Nonfilament-forming RecA dimer catalyzes homologous joint formation.

Homologous recombination is essential to genome maintenance, and also to genome diversification. In virtually all organisms, homologous recombination depends on the RecA/Rad51-family recombinases, which catalyze ATP-dependent formation of homologous joints-critical intermediates in homologous recombination. RecA/Rad51 binds first to single-stranded (ss) DNA at a damaged site to form a spiral nucleoprotein filament, after which double-stranded (ds) DNA interacts with the filament to search for sequence homology and to form consecutive base pairs with ssDNA ('pairing'). How sequence homology is recognized and what exact role filament formation plays remain unknown. We addressed the question of whether filament formation is a prerequisite for homologous joint formation. To this end we constructed a nonpolymerizing (np) head-to-tail-fused RecA dimer (npRecA dimer) and an npRecA monomer. The npRecA dimer bound to ssDNA, but did not form continuous filaments upon binding to DNA; it formed beads-on-string structures exclusively. Although its efficiency was lower, the npRecA dimer catalyzed the formation of D-loops (a type of homologous joint), whereas the npRecA monomer was completely defective. Thus, filament formation contributes to efficiency, but is not essential to sequence-homology recognition and pairing, for which a head-to-tail dimer form of RecA protomer is required and sufficient.

Unilateral Upper Lung Field Pulmonary Fibrosis Radiologically Consistent with Pleuroparenchymal Fibroelastosis after Thoracotomy: A New Disease Entity Related to Thoracotomy.

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare bilateral idiopathic interstitial pneumonia defined by pleural-parenchymal involvement. In clinical practice, we encountered patients with upper lung field pulmonary fibrosis (Upper-PF), which was radiologically consistent with PPFE, but apparently limited to the unilateral lung. OBJECTIVES: The purpose of the study was to clarify the clinical characteristics in those patients. METHODS: We examined the medical records of all the consecutive patients from 2012 to 2016 to see whether there were patients having unilateral Upper-PF. RESULTS: We found 6 patients with unilateral Upper-PF. The most common symptom was dyspnea, and all patients had a low body mass index and severe restrictive pulmonary impairment. Notably, all patients had a history of thoracotomy for resecting lung or esophageal cancer, and the lesions were limited to the operated side. Dynamic breathing chest MRI showed an impaired thoracic movement in the operated side. Serial chest CT from prethoracotomy to the first visit was obtained in 5 patients: before thoracotomy, only a slight apical cap, defined as a wedge- and triangle-shaped opacity with broad pleural contact, was observed only in the operated side, but progressed into the lesion after a median of 8.4 years following thoracotomy. After the first visit, the unilateral lesion rapidly deteriorated in all patients. CONCLUSIONS: Unilateral Upper-PF had some characteristics in common with PPFE. Because the lesion was limited to the operated side, unilateral Upper-PF would be a new disease entity related to thoracotomy. Our results indicate that thoracotomy impairs thoracic movement in the operated side and subsequently triggers unilateral Upper-PF development, especially in patients with an apical cap.

Ten-Year Trends and Clinical Relevance of the Antimicrobial Resistance Genotype in Respiratory Isolates of Streptococcus pneumoniae.

BACKGROUND: Antimicrobial resistance of Streptococcus pneumoniae, especially against ß-lactam antibiotics, is a global concern. We aimed to analyze a 10-year trend in the antimicrobial resistance genotype of respiratory isolates of S. pneumoniae and to clarify whether resistance genotypes were correlated with phenotypic drug susceptibility, pathogenicity, and host clinical background. METHODS: Respiratory isolates of S. pneumoniae from 2003 to 2012 were analyzed with polymerase chain reaction for the presence of ß-lactam resistance gene mutations on pbp1a, pbp2x, and pbp2b. Sixty-eight strains isolated from different patients in 2012 were particularly analyzed for the association between genotypes and clinical data. RESULTS: The 10-year trend analysis showed a recent increase in gPRSP (genotypic penicillin-resistant S. pneumoniae) with all 3 ß-lactam resistance genes (from 21.7 to 35.3% in 3 years) and a steady level of gPSSP (genotypic penicillin-susceptible S. pneumoniae) without any ß-lactam resistance genes (13.2% in 2012). This resistance trend in genotypes was more prominent than resistance phenotypes determined with a drug susceptibility test. The probability of being a causative pathogen did not differ in gPSSP (55.6%), gPISP (genotypic penicillin-intermediate resistant S. pneumoniae; 54.3%), and gPRSP (54.2%). There was no significant difference in the ratio of patients who presented with respiratory failure in respiratory infection caused by gPSSP, gPISP, or gPRSP. Host clinical characteristics including age and gender were not different among resistance genotypes. CONCLUSIONS: There was no difference in pathogenicity or clinical background between gPSSP, gPISP, and gPRSP. Antimicrobial resistance in respiratory isolates of S. pneumoniae was more prevalent in genotypes than in phenotypes.

Rad51 and RecA juxtapose dsDNA ends ready for DNA ligase-catalyzed end-joining under recombinase-suppressive conditions.

RecA-family recombinase-catalyzed ATP-dependent homologous joint formation is critical for homologous recombination, in which RecA or Rad51 binds first to single-stranded (ss)DNA and then interacts with double-stranded (ds)DNA. However, when RecA or Rad51 interacts with dsDNA before binding to ssDNA, the homologous joint-forming activity of RecA or Rad51 is quickly suppressed. We found that under these and adenosine diphosphate (ADP)-generating suppressive conditions for the recombinase activity, RecA or Rad51 at similar optimal concentrations enhances the DNA ligase-catalyzed dsDNA end-joining (DNA ligation) about 30- to 40-fold. The DNA ligation enhancement by RecA or Rad51 transforms most of the substrate DNA into multimers within 2-5 min, and for this enhancement, ADP is the common and best cofactor. Adenosine triphosphate (ATP) is effective for RecA, but not for Rad51. Rad51/RecA-enhanced DNA ligation depends on dsDNA-binding, as shown by a mutant, and is independent of physical interactions with the DNA ligase. These observations demonstrate the common and unique activities of RecA and Rad51 to juxtapose dsDNA-ends in preparation for covalent joining by a DNA ligase. This new in vitro function of Rad51 provides a simple explanation for our genetic observation that Rad51 plays a role in the fidelity of the end-joining of a reporter plasmid DNA, by yeast canonical non-homologous end-joining (NHEJ) in vivo.

Safety and efficacy of S-1 in combination with carboplatin in non-small cell lung cancer patients with interstitial lung disease: a pilot study.

PURPOSE: There is no established standard regimen for non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD). For them, we performed a pilot study to evaluate the feasibility of chemotherapy with carboplatin and S-1, which are known as cytotoxic drug with rare development of ILD as adverse event. METHODS: A total of 21 chemotherapy-naive NSCLC patients with ILD were prospectively enrolled between March 2009 and September 2011. Every 3 weeks, carboplatin at a dose of AUC 5 on day 1 and S-1 at a dose of 80 mg/m2 daily for 14 days were administered. RESULTS: The median age at initiating chemotherapy was 67. Histological examination revealed 10 patients (48 %) with adenocarcinoma. Before chemotherapy, partial pressure of arterial O2 (PaO2) was low with a median of 71 Torr on room air. The median number of cycles administered was four, and the overall response rate and disease control rate were 33 and 67 %, respectively. At the time of data cut-off, all patients were deceased. The median progression-free survival (PFS) and median overall survival (OS) periods were 4.2 and 9.7 months. There was no significant difference of PFS and OS according to tumor histology. Acute exacerbation (AE) of ILD following S-1 plus carboplatin occurred in two patients (10 %, 2/21) within first course treatment. However, they were successfully managed with steroid therapy and survived for 7.0 and 8.8 months, respectively, after AE-ILD development. CONCLUSIONS: This is the first prospective study to evaluate the safety and efficacy of S-1 plus carboplatin treatment for NSCLC patients with ILD. This regimen could be a feasible option for NSCLC patients with ILD, regardless of tumor histology. Our results would support to carry out a large-scale clinical trial to confirm the feasibility of this regimen.

[[COMPLIANCE RATE OF STANDARD TREATMENT REGIMEN AND OPTIMAL DOSE OF ANTI-TUBERCULOSIS DRUGS IN LATE ELDERLY PATIENTS WITH PULMONARY TUBERCULOSIS].]

The proportion of the elderly in patients with pulmonary tuberculosis is increasing, and failure to complete the standard treatment regimen is not uncommon in these patients. We examined the compliance rate and prob- lems of the standard regimen in the late elderly pulmonary tuberculosis patients. [Methods] We reviewed the medical records of late elderly patients with pulmonary tuberculosis aged 75 or above who were smear-positive and treated in Kanagawa Cardiovascular and Respiratory Center between January 2011 and December 2014. Our retrospective study examined patient characteris- tics, imaging findings, laboratory results, and outcomes. The compliance rate of standard regimen during the hospitaliza- tion period was calculated. We compared the discontinua- tion rate and the incidence of adverse drug reactions by body weight equivalent doses of anti-tuberculosis drugs. [Results] A total of 298 patients were included in this study, and 76% of those patients were aged 80 or above. Anti-tuberculosis therapy was not able to be initiated for 3 patients (1%), and treatment other than standard regimen was inevitably introduced at initiation in 21 patients. The remaining 274 patients (92%) were administered the stan- dard regimen. Among them, at least one medication was subsequently discontinued for 85 patients (29%), and the medication was changed due to drug resistance in 6 patients . (2%). The remaining 183 patients (61%) complied with the standard regimen during hospitalization. In the comparison by body weight equivalent dose, significantly more patients discontinued their medication in the group using ethambutol with a higher standard dose per weight (37% vs. 21%, p=0.02). [Conclusion] Nearly 40% of the late elderly patients could not comply with the standard regimen. We may need to be more careful when calculating ethambutol equivalent dose.

Loop L1 governs the DNA-binding specificity and order for RecA-catalyzed reactions in homologous recombination and DNA repair.

In all organisms, RecA-family recombinases catalyze homologous joint formation in homologous genetic recombination, which is essential for genome stability and diversification. In homologous joint formation, ATP-bound RecA/Rad51-recombinases first bind single-stranded DNA at its primary site and then interact with double-stranded DNA at another site. The underlying reason and the regulatory mechanism for this conserved binding order remain unknown. A comparison of the loop L1 structures in a DNA-free RecA crystal that we originally determined and in the reported DNA-bound active RecA crystals suggested that the aspartate at position 161 in loop L1 in DNA-free RecA prevented double-stranded, but not single-stranded, DNA-binding to the primary site. This was confirmed by the effects of the Ala-replacement of Asp-161 (D161A), analyzed directly by gel-mobility shift assays and indirectly by DNA-dependent ATPase activity and SOS repressor cleavage. When RecA/Rad51-recombinases interact with double-stranded DNA before single-stranded DNA, homologous joint-formation is suppressed, likely by forming a dead-end product. We found that the D161A-replacement reduced this suppression, probably by allowing double-stranded DNA to bind preferentially and reversibly to the primary site. Thus, Asp-161 in the flexible loop L1 of wild-type RecA determines the preference for single-stranded DNA-binding to the primary site and regulates the DNA-binding order in RecA-catalyzed recombinase reactions.

[Clinical characteristics of pulmonary Mycobacterium avium complex infection complicated with lung cancer].

OBJECTIVES: The coexistence of lung cancer and pulmonary Mycobacterium avium complex (MAC) infection has not been well reported. This study illustrated the clinical characteristics of pulmonary MAC infections complicated with lung cancer. PATIENTS AND METHODS: We conducted a retrospective analysis of the clinical characteristics of patients with pulmonary MAC infections complicated with newly diagnosed lung cancer between 2006 and 2012. RESULTS: Of 530 patients with pulmonary MAC infections, 13 (2.4%) were complicated with lung cancer. Six men and 7 women with a mean age of 73 years were also diagnosed with cancer, and 5 had a smoking history. Six patients were diagnosed concurrently, and 7 patients were diagnosed with pulmonary MAC infections prior to being diagnosed with cancer. Histological examination revealed adenocarcinoma, small cell carcinoma, and other cancer types in 9, 2, and 2 patients, respectively. Eleven of 13 patients had cancers of stages I-IIIA, and 10 underwent cancer resection. Analysis of the anatomical relationship between lung cancer and MAC revealed that both diseases were present in the same lobe in 10 patients. The disease extent was within one-third of a single lung field in 9 patients. Anti-MAC treatment was initiated in 7 patients, but was discontinued in 2 patients owing to side effects. Six patients did not receive anti-MAC treatment. CONCLUSION: In this study, lung cancer was frequent among patients with pulmonary MAC infections, and both diseases tended to be in the early stages. Physicians should consider coexisting lung cancer when managing MAC infections.

Clinical characteristics and prevalence of pneumothorax in patients with pulmonary Mycobacterium avium complex disease.

Pneumothorax in patients with pulmonary Mycobacterium avium complex (MAC) disease is considered to be a rare complication, and little is known about its clinical course. In this study, we aimed to define the clinical features, outcome, and prevalence of pneumothorax in patients with pulmonary MAC disease. A retrospective review of medical records identified eight men and ten women (mean age, 75 years) with active pulmonary MAC disease complicated by pneumothorax between 2003 and 2010 in our institution. None of the patients was positive for HIV infection. Pneumothorax occurred in the right lung in 12 patients and in the left in six. All but one patient had MAC disease in both lungs, and 12 patients had widespread lesions covering a total area larger than one lung field. Seven of the 18 patients (39 %) were forced to undergo surgery following unsuccessful thoracic drainage. Five patients experienced recurrence during the study period and two others eventually developed chronic pneumothorax. The complication rate of pneumothorax was calculated on the bases of the total number of patients with active pulmonary MAC disease during the same period. The overall complication rate of pneumothorax was as high as 2.4 % (18 of 746 patients with MAC disease). In conclusion, the incidence of pneumothorax in patients with active pulmonary MAC disease was unexpectedly high, especially in patients who were elderly and had advanced MAC disease. This condition is often difficult to treat and can recur easily.

Antimicrobial resistance genotype trend and its association with host clinical characteristics in respiratory isolates of Haemophilus influenzae.

BACKGROUND: ß-Lactam resistance genotype trends in clinical isolates of Haemophilus influenzae and their correlation with the clinical background were analyzed. METHODS: Five hundred and ten respiratory isolates of H. influenzae collected during the period 2002-2009 were classified by PCR into gBLNAS (genotype for ß-lactamase-negative ampicillin-susceptible), gBLNAR (genotype for ß-lactamase-negative ampicillin-resistant) and 3 other genotypes. The associations with host clinical data and antimicrobial susceptibility were analyzed in all 144 isolates between 2008 and 2009. RESULTS: The 8-year trend analysis detected an increase in gBLNAR with a decrease in gBLNAS. The probability of being a causative pathogen did not differ between genotypes. Host clinical characteristics such as age and gender did not differ with gBLNAR or gBLNAS, but the underlying respiratory diseases did differ. gBLNAR was found at the highest rate in 83% of isolates from patients with nontuberculous mycobacteriosis. In contrast, gBLNAR accounted for as little as 33% of isolates from chronic obstructive pulmonary disease. CONCLUSIONS: There were no differences in the pathogenicity of gBLNAR and gBLNAS. The underlying respiratory diseases may be related to the resistance genotype.

Metastatic brain tumors from non-small cell lung cancer with EGFR mutations: distinguishing influence of exon 19 deletion on radiographic features.

INTRODUCTION: Miliary brain metastasis is a rarity and refers to the presence of numerous small tumors in a perivascular distribution without intraparenchymal invasion and focal edema. Although the presence of epidermal growth factor receptor (EGFR) mutation and good response to gefitinib have been reported in non-small cell lung cancer (NSCLC) patients with miliary brain metastases, the influence of the EGFR mutations on the radiographic features remains unclear. PATIENTS AND METHODS: All NSCLC patients with synchronous brain metastases detected at the time of a new diagnosis of NSCLC from March 2005 through May 2011 were divided according to EGFR mutation status. The number of brain tumors, size of the largest brain tumors, and size of peritumoral brain edema were compared among the groups. RESULTS: Fifty-seven patients who met the criteria were divided into three groups: wild-type EGFR group (31 patients), exon 19 deletion group (18 patients), and exon 21 point mutation group (8 patients). The exon 19 deletion group had more multiple and smaller brain tumors with smaller peritumoral brain edema than did the wild-type group (P = 0.024, P = 0.0016, and P = 0.0036, respectively). The exon 21 point mutation group showed no significant difference in any of the radiographic values when compared with the wild-type group. CONCLUSION: Our results indicate that NSCLC patients with the exon 19 deletion have such a peculiar pattern of brain metastases as multiple small metastases with small brain edema. This metastatic pattern may be similar to that of miliary brain metastases. Because it is unclear whether or not severe neurologic symptoms develop during their clinical courses like miliary brain metastases, regular evaluation with brain magnetic resonance imaging (MRI) should be considered, regardless of the presence of neurologic symptoms. Accumulation of knowledge about specific pattern of brain metastasis will help approach to "individual" management.

Automatic tracking of the respiratory motion of lung parenchyma on dynamic magnetic resonance imaging: comparison with pulmonary function tests in patients with chronic obstructive pulmonary disease.

PURPOSE: This study evaluated the respiratory motion of the lung parenchyma using dynamic magnetic resonance imaging and clarified differences between healthy individuals and patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: The study comprised 6 healthy volunteers and 42 patients diagnosed with smoking-related COPD. We captured 80 sequential frames from the mid-sagittal portion of the right lung while repeating forced deep breathing using a balanced fast-field echo sequence (repetition time, 2.2 ms; echo time, 1.1 ms; slice thickness, 10 mm; field of view, 450 mm; matrix size, 128 × 256; and acquisition time, 0.28 s/frame). We traced 15 points on pulmonary vessels using a computer-aided system and measured the maximal motion distance of each tracked point. Movement of these points was then compared with spirometric data using the Pearson correlation coefficient. RESULTS: Patients with COPD showed reduced respiratory motion compared with healthy volunteers. Respiratory motion and spirometric data such as forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity showed highly significant positive correlations (correlation between normalized motion distance for the whole lung and FEV1, r = 0.75; P < 0.01). CONCLUSIONS: The respiratory motion of the pulmonary vessels reflects expansion and deflation of the lung parenchyma, and such motion is restricted in patients with COPD due to airflow limitation.

Interaction between NF-κB signaling and Notch signaling in gliogenesis of mouse mesencephalic neural crest cells.

In the present study, we elucidated that nuclear factor-κB (NF-κB) participates in the gliogenic specification of mouse mesencephalic neural crest cells. Whereas transfection of the NF-κB expression vector stimulated gliogenesis, treatment with the dominant negative NF-κB expression vector or NF-κB small interfering RNA suppressed the promotion of gliogenic specification by FGF treatment or Notch activation. This suppression was recovered by the treatment with the Deltex-1 expression vector or mammalian hairy and enhancer of split homologs expression vectors. Furthermore, transfection of the inhibitor of κB (IκB) expression vector inhibited gliogenesis. In addition, treatment with the NF-κB expression vector promoted the expression of Deltex-1. These data suggest that NF-κB signaling is implicated in the gliogenesis through the interaction with Notch signaling. Moreover, cells that contain Sox10 expressed NF-κB and Deltex-1 in the presumptive trigeminal ganglia of embryonic day 9.0-9.5 mouse embryos. This observation supports our notion that the interaction between NF-κB signaling and Notch signaling plays an important role in the gliogenic specification of mouse mesencephalic neural crest cells.

[Clinical features of pneumothorax in patients with active nontuberculous mycobacterial lung disease].

UNLABELLED: This study was retrospectively conducted to clarify the clinical features of pneumothorax in patients with active nontuberculous mycobacterial (NTM) lung disease. The patients were 9 men and 7 women, with a median age of 70. Pathogenic mycobacteria were 12 Mycobacterium avium complex, 2 Mycobacterium kansasii, and 2 Mycobacterium fortuitum. More than one lung field was affected by NTM disease in 11 patients, whereas 4 patients were given a diagnosis of mild NTM disease only at the onset of pneumothorax. Five patients recovered with rest only, 4 with thoracic drainage, 4 needed surgery, and 2 developed chronic pneumothorax. Five patients experienced more than one recurrence of pneumothorax during treatment for NTM disease. The rate of the complication of pneumothorax in patients with NTM lung disease was estimated at around 2.3%. CONCLUSION: Pneumothorax associated with NTM lung disease is not rare and is sometimes difficult to control.

[Trends in antibiotic susceptibility and genetic beta-lactam resistance patterns among Haemophilus influenzae cases isolated from adult patients with respiratory tract infection].

Haemophilus influenzae, a major respiratory tract pathogen, is becoming increasingly resistant to beta-lactam antibiotics. Studying annual trends in antibiotic susceptibility and genetic patterns of H. influenzae beta-lactam resistance, we isolated 122 strains from the adult respiratory tract in 2007, determined MIC for different antibiotics, and analyzed TEM-1 beta-lactamase resistant genes and ftsI encoding PBP3 mutation compared to results in 2005 and 2007. We found that ABPC-susceptible strains with MIC <1 microg/mL (BLNAS) accounted for 71.0%, ABPC-resistant strains with MIC exceeding 2 microg/mL without beta-lactamase activity (BLNAR) for 25.3%, and beta-lactamase-positive strains (BLP) for 3.7%. The BLNAS ratio showed no significant change from 2002 and 2005. The BLP ratio decreased from those in 2002 and 2005. Genetic studies of resistant genes showed that gBLNAS with no resistant genes had increased in the last five years. The ratio of all strains with PBP3 mutation (gBLNAR and gLow-BLNAR) remained constant from 2002 to 2007. The proportion of gBLNAR with two PBP3 mutations had increased, however, while gLow-BLNAR with one mutation had decreased. LVFX showed constant strong antimicrobial potency for all mutation groups. Among beta-lactam antibiotics, the lowest MIC90 was observed in parenteral CTRX and oral CDTR-PI use. Although a new MIC peak generated by gBLNAR became obvious in the ABPC and CDTR-PI MIC distribution, the MIC of the new peak was still low enough to treat with high doses of those two antibiotics.

[A case of pulmonary Mycobacterium avium infection presenting multiple nodules with substantial difference in 18F-fluorodeoxyglucose uptake].

A 56-year-old man presented with a chief complaint of chronic cough due to bronchial asthma and pulmonary emphysema in 2001, without any abnormal findings on chest CT. His symptoms improved with high-dose inhaled corticosteroid. In February 2004, multiple nodules without bronchiectasis appeared in the chest CT. Pulmonary Mycobacterium avium infection was diagnosed by bronchial lavage and sputum culture. After multiple nodules appeared and disappeared repeatedly without medication, most nodules vanished after administration of antituberculous drugs. In Feburary 2007, a rapidly growing mass appeared in the right upper lobe, and a new nodule emerged in the left upper lobe the following month. On 18F-fluorodeoxyglucose positron emission tomography (18 FDG-PET), a substantial difference in 18FDG uptake was observed although both lesions were shown to be caused by Mycobacterium avium infection by needle biopsy. The lung specimen of the lesion with high 18FDG uptake demonstrated neutrophil infiltrates, suggesting acute inflammation. On the other hand, neutrophil infiltrates were not observed in the lesion with low uptake. We conclude that the degree of 18FDG uptake is not useful to decide when to initiate therapy and evaluate the efficacy of treatment.

[Usefulness of monitoring plasma voriconazole concentration in patients with chronic necrotizing pulmonary aspergillosis].

We investigated the significance and the usefulness of monitoring plasma voriconazole levels in patients with chronic necrotizing pulmonary aspergillosis associated with underlying chronic respiratory diseases. The average trough level was 2.2 microg/ml and there was no correlation between trough levels and voriconazole doses. Orally administered drug showed no significant difference in trough or peak levels compared with parenteral injection. Six cases with visual adverse events had significantly higher nadirs compared to those without visual disturbance. All three cases who discontinued the drug due to liver dysfunction had plasma trough levels higher than 4.0 microg/ml. Those who failed to respond to the treatment had trough levels lower than 1.4 microg/ml or peak levels lower than 2.8 microg/ml, while some cases with plasma level lower than those levels responded well. Since plasma voriconazole level has a large inter-patient variability, drug monitoring may be beneficial to evaluate the drug efficacy and safety in each individual.

[Clinical features of pulmonary disease caused by Mycobacterium fortuitum].

We analyzed clinical and microbiological features of six cases involving Mycobacterium fortuitum isolated from sputum or surgical lung specimen. Patients were five men and one woman with an average age of 59. Four cases had a history of pulmonary tuberculosis and three had nontuberculous mycobacterial lung disease. Three out of six cases had underlying chronic obstructive pulmonary disease. Diabetes mellitus was complicated in five cases. All diseases were in the upper lobes of either lung. Clinical symptoms were mainly cough and sputum, while two cases developed pneumothorax. Although all strains showed low sensitivity to standard anti-tuberculous agents, chemotherapy including those drugs or fluoroquinolones and macrolides were successful in all treated cases.

[Clinical features of chronic necrotizing pulmonary aspergillosis treated with voriconazole in patients with chronic respiratory disease].

We analyzed clinical features of chronic necrotizing pulmonary aspergillosis (CNPA) in patients with underlying chronic respiratory disease, and evaluated the efficacy and tolerability of voriconazole against CNPA in those patients. Voriconazole therapy was indicated in 45 CNPA patients between October 2005 and September 2007, in 23 patients as first-line treatment and in 22 after lack of response to or intolerance of prior antifungal agent. The most common underlying respiratory disease was sequelae of tuberculosis (n = 23) followed by COPD (n = 13). Cavitary lesions were found in 32 patients. Galactomannan antigen test was positive in 29 patients while 28 patients out of 36 were positive for anti-Aspergillus serum antibody. The antibody-negative group had significantly higher levels of galactomannan antigen than the antibody-positive group. Mycological culture or hyphae were positive in 15 patients. Beta-D glucan level was within the normal limit in 27 patients. Clinical, radiological improvement, or both was obtained in 30 patients after an average voriconazole treatment of 4.8 months, with the main adverse effects being visual disturbance and hepatotoxicity. During the observation period 14 patients died due to CNPA or other causes. Although voriconazole demonstrated good efficacy against CNPA, the outcome is still unsatisfactory.

[Four cases of pulmonary infection due to Mycobacterium szulgai with a review of previous case reports in Japan].

We report 4 cases of pulmonary infection due to Mycobacterium szulgai with review of 23 cases previously reported in Japan. All 4 patients were male and two of them in their 20's were found to have abnormal chest X-ray findings recognized on a health checkup without any symptoms. One case had no previous history of illness and had never smoked. Radiographic study showed thick-walled cavities in 3 cases and multiple small nodules in 2, indicating the difficulty of distinguishing M. szulgai infection from pulmonary tuberculosis or M. kansasii infection. Three cases were treated as pulmonary tuberculosis at first, and later we changed the medication referring to the drug susceptibility. In most cases, rifampicin, ethionamide and ethanbutol were used and the medication regimen was successfully completed in all cases. Considering that the detected M. szulgai could be regarded as pathogen in almost all cases, it is important to evaluate the risk factor of patients and not to delay diagnosis and treatment with adhering to usual diagnostic criteria.