Publications by authors named "Yoshiko Tsuchihashi"

20 Publications

  • Page 1 of 1

Development of cycling probe based real-time PCR methodology for influenza A viruses possessing the PA/I38T amino acid substitution associated with reduced baloxavir susceptibility.

Antiviral Res 2021 04 10;188:105036. Epub 2021 Feb 10.

Division of International Health (Public Health), Graduate School of Medical and Dental Sciences, Niigata University, Niigata City, Japan; Infectious Diseases Research Center of Niigata University in Myanmar, Yangon, Yangon Region, Myanmar.

Baloxavir marboxil has been used for influenza treatment since March 2018 in Japan. After baloxavir treatment, the most frequently detected substitution is Ile38Thr in polymerase acidic protein (PA/I38T), and this substitution reduces baloxavir susceptibility in influenza A viruses. To rapidly investigate the frequency of PA/I38T in influenza A (H1N1)pdm09 and A (H3N2) viruses in clinical samples, we established a rapid real-time system to detect single nucleotide polymorphisms in PA, using cycling probe real-time PCR. We designed two sets of probes that were labeled with either 6-carboxyfluorescein (FAM) or 6-carboxy-X-rhodamine (ROX) to identify PA/I38 (wild type strain) or PA/I38T, respectively. The established cycling probe real-time PCR system showed a dynamic linear range of 10 to 10 copies with high sensitivity in plasmid DNA controls. This real-time PCR system discriminated between PA/I38T and wild type viruses well. During the 2018/19 season, 377 influenza A-positive clinical samples were collected in Japan before antiviral treatment. Using our cycling probe real-time PCR system, we detected no (0/129, 0.0%) influenza A (H1N1)pdm09 viruses with PA/I38T substitutions and four A (H3N2) (4/229, 1.7%) with PA/I38T substitution prior to treatment. In addition, we found PA/I38T variant in siblings who did not received baloxavir treatment during an infection caused by A (H3N2) that afflicted the entire family. Although human-to-human transmission of PA/I38T variant may have occurred in a closed environment, the prevalence of this variant in influenza A viruses was still limited. Our cycling probe-PCR system is thus useful for antiviral surveillance of influenza A viruses possessing PA/I38T.
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http://dx.doi.org/10.1016/j.antiviral.2021.105036DOI Listing
April 2021

Effectiveness of the quadrivalent inactivated influenza vaccine in Japan during the 2015-2016 season: A test-negative case-control study comparing the results by real time PCR, virus isolation.

Vaccine X 2019 Apr 29;1:100011. Epub 2019 Jan 29.

Division of International Health, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: We estimated influenza vaccine effectiveness (VE) in 2015-2016 season against medically attended, laboratory-confirmed influenza, when quadrivalent inactivated vaccine (IIV4) was first introduced in Japan, using test-negative case-control design. Influenza A(H1N1)pdm09 cocirculated with B/Yamagata and B/Victoria during the study period in Japan.

Method: We based our case definition on two laboratory tests, real-time reverse transcription polymerase chain reaction (RT PCR), and virus isolation and compared VEs based on these tests. In addition, VE was evaluated by rapid diagnostic test (RDT). Nasopharyngeal swabs were collected from outpatients who visited clinics with influenza-like illness (ILIs) in Hokkaido, Niigata, Gunma and Nagasaki prefectures.

Results: Among 713 children and adults enrolled in this study, 578 were influenza positive by RT PCR including, 392 influenza A and 186 influenza B, while 135 were tested negative controls. The adjusted VE by RT PCR for all ages against any influenza was low protection of 36.0% (95% confidence interval [CI], 3.1% to 58.6%), for influenza A was 30.0% (95% CI: -10.0% to 55.5%), and influenza B was moderate 50.2% (95% CI: 13.3% to 71.4%). Adjusted VE for virus isolation for A(H1N1)pdm09 was 37.1% (95% CI: 1.7% to 59.7%), Yamagata lineage 51.3% (95% CI: 6.4% to 74.7%) and Victoria lineage 21.3% (95% CI: -50.0% to 58.9%). VE was highest and protective in 0-5 years old group against any influenza and influenza A and B/Yamagata, but the protective effect was not observed for other age groups and B/Victoria. RDT demonstrated concordant results with RT PCR and virus isolation. Sequencing of hemagglutinin gene showed that all A(H1N1)pdm09 belong to clade 6B including 31 strains (88.6%), which belong to clade 6B.1 possessing S162N mutations that may alter antigenicity and affect VE for A(H1N1)pdm09.

Conclusions: IIV4 influenza vaccine during 2015-2016 was effective against A(H1N1)pdm09 and the two lineages of type B. Younger children was more protected than older children and adults by vaccination.
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http://dx.doi.org/10.1016/j.jvacx.2019.100011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668230PMC
April 2019

Accuracy of High-Throughput Nanofluidic PCR-Based Pneumococcal Serotyping and Quantification Assays Using Sputum Samples for Diagnosing Vaccine Serotype Pneumococcal Pneumonia: Analyses by Composite Diagnostic Standards and Bayesian Latent Class Models.

J Clin Microbiol 2018 05 25;56(5). Epub 2018 Apr 25.

Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan

The lack of reliable diagnostic tests for detecting vaccine serotype pneumococcal pneumonia (VTPP) remains a challenging issue in pneumococcal vaccine studies. This study assessed the performances of high-throughput nanofluidic PCR-based pneumococcal serotyping and quantification assay methods using sputum samples (the nanofluidic sputum quantitative PCR [Sp-qPCR] assay) to diagnose 13-valent pneumococcal conjugate VTPP compared with the performance of the serotype-specific urinary antigen detection (UAD) assay using urine samples. Adult pneumonia patients from Japan were enrolled in this study between September 2012 and August 2014. Sputum samples were subjected to the nanofluidic Sp-qPCR assay, quantitatively cultured, and serotyped by the Quellung reaction (SpQt). Urine samples were tested by the UAD method. The diagnostic performances of these tests were assessed using composite reference standards and Bayesian latent class models (BLCMs). Among 244 total patients, 27 (11.1%) tested positive with the UAD assay, while 16 (6.6%) and 34 (13.9%) tested positive with the SpQt and nanofluidic Sp-qPCR assays, respectively, with a cutoff value of ≥10 DNA copies/ml, which showed the maximum value of the Youden index. Using BLCMs, the estimated prevalence for VTPP was 12.9%, and the nanofluidic Sp-qPCR assay demonstrated the best performance (sensitivity, 90.2%; specificity, 96.9%), followed by UAD (sensitivity, 75.6%; specificity, 97.9%) and SpQt (sensitivity, 45.8%; specificity, 99.5%). However, when a higher cutoff value of ≥10 DNA copies/ml was applied, the performance of UAD became comparable to that of Sp-qPCR. The vaccine serotype-specific pneumococcal DNA load in sputum among UAD-positive patients was 3 logs higher than that among UAD-negative patients ( = 0.036). The nanofluidic Sp-qPCR assay may be accurate and useful for detecting VTPP among adults.
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http://dx.doi.org/10.1128/JCM.01874-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925721PMC
May 2018

A Semiquantitative Computed Tomographic Grading System for Evaluating Therapeutic Response in Pulmonary Alveolar Proteinosis.

Ann Am Thorac Soc 2017 Sep;14(9):1403-1411

1 Department of Internal Medicine.

Rationale: A useful semiquantitative method of using computed tomographic (CT) images to evaluate therapeutic response in pulmonary alveolar proteinosis (PAP) has not been established, although the extent score or grading score of ground-glass opacities has been used.

Objectives: The purpose of this study was to establish a semiquantitative method for evaluating therapeutic response in PAP.

Methods: CT scans were obtained within 1 month before and after therapy from 32 patients with PAP who participated in a multicenter phase II trial of granulocyte-macrophage colony-stimulating factor inhalation therapy. The scans were evaluated by two chest radiologists independently. Increased parenchymal opacity was evaluated on the basis of its intensity and extent (CT grade), and the severity scores were compared with CT scores based on the extent alone (CT extent), as well as on the basis of physiological and serological results.

Results: CT grade score and CT extent score had significant correlation with diffusing capacity of the lung for carbon monoxide percent predicted (%Dl), Pa, VC percent predicted (%VC), Krebs von den Lungen (KL)-6, and surfactant protein D. The change in CT grade score between pre- and post-treatment examinations (ΔCT grade) correlated better with difference of Pa between pre- and post-treatment examinations (ΔPa) than ΔCT extent (difference of CT extent score between pre- and post-treatment examinations). In univariate analysis, ΔCT grade, ΔCT extent, ΔKL-6, Δ%Dl, Δ%VC, and change in surfactant protein D correlated significantly with ΔPa. In multivariate analysis, ΔCT grade and ΔKL-6 correlated more closely with ΔPa.

Conclusions: Although a number of CT variables were collected, the currently proposed grading system that correlates well with Pa should be viewed as a retrospective scoring system that needs future validation with another PAP cohort.
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http://dx.doi.org/10.1513/AnnalsATS.201607-574OCDOI Listing
September 2017

Recurrence of pulmonary alveolar proteinosis after bilateral lung transplantation in a patient with a nonsense mutation in CSF2RB.

Respir Med Case Rep 2016 13;19:89-93. Epub 2016 Aug 13.

Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata, Japan.

Hereditary pulmonary alveolar proteinosis (PAP) caused by mutations in CSF2RA or CSF2RB, which encode GM-CSF receptor α and β respectively, is a rare disease. Although some experimental therapeutic strategies have been proposed, no clinical evidence has yet been reported. We herein describe the clinical course and recurrence of hereditary PAP after lung transplantation. A 36-year-old woman developed PAP of unknown etiology. She underwent bilateral lung transplantation from living donors at the age of 42 years because of severe respiratory failure complicated by pulmonary fibrosis. However, PAP recurred after 9 months, and we found that donor-origin alveolar macrophages had been almost completely replaced with recipient-origin macrophages. We performed a genetic analysis and identified a point deletion in the CSF2RB gene that caused a GM-CSF receptor-mediated signaling defect. PAP progressed with fibrosis in both transplanted lungs, and the patient died of respiratory failure 5 years after the lung transplantation. Distinct from recent reports on pulmonary macrophage transplantation in mice, this case suggests that human alveolar macrophages might not maintain their population only by self-renewal but may depend on a supply of precursor cells from the circulation. Bone marrow transplantation should be considered for treatment of severe PAP with GM-CSF receptor gene deficiency.
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http://dx.doi.org/10.1016/j.rmcr.2016.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995526PMC
September 2016

Duration of benefit in patients with autoimmune pulmonary alveolar proteinosis after inhaled granulocyte-macrophage colony-stimulating factor therapy.

Chest 2014 Apr;145(4):729-737

Niigata University Medical and Dental Hospital, Niigata. Electronic address:

Background: Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by subcutaneous injection or inhaled therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to be safe and efficacious in several reports. However, some reports of subcutaneous injection described transient benefit in most instances. The durability of response to inhaled GM-CSF therapy is not well characterized.

Methods: To elucidate the risk factors for recurrence of aPAP after GM-CSF inhalation, 35 patients were followed up, monitoring for the use of any additional PAP therapies and disease severity score every 6 months. Physiologic, serologic, and radiologic features of the patients were analyzed for the findings of 30-month observation after the end of inhalation therapy.

Results: During the observation, 23 patients remained free from additional treatments, and twelve patients required additional treatments. There were no significant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, %VC) were higher among those who required additional treatment (P<.01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A significant difference in the time to additional treatment between the high %VC group (%VC≥80.5) and the low %VC group was seen by a Kaplan-Meier analysis and a log-rank test (P<.0005).

Conclusions: These results demonstrate that inhaled GM-CSF therapy sustained remission of aPAP in more than one-half of cases, and baseline %VC might be a prognostic factor for disease recurrence.

Trial Registry: ISRCTN Register and JMACCT Clinical Trial Registry; No.: ISRCTN18931678 and JMAIIA00013; URL: http://www.isrctn.org and http://www.jmacct.med.or.jp.
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http://dx.doi.org/10.1378/chest.13-0603DOI Listing
April 2014

[A case of pacemaker-lead infection by linezolid-resistant methicillin-resistant Staphylococcus aureus in a hemodialysis patient].

Kansenshogaku Zasshi 2012 Nov;86(6):778-83

Department of Infectious Diseases, Nagasaki University Hospital.

A 76-year-old woman undergoing hemodialysis and having a permanent pacemaker during care elsewhere developed a shunt infection with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Vancomycin (VCM) and other antimicrobial agents were not effective even after her artificial shunt vessel was removed. Linezolid (LZD) was administered for 56 days to resolve fever. MRSA was detected repeatedly in blood culture for 7 months except while LZD was being administered, so she was referred to our hospital for further investigation and treatment. Blood culture isolated 3 MRSA strains, all having a minimum inhibitory concentration (MIC) of LZD above 16 microg/mL while that of VCM varied at 24 microg/mL. Based on these findings, combined VCM, rifampicin, and arbekacin therapy was started but did not resolve the MRSA bacteremia problem. Transesophageal echocardiography showed flat vegetation around the pacemaker lead passing through the tricuspid valve. Based on strongly suspected pacemaker-lead infection, the pacemaker system was removed by heart surgeons using radiographic imaging on day 16 after admission. Her blood culture then became negative. She was returned to the previous hospital on day 66 after admission, where combination antibiotic therapy was continued for about one month. MRSA was not detected again after pacemaker system removal.
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http://dx.doi.org/10.11150/kansenshogakuzasshi.86.778DOI Listing
November 2012

Transbronchial biopsy using endobronchial ultrasonography with a guide sheath increased the diagnostic yield of peripheral pulmonary lesions.

Intern Med 2012 1;51(5):455-60. Epub 2012 Mar 1.

Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Japan.

Objective: The advantage of transbronchial biopsy (TBB) using endobronchial ultrasonography (EBUS) with a guide sheath (GS) over TBB without EBUS guidance was investigated in this study.

Materials And Methods: A retrospective chart review was conducted at Nagasaki University Hospital, Japan. Data were collected from all cases of peripheral pulmonary lesions (PPLs) undergoing either EBUS-GS-guided TBB or TBB without EBUS guidance in our department from December 2003 through November 2009. The diagnostic yield in each group was compared, after adjustment for other factors.

Results: In total 110 PPLs were investigated in 102 patients: 65 (59.1%) were examined with EBUS-GS-guided TBB (EBUS-GS group) and 45 (40.9%) were TBB without EBUS guidance (non-EBUS group). Both procedures were performed under x-ray fluoroscopy. Basic characteristics were similar between the two groups. Of all EBUS examined lesions, 53 (81.5%) were visualized by EBUS. The diagnostic yields in EBUS-GS group and non-EBUS group were 64.6% and 46.7%, respectively (p=0.08). Adjusting for size and location of lesions, the yield of EBUS-GS guidance was 1.46 (95% confidence interval 1.03 to 2.05) times higher than without EBUS guidance. When the lesion was visualized by EBUS, the diagnostic yield ratio was further increased to 1.63 (95% CI 1.16 to 2.27).

Conclusion: EBUS-GS-guided TBB demonstrates a higher diagnostic yield than TBB without EBUS guidance.
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http://dx.doi.org/10.2169/internalmedicine.51.6358DOI Listing
July 2012

Direct evidence that GM-CSF inhalation improves lung clearance in pulmonary alveolar proteinosis.

Respir Med 2012 Feb 22;106(2):284-93. Epub 2011 Nov 22.

Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Niigata 951-8520, Japan.

Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is caused by granulocyte/macrophage-colony stimulating factor (GM-CSF) autoantibodies in the lung. Previously, we reported that GM-CSF inhalation therapy improved alveolar-arterial oxygen difference and serum biomarkers of disease severity in these patients. It is plausible that inhaled GM-CSF improves the dysfunction of alveolar macrophages and promotes the clearance of the surfactant. However, effect of the therapy on components in bronchoalveolar lavage fluid (BALF) remains unclear.

Objectives: To figure out changes in surfactant clearance during GM-CSF inhalation therapy.

Methods: We performed retrospective analyses of BALF obtained under a standardized protocol from the same bronchus in each of 19 aPAP patients before and after GM-CSF inhalation therapy (ISRCTN18931678, JMA-IIA00013; total dose 10.5-21 mg, duration 12-24 weeks). For evaluation, the participants were divided into two groups, high responders with improvement in alveolar-arterial oxygen difference ≥13 mmHg (n = 10) and low responders with that < 13 mmHg (n = 9).

Results: Counts of both total cells and alveolar macrophages in BALF did not increase during the therapy. However, total protein and surfactant protein-A (SP-A) were significantly decreased in high responders, but not in low responders, suggesting that clearance of surfactant materials is correlated with the efficacy of the therapy. Among 94 biomarkers screened in bronchoalveolar lavage fluid, we found that the concentration of interleukin-17 and cancer antigen-125 were significantly increased after GM-CSF inhalation treatment.

Conclusions: GM-CSF inhalation decreased the concentration of total protein and SP-A in BALF, and increase interleukin-17 and cancer antigen-125 in improved lung of autoimmune pulmonary alveolar proteinosis.
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http://dx.doi.org/10.1016/j.rmed.2011.10.019DOI Listing
February 2012

Living-donor lobar lung transplantation for pulmonary alveolar proteinosis in an adult: report of a case.

Surg Today 2011 Aug 20;41(8):1142-4. Epub 2011 Jul 20.

Division of Surgical Oncology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.

A 43-year-old woman with pulmonary alveolar proteinosis (PAP) was successfully treated with living-donor lobar lung transplantation (LDLLT). The patient's PAP had been diagnosed at age 35. She had been treated with repeated bronchoalveolar lavage and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy despite having no serum anti-GM-CSF autoantibodies. At age 42, her respiratory condition became critical and she underwent transplantation from two donors. While careful observation was needed for the recurrence of PAP in the transplanted lungs, she was functioning well without oxygen therapy 1 year after transplantation. This appears to be the first report of LDLLT for PAP in an adult.
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http://dx.doi.org/10.1007/s00595-010-4411-0DOI Listing
August 2011

Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB.

J Med Genet 2011 Mar 12;48(3):205-9. Epub 2010 Nov 12.

Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.

Background: Disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signalling causes pulmonary alveolar proteinosis (PAP). Rarely, genetic defects in neonatal or infant-onset PAP have been identified in CSF2RA. However, no report has clearly identified any function-associated genetic defect in CSF2RB.

Methods And Results: The patient was diagnosed with PAP at the age of 36 and developed respiratory failure. She was negative for GM-CSF autoantibody and had no underlying disease. Signalling and genetic defects in GM-CSF receptor were screened. GM-CSF-stimulated STAT5 phosphorylation was not observed and GM-CSF-Rβc expression was defective in the patient's blood cells. Genetic screening revealed a homozygous, single-base deletion at nt 631 in exon 6 of CSF2RB on chromosome 22, which caused reductions in GM-CSF dependent signalling and function. Both parents, who were second cousins, showed no pulmonary symptoms, and had normal GM-CSF-signalling, but had a CSF2RB allele with the identical deletion, indicating that the mutant allele may give rise to PAP in an autosomal recessive manner.

Conclusions: This is the first report identifying a genetic defect in CSF2RB that causes deficiency of GM-CSF-Rβc expression and impaired signalling downstream. These results suggested that GM-CSF signalling was compensated by other signalling pathways, leading to adult-onset PAP.
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http://dx.doi.org/10.1136/jmg.2010.082586DOI Listing
March 2011

[An autopsied case of pulmonary clear cell adenocarcinoma].

Nihon Kokyuki Gakkai Zasshi 2010 May;48(5):364-9

Department of Respiratory Medicine, Chikamori Hospital, Chikamori-kai Medical Corporation.

We report a case of a 72-year-old woman who died of primary lung clear cell adenocarcinoma. She was an active smoker, but with no other significant previous medical abnormalities. She visited our hospital with complaining of hemoptysis lasting for a month. Her sputum production and coughing had also increased. Chest X-ray films showed obstructive pneumonia in the left lower lobe. Chest computed tomography (CT) showed a tumor shadow and collapsed portion in the left hilar area. Sputum cytology and further diagnostic tests revealed stage IV lung adenocarcinoma. Chemotherapy with carboplatin and paclitaxel was initiated, but no improvement was obtained. She died from progressive cancer invasion into the airway. An autopsy revealed that more than 90% of the cancer cells were clear cells. These cancer calls were positive for PAS and occasionally showed Alcian blue-positive intracytoplasmic mucin and glandular structures. They were immunocytochemically stained with cytokeratin 7 but not with cytokeratin 20. According to previous reports in the literature, cases of primary lung clear cell adenocarcinoma are very rare.
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May 2010

Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis.

Am J Respir Crit Care Med 2010 Jun 18;181(12):1345-54. Epub 2010 Feb 18.

Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Niigata, Japan.

Rationale: Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied.

Objectives: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP.

Methods: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa(O(2)) of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO(2)] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 microg Days 1-8, none Days 9-14; x six cycles; 12 wk); low-dose therapy (125 microg Days 1-4, none Days 5-14; x six cycles; 12 wk), and follow-up (52 wk).

Measurements And Main Results: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO(2) of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO(2) and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year.

Conclusions: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN18931678), www.jmacct.med.or.jp/english (JMA-IIA00013).
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http://dx.doi.org/10.1164/rccm.200906-0978OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2894410PMC
June 2010

[A case of pulmonary nocardiosis with simultaneous identification of N. farcinica and N. cyriacigeorgica].

Nihon Kokyuki Gakkai Zasshi 2009 Jul;47(7):647-51

Department of Infectious Diseases, Nagasaki University Hospital of Medicine and Dentistry.

A 51-year-old man with bronchiectasis and persistent lower respiratory tract infection was referred to our hospital for further evaluation of a mass shadow in the upper lung field on his chest X-ray film in February 2006. Two Nocardia spp (N. cyriacigeorgica and N. farcinica) were simultaneously identified from sputum collected through bronchoscopy by culture. We diagnosed pulmonary nocardiosis and commenced minocycline treatment. The possibility of lung cancer was excluded by sputum cytology and CT guided lung biopsy. Remarkable improvement of the mass lesion was recognized after treatment for 6 months. To the best of our knowledge, double infection of two species of Nocardia is very rare.
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July 2009

Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan.

Am J Respir Crit Care Med 2008 Apr 17;177(7):752-62. Epub 2008 Jan 17.

Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, 754 Ichibannchoh, Asahimachi-Tohri, Niigata 951-8520, Japan.

Rationale: Acquired pulmonary alveolar proteinosis (PAP) is a syndrome characterized by pulmonary surfactant accumulation occurring in association with granulocyte/macrophage colony-stimulating factor autoantibodies (autoimmune PAP) or as a consequence of another disease (secondary PAP). Because PAP is rare, prior reports were based on limited patient numbers or a synthesis of historical data.

Objectives: To describe the epidemiologic, clinical, physiologic, and laboratory features of autoimmune PAP in a large, contemporaneous cohort of patients with PAP.

Methods: Over 6 years, 248 patients with PAP were enrolled in a Japanese national registry, including 223 with autoimmune PAP.

Measurements And Main Results: Autoimmune PAP represented 89.9% of cases and had a minimum incidence and prevalence of 0.49 and 6.2 per million, respectively. The male to female ratio was 2.1:1, and the median age at diagnosis was 51 years. A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur. Dyspnea was the most common presenting symptom, occurring in 54.3%. Importantly, 31.8% of patients were asymptomatic and were identified by health screening. Intercurrent illnesses, including infections, were infrequent. A disease severity score reflecting the presence of symptoms and degree of hypoxemia correlated well with carbon monoxide diffusing capacity and serum biomarkers, less well with pulmonary function, and not with granulocyte/macrophage colony-stimulating factor autoantibody levels or duration of disease.

Conclusions: Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses. The disease severity score and biomarkers provide novel and potentially useful outcome measures in PAP.
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http://dx.doi.org/10.1164/rccm.200708-1271OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720118PMC
April 2008

[Antibiotic therapy for bacterial meningitis].

Nihon Naika Gakkai Zasshi 2006 Nov;95(11):2232-7

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http://dx.doi.org/10.2169/naika.95.2232DOI Listing
November 2006

Tacrolimus as a reinforcement therapy for a patient with MPO-ANCA-associated diffuse alveolar hemorrhage.

Clin Rheumatol 2007 Jul 10;26(7):1211-4. Epub 2006 Aug 10.

The First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki City, Nagasaki 852-8501, Japan.

A 67-year-old woman, suffering from continuous hemoptysis, was admitted to our hospital where she was managed with mechanical ventilation. Computed tomography of the chest demonstrated bilateral massive alveolar hemorrhage without evidence of infectious disease. She was diagnosed with anti-myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated diffuse alveolar hemorrhage because a high titer of MPO-ANCA was found in the serum. Plasmapheresis as well as methylprednisolone pulse therapy were initiated, followed by intravenous administration of cyclophosphamide. Tacrolimus was employed for the maintenance therapy, and the oral prednisolone dosage could successfully be tapered without recurrence, along with the decrement of the titer of MPO-ANCA.
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http://dx.doi.org/10.1007/s10067-006-0355-6DOI Listing
July 2007

Fourteen-member macrolides promote the phosphatidylserine receptor-dependent phagocytosis of apoptotic neutrophils by alveolar macrophages.

Antimicrob Agents Chemother 2003 Jan;47(1):48-53

Department of Internal Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.

An inflammation of the airway of patients with diffuse panbronchiolitis (DPB), is characterized by dense neutrophil infiltration. Resolution of the inflammation can be achieved by the removal of apoptotic neutrophils by human alveolar macrophages (AM) without liberating neutrophil proteases in the airway. To understand clinical efficacy for the treatment of DPB by 14- or 15-member macrolides, their effects on the phagocytosis of apoptotic neutrophils by AM were examined. Treatment of AM with erythromycin (ERY) or clarithromycin at clinically achievable levels significantly increased the levels of phagocytosis of apoptotic neutrophils. A serum factor was not essential for the enhancement by these 14-member macrolides. Of the antibiotics tested, these effects were specific for the 14-member macrolides and a 15-member macrolide, azithromycin, but not for the 16-member macrolides, clindamycin or beta-lactam antibiotics. The enhanced phagocytosis of apoptotic neutrophils by ERY had no effect on the levels of interleukin-8 or tumor necrosis factor alpha production by lipopolysaccharide-stimulated AM after phagocytosis of the apoptotic neutrophils. The increased phagocytosis of apoptotic neutrophils by ERY was also found to be phosphatidylserine receptor-dependent for AM. These data indicate a novel anti-inflammatory action of 14-member and 15-member macrolides, and suggest that such antibiotics achieve clinical efficacy for patients with DPB, in part, through enhancing the nonphlogistic phagocytosis of apoptotic neutrophils by AM.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC148990PMC
http://dx.doi.org/10.1128/AAC.47.1.48-53.2003DOI Listing
January 2003

Fourteen-member macrolides suppress interleukin-8 production but do not promote apoptosis of activated neutrophils.

Antimicrob Agents Chemother 2002 Apr;46(4):1101-4

Department of Internal Medicine, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.

A 14-member macrolide was found to inhibit interleukin-8 (IL-8) synthesis in lipopolysaccharide-stimulated neutrophils but did not accelerate apoptosis in activated neutrophils. These data suggest that 14-member macrolides achieve clinical efficacy for chronic airway diseases partly by suppressing IL-8 production by activated neutrophils, but not by enhancing apoptosis in these cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC127094PMC
http://dx.doi.org/10.1128/AAC.46.4.1101-1104.2002DOI Listing
April 2002