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In a nationwide survey of ATL in Japan, a total of 910 cases of ATL and 7,164 cases of B-NHL as a control disease, newly diagnosed from January 2006 to December 2007 (2 years), were enrolled from 156 hospitals. Male-female ratios were 1.16 for ATL and 1.22 for B-NHL. Among all ATL cases registered, 59.8% were from an HTLV-1 endemic area in Kyushu, and the ratio of ATL to B-NHL in this area was 1 to 3, while that in a non-endemic area in Tokyo was 1 to 40. Compared to previous nationwide studies, the age of ATL patients shifted toward older ages and the mean age gradually increased from 52.7 years in the first survey (cases before 1980) to 61.1 years in the ninth survey (1996-1997) and, finally, to 66.0 years in the present study (range: 19 to 94, median: 67). On subtype classification, 46.7% were classified as the acute type, 34.8% the lymphoma type, 10.3% the smoldering type, and 8.2% the chronic type, and the rate of the acute type decreased with an increase in the lymphoma type compared to that in previous studies. An increase in the mean age is explained by the high HTLV-1 prevalence in elderly people over 64 years old in endemic areas (20%), and by the continual development of ATL from this large pool of HTLV-1 carriers. According to mortality statistics from the Ministry of Health, Labor and Welfare in Japan, approximately 1,000 people die annually from ATL, a statistic that has not changed at least for the past decade.

The genus Aeromonas comprises flagellated gram-negative rods widely distributed in freshwater, estuarine and marine environments. Aeromonas species may cause a variety of illnesses in humans, such as enterocolitis and septicemia, especially in warmer tropical or subtropical environments. To recognize the characteristics of Aeromonas septicemia in Japan, we reviewed laboratory data and medical records in our hospital. During 11 years (from 2000 to 2010), Aeromonas septicemia was observed in seven patients involving six female subjects. Six patients were observed in summer or fall. The incidence of Aeromonas septicemia was about 0.07 per 1000 admissions, and two out of the seven patients died. All patients had underlying diseases such as malignancy (six patients) and choledocholithiasis (one patient). Two patients developed septicemia within two days after ingesting raw seafood. Five patients developed Aeromonas septicemia > 48 h after admission. Fever was present in all patients, and four out of the seven patients developed septic shock. All patients developed monomicrobial septicemia. A. hydrophila was isolated from five patients, and A. caviae and A. veronii biovar sobria were isolated from one patient each. Most antimicrobial agents had high activity against the isolated strains. However, a carbapenem-resistant strain appeared in one patient during treatment and led to death. Aeromonas septicemia is uncommon in temperate areas but can occur particularly in warm seasons. Immunocompromised conditions and recent ingestion of raw fish or shellfish are important characteristics of developing Aeromonas septicemia.

Aberrant overexpression of membrane-associated mucin (MUC1) is implicated in the pathogenesis of cancer, particularly of adenocarcinomas. Adult T-cell leukemia/lymphoma (ATL), an aggressive neoplasm etiologically associated with human T-lymphotropic virus type-1 (HTLV-1), exhibits invasive tropism into various organs, resulting in disease progression and resistance to treatment. In the present study, we showed that MUC1 is overexpressed exclusively in cells of ATL among hematological malignancies. Furthermore, increased expression of MUC1 correlated with a poor prognosis, suggesting MUC1 to be a prognostic marker in ATL. Various functional analyses with knockdown experiments using a specific siRNA for MUC1 revealed that MUC1 is involved in cell growth, cell aggregation, and resistance to apoptosis. Although it has been shown that the anti-adhesive properties of MUC1 facilitate migration and metastasis of tumor cells, our findings indicated that MUC1 contributes to cell-cell adhesion. Mucins thus seem to play a role in the pathogenesis and/or progression of ATL.

Doripenem is a carbapenem antibiotic with broad-spectrum coverage of gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa, and is considered to be as effective as meropenem. The in vivo activity of doripenem was thus compared with that of meropenem in a chronic lower respiratory P. aeruginosa infection mouse model. The number of viable bacteria in the lungs of mice after treatment with doripenem, meropenem, and saline was 2.01 ± 0.69, 2.03 ± 0.48, and 3.90 ± 1.40 log₁₀ CFU/lung, respectively. The number of viable bacteria in the lungs of mice treated with doripenem and meropenem was significantly lower than that in lungs of controls. Histopathological examination of lung specimens from the control group revealed promotion of the inflammatory response in chronic bronchial infection. However, the groups treated with doripenem and meropenem showed weaker inflammatory responses. These results suggest that doripenem treatment is effective against chronic airway infection with P. aeruginosa.

Background: Analysis of circulating immune complexes (CICs) produced during an immune response may be useful in elucidating some aspects of this process. Identification of antigens incorporated into CICs provides information that may be helpful in developing diagnostic and treatment strategies for autoimmune diseases, infection, cancer, and transplantation therapy, and such information might be more relevant than information on free antigens. Because CICs may contain many antigens, comprehensive identification and profiling of such antigens is more effective than immunoblotting detection., Methods: We developed a novel proteomic strategy (immune complexome analysis) in which immune complexes (ICs) are separated from serum, digested directly with trypsin, and then subjected to nano-liquid chromatography-tandem mass spectrometry for identifying and profiling antigens in CICs. We applied this strategy to the analysis of CICs in 21 rheumatoid arthritis (RA) patients. Serum samples from 13 healthy donors and 8 osteoarthritis patients were used as controls., Results: CICs containing thrombospondin-1 (TSP-1) and platelet factor 4 (PF4) were found in the serum of 81% and 52% of RA patients, respectively, and in none of the controls., Conclusions: The ICs in the serum of a majority of the RA patients contained TSP-1 or PF4, and these ICs may have potential as alternative biomarkers. Our technique for immune complexome analysis uses routine clinical samples, simple protocols, and widely available equipment. This method may be generally applicable to the study of the relationship between CICs and certain diseases associated with the immune response in animals and humans.

Tobramycin inhalation therapy is an effective therapy for cystic fibrosis as well as severe bronchiectasis that is colonized with Pseudomonas aeruginosa. The mechanism responsible for the efficacy of tobramycin in the treatment of severe chronic infectious diseases has not been elucidated. We demonstrate that high-dose tobramycin decreases MUC5AC gene expression and protein production in NCI-H292 cell stimulated with lipopolysaccharide of P. aeruginosa. MUC5AC protein of NCI-H292 cell stimulated by lipopolysaccharide was analyzed by an enzyme-linked immunosorbent assay and MUC5AC expression at the mRNA level was analyzed by RT-PCR. Western blot was performed to examine a potential role for the signaling molecules upstream of NFκB. High-dose tobramycin (500μg/ml) decreased the level of MUC5AC protein released into the supernatant of the NCI-H292 cell line at 24h after lipopolysaccharide stimulation (P<0.001). The tobramycin treatment also inhibited MUC5AC mRNA expression at 12h after lipopolysaccharide stimulation (P<0.05) and suppressed NFκB activation 60min after lipopolysaccharide stimulation (P<0.001). Tobramycin suppressed the phosphorylation of extracellular signal-regulated protein kinase, p38 MAP kinase. These results suggest that high-dose tobramycin, such as inhalation therapy, can inhibit MUC5AC gene expression and MUC5AC protein production in NCI-H292 cells, in part through the mitogen-activated protein kinase pathway. Thus, the activation of TLR4 and the subsequent immune/inflammatory responses induced by chronic infections such as P. aeruginosa might be modulated by tobramycin. Our data may reveal one of the mechanisms responsible for the clinical effect of tobramycin inhalation therapy against severe chronic respiratory diseases due to P. aeruginosa., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Methicillin-resistant Staphylococcus aureus (MRSA) has become a leading cause of infections in both the community and in hospitals. MRSA bacteremia is a serious infection with a very high mortality rate. The aim of this study was to assess the clinical features of MRSA bacteremia and to evaluate predictors of mortality in patients with this infection. The medical records of 83 patients with MRSA bacteremia, who had been admitted to Nagasaki University Hospital between January 2003 and December 2007, were retrospectively reviewed. Underlying disease, presumed source, MRSA sensitivity, Staphylococcal cassette chromosome mec (SCCmec) types, virulence genes and prognosis were evaluated. Of the 83 patients (44 men and 39 women; mean age: 63.7 years) with MRSA bacteremia, 30 (36.1%) had malignancy and 25 (30.1%) had been treated with immunosuppressive drugs. Fifteen patients (18.1%) were intravascular catheter related. SCCmec typeII accounted for 80% of SCCmec types of MRSA isolates. The mortality rate was 39.8% (33/83), which is similar to that of previous reports. The ratio of males to females, the mean age or the body temperature did not differ between survivors and nonsurvivors. Independent predictors associated with mortality in the multivariate analyses are pneumonia (P = 0.016), treatment with VCM (P = 0.039), and transplantation (P = 0.021). We suggest that poor prognosis achieved with VCM is in part due to its low blood concentration and poor tissue penetration. VCM should not be selected when presumed source of MRSA bacteremia is pneumonia.

Few studies have specifically examined defective provirus in asymptomatic human T-lymphotropic virus Type 1 (HTLV-1) carriers and its relation to proviral DNA loads (PVLs). To assess the significance of defective provirus in asymptomatic carriers, we examined PVLs in peripheral blood mononuclear cells of 208 asymptomatic HTLV-1 carriers. The mean PVLs determined using primers for the pol region were less than that for the pX region in these carriers. Analysis of seven carriers with high PVLs for the pX region but lower PVLs for the pol region showed that four had single nucleotide polymorphisms of proviral genomes for the pol region and three had HTLV-1-infected cells with defective provirus. Three carriers with defective provirus showed high PVLs at their initial screens, and PVLs increased after a 10- to 12-year interval in two carriers. Southern blot assay showed clonal expansion of HTLV-1-infected cells, and the predominant clones changed during the observation period. These data suggest that although HTLV-1-infected cells with defective provirus may have a growth advantage, the predominant clones of HTLV-1-infected cells do not always survive for many years in asymptomatic carriers., (Copyright © 2010 UICC.)

Dendritic cells (DCs) play a pivotal role in the pathogenesis of inflammatory disorders, so suppressing the activity of DCs is instrumental in treating such diseases. In the present study, we show that a proteasome inhibitor, bortezomib, suppresses the survival and immunostimulatory function of human plasmacytoid DCs (pDCs) by targeting 2 critical points, intracellular trafficking of nucleic acid-sensingToll-like receptors (TLRs) and endoplasmic reticulum (ER) homeostasis. Among the immune cells in blood, pDCs were the most susceptible to the killing effect of bortezomib. This correlates with a decrease in the spliced form of a transcription factor XBP1, which rescues cells from apoptosis by maintaining ER homeostasis. Bortezomib suppressed the production of interferon-α and interleukin-6 by pDCs activated with a TLR9-stimulating CpG DNA and a TLR7-stimulating influenza virus, which appears to be partially independent of apoptosis. Bortezomib inhibited translocation of TLR9 from the ER to endolysosomes but not of an ER membrane protein, Unc93B1, that delivers TLR9 to endolysosomes. Thus, bortezomib suppresses the activity of pDCs by inhibiting intracellular trafficking of TLRs through disrupting the coordinated translocation of TLRs and Unc93B1 and by disturbing ER homeostasis. This study suggests that proteasome inhibitors may alleviate inflammatory disorders such as lupus and psoriasis that involve pDCs.

The Cica Fungi Test Candida is a novel immunoassay test that is used in Japan to detect Candida mannan antigens. A total of 130 samples from 89 cases in which the β-D-glucan assay (MK method) was positive were collected between July 2007 and August 2008 at Nagasaki University Hospital, and the Cica Fungi Test Candida and Cand-Tec were performed. Diagnosis of candidemia was based on a positive culture for Candida spp. from blood or other sterile clinical specimens. A total of 19 samples from 16 cases with candidemia, and 111 samples from 73 cases without microbiological evidence of candidemia, were obtained. The sensitivity and specificity of the Cica Fungi Test and Cand-Tec were 63.2 and 95.5%, and 52.6 and 50.5%, respectively. The Cica Fungi Test showed significantly higher specificity than Cand-Tec (P<0.01). The β-D-glucan assay values were significantly higher in the candidemia samples than in the non-candidemia samples (P=0.0003), a result that was well correlated with the Cica Fungi Test (P=0.0005). The Cica Fungi Test was thus found to be more reliable and specific than Cand-Tec, and the combined evaluation with the β-D-glucan assay was more efficient for diagnosis of candidemia.

Background: Legionella pneumophila (LPN) can cause a lethal infectious disease with a marked inflammatory response in humans. However, the mechanism of this severe inflammation remains poorly understood. Since necrosis is known to induce inflammation, we investigated whether LPN induces necrosis in macrophages. We also analyzed the involvement of lysosomal cathepsin B in LPN-induced cell death., Methods: The human monocytic cell line THP-1 was infected with LPN, NUL1 strain. MG132-treated cells were used as apoptotic control cells. After infection, the type of cell death was analyzed by using microscopy, LDH release and flow cytometry. As a proinflammatory mediator, high-mobility group box 1 (HMGB-1), was measured. Cathepsin B activity was also measured and the inhibitory effects of cathepsin B on LPN-induced cell death were analyzed., Results: THP-1 cells after treatment with high dose of LPN showed necrotic features with releasing HMGB-1. This necrosis and the HMGB-1 release were inhibited by a specific lysosomal cathepsin B inhibitor and were characterized by a rapid and high activation of cathepsin B that was not observed in apoptotic control cells. The necrosis was also accompanied by cathepsin B-dependent poly(ADP-ribose) polymerase (PARP) cleavage., Conclusions: We demonstrate here that L. pneumophila rapidly induces cathepsin B-dependent necrosis in a dose-dependent manner and releases a proinflammatory mediator, HMGB-1, from macrophages. This report describes a novel aspect of the pathogenesis of Legionnaires' disease and provides a possible therapeutic target for the regulation of inflammation.

Human T-cell leukemia virus type-1 (HTLV-1) proviral load (VL) is an important determinant of viral pathogenesis and malignant evolution. Although VL has been quantified by in-house real-time quantifiable polymerase chain reaction (qPCR) technology, little is known about the harmonization among different VL assay systems. We evaluated intra- and inter-laboratory variability of VL measured at six laboratories using the same DNA samples seropositive for HTLV-1 in a two-step manner. The first study measured 60 samples by original in-house assays, finding that the median intra- and inter-laboratory coefficient of variation (CV) was 44.9% (range, 25.4-71.8%) and 59.9% (34.2-93.4%), respectively. The inter-laboratory correlation coefficients ranged from 0.760 to 0.875, indicating that VL were measured with good precision in each laboratory, but inter-laboratory regression slopes differed from 0.399 to 2.206, indicating that VL were measured with a wide variation between laboratories. To examine the effect of standardization of reference materials (RM) on the VL variability, we performed a second study using only 20 samples by substituting RM for plasmid including the HTLV-1 pX region. The median inter-laboratory CV for raw pX copy number was reduced significantly from 66.9% to 35.7%, whereas the median CV for the internal control remained almost unchanged, resulting in no improvement in inter-laboratory CV for VL. This indicates that each in-house assay system worked well with good precision, but standardizing RM alone was insufficient for harmonization. The relevant choice of not only RM, but also internal control genes for data normalization is expected to be realistic to standardize HTLV-1 VL measurement., (© 2010 Japanese Cancer Association.)

Nontypeable Haemophilus influenzae (NTHi) is one of the most common pathogens in chronic airway infections and exacerbation. The hallmark of chronic respiratory diseases, including cystic fibrosis, diffuse panbronchiolitis and chronic obstructive pulmonary disease, is mucin overproduction. Prolonged macrolide antibiotic therapy at low doses is known to improve clinical outcome in patients with chronic respiratory diseases via anti-inflammatory effects. In this study, we investigated the effects of macrolide therapy on NTHi-induction of the MUC5AC mucin in human airway epithelial cells. A 15-membered macrolide, azithromycin, but not a 14-membered macrolide, clarithromycin, inhibited NTHi-induction of MUC5AC at both the mRNA and protein levels through selective suppression of activation of the transcription factor activator protein-1. Our findings suggest that each macrolide affects MUC5AC production in different ways and that azithromycin is more suitable for the treatment of NTHi-induced respiratory infection., (Copyright 2010 Elsevier B.V. All rights reserved.)

It is important to regulate excessive inflammation when patients with severe infectious disease are treated. Sivelestat sodium hydrate (sivelestat), a neutrophil elastase inhibitor, is used in the treatment of lung injury but its effect on bacterial pneumonia is unknown. The authors examined the efficacy of sivelestat in combination with a fluoroquinolone in a Legionella pneumophila pneumonia mouse model. The combination therapy did not show a significant survival improvement compared to the treatment with fluoroquinolone alone, but reduced bacteria number and inflammatory cells in the early phase. The combination therapy can contribute to treatment of L. pneumophila pneumonia with protecting lungs.

Definitive risk factors for the development of adult T-cell leukemia (ATL) among asymptomatic human T-cell leukemia virus type I (HTLV-1) carriers remain unclear. Recently, HTLV-1 proviral loads have been evaluated as important predictors of ATL, but a few small prospective studies have been conducted. We prospectively evaluated 1218 asymptomatic HTLV-1 carriers (426 males and 792 females) who were enrolled during 2002 to 2008. The proviral load at enrollment was significantly higher in males than females (median, 2.10 vs 1.39 copies/100 peripheral blood mononuclear cells [PBMCs]; P < .001), in those 40 to 49 and 50 to 59 years of age than that of those 40 years of age and younger (P = .02 and .007, respectively), and in those with a family history of ATL than those without the history (median, 2.32 vs 1.33 copies/100 PBMCs; P = .005). During follow-up, 14 participants progressed to overt ATL. Their baseline proviral load was high (range, 4.17-28.58 copies/100 PBMCs). None developed ATL among those with a baseline proviral load lower than approximately 4 copies. Multivariate Cox analyses indicated that not only a higher proviral load, advanced age, family history of ATL, and first opportunity for HTLV-1 testing during treatment for other diseases were independent risk factors for progression of ATL.

The long-term prognosis of indolent adult T-cell leukemia-lymphoma (ATL) is not clearly elucidated. From 1974 to 2003, newly diagnosed indolent ATL in 90 patients (65 chronic type and 25 smoldering type) was analyzed. The median survival time was 4.1 years; 12 patients remained alive for more than 10 years, 44 progressed to acute ATL, and 63 patients died. The estimated 5-, 10-, and 15-year survival rates were 47.2%, 25.4%, and 14.1%, respectively, with no plateau in the survival curve. Although most patients were treated with watchful waiting, 12 patients were treated with chemotherapy. Kaplan-Meier analyses showed that advanced performance status (PS), neutrophilia, high concentration of lactate dehydrogenase, more than 3 extranodal lesions, more than 4 total involved lesions, and receiving chemotherapy were unfavorable prognostic factors for survival. Multivariate Cox analysis showed that advanced PS was a borderline significant independent factor in poor survival (hazard ratio, 2.1, 95% confidence interval, 1.0-4.6; P = .06), but it was not a factor when analysis was limited to patients who had not received chemotherapy. The prognosis of indolent ATL in this study was poorer than expected. These findings suggest that even patients with indolent ATL should be carefully observed in clinical practice. Further studies are required to develop treatments for indolent ATL.

Primary pulmonary leiomyosarcoma is a rare malignant tumor of the lungs. A 79-year-old woman showed a mass of 9 cm in diameter in a chest X-ray and computed tomography (CT) scan. A malignant tumor was suspected and left lower lobectomy was performed. From pathological findings, pulmonary leiomyosarcoma was diagnosed. The disease stage was pT2N0M0, p0d0e0pm0 (p0), pIB. From histopathological findings, the tumor appeared to be high grade, but no recurrences have occurred 2 years postoperatively and surgical treatment was considered effective.

Background: The leptin:adiponectin ratio (L:A ratio) is an independent predictor of carotid intima-media thickness (CIMT)., Objective: To evaluate whether the leptin:high-molecular-weight adiponectin ratio (L:HA ratio) is associated with CIMT in the general population., Methods: We investigated the relationship between the L:HA ratio and CIMT in 233 Japanese study participants (106 men and 127 women)., Results: After adjustment for confounding factors, CIMT was significantly correlated with the log L:HA ratio (beta = 0.11, p = 0.014) in men, whereas no correlation was observed in women (beta = 0.01, p = 0.50)., Conclusion: The L:HA ratio is closely correlated with CIMT in men, but not in women.

CADM1 encodes a multifunctional immunoglobulin-like cell adhesion molecule whose cytoplasmic domain contains a type II PSD95/Dlg/ZO-1 (PDZ)-binding motif (BM) for associating with other intracellular proteins. Although CADM1 lacks expression in T lymphocytes of healthy individuals, it is overexpressed in adult T-cell leukemia-lymphoma (ATL) cells. It has been suggested that the expression of CADM1 protein promotes infiltration of leukemic cells into various organs and tissues, which is one of the frequent clinical manifestations of ATL. Amino acid sequence alignment revealed that Tiam1 (T-lymphoma invasion and metastasis 1), a Rac-specific guanine nucleotide exchange factor, has a type II PDZ domain similar to those of membrane-associated guanylate kinase homologs (MAGUKs) that are known to bind to the PDZ-BM of CADM1. In this study, we demonstrated that the cytoplasmic domain of CADM1 directly interacted with the PDZ domain of Tiam1 and induced formation of lamellipodia through Rac activation in HTLV-I-transformed cell lines as well as ATL cell lines. Our results indicate that Tiam1 integrates signals from CADM1 to regulate the actin cytoskeleton through Rac activation, which may lead to tissue infiltration of leukemic cells in ATL patients.

Respiratory tract infection (RTI) is a common and potentially life-threatening illness that continues to be a major medical problem. The rapid detection system such as Gram staining or urinary antigen detection for respiratory infection is useful. However, the genetic diagnosis for resistant pathogens has been expected because they have been prevalent. We evaluated the RQ-mPCR (real-time quantitative PCR combined with multiplex PCR) assay for drug resistant S. pneumonia infection. The RQ-mPCR method developed here had high sensitivity and specificity for pneumococci and could detect drug resistance in both clinical S. pneumoniae strains and in sputum samples. Furthermore, the results can be obtained directly from clinical samples within 3h. This method may be helpful for the rapid screening of resistance in pneumococcal isolates, and should allow the administration of earlier, more focused and effective treatment of drug-resistant S. pneumonia. We also established the rapid quantitative detection of metallo-beta-lactamase-producing P. aeruginosa in clinical isolates and samples using real-time PCR targeting gyrB (identification of P. aeruginosa) and blaIMP (identification of metallo-beta-lactamase). The present PCR assay was thus easily and quickly performed, and accurately detected Pseudomonas aeruginosa and metallo-beta-lactamase, and it should be helpful in the diagnosis and control of nosocomial infection. We expect that the genetic diagnosis will be an adjunct to, or a replacement of, conventional culture methods and susceptibility tests.

Background: To address the clinical and virological significance of a high HTLV-1 proviral load (VL) in practical blood samples from asymptomatic and symptomatic carriers, we simultaneously examined VL and clonal expansion status using polymerase chain reaction (PCR) quantification (infected cell % of peripheral mononuclear cells) and Southern blotting hybridization (SBH) methods., Results: The present study disclosed extremely high VL with highly dense smears with or without oligoclonal bands in SBH. A high VL of 10% or more was observed in 16 (43.2%) of a total of 33 samples (one of 13 asymptomatic carriers, 8 of 12 symptomatic carriers, and 7 of 8 patients with lymphoma-type ATL without circulating ATL cells). In particular, an extremely high VL of 50% or more was limited to symptomatic carriers whose band findings always contained at least dense smears derived from polyclonally expanded cells infected with HTLV-1. Sequential samples revealed that the VL value was synchronized with the presence or absence of dense smears, and declined at the same time as disappearing dense smears. Dense smears transiently emerged at the active stage of the underlying disease. After disappearance of the smears, several clonal bands became visible and were persistently retained, explaining the process by which the clonality of HTLV-1-infected cells is established. The cases with only oligoclonal bands tended to maintain a stable VL of around 20% for a long time. Two of such cases developed ATL 4 and 3.5 years later, suggesting that a high VL with oligoclonal bands may be a predisposing risk to ATL., Conclusion: The main contributor to extremely high VL seems to be transient emergence of dense smears detected by the sensitivity level of SBH, corresponding to polyclonal expansion of HTLV-1-infected cells including abundant small clones. Major clones retained after disappearance of dense smears stably persist and acquire various malignant characteristics step by step.

Most previous studies aimed at estimating the number of human T-cell leukemia virus type-1 (HTLV-1) carriers in endemic areas have been based on seroprevalence rates in blood donors; however, this may result in underestimation because of the healthy donor effect. People who have health problem do not donate blood. In the present study, the number of HTLV-1 carriers in Nagasaki City was estimated based on the seroprevalence rates in a hospital-based population from Nagasaki University Hospital. In accordance with previous reports, seroprevalence of HTLV-1 was higher in females, and year of birth-specific seroprevalence showed a significant annual decline in both genders (P for trend: <0.0001). The estimated number of HTLV-1 carriers in Nagasaki City was 36,983. The incidence of adult T-cell leukemia/lymphoma (ATLL) among HTLV-1 carriers was estimated using data from the Nagasaki Prefectural Cancer Registry. The estimated annual incidence of ATLL was 61 per 100,000 HTLV-1 carriers, and the crude lifetime risk of the development was 7.29% for males and 3.78% for females. There is a large pool of HTLV-1 carriers aged over 70 years, and a continuing development of cases of ATLL among the elderly is therefore expected., (2010 Wiley-Liss, Inc.)

Methicillin-resistant Staphylococcus aureus (MRSA) causes a wide range of infections in health care settings and community environments. In particular, community-acquired MRSA (CA-MRSA) is important for clinicians because many fatal cases in healthy populations have been reported. Staphylococcal cassette chromosome mec (SCCmec) is a mobile genetic element and carries the central determinant for broad-spectrum beta-lactam resistance encoded by the mecA gene. The emergence of MRSA is due to the acquisition and insertion of the SCCmec element into the chromosome. CA-MRSA is characterized as SCCmec type IV. Thus, we aimed to establish a novel multiplex real-time PCR method to distinguish SCCmec type, which enables us to evaluate the pathogenicity of MRSA. A total of 778 MRSA were isolated at Nagasaki University Hospital from 2000 to 2007. All isolates were subjected to minimal inhibitory concentration testing and PCR for SCCmec typing and detecting genes of toxins: tst (toxic shock syndrome toxin 1), sec (encoded enterotoxin type c), etb (exfoliative toxin type b), and lukS/F-PV (Panton-Valentine leukocidin). PCR was performed to amplify a total of 10 genes in the same run. The 667 MRSA clones detected from pus in 778 clones were classified as SCCmec type II (77.7%), type IV (19.2%), and type I (3.0%). 87.5% of SCCmec type II clone had tst and sec genes. No isolate was lukS/F-PV positive. The present study indicates the high rate of lukS/F-PV-negative SCCmec type IV in Nagasaki. Our PCR method is convenient for typing MRSA and detecting toxins in Japan.

Clarithromycin is a 14-member lactone ring macrolide with potent activity against Haemophilus influenzae, including ampicillin-resistant strains. We evaluated the in vivo efficacy of clarithromycin at 40 mg/day and 100 mg/day for 3 days in the treatment of a murine model of pneumonia using a macrolide-resistant H. influenzae strain, which was also ampicillin resistant. The MIC of clarithromycin was 64 microg/ml. The viable bacterial counts in infected tissues after treatment with 100 mg clarithromycin/kg of body weight were lower than the counts obtained in control and 40-mg/kg clarithromycin-treated mice. The concentrations of macrophage inflammatory protein 2 (MIP-2) and interleukin 1beta (IL-1beta) in bronchoalveolar lavage fluid (BALF) samples from mice treated at both concentrations were lower than in the control group. Pathologically, following infection, clarithromycin-treated mice, particularly at a dose of 100 mg/kg, showed lower numbers of neutrophils in alveolar walls, and inflammatory changes had apparently improved, whereas large aggregates of inflammatory cells were observed within the alveoli of control mice. In addition, we demonstrated that clarithromycin has bacteriological effects against intracellular bacteria at levels below the MIC. Our results indicate that clarithromycin may be useful in vivo for macrolide-resistant H. influenzae, and this phenomenon may be related to the good penetration of clarithromycin into bronchoepithelial cells. We also believe that conventional drug susceptibility tests may not reflect the in vivo effects of clarithromycin.

Corynebacterium pseudodiphtheriticum, one cause of respiratory tract infection, is rarely considered as a pathogen because it is among normal bacterial flora colonizing the oral cavity. We report two cases of C. pseudodiphtheriticum causing respiratory tract infection--an exacerbation of chronic obstructive pulmonary disease and pneumonia--, both in the presence of underlying respiratory disease. Both required antibiotics after first-line chemotherapy failed. Isolates were susceptible to beta-lactams. Gram-staining of respiratory tract specimens is important in diagnosing this infection and determining appropriate antimicrobial use.

Introduction: Sepsis is a serious medical condition that requires rapidly administered, appropriate antibiotic treatment. Conventional methods take three or more days for final pathogen identification and antimicrobial susceptibility testing. We organized a prospective observational multicenter study in three study sites to evaluate the diagnostic accuracy and potential clinical utility of the SeptiFast system, a multiplex pathogen detection system used in the clinical setting to support early diagnosis of bloodstream infections., Methods: A total of 212 patients, suspected of having systemic inflammatory response syndrome (SIRS) caused by bacterial or fungal infection, were enrolled in the study. From these patients, 407 blood samples were taken and blood culture analysis was performed to identify pathogens. Whole blood was also collected for DNA Detection Kit analysis immediately after its collection for blood culture. The results of the DNA Detection Kit, blood culture and other culture tests were compared. The chosen antimicrobial treatment in patients whose samples tested positive in the DNA Detection Kit and/or blood culture analysis was examined to evaluate the effect of concomitant antibiotic exposure on the results of these analyses., Results: SeptiFast analysis gave a positive result for 55 samples, while 43 samples were positive in blood culture analysis. The DNA Detection Kit identified a pathogen in 11.3% (45/400) of the samples, compared to 8.0% (32/400) by blood culture analysis. Twenty-three pathogens were detected by SeptiFast only; conversely, this system missed five episodes of clinically significant bacteremia (Methicillin-resistant Staphylococcus aureus (MRSA), 2; Pseudomonas aeruginosa, 1; Klebsiella spp, 1; Enterococcus faecium, 1). The number of samples that tested positive was significantly increased by combining the result of the blood culture analysis with those of the DNA Detection Kit analysis (P = 0.01). Among antibiotic pre-treated patients (prevalence, 72%), SeptiFast analysis detected more bacteria/fungi, and was less influenced by antibiotic exposure, compared with blood culture analysis (P = 0.02)., Conclusions: This rapid multiplex pathogen detection system complemented traditional culture-based methods and offered some added diagnostic value for the timely detection of causative pathogens, particularly in antibiotic pre-treated patients. Adequately designed intervention studies are needed to prove its clinical effectiveness in improving appropriate antibiotic selection and patient outcomes.

A 54-year-old Japanese man without underlying disease developed pneumococcal bacteremia and meningitis after traveling to the Philippines. The isolate demonstrated high affinity to the lung and invasiveness in vivo. The international travelers can import indigenous high virulent strains even if the bacterium is commonly isolated in the home country.

Background: Airway mucus hypersecretion is an important problem in chronic respiratory diseases including bronchial asthma. Chlamydophila pneumoniae is recently confirmed to be a pathogen in bronchial asthma, but the relationship between C. pneumoniae and mucus hypersecretion is uncertain. In this study, we examined whether C. pneumoniae induces MUC5AC mucin in airway epithelial cells. We also examined the effects of macrolide and ketolide antibiotics on the C. pneumoniae-induced mucus production., Methods: MUC5AC production in bronchial epithelial cells after stimulation with C. pneumoniae was analyzed by ELISA and quantitative RT-PCR. NF-kappaB and phosphorylated ERK were also analyzed. For inhibition study, cells were pretreated with azithromycin, clarithromycin and telithromycin before stimulation., Results: C. pneumoniae dose-dependently induced MUC5AC production and gene expression. The ERK-NF-kappaB pathway was involved in C. pneumoniae-induced MUC5AC production. Macrolides and ketolides dose-dependently reduced C. pneumoniae-induced MUC5AC production. However, azithromycin was apparently less effective than the other antibiotics. Clarithromycin and telithromycin, but not azithromycin, reduced NF-kappaB activation., Conclusions: Clarithromycin and telithromycin were thought to interfere with the signal pathways between ERK and NF-kappaB. These results suggest that airway mucus hypersecretion is one of the mechanisms of C. pneumoniae-induced bronchial asthma, and that macrolide and ketolide antibiotics represent a novel therapeutic intervention in these patients.

Many strains of community-acquired meticillin-resistant Staphylococcus aureus (MRSA) have a pore-forming leukotoxin, known as Panton-Valentine leukocidin (PVL), which can cause severe necrotising pneumonia. Linezolid (LZD) is a new antibacterial agent with potent antibacterial activity against MRSA. In this study, a mouse model of haematogenous pulmonary infection was used to compare the efficacies of LZD and vancomycin (VAN) against pulmonary infection caused by PVL-positive S. aureus. Following antibiotic administration for 3 days, the number of viable bacteria (mean+/-standard error of the mean) in the control, VAN and LZD groups was 6.77+/-0.14, 5.29+/-0.27 and 4.25+/-0.33 log colony-forming units/lung, respectively. LZD significantly decreased the number of viable bacteria in the lungs compared with the control and VAN groups (P<0.05). The survival rate at Day 7 post-inoculation was higher in the LZD group (100%) than in the VAN group (50%) or the control group (0%). Histopathological examination and cytokine analysis also showed the beneficial efficacy of LZD compared with VAN. In conclusion, LZD significantly reduced bacterial numbers and inflammation in a mouse model of PVL-positive S. aureus haematogenous infection and improved the survival rate of infected mice compared with VAN. LZD is clinically effective against PVL-positive S. aureus.

Human T cell leukemia virus type-1 (HTLV-1) is the established cause of adult T cell leukemia/lymphoma. Monitoring time trends in HTLV-1 seroprevalence in blood donors is important to assess the safety of the blood supply in the viral endemic area. We analyzed changes in HTLV-1 seroprevalence in 48415 first-time blood donors who donated blood from 2000 to 2006 in Nagasaki prefecture, an endemic area in Japan. The donors were divided into 10-year birth cohorts: before 1950, 1951-1960, 1961-1970, 1971-1980, and 1981-1990. Among the first-time blood donors, 622 were tested positive for HTLV-1 [overall seroprevalence: 1.28%, (95% CI 1.19-1.39)]. Seroprevalence was significantly high in the birth cohort of before 1950 (6.22%) and declined with birth-year. The time trend of the birth-cohort-specific seroprevalence showed almost no change within each birth cohort, except for the birth cohort of 1981-1990 that showed a significantly declining trend (P for trend = 0.006). Among the birth cohort of 1981-1990, the seroprevalence was stable among those born during 1981-1986 (0.66-0.83%), but was lower among those born during 1987-1990 (0-0.38%). Detail analyses showed that HTLV-1 seroprevalence among blood donors clearly declined in those born after 1987.

A novel murine model of non-typeable Haemophilus influenzae (NTHi) pneumonia was established. A plastic tube was inserted into the trachea 7 days before bacterial inoculation. Numbers of NTHi recovered from the lungs and trachea were determined for 7 days. Histologically, bronchioles and adjacent alveoli in the intubation group were filled with numerous inflammatory cells. The efficacy of sitafloxacin was compared with ciprofloxacin using the new murine pneumonia model. The data suggest that sitafloxacin displays equivalent efficacy to ciprofloxacin against H. influenzae pneumonia. This new murine NTHi pneumonia model appears useful not only for in vivo evaluation of antibiotics but also for analysis of the pathogenesis of H. influenzae pneumonia.

Calcium-deficient hydroxyapatite (HA) granules with a unique spherical shape were prepared using an applied hydrothermal method. Spherical stoichiometric HA granules were also prepared by normal sintering and both granules were used for implantation into rat tibiae to compare the biological responses to each implant. Twelve and 24 weeks after implantation, the volume of calcium-deficient HA granules was significantly less than that of stoichiometric HA granules, and the biodegradability of calcium-deficient HA granules was confirmed. The larger number of osteoclasts, larger osteoblast surface and larger bone volume in the implanted area of calcium-deficient HA than those of stoichiometric HA suggested that osteoclastic resorption of calcium-deficient HA affected osteogenesis in that area. To analyze the direct contribution of osteoclasts to osteogenesis, C2C12 multipotent myoblastic cells, which have the potential to differentiate into osteoblasts in the presence of bone morphogenetic protein 2, were cultured with supernatants of osteoclasts cultured on calcium-deficient HA, stoichiometric HA, beta-tricalcium phosphate disks or plastic dishes, or bone marrow macrophages cultured on plastic dishes. Supernatants of osteoclasts but not bone marrow macrophages stimulated the expression of Runx2 and osteocalcin in C2C12 cells in concert with bone morphogenetic protein 2. The expression of alkaline phosphatase was stimulated with supernatants of osteoclasts cultured on ceramic disks. These results suggested that osteoclasts produced certain soluble factors which stimulated osteoblastic differentiation and they were thought to be associated with the induction of a larger osteoblast surface and bone volume in the animals implanted with calcium-deficient HA granules.

Vacuum-assisted closure (VAC) therapy is a unique system that helps promote wound healing. We report a case of severe ischemic foot in which VAC therapy markedly improved wound healing. A 73-year-old man underwent left axillopopliteal bypass and left 3rd, 4th , and 5th digital amputations for gangrene. Although his amputation stumps were complicated with methicillin-resistant Staphylococcus aureus (MRSA) infection, the stumps were successfully healed by VAC. He also had gangrene in his right 1st toe, which could not healed by VAC alone, and we performed right femoropopliteal bypass and right 1st digital amputation. The stump with MRSA infection was also successfully healed by VAC. Histopathologic examination revealed a lot of microvessels in the increased granulation tissue.

We evaluated the potency of garenoxacin in selecting resistant Streptococcus pneumoniae mutants by determining its mutant prevention concentration, using strains with and without topoisomerase gene mutations, and compared its potency to that of other quinolones. Garenoxacin had a significantly greater potency against pneumococci, including strains containing topoisomerase mutations. Genetic analysis of the S. pneumoniae mutants created by garenoxacin revealed that the gyrA gene was a primary target of garenoxacin.

For relevant imatinib therapy against Philadelphia (Ph)-positive leukemias, it is essential to monitor mutations in the chimerical bcr-abl tyrosine kinase domain (TKD). However, there is no universally acceptable consensus on how to efficiently identify mutations in the target TKD. Recently, high-resolution melting (HRM) technology was developed, which allows gene scanning using an inexpensive generic heteroduplex-detecting dsDNA-binding dye. This study aimed to validate the introduction of HRM in a practical clinical setting for screening of mutations in sporadic sites of the chimerical bcr-abl TKD. All chimerical and wild-type abl TKD regions selectively amplified were used for HRM assays and direct sequencing. The HRM test had approximately 5-90% detection sensitivity for mutations. In contrast to mixture samples with mutant and wild-type cells, all mutant cell samples had indeterminate melting curves equivalent to those of the wild-type due to formation of only a homodulex. This issue was improved by the addition of exogenous wild-type DNA after PCR. Subsequently, HRM results gave a high accordance rate of 97.8% (44/45 samples) compared to the sequencing data. The discordant results in one appear to be due to unsuccessful amplification. Thus, HRM may be considered to be suitable for reliable scanning of mutations in the chimerical abl TKD in a clinical setting.

Patients with hematological malignancies frequently suffer from lung diseases as a complication. However, it is difficult to discriminate leukemic invasion into the lung from infectious pulmonary complications. The serum level of Krebs von den Lungen-6 (KL-6), which is a mucin-like glycoprotein, is increased in more than 70% of patients with interstitial pneumonia. Surfactant protein-D (SP-D) is produced mainly in the lung by alveolar type II and bronchiolar epithelial cells and is a useful serum marker for interstitial pneumonia. We therefore measured the levels of KL-6 and SP-D in sera from 128 patients (76 males and 52 females, mean age: 59 years) with hematological malignancies, including adult T-cell leukemia (ATL). Overall, the increase in KL-6 or SP-D, above each cut-off value (500 U/ml for KL-6 and 110 ng/ml for SP-D), was detected in 11 patients (8.6%) or 10 patients (7.8%), respectively. In contrast, among 67 ATL patients, 15 patients had high serum levels of KL-6 and/or SP-D; both were elevated in 2 patients, only KL-6 was elevated in 6 patients and only SP-D was elevated in 7 patients. Thus, serum KL-6 and SP-D appear to be elevated in a mutually exclusive manner in ATL. Indeed, high serum levels of KL-6 were closely related to the stage of ATL, while the serum SP-D was elevated in ATL patients with pulmonary infection. In conclusion, the combined measurement of KL-6 and SP-D in ATL may become a useful means to discriminate leukemic pulmonary lesions from infectious pulmonary complications.

We evaluated a multiplex real-time quantitative polymerase chain reaction (PCR) method for quantification of Haemophilus influenzae and rapid detection of beta-lactam-resistant strains. We designed 5 PCR primer sets to simultaneously detect the beta-lactam-resistant genes and quantify the pathogen. To demonstrate the validity of this assay, we used 191 clinical isolates, including 141 H. influenzae strains, and 100 purulent sputum samples, including 30 samples from which H. influenzae had been isolated. This assay showed 92.9% sensitivity and 91.8% specificity for detecting beta-lactam-resistant genes, relative to the conventional phenotypic method, and this assay correlated well with conventional quantitative culture counts. By using this assay, we could quantify H. influenzae and identify beta-lactam susceptibility in only 3 h and with only one tube. This method will be helpful for the rapid detection of H. influenzae infections and the selection of appropriate antibiotics.

The p53 gene is one of the most important genes involved in carcinogenesis and its role in part has been clarified by research using cell lines. To know the comprehensive characteristics of 22 hematopoietic cell lines (T, 13 and non-T, nine lines), the relationship between p53 mutational status, its altered functioning, and its mRNA and protein levels were examined. p53 mutations were less frequent in T-cell lines (38% vs. 78%) with mainly single nucleotide substitutions generating missense codons. Of 22 different p53 mutations, 12 (54.5%) resulted in mutated proteins, with the mutations clustering mainly in the sequence-specific DNA-binding site region located from amino acid residues 102 to 292. p53 mRNA and protein assays determined that wild-type cell lines expressed constant levels of both mRNA and protein, but mutated cell lines demonstrated two expression patterns: protein over-expression with reduced mRNA levels, because of missense mutations; and protein under-expression with little mRNA expression, because of other mutations. The resistance to Nutlin (MDM2 inhibitor)-induced apoptosis was associated with p53 mutations independently of MDM2 expression levels. This clarification of the unique associations in cell lines useful for bio-medical studies will contribute to a better understanding of p53-associated carcinogenesis.

Purpose: This study aimed to evaluate serum cytochrome c (cyto-c) levels as a novel role of tumor marker in patients with operable malignant tumors., Methods: Serum cyto-c levels and lactate dehydrogenase (LD) activity were measured in a total of 257 cases (232 malignant and 25 benign). To identify the relationship between serum cyto-c and current tumor markers, six variables, such as gender, age, invasion, lymph node metastasis, distant metastasis, and LD, were analyzed by uni- and multivariate regression analysis methods. The test performance of serum cyto-c for the prediction of malignant behavior was evaluated by receiver operating characteristic (ROC) curves., Results: The serum cyto-c level was significantly higher in patients with malignant tumors than patients with benign tumors (20.6 vs. 15.5 ng/mL; P = 0.017, Mann-Whitney U test). No difference in the levels among subtypes of cancer was found, indicating that the change in serum cyto-c levels reflect cancer individually and not specific subtypes of cancer. The survival in patients with serum cyto-c levels over 40 ng/mL was poor (Kaplan-Meier test, P < 0.0001, Hazard ratio 16.76, 95% confidential interval 4.45-63.04). Multiple linear regression analyses disclosed the close association of serum cyto-c levels with invasion (P = 0.0004), metastasis (P = 0.0262) except for regional lymph node metastasis, and activity of serum LD (P < 0.0001), all of which are well known to represent malignant behavior. Conversely, the measurement of serum cyto-c was verified to have excellent diagnostic accuracy of 0.802 and 0.781 for the detection of invasion and metastasis (the area under curves of the constructed ROCs)., Conclusion: Serum cyto-c is a potent tumor marker as a predictor for malignant potential in cancers.

We established a real-time PCR assay with melting curve analysis to rapidly genotype quinolone resistance-determining regions (QRDRs) of gyrase A and topoisomerase IV genes in Haemophilus influenzae. This assay is a useful tool for the detection of fluoroquinolone resistance and for the early detection of preexisting QRDR mutations.

Radiation exposure is a possible predisposing factor for monoclonal gammopathy of undetermined significance (MGUS), but the association has been uncertain. We investigated the relationship between radiation exposure and MGUS prevalence by using data from the M-protein screening for Nagasaki atomic bomb survivors between 1988 and 2004. Radiation exposure was assessed by exposure distance from the hypocenter and exposure radiation dose. We computed prevalence ratios (PRs) and the 95% confidence intervals (CIs) adjusting for exposure age and sex. A total of 1082 cases of MGUS were identified from 52 525 participants. MGUS prevalence was significantly higher in people exposed at distance within 1.5 km than beyond 3.0 km (PR, 1.4; 95% CI, 1.1-1.9) among those exposed at age 20 years or younger, but it was not found among those exposed at age 20 years or older. MGUS prevalence was also significantly higher in people exposed to more than 0.1 Gy than those exposed to less than 0.01 Gy (PR, 1.7; 95% CI, 1.0-2.8) among those exposed at age 20 years or younger. Thus, people exposed at younger age exhibited a significantly high risk of MGUS when exposed to a high radiation dose. There was no clear association between radiation exposure and the malignant progression of MGUS. Further detailed analysis is needed.

Idiopathic CD4+ T-lymphocytopenia (ICL) is a new disease entity characterized by CD4+ T-lymphocyte depletion without evidence of HIV infection. We report a 27-year-old ICL patient with a long history of multiple immune abnormalities. His CD4+ T-lymphocyte count started to decrease after generalized lymphadenopathy of an unknown cause at age 3. He satisfied the criteria for ICL at age 9, and the decreased CD4+ T-lymphocyte count persisted for more than 18 years. This is probably the first childhood-onset ICL case in which the trigger event for the development was known together with the patient's autoimmune background.

A 60-year-old male who had been treated for polymyalgia rheumatica (PMR) with Raynaud's phenomenon was admitted to our hospital with acrocyanosis and rapid progressive anemia. Hemolytic anemia with reduction of haptoglobin and cold agglutinin was detected, and the patient had a negative Donath-Landsteiner test. A skin biopsy from his toe revealed microthromboembolism without vasculitis, resulting in the diagnosis of cold agglutinin disease (CAD). This is a first case report of CAD complicated with PMR.

In order to better understand the biology of adult T cell leukemia (ATL), we aimed to establish a novel method, which allows the primary growth of ATL cells using a co-culture system with murine bone marrow-derived stromal cells, MS-5. ATL cells grew in close contact with MS-5 layers and formed so-called "cobblestone areas" (CAs) without the addition of IL-2. In clinical samples, eight of ten (80.0%) cases of acute or lymphoma type ATL cells formed CAs. The frequency of CA forming cells in ATL cells ranged from 0.03 to 1.04%. The morphology, immunophenotyping, and DNA analysis indicated that cells composing CA were compatible with ATL cells, and clonally identical to primary CD4-positive ATL cells. Furthermore, in ATL cells composing CA, the expression of p40Tax was down-regulated in transcriptional and translational level, while that of HTLV-I basic leucine zipper factor (HBZ) gene was comparable to the level of primary ATL cells, resembling expression pattern of proviral genes in in vivo ATL cells. By microarray analysis, several genes which coded products involved in cell-cell interaction, and cellular survival and proliferation, were differentially expressed in ATL cells composing CA compared with primary samples. In conclusion, our co-culture system allows for the first time the growth of primary ATL cells in vitro, and might be useful as an in vitro assay for biological and clinical studies to develop molecular targeting drugs against ATL.

ME1036, a novel parenteral carbapenem, was developed for the treatment of meticillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate S. aureus (VISA). A model of haematogenous pulmonary infection was induced in mice by tail vein injection of MRSA strain NUMR101 or VISA Mu50 enmeshed in agar beads. After 24h of infection, mice were treated twice daily for 7 days with 200mg/kg/day vancomycin (VCM) or ME1036. Mice infected with VISA were also pre-treated with cyclophosphamide to induce an immunocompromised state. The number of viable bacteria in the lungs was counted 12h after the final drug treatment. VCM decreased the number of viable MRSA in the lungs in comparison with the control, although the difference was not significant (mean+/-standard error of the mean log(10) colony-forming units (CFU)/lung=6.876+/-0.54 vs. 8.25+/-0.41, respectively). In contrast, treatment with ME1036 resulted in a significant decrease in the number of viable MRSA (log(10)CFU/lung=2.69+/-0.44 (n=6); P<0.0001) compared with both the VCM-treated and control mice. In the VISA-infected mice, ME1036 significantly reduced the number of viable bacteria compared with VCM and control (log(10)CFU/lung=3.65+/-0.68 for ME1036 vs. 5.71+/-0.75 for VCM (P<0.05) and 7.07+/-0.45 for control (P<0.001)). ME1036 produced >3 log(10) reduction versus control against both MRSA strains (>5 log for the VCM-susceptible strain and 3.4 log for the VISA), whereas VCM produced <1.3 log for both strains.