Yasuhiro Kawai

Kawasaki Medical University, Kurasiki, Okayama, Japan

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Publications (30)69.27 Total impact

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    ABSTRACT: We conducted nationwide surveillance to investigate regional differences in macrolide-resistant (MR) Mycoplasma pneumoniae strains in Japan. The prevalence of MR M. pneumoniae has increased gradually in pediatric patients between 2008 and 2012. Although regional differences were observed, high levels of MR genes were detected in all seven surveillance areas throughout Japan, ranging from 50% to 93%. These regional differences were closely related to the previous administration of macrolides.
    Antimicrobial Agents and Chemotherapy 05/2013; · 4.57 Impact Factor
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    ABSTRACT: Outbreaks of Mycoplasma pneumoniae have occurred in closed surroundings, including among families, university students, in military camps, and in schools, but available data on outbreaks of macrolide-resistant (MR) M. pneumoniae are limited. We encountered a family outbreak of MR M. pneumoniae pneumonia in four sisters (16, 14, 10, and 8 years of age). M. pneumoniae was isolated from all four patients, and an A-to-G transition at position 2063 in domain V of the 23S rRNA gene was identified. Although three of four patients received azithromycin, which is the first-choice antimycoplasmal agent, this agent was not effective. All isolates had an identical antibiotic susceptibility pattern. The MIC values for 14- and 15-membered macrolides, such as erythromycin, clarithromycin, and azithromycin, were >128, >128, and 64 μg/ml, respectively. On admission, all four patients were diagnosed with suspected M. pneumoniae pneumonia using the Japanese Respiratory Society (JRS) guidelines scoring system. We carried out culture and polymerase chain reaction tests for the detection of M. pneumoniae in their parents (mother, 49 years old, and father, 56 years old) four times, but no M. pneumoniae organism was detected using either test. In conclusion, MR M. pneumoniae strains can occur in outbreaks in closed surroundings, such as within families, as well as macrolide-sensitive strains. To prevent outbreaks of M. pneumoniae infection, especially MR M. pneumoniae, in closed populations, physicians should pay careful attention to the potential occurrence of infections involving MR M. pneumoniae.
    Journal of Infection and Chemotherapy 04/2013; · 1.55 Impact Factor
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    ABSTRACT: BACKGROUND: Several symptoms are classically thought to be suggestive of pertussis in children, but the diagnostic value of these symptoms in adolescent and adult patients is unclear. We evaluated the accuracy of the clinical findings for the early presumptive diagnosis of pertussis in adolescent and adult patients. Furthermore, we measured fractional exhaled nitric oxide (FeNO) with regard to whether we could distinguish eosinophilic inflammation of the airway and pertussis. FeNO is not expected to be associated with pertussis. METHODS: We compared 183 cases with laboratory-confirmed pertussis using serology and polymerase chain reaction and 1,132 cases without laboratory-confirmed pertussis. RESULTS: Among pertussis patients, paroxysmal cough was common with 90% sensitivity, but the specificity was low (25%). Posttussive vomiting and whoop were less common (sensitivity 25% and 19%, respectively), but both showed greater specificity for pertussis (80% and 86%, respectively). Posttussive gagging was observed with intermediate frequency and provided greater specificity (49% and 77%, respectively). Pertussis cases were most frequent between May and August with a peak in June. The mean FeNO value for the pertussis patients was 18.2 +/- 9.2 ppb, which was significantly lower than that in asthma patients (56.9 +/- 20.3 ppb, p <0.001). The most useful definition was posttussive vomiting and/or gagging, and a plus normal FeNO value, which had a sensitivity of 72% and a specificity of 70%. CONCLUSIONS: Clinical symptoms and laboratory data are of limited value in making the diagnosis of pertussis, and it was clinically difficult to differentiate adolescent and adult patients with or without pertussis. However, pertussis should be considered if patients have posttussive vomiting and/or gagging and a normal FeNO concentration.
    BMC Infectious Diseases 03/2013; 13(1):129. · 3.03 Impact Factor
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    ABSTRACT: A 27-year-old, previously healthy woman was admitted to our hospital for mild pneumonia. After 2 days ceftriaxone sodium administration, her chest radiograph revealed a rightward mediastinal shift caused by atelectasis of the upper portion of the right lung. Bronchoscopic examination showed swelling in the right upper lobe bronchus and obstruction in the B1 segmental bronchus caused by complete edematous swelling. Histopathology showed acute cellular bronchitis with edema of the bronchial wall containing lymphocytes, plasma cells, and macrophages. Mycoplasma pneumoniae was detected by culture and a polymerase chain reaction test using sputum collected during bronchoscopy, and treatment was changed to minocycline. After 7 days antibiotic therapy, her condition improved and no relapse was observed. Identification of point mutations in domain V of the 23S rRNA for macrolide-resistant M. pneumoniae was performed, and an A-to-G transition at position 2063 in domain V of the 23S rRNA gene was identified. Atelectasis caused by M. pneumoniae is thought to be a common associated finding in pediatric patients, but it is rare in adults. In addition, our patient showed extremely unusual findings with obstruction caused by complete edematous swelling.
    Journal of Infection and Chemotherapy 03/2013; · 1.55 Impact Factor
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    ABSTRACT: The importance of macrolide-resistant (MR) Mycoplasma pneumoniae has become much more apparent in the past decade. We investigated differences in the therapeutic efficacy of macrolides, minocycline, and tosufloxacin against MR M. pneumoniae. A total of 188 children with M. pneumoniae pneumonia confirmed by culture and polymerase chain reaction (PCR) were analyzed. Of these, 150 patients had a MR gene; 134 patients had an A to G mutation at position 2,063 of M. pneumoniae 23S ribosomal RNA domain V. Azithromycin (n = 27), clarithromycin (n = 23), tosufloxacin (n = 62), or minocycline (n = 38) were used for definitive treatment of patients with MR M. pneumoniae. Defervescence within 48 hours after initiation of antibiotics was observed in 41% of patients in the azithromycin group, 48% of the clarithromycin group, 69% of the tosufloxacin group, and 87% of the minocycline group. The average days of fever after administration of antibiotic treatment was shorter in the minocycline and tosufloxacin groups than in the macrolide groups. The decrease in M. pneumoniae burden, as estimated by DNA copies, after 48 to 96 hours' treatment was more rapid in patients receiving minocycline (p = 0.016) than in those receiving tosufloxacin (p = 0.049), azithromycin (p = 0.273) or clarithromycin (p = 0.107). We found that the clinical and bacteriological efficacy of macrolides for treating cases of MR M. pneumoniae was low. Our results indicated that minocycline rather than tosufloxacin can be considered as the first choice drug for the treatment of M. pneumoniae pneumonia in children aged ≥8 years.
    Antimicrobial Agents and Chemotherapy 03/2013; · 4.57 Impact Factor
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    ABSTRACT: Nursing and healthcare-associated pneumonia (NHCAP) is a new category that is distinct from community-acquired pneumonia that has been documented in the 2011 Japanese Respiratory Society (JRS) guidelines. We aimed to evaluate an ELNAS Plate test for detecting anti-Chlamydophila pneumoniae-specific immunoglobulin M (IgM) antibodies in patients with NHCAP, by comparing the results of the ELNAS test with those of the Hitazyme enzyme-linked immunosorbent assay (Hitazyme-ELISA) and those of immunoblotting and microimmunofluorescence (MIF) tests. During the study period, we enrolled 739 patients with pneumonia in a university hospital and 812 patients with pneumonia in a community hospital; of these, 250 (34 %) and 349 (43 %), respectively, were classified as having NHCAP. C. pneumoniae pneumonia was detected in five cases by the MIF test and ELNAS test. All five cases demonstrated significant IgG antibody seroconversion, while one case was IgM-positive. Sixty-seven of the total of 599 patients (11 %) were C. pneumoniae IgM-positive on the Hitazyme-ELISA. One of the IgM-positive cases was confirmed by other methods and was shown to be a true positive. In the remaining cases, however, three other tests-the ELNAS test, the MIF test, and immunoblotting analysis-did not reveal any positive cases. The ELNAS, Hitazyme-ELISA, and MIF tests did not detect any significant increases in IgG or IgA antibody titers between paired sera. The results of the newly available ELNAS test for detecting anti-C. pneumoniae-specific IgM antibody correlated well with the results of the other established serological tests. To increase the diagnostic rate in patients with NHCAP, physicians should measure IgG antibody rather than IgM antibody using paired sera.
    Journal of Infection and Chemotherapy 10/2012; · 1.55 Impact Factor
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    ABSTRACT: Atypical pathogens Mycoplasma pneumoniae and Chlamydophila pneumoniae play an important role in community-acquired pneumonia. However, it has been pointed out that positive enzyme-linked immunosorbent assay (ELISA, Hitazyme C. pneumoniae) IgM reactivity is frequent among M. pneumoniae pneumonia patients. To clarify the reactivity of ELISA IgM in M. pneumoniae pneumonia, findings were compared with immunoblotting, ELNAS Plate C. pneumoniae (ELNAS) and the micro-immunofluorescence (MIF) test. Ninety-eight serologically confirmed cases with M. pneumoniae pneumonia and 10 cases with C. pneumoniae pneumonia were enrolled in this study. C. pneumoniae IgM-positive cases measured by the ELISA were observed in 30 (30 %) patients with M. pneumoniae pneumonia. However, there were no positive cases by immunoblotting, ELNAS, or MIF test. These cases determined to be IgM positive only in the ELISA were all negative by another serological test, recombinant enzyme immunoassay (rEIA), and these positive results in the ELISA were considered to be false-positive reactions. In contrast, IgM-positive findings in patients with C. pneumoniae pneumonia did not show any positive reaction in M. pneumoniae antibody titer. ELISA showed a high frequency of false-positive findings in patients with M. pneumoniae pneumonia, which included false-positive cases with a high titer for IgM. To accurately diagnose C. pneumoniae infection in various studies, including respiratory infections, researchers should consider the IgM false-positive reaction with ELISA in patients with suspected atypical pneumonia.
    Journal of Infection and Chemotherapy 10/2012; · 1.55 Impact Factor
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    ABSTRACT: BACKGROUND: Although the prevalence of macrolide-resistant Mycoplasma pneumoniae isolates in Japanese pediatric patients has increased rapidly, there have been no reports concerning macrolide-resistant M. pneumoniae infection in adolescents aged 16 to 19 years old. The purpose of this study was to clarify the prevalence and clinical characteristics of macrolide-resistant M. pneumoniae in adolescent patients with community-acquired pneumonia. METHODS: A total of 99 cases with M. pneumoniae pneumonia confirmed by polymerase chain reaction (PCR) and culture were analyzed. Forty-five cases were pediatric patients less than 16 years old, 26 cases were 16 to 19-year-old adolescent patients and 28 cases were adult patients. Primers for domain V of 23S rRNA were used and DNA sequences of the PCR products were compared with the sequence of an M. pneumoniae reference strain. RESULTS: Thirty of 45 pediatric patients (66%), 12 of 26 adolescent patients (46%) and seven of 28 adult patients (25%) with M. pneumoniae pneumonia were found to be infected with macrolide-resistant M. pneumoniae (MR patients). Although the prevalence of resistant strains was similar in pediatric patients between 2008 and 2011, an increase in the prevalence of resistant strains was observed in adolescent patients. Among 30 pediatric MR patients, 26 had an A-to-G transition at position 2063 (A2063G) and four had an A-to-G transition at position 2064 (A2064G). In 12 adolescent MR patients, 10 showed an A2063G transition and two showed an A2064G transition, and in seven adult MR patients, six showed an A2063G transition and one showed an A2064G transition. CONCLUSIONS: The prevalence of macrolide-resistant M. pneumoniae is high among adolescent patients as well as pediatric patients less than 16-years old. To prevent outbreaks of M. pneumoniae infection, especially macrolide-resistant M. pneumoniae, in closed populations including among families, in schools and in university students, physicians should pay close attention to macrolide-resistant M. pneumoniae.
    BMC Infectious Diseases 05/2012; 12(1):126. · 3.03 Impact Factor
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    ABSTRACT: Background and objective:  The Japanese Respiratory Society (JRS) scoring system is a useful tool for the early and simple presumptive diagnosis of atypical pneumonia (Mycoplasma pneumoniae and Chlamydia pneumoniae pneumonia). However, it has been suggested that it is difficult to diagnose atypical pneumonia in the elderly using this system. In the present study, we evaluated the accuracy and usefulness of the JRS scoring system for diagnosing atypical pneumonia in different age groups. Methods:  Cases of M. pneumoniae (n = 262), C. pneumoniae (n = 98) and common bacterial pneumonia (n = 364) were analysed. Results:  For both atypical pneumonias, the frequency of comorbid illnesses and being in a higher risk category were significantly greater in elderly (age ≥60 years) than in non-elderly patients (age <60 years). One or more additional aetiological factors were more frequently present in elderly than in non-elderly patients. The diagnostic sensitivity and specificity for atypical pneumonia were 39% and 88%, respectively, in the elderly group, and 86% and 88%, respectively, in the non-elderly group. When the patients were stratified into 10-year age groups, the diagnostic sensitivity was highest in the 18- to 29-year age group and decreased from the youngest to the oldest age group. Conclusions:  These results indicate that it is difficult to distinguish between atypical pneumonia and bacterial pneumonia in the elderly using the JRS scoring system. When treating patients aged ≥60 years, physicians should use fluoroquinolones or β-lactam antibiotics + macrolides as empirical first-choice drugs so as to always provide antibiotic protection against potential atypical pathogens.
    Respirology 05/2012; 17(7):1073-9. · 2.78 Impact Factor
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    ABSTRACT: Chlamydophila pneumoniae, an obligate intracellular human pathogen, causes respiratory tract infections. The most common techniques used for the serological diagnosis of C. pneumoniae infections are microimmunofluorescence tests and commercial serological ELISA tests; these are based on the detection of antibodies against whole chlamydial elementary bodies and lipopolysaccharide/outer membrane protein, respectively. Identification of more specific and highly immunodominant antigens is essential for the development of new serodiagnostic assays. To identify novel specific antigens from C. pneumoniae, we screened 455 genes with unknown function in the genome of C. pneumoniae J138. Extracts of Saccharomyces cerevisiae cells expressing GFP-tagged C. pneumoniae proteins were subjected to Western blot analysis using serum samples from C. pneumoniae-infected patients as the primary antibodies. From this comprehensive analysis, 58 clones expressing C. pneumoniae open reading frames, including hypothetical proteins, were identified as antigens. These results have provided useful information for the development of new serological tools for the diagnosis for C. pneumoniae infections and for the development of vaccines in future.
    FEMS Microbiology Letters 02/2012; 329(2):168-76. · 2.05 Impact Factor
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    ABSTRACT: The Japan Respiratory Society documented a new category of guidelines for nursing and healthcare-associated pneumonia (NHCAP), which is distinct from community acquired pneumonia (CAP). The objective of this study was to determine the epidemiological differences between NHCAP patients in a teaching university hospital and a community hospital. In addition, to clarify the strategy for treatment of NHCAP, we investigated the role of atypical pathogens. We analyzed 250 NHCAP and 421 CAP cases in a university hospital and 349 NHCAP and 374 CAP cases in a community hospital. Patient age and the incidences of poor general condition were significantly higher in the community hospital compared with those in the university hospital. The distribution and frequency of pathogens, especially multidrug-resistant (MDR) pathogens, were significantly different between the two hospitals. Central nervous system disorders, dementia and poor performance status, which was possibility related to aspiration pneumonia, were significantly more frequent in patients with NHCAP compared with those with CAP in both hospitals. Atypical pathogens were detected in a few cases in patients with NHCAP. There were many differences in the clinical characteristics between NHCAP patients in a university hospital and a community hospital even for hospitals located in the same area. Aspiration pneumonia was thought to be the main characteristic of NHCAP in both hospitals. Thus, all NHCAP patients did not need the same empiric therapy with a multidrug regimen directed against MDR pathogens. In addition, physicians rarely need to consider atypical pathogens in NHCAP treatment.
    Internal Medicine 01/2012; 51(6):585-94. · 0.97 Impact Factor
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    ABSTRACT: Macrolide-resistant Mycoplasma pneumoniae is emerging in several countries, and it is mainly observed in children. To our knowledge, we conducted the first multicenter prospective epidemiological study of macrolide-resistant M. pneumoniae in order to investigate regional differences in the susceptibility of macrolide-resistant M. pneumoniae to antibacterial agents. The in vitro activities of 11 antimicrobial agents against macrolide-resistant M. pneumoniae isolates from 5 different areas of Japan were investigated. Among 190 M. pneumoniae isolates from pediatric patients, 124 (65.2%) isolates showed macrolide resistance and possessed an A2063G transition in domain V of the 23S rRNA. These isolates showed high resistance to erythromycin, clarithromycin, and azithromycin with minimum inhibitory concentrations (MICs) ≥16 μg/ml. Conversely, quinolones such as garenoxacin, moxifloxacin, tosufloxacin, and levofloxacin exhibited potent antimycoplasmal activity. No regional differences were observed with respect to the MICs among the 5 areas in Japan.
    Japanese journal of infectious diseases. 01/2012; 65(6):535-538.
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    ABSTRACT: Since 2000, the prevalence of macrolide-resistant (MR) Mycoplasma pneumoniae has increased among paediatric patients in Japan. To determine the efficacy of macrolides against MR M. pneumoniae pneumonia, microbiological and clinical efficacies were compared during the antibiotic treatment. Samples from a total of 30 children with M. pneumoniae pneumonia, as confirmed by PCR and serology, were analyzed. Primers for domain V of 23S rRNA were used, and DNA sequences of the PCR products were compared with the sequence of an M. pneumoniae reference strain. Isolates from 21 patients demonstrated point mutations, and these patients were defined as MR. The remaining nine patients, whose isolates showed no point mutations, were categorized as control (macrolide-sensitive) patients. The number of M. pneumoniae in nasopharyngeal samples from the control group decreased rapidly 48 h after initiation of macrolide treatment and showed a close relationship with clinical outcome. In contrast, the number of M. pneumoniae 48 h after initiation of macrolide treatment were significantly higher in samples from MR patients than in samples from macrolide-sensitive patients. In 15 of 21 MR patients, fever persisted for more than 48 h after the initiation of macrolide treatment. When treatment was changed to minocycline, fever disappeared within 48 h in all these MR patients. There were no differences between MR patients who demonstrated a reduction in fever and those in whom fever persisted after 48 h of macrolide treatment. The microbiological and clinical efficacies of macrolides for treating patients with MR M. pneumoniae pneumonia were low. These results show that macrolides are clearly less effective in patients with MR M. pneumoniae pneumonia.
    Respirology 11/2011; 17(2):354-62. · 2.78 Impact Factor
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    ABSTRACT: Bacterial agglutination antibodies against Bordetella pertussis, Yamaguchi and Tohama strains, are frequently measured for serodiagnosis of pertussis infection in Japan. To determine the serological criteria, the comparative titres of bacterial agglutination antibody and anti-pertussis toxin (PT) antibody were evaluated. Antibody titres were analysed in 36 definitive (fourfold increase in agglutination antibody) and 137 presumptive (high titre of single-antibody) cases of B. pertussis infection among adolescents and adults, and in a control group of 318 healthy volunteers. When a single Yamaguchi agglutinin titre of ≥ 1:1280 (> three SD above the geometric mean for the control group) was taken as diagnostic, the sensitivity and specificity at 4-5 weeks after onset of cough were 58% and 98%, respectively. Using this criterion, the clinical findings in presumptive cases were almost identical to those in definitive cases. When the two tests were compared using 318 control sera, there was no association between the Tohama agglutinin titre and the anti-PT antibody titre, whereas a weak association between the Yamaguchi agglutinin titre and the anti-PT antibody titre was observed. When the numbers of pertussis cases with high antibody titres in the two tests were compared, 60% of cases with a Yamaguchi agglutinin titre of ≥1:1280 showed an anti-PT antibody titre of ≥100 EU/mL. These results indicate that the bacterial agglutination test is a method with low sensitivity and specificity for the diagnosis of B. pertussis infection. Therefore, to yield an accurate diagnosis, anti-PT antibody levels should be measured instead of bacterial agglutination antibody.
    Respirology 07/2011; 16(8):1189-95. · 2.78 Impact Factor
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    ABSTRACT: A macrolide-resistant Mycoplasma pneumoniae strain was isolated from two patients with community-acquired pneumonia. The pneumonia severity score of both patients was mild, and rapid clinical improvement was seen after administration of fluoroquinolone. Clinical features of macrolide-resistant M. pneumoniae pneumonia were identical to those of macrolide-sensitive M. pneumoniae pneumonia. An A-to-G transition at position 2063 and 2064, respectively, in domain V of the 23S rRNA gene was identified. The minimum inhibitory concentration of erythromycin of these isolates was greatly elevated. In Japan, macrolide-resistant M. pneumoniae infections are common in pediatric patients but not in adults. However, physicians should pay attention to macrolide-resistant M. pneumoniae not only in children but also in adults.
    Journal of Infection and Chemotherapy 02/2011; 17(1):114-8. · 1.55 Impact Factor
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    ABSTRACT: Analysis of an outbreak of Bordetella pertussis infection in a university laboratory. To prevent and control the outbreak, we conducted a survey of the laboratory staff and their family members, and we investigated the clinical features of adult pertussis. During the outbreak, four out of the 10 laboratory staff and five out of 16 family members had a primary complaint of cough. Seven of nine patients were diagnosed as definitive B. pertussis infection using serology and PCR. Clinical findings and laboratory data in adult patients with B. pertussis infection demonstrated non-specific cough and normal WBC and lymphocyte count. The patients who received clarithromycin prior to 14 days after clinical onset demonstrated a shorter duration of cough symptoms than patients who received clarithromycin at 14 days or more after clinical onset (duration of cough after administration of clarithromycin: 17.8 ± 6.48 days versus 35.3 ± 5.38 days; duration of total cough after clinical onset: 24.8 ± 6.65 days versus 56.8 ± 6.50 days). The clinical findings of adult pertussis are different from pertussis in children. The efficacy of macrolide therapy clearly differed between the catarrhal phase and paroxysmal phase. Physicians should consider B. pertussis in the differential diagnosis of an outbreak of non-specific respiratory infection even in adult populations.
    Internal Medicine 01/2011; 50(8):879-85. · 0.97 Impact Factor
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    ABSTRACT: The purpose of the present study was to evaluate the accuracy and usefulness of three rapid diagnostic methods, ImmunoCard Mycoplasma kit, chest high-resolution computed tomography (HRCT) findings, and the Japanese Respiratory Society (JRS) scoring system (including six parameters), for the early presumptive diagnosis of Mycoplasma pneumoniae pneumonia in adults. We performed three rapid diagnostic methods at the same time in four pneumonia groups: 68 cases with M. pneumoniae pneumonia, 133 cases with Streptococcus pneumoniae pneumonia, 30 cases with Haemophilus influenzae pneumonia, and 20 cases with Legionella pneumonia. The sensitivity and specificity were 35% and 68% for ImmunoCard, 73% and 85% with HRCT, and 83% and 90% with the JRS scoring system, respectively. Among the three rapid diagnostic methods, the JRS scoring system was the most useful tool for initiating the administration of adequate antibiotic therapy for probable M. pneumoniae pneumonia. We suggest that M. pneumoniae pneumonia should be suspected when there is a correlation of more than five parameters in the JRS scoring system (99% specificity). If there is a correlation of three or four parameters in the JRS scoring system, chest computed tomography (CT) findings are helpful for the presumptive diagnosis of M. pneumoniae pneumonia.
    European Journal of Clinical Microbiology 11/2010; 30(3):439-46. · 3.02 Impact Factor
  • International journal of antimicrobial agents 10/2010; 36(4):384-5. · 3.03 Impact Factor
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    ABSTRACT: Endosomal recycling of the mammalian iron transporter DMT1 is assumed to be important for efficient and rapid uptake of iron across the endosomal membrane in the transferrin cycle. Here, we show that the retromer, a complex that mediates retrograde transport of transmembrane cargoes from endosomes to the trans-Golgi network, is required for endosomal recycling of DMT1-II, an alternative splicing isoform of DMT1. Bacterially expressed Vps26-Vsp29-Vsp35 trimer, a retromer cargo recognition complex, specifically binds to the cytoplasmic tail domain of DMT1-II in vitro. In particular, this binding is dependent on a specific hydrophobic motif of DMT1-II, which is required for its endosomal recycling. DMT1-II colocalizes with the Vps35 subunit of the retromer in TfR-positive endosomes. Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling.
    Journal of Cell Science 03/2010; 123(Pt 5):756-66. · 5.88 Impact Factor
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    Japanese journal of infectious diseases. 03/2010; 63(2):150-1.