of the left pneumothorax. Air leak was found from the bulla which was partially incarcerated into the pericardial space.
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February 2020

Possible role of EphA4 and VEGFR2 interactions in neural stem and progenitor cell differentiation.

Exp Ther Med 2020 Mar 3;19(3):1789-1796. Epub 2020 Jan 3.

Centre for Tissue Engineering and Regenerative Medicine, Liaocheng People's Hospital, Liaocheng University, Liaocheng, Shandong 252000, P.R. China.

Neural stem and progenitor cells (NSPCs) are important pluripotent stem cells, which have potential applications for cell replacement therapy. Ephrin receptors (Ephs) and angiogenic growth factor receptors have a major impact on the proliferation and differentiation of NSPCs. Potential interactions between EphA4 and vascular endothelial growth factor (VEGF) receptor (VEGFR) 2, and their roles in NSPC differentiation remain unknown. In the present study, mouse embryonic NSPCs were treated with ephrin-A1 or VEGF165 alone as well as with combination treatment (ephrin-A1 + VEGF165). Immunoprecipitation and immunoblot assays demonstrated that wild-type EphA4, but not the EphA4 kinase-dead mutant, interacted with VEGFR2 when overexpressed in 293T cells. This interaction was inhibited by dominant-negative EphA4. The percentage of β-tubulin III (Tuj1), but not glial fibrillary acid protein (GFAP) cells, was increased in the ephrin-A1 + VEGF165 combination group as compared to the VEGF165 alone group in mouse embryonic NSPCs. VEGF165-induced neuronal differentiation was potentiated by ephrin-A1 in NSPCs and ephrin-A1- or VEGF165-stimulated EphA4 and VEGFR2 interactions may mediate the signaling pathway.
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http://dx.doi.org/10.3892/etm.2020.8419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027147PMC
March 2020

Early and Mid-Term Vascular Responses to Optical Coherence Tomography-Guided Everolimus-Eluting Stent Implantation in Stable Coronary Artery Disease.

Can J Cardiol 2019 11 8;35(11):1513-1522. Epub 2019 Aug 8.

Yodogawa Christian Hospital, Osaka, Japan.

Background: Analysis of pooled clinical data has shown the safety of 3 months of dual antiplatelet therapy with everolimus-eluting cobalt-chromium stents (Co-Cr EESs). This study evaluated early and mid-term vascular responses to Co-Cr EESs in patients with stable coronary artery disease.

Methods: The Multicenter Comparison of Early and Late Vascular Responses to Everolimus-Eluting Cobalt-Chromium Stent and Platelet Aggregation Studies in Patients With Stable Angina Managed as Elective Case (MECHANISM-Elective) study (NCT02014818) is a multicenter optical coherence tomography (OCT) registry. Enrolled patients were evaluated by OCT immediately after everolimus-eluting stent implantation were prospectively allocated to 1 month (n = 50) or 3 months (n = 50) OCT follow-up and then received a 12-month OCT evaluation. The incidences of intrastent thrombus (IS-Th) and irregular protrusion (IRP) were also assessed.

Results: The percentage of uncovered struts was 6.4% ± 10.3% at 1 month (P < 0.001 vs. postprocedure) and 0.5% ± 0.9% at 12 months (P < 0.001 vs. 1 month). The corresponding values in the 3-month cohort were 2.0% ± 2.5% (P < 0.001 vs. postprocedure) and 0.5% ± 1.5% (P < 0.001 vs. 3 months). The incidence of IS-Th was 32.7% at 1 month, 5.4% at 3 months, and 2.0% at 12 months. IRP was observed in 21.8% of patients post-EES but had totally resolved at 1, 3, and 12 months.

Conclusion: Early and mid-term vascular reactions after Co-Cr EES implantation in stable patients with coronary artery disease in the MECHANISM-Elective included dynamic resolution of IS-Th and IRP and rapid decrease in uncovered struts. Thus, EES may allow shortening of dual antiplatelet therapy duration less than 3 months in this patient subset.
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http://dx.doi.org/10.1016/j.cjca.2019.07.633DOI Listing
November 2019

Empagliflozin's Ameliorating Effect on Plasma Triglycerides: Association with Endothelial Function Recovery in Diabetic Patients with Coronary Artery Disease.

J Atheroscler Thromb 2020 Jul 18;27(7):644-656. Epub 2019 Oct 18.

Hyogo Prefectural Himeji Cardiovascular Center, Division of Cardiovascular Medicine.

Aim: So far, the mechanisms behind the cardiovascular benefits of sodium/glucose cotransporter 2 (SGLT2) inhibitors have not been fully clarified.

Methods: In order to evaluate the effects of SGLT2 inhibitors on systemic hemodynamics, glucose metabolism, lipid profile, and endothelial function, 50 diabetic patients with established coronary artery disease (CAD) were included in this analysis and were given empagliflozin 10 mg/d. Cookie meal testing (carbohydrates: 75 g, fats: 28.5 g), endothelial function testing using flow-mediated dilatation (FMD), and body composition evaluation were performed before and after six months of treatment. Changes in %FMD between the treatment periods and its association with metabolic biomarkers were evaluated.

Results: After six months of treatment, the body weight and body fat percentage decreased significantly, while the body muscle percentage increased significantly. The hemoglobin A1c level and fasting and postprandial plasma glucose levels were significantly decreased with treatment. Postprandial insulin secretion was also significantly suppressed and the insulin resistance index was significantly decreased. Furthermore, the fasting and postprandial triglyceride (TG) levels decreased significantly, while total ketone bodies increased significantly after the six-month treatment. While the plasma brain natriuretic peptide level was not changed, the C-reactive protein level was decreased and FMD was significantly improved after the six-month treatment. Multiple regression analysis showed that the strongest predictive factor of FMD improvement is change in the plasma TG levels.

Conclusion: SGLT2 inhibitors improve multiple metabolic parameters. Of these, a reduction in plasma TGs was strongly associated with endothelial function recovery in diabetic patients with CAD, and this reduction may be related to the cardiovascular benefits of SGLT2 inhibitors.
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http://dx.doi.org/10.5551/jat.50807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406405PMC
July 2020

Clinical and immune profiling for cancer of unknown primary site.

J Immunother Cancer 2019 09 13;7(1):251. Epub 2019 Sep 13.

Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.

Background: Immune checkpoint inhibitors (ICIs) confer a survival benefit in many cancer types. Given that the survival outcome for cancer of unknown primary site (CUP) remains poor, we investigated the potential of CUP for immunotherapy.

Methods: A total of 164 patients with CUP (favorable subset, 34 patients; unfavorable subset, 130 patients) who were treated between January 2009 and March 2017 was identified from a review of medical records at Kindai University Hospital. They included 92 patients for whom pretreatment tumor tissue was available both for determination of programmed cell death-ligand 1 expression and tumor-infiltrating lymphocyte (TIL) density by immunohistochemistry (IHC) and for immune-related gene expression profiling (irGEP). The results of irGEP for CUP were compared with published data for ICI-treated solid cancers classified into progressive disease (PD) and non-PD subsets according to their best response to ICIs.

Results: The median overall survival of all CUP patients was 29.3 months (95% confidence interval [CI], 15.7-not reached) and 7.1 months (95% CI, 5.0-9.4) for favorable and unfavorable subsets, respectively. IHC and irGEP revealed that pretreatment immune activity-including expression of immune checkpoint molecules-for CUP was similar to that for ICI-responsive malignancies (antitumor immune cell signatures: CUP versus PD, P = 0.002-0.067; CUP versus non-PD, P = 0.591-0.999), although VEGFA expression was associated with suppression of antitumor immunity in CUP (P = 0.008, false discovery rate = 0.010). In addition, one case of CUP in the unfavorable subset that was associated with prominent PD-L1 expression on TILs and showed a durable response to nivolumab is presented.

Conclusions: The survival outcome of CUP remains unsatisfactory. However, our clinical and immune profiling of CUP has revealed a potential to benefit from immunotherapy, with ICIs thus being a potential option for CUP treatment.
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http://dx.doi.org/10.1186/s40425-019-0720-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743146PMC
September 2019

Preventing brain embolism by using a modified isolation technique in transcatheter aortic valve implantation for a patient with shaggy and porcelain aorta.

J Cardiol Cases 2019 Aug 1;20(2):65-68. Epub 2019 May 1.

Department of Cardiovascular Surgery, Hyogo Brain and Heart Center at Himeji, Himeji, Hyogo, Japan.

Transcatheter aortic valve implantation (TAVI) has become a useful and effective treatment for surgical high-risk patients with severe aortic valve stenosis (AS). Stroke is one of the most frequent complications associated with TAVI. Shaggy and porcelain aortas are a risk factor for procedure-related strokes. Preventing brain embolism is one of the most important goals in patients with diseased aortas. We present a case where we performed TAVI in an 89-year-old man with severe AS, a shaggy aorta, a porcelain aorta, and congestive heart failure. TAVI via a transfemoral approach was performed using a modified isolation technique with cannulation from bilateral axillary arteries and cardiopulmonary bypass to prevent brain embolism. The catheter-delivered embolic protection device is necessary to pass the diseased aorta, but the modified isolation technique can be used without any contact with the shaggy aorta. Embolism did not occur, and his heart failure improved immediately. < Transcatheter aortic valve implantation (TAVI) is a therapeutic option for patients with severe aortic stenosis considered to be at high risk for aortic valve replacement. Cerebral embolism is the most frequent complication of TAVI. A shaggy or porcelain aorta is associated with a high risk of stroke during TAVI. We report a case of TAVI in a shaggy and porcelain aorta and prevention of cerebral embolism by adopting a modified isolation technique without using conventional protection devices.>.
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http://dx.doi.org/10.1016/j.jccase.2019.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698247PMC
August 2019

Targeted next-generation sequencing of cancer-related genes in thyroid carcinoma: A single institution's experience.

Oncol Lett 2018 Dec 2;16(6):7278-7286. Epub 2018 Oct 2.

Department of Biology and Genetics, Laboratory of Cancer Medical Science, Hokuto Hospital, Obihiro, Hokkaido 080-0833, Japan.

Thyroid carcinoma (TC) has characteristic genetic alterations, including point mutations in proto-oncogenes and chromosomal rearrangements that vary by histologic subtype. Recent developments in next-generation sequencing (NGS) technology enable simultaneous analysis of cancer-associated genes of interest, thus improving diagnostic accuracy and allowing precise personalized treatment for human cancer. A total of 50 patients who underwent thyroidectomy between 2014 and 2016 at Hokuto Hospital were enrolled. Total DNA was extracted from formalin-fixed, paraffin-embedded tissue sections and quantified. Targeted regions of 24 cancer-associated genes were amplified by PCR, barcoded and sequenced using an Illumina MiSeq platform. Subjects included 30 patients with papillary carcinoma (PC), two with PC tall cell variant (TVPC), two with PC follicular variant (FVPC), eight with follicular carcinoma, seven with poorly differentiated carcinoma (PDC), and one with anaplastic carcinoma (AC). The V600E mutation was present in 25 of 30 (83%) patients with PC, 2 of 2 (100%) patients with TVPC, 6 of 7 (86%) patients of PDC, and one patient with AC. mutations were present in 3 of 30 (delPV104P, A1046T and C420R; 10%) patients with PC and 1 of 7 (H1047R; 14%) patients with PDC. The mutation was present in 1 of 30 (R306*; 3.3%) patients with PC and 1 of 7 (Q152*; 14%) patients with PDC. The mutation was present in 1 of 2 (Q61K, 50%) patients with FVPC. Statistical analysis showed that patients without the V600E mutation had advanced pathologic T and N stages compared with those with the mutation (P=0.047 and P=0.019, respectively). The V600E mutation was not correlated with overall and disease-free survival in patients with PC. A patient with PC with a mutation in (K852Q) and the mutation had an aggressive course with multiple bone and lung metastases. Detection of mutations in cancer-associated genes using NGS could enhance the understanding of the clinical behavior of TC.
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http://dx.doi.org/10.3892/ol.2018.9538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256352PMC
December 2018

[Primary Lung Cancer Initially Suspected of Pulmonary Extranodal Marginal Zone Lymphoma of Mucosa Associated Lymphoid Tissue(MALT)].

Kyobu Geka 2018 11;71(12):1013-1017

Department of General Thoracic Surgery, Fukuoka Higashi Medical Center, Koga, Japan.

Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is associated with pre-existing infections or autoimmune disorders. We report a case of lung cancer initially suspected of MALT lymphoma. The patient was a 73-year-old woman. Complete screening examinations identified a tumor in the right middle lobe. Transbronchial lung biopsy revealed the infiltration of CD20+/CD79a+ lymphocytes invading the structure of the alveolus. MALT lymphoma was suspected, and the middle lobe was resected. The tumor was primarily invasive mucinous carcinoma, and lymphocytic infiltration was observed around the tumor. The monoclonal expansion of B cells and genetic and chromosomal abnormalities which are criteria for the diagnosis of MALT lymphoma were not demonstrated and the lesion was diagnosed as reactive lymphoid infiltrates. Marked lymphocytic infiltration regardless of neoplastic or reactive may suggest the presence of latent lesions.
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November 2018

MexEF-OprN multidrug efflux pump transporter negatively controls N-acyl-homoserine lactone accumulation in pseudomonas syringae pv. Tabaci 6605.

Mol Genet Genomics 2018 Aug 16;293(4):907-917. Epub 2018 Mar 16.

Graduate School of Environmental and Life Science, Okayama University, Tsushima-naka 1-1-1, Kita-ku, Okayama, 700-8530, Japan.

Our previous studies revealed that flagellar-motility-defective mutants such as ∆fliC of Pseudomonas syringae pv. tabaci 6605 (Pta6605) have remarkably reduced production of N-acyl-homoserine lactones (AHL), quorum-sensing molecules. To investigate the reason of loss of AHL production in ∆fliC mutant, we carried out transposon mutagenesis. Among approximately 14,000 transconjugants, we found 11 AHL production-recovered (APR) strains. In these APR strains, a transposon was inserted into either mexE or mexF, genes encoding for the multidrug efflux pump transporter MexEF-OprN, and mexT, a gene encoding a putative transcriptional activator for mexEF-oprN. These results suggest that MexEF-OprN is a negative regulator of AHL production. To confirm the negative effect of MexEF-OprN on AHL production, loss- and gain-of-function experiments for mexEF-oprN were carried out. The ∆fliC∆mexF and ∆fliC∆mexT double mutant strains recovered AHL production, whereas the mexT overexpressing strain abolished AHL production, although the psyI, a gene encoding AHL synthase, is transcribed as wild type. Introduction of a mexF or mexT mutation into another flagellar-motility- and AHL production-defective mutant strain, ∆motCD, also recovered the ability to produce AHL. Furthermore, introduction of the mexF mutation into other AHL production-defective mutant strains such as ∆gacA and ∆aefR also recovered AHL production but not to the ∆psyI mutant. These results indicate that MexEF-OprN is a decisive negative determinant of AHL production and accumulation.
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http://dx.doi.org/10.1007/s00438-018-1430-9DOI Listing
August 2018

Comparison of the 9-month intra-stent conditions and 2-year clinical outcomes after Resolute zotarolimus-eluting stent implantation between 3-month and standard dual antiplatelet therapy.

J Cardiol 2018 07 16;72(1):66-73. Epub 2018 Feb 16.

Hyogo Prefectural Himeji Cardiovascular Center, Division of Cardiovascular Medicine, Himeji, Hyogo, Japan.

Background: The use of short-duration dual antiplatelet therapy (DAPT) remains controversial. To investigate efficacy and safety of short-duration DAPT, we performed a detailed comparison of intra-stent conditions by optical coherence tomography (OCT) after second-generation drug-eluting stent implantation with short-term and standard DAPT.

Methods And Results: Eighty-two consecutive patients with stable angina pectoris who received Resolute zotarolimus-eluting stents (R-ZESs; Medtronic Cardiovascular, Santa Rosa, CA, USA) were enrolled. Patients were assigned to 3-month (3M group: 41 patients) and standard (standard group: 41 patients) DAPT. In the 3M group, clopidogrel was discontinued 3 months after stent implantation. In the standard group, DAPT was maintained until follow-up OCT. At 9 months, neointimal proliferation was significantly larger in the 3M group, but there were no significant between-group differences in the proportion of uncovered and malapposed strut. The prevalence of abnormal intra-stent tissue (AIT) at 9 months was equivalent between groups. A multiple regression analysis revealed malapposition at 9 months as the strongest independent predictor of AIT at 9 months, and the prevalence of AIT was not associated with DAPT duration. Over 2 years, cardiac events were equal between groups; however, major bleeding was higher tendency in the standard group than in the 3M group.

Conclusion: This OCT study indicated that reducing DAPT's duration may provide acceptable arterial healing in patients with implanted R-ZESs.
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http://dx.doi.org/10.1016/j.jjcc.2018.01.006DOI Listing
July 2018

Monocyte chemoattractant protein 1 expression and proliferation in primary central nervous system lymphoma.

Oncol Lett 2017 Jul 4;14(1):264-270. Epub 2017 May 4.

Department of Neurosurgery, Hokuto Hospital, Obihiro, Hokkaido 080-0033, Japan.

Whether the poor prognosis of primary central nervous system lymphoma (PCNSL) compared with systemic diffuse large B cell lymphoma (DLBCL) is attributable to the immune privilege of the intracerebral location or to intrinsic differences in the biological characteristics of two types of lymphoma remains unclear. Monocyte chemoattractant protein 1 (MCP-1) is essential to support tumor cell survival and growth, and the present study aimed to compare MCP-1 expression in PCNSL and peripheral DLBCL. The present study included 19 patients with PCNSL and 16 patients with DLBCL, all of whom had tissue diagnosis and lymphoma tissue samples available for analysis. Histology included immunohistochemistry using antibodies against a panel of lymphoma markers, antibodies specific to MCP-1, and antibodies specific to tumor-associated macrophages. MCP-1 expression was quantified using immunostaining scoring. RNA extraction and reverse transcription-quantitative polymerase chain reaction were used to determine mRNA expression. In addition, a human brain-derived lymphoma cell line, HKBML, was stimulated with MCP-1 and cell proliferation was measured by 5-bromo-2'-deoxyuridine incorporation. The expression levels of mRNA and MCP-1 protein were significantly increased in PCNSL compared with peripheral DLBCL. MCP-1 induced tyrosine phosphorylation of mitogen-activated protein kinase in HKBML cells, as analyzed by western blotting. The results of the present study indicated that MCP-1 expression in PCNSL promoted cell proliferation in an autocrine manner.
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http://dx.doi.org/10.3892/ol.2017.6122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494900PMC
July 2017

Molecular interactions of EphA4, growth hormone receptor, Janus kinase 2, and signal transducer and activator of transcription 5B.

PLoS One 2017 7;12(7):e0180785. Epub 2017 Jul 7.

Department of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.

We previously reported that EphA4, a member of the Eph family of receptor tyrosine kinases, is an important modulator of growth hormone (GH) signaling, leading to augmented synthesis of insulin-like growth factor 1 (IGF1) for postnatal body growth. In the present study, we report the molecular interactions of EphA4, GH receptor (GHR), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 5B (STAT5B). EphA4 binds to GHR at both its extracellular and intracellular domains and phosphorylates GHR when stimulated with a ligand. The cytoplasmic domain of EphA4 binds to the carboxy-terminus of JAK2 in contrast to the known binding of GHR to the amino-terminus. STAT5B binds to the amino-terminal kinase domain of EphA4. Ligand-activated EphA4 and JAK2 phosphorylate each other and STAT5B, but JAK2 does not appear to phosphorylate EphA4-bound STAT5B. Ligand-activated EphA4 induces the nuclear translocation of STAT5B in a JAK2-independent manner. GHR expression is required for the activation of STAT5B signaling, even via the JAK2-independent pathway. Various ephrins that have affinity for EphA4 induce STAT5B phosphorylation. These findings suggest the molecular mechanisms by which ephrin/EphA4 signaling enhances the canonical GH-IGF1 axis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180785PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501605PMC
September 2017

[Benign Metastasizing Leiomyoma of the Lung;Report of a Case].

Kyobu Geka 2017 Feb;70(2):143-146

Department of Thoracic Surgery, Takagi Hospital, Okawa, Japan.

A 71-year-old woman, in whom computed tomography revealed a solitary mass shadow at the base of the left lung, underwent resection of the mass. Histopathological examination showed estrogen receptor-positive leiomyoma cells growing in cords and mixed with glandular structures composed of alveolar cells. These findings led to a diagnosis of benign metastatic leiomyoma. Benign metastatic leiomyoma is a rare disease in which histologically benign uterine leiomyoma cells metastasize to different sites of the body. However, in this patient, the presence of uterine myoma was not confirmed in the past or at present. She had a history of cervical conization, which suggests that a small amount of the leiomyoma component contained in cervical tissue may have been forced into blood vessels during surgical manipulation, causing lung metastasis.
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February 2017

Longitudinal strain combined with delayed-enhancement magnetic resonance improves risk stratification in patients with dilated cardiomyopathy.

Heart 2017 05 31;103(9):679-686. Epub 2016 Oct 31.

Himeji Cardiovascular Center, Himeji, Japan.

Objective: Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging has been reported to be associated with unfavourable outcomes; however, few studies have addressed the prognostic value of left ventricular (LV) deformation parameter indicated by global longitudinal strain (GLS) in two-dimensional speckle-tracking (2DST) echocardiography in patients with non-ischaemic dilated cardiomyopathy (DCM). This study aims to investigate whether the combination of GLS and LGE is useful in stratifying the risk in patients with DCM.

Methods: We studied 179 consecutive symptomatic patients with DCM (age, 61±15 years; 121 males; left ventricular ejection fraction (LVEF) 33%±9%; New York Heart Association (NYHA) class II: n=71, III: n=107, IV: n=1) who underwent CMR and echocardiography with conventional assessment and 2DST analysis.

Results: There were 40 rehospitalisations for heart failure, including 7 cardiac deaths and 2 implantations of LV assist device during follow-up (3.8±2.5 years). Univariable Cox proportional hazard regression analysis showed that NYHA class, blood pressure, B-type natriuretic peptide, LV end-diastolic and end-systolic volumes, LVEF, left atrium volume, GLS and LGE were significantly associated with long-term outcome. Multivariable analysis revealed that GLS and LGE were independently associated with long-term outcome (p<0.05, both). In additional analyses, we found independent associations between GLS and LV reverse remodelling after the optimal medical therapy, and between LGE and life-threatening arrhythmias (p<0.05, both).

Conclusion: Combining GLS and LGE could be useful for risk stratification and prognostic assessment in patients with DCM.
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http://dx.doi.org/10.1136/heartjnl-2016-309746DOI Listing
May 2017

Effects of 6-month eicosapentaenoic acid treatment on postprandial hyperglycemia, hyperlipidemia, insulin secretion ability, and concomitant endothelial dysfunction among newly-diagnosed impaired glucose metabolism patients with coronary artery disease. An open label, single blinded, prospective randomized controlled trial.

Cardiovasc Diabetol 2016 08 26;15(1):121. Epub 2016 Aug 26.

Division of Cardiovascular Medicine, Department of Internal Medicine, Hyogo Prefectural Himeji Cardiovascular Center, 520 Saisho-Kou, Himeji, Hyogo, 670-0981, Japan.

Background: Recent experimental studies have revealed that n-3 fatty acids, such as eicosapentaenoic acid (EPA) regulate postprandial insulin secretion, and correct postprandial glucose and lipid abnormalities. However, the effects of 6-month EPA treatment on postprandial hyperglycemia and hyperlipidemia, insulin secretion, and concomitant endothelial dysfunction remain unknown in patients with impaired glucose metabolism (IGM) and coronary artery disease (CAD).

Methods And Results: We randomized 107 newly diagnosed IGM patients with CAD to receive either 1800 mg/day of EPA (EPA group, n = 53) or no EPA (n = 54). Cookie meal testing (carbohydrates: 75 g, fat: 28.5 g) and endothelial function testing using fasting-state flow-mediated dilatation (FMD) were performed before and after 6 months of treatment. The primary outcome of this study was changes in postprandial glycemic and triglyceridemic control and secondary outcomes were improvement of insulin secretion and endothelial dysfunction. After 6 months, the EPA group exhibited significant improvements in EPA/arachidonic acid, fasting triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C). The EPA group also exhibited significant decreases in the incremental TG peak, area under the curve (AUC) for postprandial TG, incremental glucose peak, AUC for postprandial glucose, and improvements in glycometabolism categorization. No significant changes were observed for hemoglobin A1c and fasting plasma glucose levels. The EPA group exhibited a significant increase in AUC-immune reactive insulin/AUC-plasma glucose ratio (which indicates postprandial insulin secretory ability) and significant improvements in FMD. Multiple regression analysis revealed that decreases in the TG/HDL-C ratio and incremental TG peak were independent predictors of FMD improvement in the EPA group.

Conclusions: EPA corrected postprandial hypertriglyceridemia, hyperglycemia and insulin secretion ability. This amelioration of several metabolic abnormalities was accompanied by recovery of concomitant endothelial dysfunction in newly diagnosed IGM patients with CAD. Clinical Trial Registration UMIN Registry number: UMIN000011265 ( https://www.upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000013200&language=E ).
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http://dx.doi.org/10.1186/s12933-016-0437-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002116PMC
August 2016

Cutaneous Leukocytoclastic Vasculitis Associated with Erlotinib.

Indian J Dermatol 2016 Mar-Apr;61(2):238

Department of Respiratory Medicine, Otsu Municipal Hospital, 2-9-9, Motomiya, Otsu, Shiga 520-0804, Japan.

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http://dx.doi.org/10.4103/0019-5154.177793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817483PMC
April 2016

Lower-leg Cellulitis-like Manifestations of Erythema Nodosum Induced by Chlamydophila pneumoniae Infection.

Indian J Dermatol 2016 Mar-Apr;61(2):237

Department of General Medicine, Otsu Municipal Hospital, 2-9-9, Motomiya, Otsu, Shiga, 520-0804, Japan.

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http://dx.doi.org/10.4103/0019-5154.177786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817480PMC
April 2016
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