論文 - 宮崎 泰可
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Okuno D., Oshima K., Miyazaki T., Ashizawa N., Hirayama T., Takazono T., Saijo T., Yamamoto K., Imamura Y., Yamaguchi H., Sakamoto N., Obase Y., Izumikawa K., Yanagihara K., Mukae H.
Clinical Case Reports 9 ( 2 ) 707 - 710 2021年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Clinical Case Reports
The treatment duration for candidemia with septic pulmonary embolism should be determined based on the clearance of fungus from the bloodstream and improvement of symptoms. The remaining lung nodules may not necessarily indicate persistent infection.
DOI： 10.1002/ccr3.3628
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Ota Y, Obata Y, Takazono T, Tashiro M, Wakamura T, Takahashi A, Shiozawa Y, Miyazaki T, Nishino T, Izumikawa K.
BMC Nephrol 22 ( 1 ) 240 2021年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：BMC Nephrology
Background: Hypokalemia and acute kidney injury (AKI) occur in patients administered liposomal amphotericin B (L-AMB), a wide-spectrum anti-fungicidal drug. However, the association between potassium supplementation and the occurrence of AKI in patients with hypokalemia who were administered L-AMB is not well understood. Methods: Using nationwide claims data and laboratory data, the occurrence of AKI during L-AMB treatment was retrospectively compared between patients with hypokalemia who were or were not supplemented with potassium and between those adequately or inadequately supplemented with potassium (serum potassium levels corrected to ≥3.5 mEq/L or remained < 3.5 mEq/L, respectively) before or after L-AMB treatment initiation. Results: We identified 118 patients who developed hypokalemia before L-AMB treatment initiation (43 received potassium supplementation [25 adequate and 18 inadequate supplementation] and 75 did not receive potassium supplementation), and 117 patients who developed hypokalemia after L-AMB initiation (79 received potassium supplementation [including 23 adequate and 15 inadequate supplementation] and 38 did not receive potassium supplementation). The occurrence of any stage of AKI was similar between patients with hypokalemia, regardless of potassium supplementation (i.e., before L-AMB treatment initiation [supplementation, 51%; non-supplementation, 45%; P = 0.570] or after L-AMB initiation [supplementation, 28%; non-supplementation, 32%; P = 0.671]). After adjusting for confounding factors, we found that the occurrence of any stage of AKI was not associated with potassium supplementation before L-AMB initiation (odds ratio [OR]: 1.291, 95% confidence interval [CI]: 0.584–2.852, P = 0.528) or after L-AMB initiation (OR: 0.954, 95% CI: 0.400–2.275, P = 0.915). The occurrence of any stage of AKI tended to decline in patients with hypokalemia who were adequately supplemented with potassium (44%) before, but not after, L-AMB initiation relative to that in patients inadequately supplemented with potassium (61%), however this result was not significant (P = 0.358). Conclusion: Potassium supplementation was not associated with any stage of AKI in patients with hypokalemia who were administered L-AMB.
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Ota K, Yanagihara K, Sasaki D, Kaku N, Uno N, Sakamoto K, Kosai K, Miyazaki T, Hasegawa H, Fujita A, Tashiro M, Tanaka T, Izumikawa K, Ariyoshi K, Mukae H, Yasuda J, Morita K, Kohno S.
PLoS One 16 ( 6 ) e0252964 2021年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：PLoS ONE
Objectives The accurate detection of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is essential for the diagnosis of coronavirus disease 2019 (COVID-19). We compared the quantitative RT-PCR results between nasopharyngeal swabs and saliva specimens. Methods A COVID-19 outbreak occurred on a cruise ship at Nagasaki port, Japan. We obtained 123 nasopharyngeal swabs and saliva each from asymptomatic or mild patients in the late phase of infection. Results The intervals from the diagnosis to the sampling were 25.5 days for nasopharyngeal swabs and 28.9 days for saliva. The positive rate was 19.5% (24/123) for nasopharyngeal swabs and 38.2% (47/123) for saliva (P = 0.48). The quantified viral copies (mean ± SEM copies/ 5 μl) were 9.3±2.6 in nasopharyngeal swabs and 920±850 in saliva (P = 0.0006). Conclusions The advantages of saliva specimens include positive rate improvement and accurate viral load detection. Saliva may be used as a reliable sample for SARS-CoV-2 detection.
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Dotsu Y, Fukuda M, Honda N, Gyotoku H, Kohno Y, Suyama T, Umeyama Y, Taniguchi H, Takemoto S, Yamaguchi H, Miyazaki T, Sakamoto N, Obase Y, Ikeda H, Ashizawa K, Mukae H.
Thorac Cancer 12 ( 2 ) 272 - 276 2021年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Thoracic Cancer
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this “oldest old” elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
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Hirayama T., Miyazaki T., Sumiyoshi M., Ashizawa N., Takazono T., Yamamoto K., Imamura Y., Izumikawa K., Yanagihara K., Kohno S., Mukae H.
Pathogens 10 ( 1 ) 1 - 9 2021年1月
担当区分：責任著者 記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Pathogens
Gastrointestinal colonization by Candida species is considered the main source of candidemia. The ERG3 gene in Candida albicans encodes a sterol C5,6-desaturase, which is essential for ergosterol biosynthesis. Although ERG3 inactivation shows reduced virulence in mouse models of disseminated candidiasis, the role of ERG3 in intestinal infections is unknown. Here, we infected mice with the C. albicans strains CAE3DU3 and CAF2-1, containing mutant and wild-type ERG3, respectively, and studied gut infection and colonization by these strains. We found that the CAE3DU3 strain showed reduced colonization, pathogenesis, damage to gut mucosa, and chemokine production in the mouse model of invasive candidiasis. Additionally, mice inoculated with CAE3DU3 showed lower mortality than mice inoculated with CAF2-1 (p < 0.0001). Chemokines were less induced in the gut inoculated with CAE3DU3 than in the gut inoculated with CAF2-1. Histopathologically, although the wild-type gene was associated with a higher pathogenicity and invasion of the gut mucosa and liver tissues causing remarkable tissue necrosis, the erg3/erg3 mutant was associated with a higher accumulation of cells and lower damage to surrounding tissues than wild-type ERG3. These results establish that the ergosterol biosynthetic pathway may be associated with C. albicans gut colonization and subsequent dissemination.
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Klionsky D.J., Abdel-Aziz A.K., Abdelfatah S., Abdellatif M., Abdoli A., Abel S., Abeliovich H., Abildgaard M.H., Abudu Y.P., Acevedo-Arozena A., Adamopoulos I.E., Adeli K., Adolph T.E., Adornetto A., Aflaki E., Agam G., Agarwal A., Aggarwal B.B., Agnello M., Agostinis P., Agrewala J.N., Agrotis A., Aguilar P.V., Ahmad S.T., Ahmed Z.M., Ahumada-Castro U., Aits S., Aizawa S., Akkoc Y., Akoumianaki T., Akpinar H.A., Al-Abd A.M., Al-Akra L., Al-Gharaibeh A., Alaoui-Jamali M.A., Alberti S., Alcocer-Gómez E., Alessandri C., Ali M., Alim Al-Bari M.A., Aliwaini S., Alizadeh J., Almacellas E., Almasan A., Alonso A., Alonso G.D., Altan-Bonnet N., Altieri D.C., Álvarez É.M.C., Alves S., Alves da Costa C., Alzaharna M.M., Amadio M., Amantini C., Amaral C., Ambrosio S., Amer A.O., Ammanathan V., An Z., Andersen S.U., Andrabi S.A., Andrade-Silva M., Andres A.M., Angelini S., Ann D., Anozie U.C., Ansari M.Y., Antas P., Antebi A., Antón Z., Anwar T., Apetoh L., Apostolova N., Araki T., Araki Y., Arasaki K., Araújo W.L., Araya J., Arden C., Arévalo M.A., Arguelles S., Arias E., Arikkath J., Arimoto H., Ariosa A.R., Armstrong-James D., Arnauné-Pelloquin L., Aroca A., Arroyo D.S., Arsov I., Artero R., Asaro D.M.L., Aschner M., Ashrafizadeh M., Ashur-Fabian O., Atanasov A.G., Au A.K., Auberger P., Auner H.W., Aurelian L.
Autophagy 17 ( 1 ) 1 - 382 2021年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Autophagy
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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Okuno D., Kido T., Muramatsu K., Tokutsu K., Moriyama S., Miyamura T., Hara A., Ishimoto H., Yamaguchi H., Miyazaki T., Sakamoto N., Obase Y., Ishimatsu Y., Fujino Y., Yatera K., Matsuda S., Mukae H.
Journal of Clinical Medicine 10 ( 3 ) 1 - 10 2021年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Clinical Medicine
Influenza pneumonia, which causes acute respiratory distress syndrome and multiple organ failure, has no established management protocol. Recently, corticosteroid therapy was used to treat coronavirus disease 2019 with respiratory failure; however, its effectiveness as a treatment for influenza pneumonia remains controversial. To investigate the impact of corticosteroid therapy for the early phase of severe influenza pneumonia, we compared influenza pneumonia patients with respiratory failure treated with or without corticosteroids within 7 days after hospital admission using a Japanese nationwide administrative database. The primary endpoint was the mortality rate. The secondary endpoints were duration of intensive-care unit management, invasive mechanical ventilation, and hospital stay. The inverse probability weighting method with estimated propensity scores was used to minimize the data collection bias. We included 3519 patients with influenza pneumonia with respiratory failure. Of these, 875 were treated with corticosteroids. There was no significant difference between the groups regarding 30-day and 90-day mortality, duration of intensive-care unit management, invasive mechanical ventilation, and hospital stay. However, the in-hospital mortality rate was higher in the corticosteroid group. The use of systematic corticosteroid therapy in patients with influenza pneumonia was associated with a higher in-hospital mortality rate.
DOI： 10.3390/jcm10030494
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Takazono T., Tashiro M., Ota Y., Obata Y., Wakamura T., Miyazaki T., Nishino T., Izumikawa K.
Scientific Reports 10 ( 1 ) 2020年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
Liposomal amphotericin B (L-AMB) is a broad-spectrum antifungal drug that is used to treat fungal infections. However, clinical evidence of its use in patients with renal failure is limited. Here, we aimed to identify factors associated with acute kidney injury (AKI) in patients administered L-AMB. We retrospectively utilized a combination of Diagnosis Procedure Combination data and laboratory data obtained from hospitals throughout Japan between April 2008 and January 2018. In total, 507 patients administered L-AMB were identified. After L-AMB treatment initiation, AKI, which was defined as a ≥ 1.5-fold increase within 7 days or ≥ 0.3 mg/dL increase within 2 days in serum creatinine according to the KDIGO criteria, was recognized in 37% of the total patients (189/507). The stages of AKI were stage 1 in 20%, stage 2 in 11%, and stage 3 in 7%. Five factors were associated with AKI of all stages: prior treatment with angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers or carbapenem; concomitant administration of catecholamines or immunosuppressants; and ≥ 3.52 mg/kg/day of L-AMB dosing. Serum potassium < 3.5 mEq/L before L-AMB therapy was associated with severe AKI of stage 2 and 3. Altogether, these factors should be carefully considered to reduce the occurrence of AKI in patients administered L-AMB.
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Hirayama T., Miyazaki T., Ito Y., Wakayama M., Shibuya K., Yamashita K., Takazono T., Saijo T., Shimamura S., Yamamoto K., Imamura Y., Izumikawa K., Yanagihara K., Kohno S., Mukae H.
Scientific Reports 10 ( 1 ) 2020年12月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
Gastrointestinal colonization has been considered as the primary source of candidaemia; however, few established mouse models are available that mimic this infection route. We therefore developed a reproducible mouse model of invasive candidiasis initiated by fungal translocation and compared the virulence of six major pathogenic Candida species. The mice were fed a low-protein diet and then inoculated intragastrically with Candida cells. Oral antibiotics and cyclophosphamide were then administered to facilitate colonization and subsequent dissemination of Candida cells. Mice infected with Candida albicans and Candida tropicalis exhibited higher mortality than mice infected with the other four species. Among the less virulent species, stool titres of Candida glabrata and Candida parapsilosis were higher than those of Candida krusei and Candida guilliermondii. The fungal burdens of C. parapsilosis and C. krusei in the livers and kidneys were significantly greater than those of C. guilliermondii. Histopathologically, C. albicans demonstrated the highest pathogenicity to invade into gut mucosa and liver tissues causing marked necrosis. Overall, this model allowed analysis of the virulence traits of Candida strains in individual mice including colonization in the gut, penetration into intestinal mucosa, invasion into blood vessels, and the subsequent dissemination leading to lethal infections.
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Roles of Elm1 in antifungal susceptibility and virulence in Candida glabrata 査読あり
Ito Y., Miyazaki T., Tanaka Y., Suematsu T., Nakayama H., Morita A., Hirayama T., Tashiro M., Takazono T., Saijo T., Shimamura S., Yamamoto K., Imamura Y., Izumikawa K., Yanagihara K., Kohno S., Mukae H.
Scientific Reports 10 ( 1 ) 2020年12月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
Elm1 is a serine/threonine kinase involved in multiple cellular functions, including cytokinesis, morphogenesis, and drug resistance in Saccharomyces cerevisiae; however, its roles in pathogenic fungi have not been reported. In this study, we created ELM1-deletion, ELM1-reconstituted, ELM1-overexpression, and ELM1-kinase-dead strains in the clinically important fungal pathogen Candida glabrata and investigated the roles of Elm1 in cell morphology, stress response, and virulence. The elm1Δ strain showed elongated morphology and a thicker cell wall, with analyses of cell-wall components revealing that this strain exhibited significantly increased chitin content relative to that in the wild-type and ELM1-overexpression strains. Although the elm1Δ strain exhibited slower growth than the other two strains, as well as increased sensitivity to high temperature and cell-wall-damaging agents, it showed increased virulence in a Galleria mellonella-infection model. Moreover, loss of Elm1 resulted in increased adhesion to agar plates and epithelial cells, which represent important virulence factors in C. glabrata. Furthermore, RNA sequencing revealed that expression levels of 30 adhesion-like genes were elevated in the elm1Δ strain. Importantly, all these functions were mediated by the kinase activity of Elm1. To our knowledge, this is the first report describing the functional characterization of Elm1 in pathogenic fungi.
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Novel and potent antimicrobial effects of caspofungin on drug-resistant Candida and bacteria 査読あり
Sumiyoshi M., Miyazaki T., Makau J.N., Mizuta S., Tanaka Y., Ishikawa T., Makimura K., Hirayama T., Takazono T., Saijo T., Yamaguchi H., Shimamura S., Yamamoto K., Imamura Y., Sakamoto N., Obase Y., Izumikawa K., Yanagihara K., Kohno S., Mukae H.
Scientific Reports 10 ( 1 ) 2020年12月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
Echinocandins, including caspofungin, micafungin, and anidulafungin, are first-line antifungal agents for the treatment of invasive candidiasis. They exhibit fungicidal activity by inhibiting the synthesis of β-1,3-d-glucan, an essential component of the fungal cell wall. However, they are active only against proliferating fungal cells and unable to completely eradicate fungal cells even after a 24 h drug exposure in standard time-kill assays. Surprisingly, we found that caspofungin, when dissolved in low ionic solutions, had rapid and potent antimicrobial activities against multidrug-resistant (MDR) Candida and bacteria cells even in non-growth conditions. This effect was not observed in 0.9% NaCl or other ion-containing solutions and was not exerted by other echinocandins. Furthermore, caspofungin dissolved in low ionic solutions drastically reduced mature biofilm cells of MDR Candida auris in only 5 min, as well as Candida-bacterial polymicrobial biofilms in a catheter-lock therapy model. Caspofungin displayed ion concentration-dependent conformational changes and intracellular accumulation with increased reactive oxygen species production, indicating a novel mechanism of action in low ionic conditions. Importantly, caspofungin dissolved in 5% glucose water did not exhibit increased toxicity to human cells. This study facilitates the development of new therapeutic strategies in the management of catheter-related biofilm infections.
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Nagayoshi Y., Yamamoto K., Sato S., Suyama N., Izumikawa T., Izumikawa K., Miyazaki T., Izumikawa K., Yanagihara K., Mukae H.
Geriatrics and Gerontology International 20 ( 12 ) 1138 - 1144 2020年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Geriatrics and Gerontology International
Aim: Clostridioides difficile infection worsens the outcome of older hospitalized patients; thus, its diagnosis is necessary for the nosocomial infection control. The standard diagnostic test's limited sensitivity for Clostridioides difficile infection, an enzyme immunoassay for Clostridioides difficile toxins, is of clinical concern. Glutamate dehydrogenase detection is usually tested combined with Clostridioides difficile toxins. However, the clinical significance of a positive glutamate dehydrogenase result is unclear. We evaluated the association between positive glutamate dehydrogenase results, in-hospital mortality and hospital stay length among older patients with suspected Clostridioides difficile infection. Methods: In this retrospective cohort study, we examined the data of patients who received antibiotics (except for Clostridioides difficile infection treatment) after admission and tested for Clostridioides difficile infection using an enzyme immunoassay for Clostridioides difficile toxins and glutamate dehydrogenase in a secondary care hospital located in a rural region with high aging rate, between 2015 and 2018. Results: In total, 188 patients were included (83.5% of them aged >75 years). Glutamate dehydrogenase positivity was independently associated with in-hospital mortality (adjusted odds ratio 2.19, 95% confidence interval 1.14–4.21) and hospital stay length (regression coefficient 16.0, 95% confidence interval 5.15–26.9). Clostridioides difficile toxin positivity was independently associated with hospital stay duration (regression coefficient 14.5, 95% confidence interval 0.04–29.1), unlike in-hospital mortality. Conclusions: Glutamate dehydrogenase was closely related to in-hospital mortality and prolonged hospitalization compared with Clostridioides difficile toxin. Clinicians should not neglect glutamate dehydrogenase-positive patients, even when they are Clostridioides difficile toxin-negative, and consider them as having poor prognostic potential. Geriatr Gerontol Int 2020; 20: 1138–1144.
DOI： 10.1111/ggi.14054
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Takazono T., Imamura Y., Kawakami K., Yamasaki N., Shimizu H., Usuki K., Kiyohara M., Hirayama T., Tashiro M., Hosogaya N., Saijo T., Yamamoto K., Miyazaki T., Yanagihara K., Izumikawa K., Mukae H.
Respiratory Investigation 58 ( 6 ) 488 - 494 2020年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Respiratory Investigation
Background: Before advance care planning, it is essential to understand the differences in preferences for medical care of terminal-phase pneumonia in elderly patients among the patients, their families, and their doctors. This study aimed to clarify these differences and investigate the actual care provided to elderly patients with pneumonia in nursing hospitals. Methods: Multicenter questionnaire surveys of 179 patients admitted to nursing homes and long-term care beds in hospitals of three healthcare corporations, their families, and their physicians were conducted between January and August 2018. The questionnaires mainly assessed preferences for life-prolonging medical care procedures, including antibiotic treatments, in terminal-phase pneumonia. A follow-up survey regarding the prognosis and the actual care provided by the physicians was conducted 1 year after the first survey. Results: Only 16.2% of the patients had sufficient prior discussions with their families about their care. More families preferred cardiac massage, intubation, and tracheostomy, while fewer families preferred peripheral intravenous fluids or antibiotics than physicians. A total of 30 patients’ families (16.7%) answered to withhold antibiotic treatment, while all physicians supported antibiotic administration. The only significant factor related to withholding antibiotics was high age (P = 0.0057). The follow-up survey administered to the doctors revealed that 49 patients (35.7%) had died within one year. Of the 137 patients, 54 patients (39.4%) had developed pneumonia during this observation period and all were treated with antibiotics. Conclusions: This study revealed large discrepancies between patients/families and physicians regarding preferences for care. Medical staff should make efforts to fill the gap by ensuring advance care planning.
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Hayashi F., Kido T., Sakamoto N., Zaizen Y., Ozasa M., Yokoyama M., Yura H., Hara A., Ishimoto H., Yamaguchi H., Miyazaki T., Obase Y., Ishimatsu Y., Eishi Y., Fukuoka J., Mukae H.
Medicina (Lithuania) 56 ( 11 ) 1 - 12 2020年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Medicina (Lithuania)
Background: Chronic beryllium disease (CBD) is a granulomatous disease that resembles sarcoidosis but is caused by beryllium. Clinical manifestations similar to those observed in CBD have occasionally been reported in exposure to dusts of other metals. However, reports describing the clinical, radiographic, and pathological findings in conditions other than beryllium-induced granulomatous lung diseases, and detailed information on mineralogical analyses of metal dusts, are limited. Case presentation: A 51-year-old Japanese man with rapidly progressing nodular shadows on chest radiography, and a 10-year occupation history of underground construction without beryllium exposure, was referred to our hospital. High-resolution computed tomography showed well-defined multiple centrilobular and perilobular nodules, and thickening of the intralobular septa in the middle and lower zones of both lungs. No extrathoracic manifestations were observed. Pathologically, the lung specimens showed 5-12 mm nodules with dust deposition and several non-necrotizing granulomas along the lymphatic routes. X-ray analytical electron microscopy of the same specimens revealed aluminum, iron, titanium, and silica deposition in the lung tissues. The patient stopped smoking and changed his occupation to avoid further dust exposure; the chest radiography shadows decreased 5 years later. Conclusion: The radiological appearances of CBD and sarcoidosis are similar, although mediastinal or hilar lymphadenopathy is less common in CBD and is usually seen in the presence of parenchymal opacities. Extrathoracic manifestations are also rare. Despite limited evidence, these findings are similar to those observed in pneumoconiosis with a sarcoid-like reaction due to exposure to dust other than of beryllium. Aluminum is frequently detected in patients with pneumoconiosis with a sarcoid-like reaction and is listed as an inorganic agent in the etiology of sarcoidosis. It was also detected in our patient and may have contributed to the etiology. Additionally, our case suggests that cessation of dust exposure may contribute to improvement under the aforementioned conditions.
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Yoshida M., Tashiro M., Nishi K., Mishima M., Kawano K., Takazono T., Saijo T., Yamamoto K., Imamura Y., Miyazaki T., Kudo T., Yanagihara K., Mukae H., Izumikawa K.
Medical Mycology 58 ( 7 ) 965 - 972 2020年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Medical Mycology
There is an urgent need for development of better diagnostic strategies to improve outcomes in patients with invasive pulmonary aspergillosis (IPA). We hypothesized that lung perfusion single-photon emission computed tomography (SPECT) may be more sensitive and specific than computed tomography (CT) of the chest for detection of IPA because it is an angioinvasive pulmonary infection with characteristics that are different from those of bacterial pneumonia. We used SPECT with injection of technetium-99m-labeled macroaggregated albumin ([99mTc]MAA) to measure pulmonary perfusion in noninfected mice, mice with IPA, and mice with bacterial pneumonia. Histopathologic analysis was performed to evaluate the correlation between the perfusion defect and mould invasion. We also attempted to quantitatively evaluate the SPECT images to identify differences in decreased perfusion levels in affected areas in the mouse lung. Histopathologic analysis in the IPA mouse model showed a clear match between areas with a perfusion defect and the presence of mold, indicating that the location of the perfusion defect on a SPECT image reflects angioinvasion of the mould in the lungs. Some of these perfusion defects could be seen before appearance of the infiltrate of CT images. Quantitative analysis confirmed that perfusion in the affected areas was significantly decreased in the IPA model but not in the bacterial pneumonia model (P < .0001). This imaging method may be preferable to the alternative methods presently used to identify the presence of mold in a patient’s lungs.
DOI： 10.1093/mmy/myz131
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Nakano Y., Tashiro M., Urano R., Kikuchi M., Ito N., Moriya E., Shirahige T., Mishima M., Takazono T., Miyazaki T., Izumikawa K.
Journal of Infection and Chemotherapy 26 ( 10 ) 1021 - 1025 2020年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Infection and Chemotherapy
Due to the increase in the number of azole-resistant Aspergillus fumigatus, there is an urgent need of data to predict future trends and prevent further spreading. The intercountry transfer of resistant A. fumigatus on plant bulbs have been reported. We investigated existence and characteristics of resistant isolates attached to agricultural products imported to Japan. We purchased 292 samples in Japan. All samples were screened for the existence of azole-resistant A. fumigatus. For positive isolates, minimum inhibitory concentrations of the drugs were determined. We also analyzed Cyp51A, Hmg1, and Erg6 mutations of these isolates and conducted microsatellite genotyping. Fourteen azole-resistant isolates were detected, of which 13 were cultured from flower bulbs imported from the Netherlands. Among them 5 were from 11 bulbs of Hippeastrum (45.5%), 5 were from 24 bulbs of Gladiolus (20.8%), 2 were from 4 bulbs of Ixia (50.0%), and 1 was from 22 bulbs of Tulipa (4.5%). Only 1 resistant isolate was cultured from the 10 bulbs of Narcissus (10.0%) originating in Japan. Various novel mutations including Y121F/T289A in Cyp51A with no tandem repeat in promoter region were discovered from imported strains. Our study provides important data showing that agricultural imports provide a possible route for their intercontinental spread and raises the concern that strains harboring highly diverse Cyp51A mutations might increase in clinical settings in the future.
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Small molecule inhibitor of HSP47 prevents pro-fibrotic mechanisms of fibroblasts in vitro 査読あり
Miyamura T., Sakamoto N., Kakugawa T., Taniguchi H., Akiyama Y., Okuno D., Moriyama S., Hara A., Kido T., Ishimoto H., Yamaguchi H., Miyazaki T., Obase Y., Ishimatsu Y., Tanaka Y., Mukae H.
Biochemical and Biophysical Research Communications 530 ( 3 ) 561 - 565 2020年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical and Biophysical Research Communications
Excessive extracellular matrix deposition, in particular collagen, is an important cause of lung fibrosis. Heat shock protein 47 (HSP47), a collagen-binding protein, plays an important role in the intracellular processing of procollagen. A small molecule that blocks the collagen chaperone function of HSP47 has been reported as an HSP47 inhibitor. The aim of this study was to assess the effect of the HSP47 inhibitor on collagen synthesis and other fibrotic process in vitro. We evaluated collagen expression by western blot, and determined cell viability and migration by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and scratch test, respectively, in human and mouse lung fibroblasts. Treatment of lung fibroblasts with HSP47 siRNA decreased collagen type I expression. Similarly, the HSP47 inhibitor decreased collagen type I expression in transforming growth factor beta 1 (TGF-β1)-treated lung fibroblasts in a dose-dependent manner. The inhibitor also decreased the viability and cell migration ability of TGF-β1-treated lung fibroblasts. Overall, we demonstrated that HSP47 is a potential therapeutic target for pulmonary fibrosis. The small molecule HSP47 inhibitor may mediate antifibrotic effects by suppressing the overexpression of collagen, and inhibiting the viability and migration of fibroblasts. Further research is needed to clarify the therapeutic potential of this HSP47 inhibitor for pulmonary fibrosis.
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Miyamura T., Sakamoto N., Ishida K., Kakugawa T., Taniguchi H., Akiyama Y., Okuno D., Hara A., Kido T., Ishimoto H., Miyazaki T., Matsumoto K., Tsuchiya T., Yamaguchi H., Miyazaki T., Obase Y., Ishimatsu Y., Nagayasu T., Mukae H.
Respiratory Research 21 ( 1 ) 2020年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Respiratory Research
Background: Heat shock protein 47 (HSP47), a collagen-binding protein, has a specific role in the intracellular processing of procollagen production. HSP47 expression is associated with cancer growth and metastasis in several types of cancers. However, none of the studies have assessed whether HSP47 expression is associated with the risk of postoperative recurrence of lung cancer until now. Therefore, we aimed to assess this association. Methods: The study population consisted of a cohort of consecutive patients who underwent surgery for lung cancer at Nagasaki University Hospital, Nagasaki, Japan, from January 2009 to December 2010. Patient characteristics, survival and disease-free survival (DFS), and laboratory findings were compared between patients who tested positive and negative for HSP47 expression in lung cancer cells and between those who showed high and low numbers of HSP47-positive fibroblasts in cancer stroma. Results: A total of 133 patients underwent surgery for lung cancer. Sixty-seven patients (50.4%) had HSP47-positive cancer cells, and 91 patients (68.4%) had a higher number of HSP47-positive fibroblasts. The patients with a high number of HSP47-positive fibroblasts had a shorter DFS than those with a low number of HSP47-positive fibroblasts. Multivariate analysis identified only the presence of a high number of HSP47-positive fibroblasts as an independent risk factor for recurrence of lung cancer after surgery (odds ratio, 4.371; 95% confidence interval, 1.054-29.83; P = 0.042). Conclusion: The present study demonstrated that the presence of a high number of HSP47-positive fibroblasts in the cancer stroma was a risk factor for recurrence of lung cancer after surgery.
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Hamada Y., Ueda T., Miyazaki Y., Nakajima K., Fukunaga K., Miyazaki T., Nakada-Motokawa N., Nagao M., Kawamura H., Shigemi A., Ebihara F., Kimura T., Ikegame K., Uchino M., Ikeuchi H., Takesue Y.
Mycoses 63 ( 8 ) 779 - 786 2020年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Mycoses
Background: Hepatotoxicity and visual symptoms are common adverse effects (AEs) of voriconazole therapy. Objective: To retrospectively evaluate the effects of treatment modification based on therapeutic drug monitoring on AEs in patients undergoing voriconazole therapy. Methods: The target voriconazole trough concentration (Cmin) was 1-5 µg/mL. Receiver operating characteristic curves were used to determine Cmin cut-offs for AEs. Results: A total of 401 patients were included. Among 108 patients with high initial Cmin, voriconazole was discontinued in 32 and the dose was reduced in 71. Among 44 patients with low initial Cmin, voriconazole was discontinued in 4 and the dose was increased in 19. Hepatotoxicity occurred in 6.0% of patients, after a median of 10 days. Visual symptoms were evident in 9.5% of patients after a median of 4 days. Initial Cmin was significantly associated with visual symptoms but not hepatotoxicity, which suggested the effect of treatment modification on hepatotoxicity. However, both hepatotoxicity and visual symptoms were significantly correlated with Cmin at the onset of AEs, and the Cmin cut-offs were 3.5 μg/mL for hepatotoxicity and 4.2 μg/mL for visual symptoms. Voriconazole was discontinued after the occurrence of AEs in 62.5% of patients with hepatotoxicity but only 26.3% of patients with visual symptoms. With dose adjustment, treatment was completed in 8/9 patients with hepatotoxicity and 27/28 patients with visual symptoms. Conclusions: A significant preventive effect was demonstrated on hepatotoxicity, but not on visual symptoms because of earlier occurrence. With treatment modification after the occurrence of AEs, most patients completed therapy.
DOI： 10.1111/myc.13129
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Akagi K., Yamamoto K., Umemura A., Ide S., Hirayama T., Takazono T., Imamura Y., Miyazaki T., Sakamoto N., Shiraishi H., Takahata H., Zaizen Y., Fukuoka J., Morikawa M., Ashizawa K., Teruya K., Izumikawa K., Mukae H.
AIDS Research and Therapy 17 ( 1 ) 2020年7月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：AIDS Research and Therapy
Background: Vacuolar encephalomyelopathy, a disregarded diagnosis lately, was a major neurological disease in the terminal stages of human immunodeficiency virus (HIV)-1 infection in the pre-antiretroviral therapy (ART) era. Granulomatous-lymphocytic interstitial lung disease (GLILD) was classically identified as a non-infectious complication of common variable immunodeficiency; however, it is now being recognized in other immunodeficiency disorders. Here, we report the first case of GLILD accompanied by vacuolar encephalomyelopathy in a newly diagnosed HIV-infected man. Case presentation: A 40-year-old Japanese man presented with chronic dry cough and progressing paraplegia. Radiological examination revealed diffuse pulmonary abnormalities in bilateral lungs, focal demyelinating lesions of the spinal cord, and white matter lesions in the brain. He was diagnosed with GLILD based on marked lymphocytosis detecting in bronchoalveolar lavage, and transbronchial-biopsy proven T-cellular interstitial lung disease with granulomas. Microbiological examinations did not reveal an etiologic agent. The patient was also diagnosed with HIV-associated vacuolar encephalomyelopathy on the basis of an elevated HIV viral load in cerebrospinal fluid. After initiating ART, the brain lesions and paraplegia improved significantly, and interstitial abnormalities of the lungs and cough disappeared. Conclusion: This report highlights that even in the post-ART era in developed countries with advanced healthcare services, HIV-associated vacuolar encephalomyelopathy should be considered in the differential diagnosis of a progressive neurological disorder during the first visit. Furthermore, GLILD may represent an HIV-associated pulmonary manifestation that can be treated by ART.